I. Siletanylmethyllithium, an ambiphilic siletane. II. Synthetic approach to basiliolide B

I. Siletanylmethyllithium, an ambiphilic siletane. II. Synthetic approach to basiliolide B
FLORIDA STATE UNIVERSITY
COLLEGE OF ARTS AND SCIENCES
I. SILETANYLMETHYLLITHIUM, AN AMBIPHILIC SILETANE
II. SYNTHETIC APPROACH TO BASILIOLIDE B
By
MARIYA V. KOZYTSKA
A Dissertation submitted to the
Department of Chemistry and Biochemistry
in partial fulfillment of the
requirements for the degree of
Doctor of Philosophy
Degree Awarded:
Fall Semester, 2008
The members of the Committee approve the dissertation of Mariya V. Kozytska defended on
August 19, 2008.
__________________________
Gregory B. Dudley
Professor Directing Dissertation
__________________________
Laura Keller
Outside Committee Member
__________________________
Marie E. Krafft
Committee Member
__________________________
Jack Saltiel
Committee Member
___________________________
Michael Shatruk
Committee Member
Approved:
___________________________________
Joseph B. Schlenoff, Chair, Department of Chemistry and Biochemistry
The Office of Graduate Studies has verified and approved the above named committee members.
ii
ACKNOWLEDGEMENTS
Many people deserve my sincerest thanks for their help during my graduate studies. In
these few lines I will try to acknowledge them and I apologize if I forget to mention anyone. I
would like express my gratitude to:
Professor Gregory B. Dudley for his guidance, support and assistance over the past years
of my graduate studies;
the past and present members of Dudley group: Susana S. Lopez, Doug Engel, David
Jones, Dr Philip Albiniak, Dr Jeannie Jeong, Jingyue Yang, Sami Tlais, Jumreang Tummatorn,
Dani Barker and others for their friendship, assistance and support;
Dr Shin Kamijo, Dr Hubert Lam and Dr Timothy Briggs for being inspiring examples for
me and for helping with my research during the first years of the graduate program, when I
needed it the most;
my family for their continual understanding and encouragement;
Ludmila V. Vasetskaya, my chemistry teacher in high school and college who first
involved me in the exciting world of chemistry and who believed in me and supported me over
my entire career.
iii
TABLE OF CONTENTS
LIST OF TABLES…………………………………………………………………………….
vii
LIST OF FIGURES…………………………………………………………………………...
ix
LIST OF ABBREVIATIONS…………………………………………………………………
xiv
ABSTRACT…………………………………………………………………………………..
xix
Part I SILETANYLMETHYLLITHIUM, AN AMBIPHILIC SILETANE
I. Silacyclobutane and derivatives…………………………………………………………….
1
I.1 Introduction……………………………………………………………………………
1
I.2 Structure of silacyclobutanes………………………………………………………….
2
I.3 Preparation of silacyclobutanes and derivatives from the acyclic as well as cyclic
compounds……………………………………………………………...............................
6
I.4 Pyrolysis and photolysis……………………………………………………………….
6
I.5 Ring-opening reactions of silacyclobutanes…………………………………………...
10
I.5.1 Ring-opening reactions leading to polymerization……………………………...
10
I.5.2 Ring-opening reactions leading to activated silanes for other reaction…………
17
I.6 Ring-expansion reactions……………………………………………………………...
22
I.6.1 Ring expansions of silacyclobutanes using nucleophilic or carbenoid
reagents………………………………………………………………………..............
22
I.6.2 Ring expansions triggered by transition metal catalysis. Mechanistic aspects of
transition metal insertion into siletanes……………………………………………….
30
I.7 Reactions of substituents attached to the ring carbon atoms…………………………..
37
I.8 Reactivity of substituents attached to the ring silicon…………………………………
40
II. Siletanylmethyllithium …………………………………………………………………….
47
II.1 Introduction…………………………………………………………………………...
47
II.2 Results and discussion.……………………………………………………………….
48
iv
II.2.1 Generation of siletanylmethyllithium…………………………………..............
48
II.2.2 Reactivity of silethanylmethyllithium, reaction with
benzophenone……………………………………………………………....................
51
III. Experimental part………………………………………………………………………….
54
Part II SYNTHETIC APPROACH TO BASILIOLIDE B
I. Basiliolide B, literature review……………………………………………...........................
63
I.1 Introduction…………………………………………………………….……………...
63
I.2 Isolation, biological activity and structure of basiliolide B…………………………...
65
I.3 Retrosynthetic plan…………………………………………………………………….
68
I.4 Diels-Alder reactions of pyrones……………………………………………………...
70
I.4.1 Diels-Alder cycloadditions of pyrones and halopyrone ………………………...
70
I.4.2 Intramolecular Diels-Alder cycloadditions of pyrones …………………………
75
I.5 Formation of oxepine ring via cycloisomerization of methoxyacetylene or alternative
routes……………………………………………………………………………………...
77
I.6 Generation of 5-iodopyrones by iodocyclization ……………………………………..
81
II. Results and discussion.…………………………………………………………………….
88
II.1 Model studies toward bridged decalin system and on diastereoselectivity of
Intramolecular Pyrone Diels-Alder reaction (IMPDA)…………………………………...
88
II.2 Synthetic approach toward basiliolide B……………………………………………..
95
II.2.1 Conjugate addition to butenolide 37……………………………………………
95
II.2.2 Stereoselective alkylations of butyrolactone 77………………………..............
105
II.2.3 Generation of terminal alkyne………………………………………………….
109
II.2.4 Synthesis of the lactone intermediates 91, 96 and lactol intermediates 102,
103 and their Diels-Alder cycloaddition reactions……………………………………
117
II.2.5 Synthesis of the alkene intermediates for Diels-Alder reaction and their
further synthetic elaboration. Iodocyclization………………………………………...
v
124
III. Summary and future challenges…………………………………………………………...
131
IV. Experimental ……………………………………………………………………………...
135
REFERENCES………………………………………………………………………………..
261
BIOGRAPHICAL SKETCH………………………………………………………………….
275
vi
LIST OF TABLES
Table 1.
1 2
SiR R
Geometric parameters of silacyclobutanes
, silacyclobutenes 2 and
benzometallacyclobutenes 3……………………………………………………
3
Ring expansion reactions of 1,1-dimethyl-1-silacyclobutane with lithium
carbenoids………………………………………………………………………
24
Table 3.
Stereoselectivity in ring-expansion reactions of substituted silcyclobutanes…..
26
Table 4.
Uncatalyzed aldol addition reactions of silacyclobutyl ketene acetals to
aliphatic and aromatic aldehydes……………………………………………….
42
Reaction of O-silacyclobutyl S,O-ketene acetals (derived from thioesters) with
aldehydes………………………………………………………………………..
43
Table 6.
Reaction of O-silacyclobutyl N,O-ketene acetals with aldehydes……………...
43
Table 7.
Reaction of 1-(2-hexenyl)-1-phenylsilacyclobutenes with aldehydes………….
45
Table 8.
Formation and trapping of silylmethyllithium 20………………………………
50
Table 9.
Reaction of 20 with benzophenone……………………………………………..
51
Table 10.
Diels-Alder cycloaddition of 3- and 5-halosubstituted α-pyrones……………...
74
Table 11.
Intramolecular cycloadditions of 5-bromo-2-pyrones………………………….
75
Table 12.
Cycloisomerization of carboxylic acid with terminal alkyne…………………..
79
Table 13.
Iodocyclization of alkenynoic acids…………………………………………….
83
Table 14.
Iodocyclization of alkynenoates………………………………………………..
84
Table 15.
Conjugate addition of acetylides………………………………………………..
97
Table 16.
Results on conjugate addition to butenolide 37………………………………...
100
Table 17.
Conjugate addition of vinylcuprates to butenolide……………………………..
102
Table 2.
Table 5.
vii
Table 18.
Further optimization of the conjugate addition step and scaling up……………
104
Table 19.
Alkylation of butyrolactone 77…………………………………………………
106
Table 20.
Stereoselective methylation of 80……………………………………………… 108
Table 21.
Generation of alkyne 82 via phosphate enol ester functionality……………….. 111
Table 22.
Generation of triflate enol ester 87……………………………………………..
115
Table 23.
Generation of terminal alkyne 82 from enol triflate 87………………………...
116
Table 24.
Iodocyclization of TBDPS protected alkynenoates…………………………….
128
Table 25.
Removal of TBDPS protecting group from 123………………………………..
131
viii
LIST OF FIGURES
Figure 1.
An ambiphilic siletanylmethyllithium………………………………………..
1
Figure 2.
Ring puckering potential energy and wave functions of the first six
vibrational states of 1-chlorosilacyclobutane………………………………...
5
Figure 3.
300 MHz 1H-NMR spectrum of compound 19……………………………….
58
Figure 4.
75 MHZ 13C-NMR spectrum of compound 19……………………………….
59
Figure 5.
300 MHz 1H-NMR spectrum of compound 26……………………………….
60
Figure 6.
75 MHZ 13C-NMR spectrum of compound 26……………………………….
61
Figure 7.
300 MHz 1H-NMR spectrum of compound 28……………………………….
62
Figure 8.
75 MHZ 13C-NMR spectrum of compound 28.................................................
63
Figure 9.
Structure of (-)-haouamine, (-)-okilactomycin and spongistatin 1…………...
65
Figure 10.
Structure 32 after Molecular Mechanics conformational minimization……...
78
Figure 11.
300 MHz 1H-NMR spectrum of compound 61………………………………. 167
Figure 12.
75 MHZ 13C-NMR spectrum of compound 61……………………………….
Figure 13.
300 MHz 1H-NMR spectrum of compound 63………………………………. 169
Figure 14.
75 MHZ 13C-NMR spectrum of compound 63……………………………….
Figure 15.
300 MHz 1H-NMR spectrum of compound 64………………………………. 171
Figure 16.
75 MHZ 13C-NMR spectrum of compound 64……………………………….
Figure 17.
300 MHz 1H-NMR spectrum of compound 65………………………………. 173
Figure 18.
75 MHZ 13C-NMR spectrum of compound 65……………………………….
Figure 19.
300 MHz 1H-NMR spectrum of compound 67………………………………. 175
ix
168
170
172
174
Figure 20.
75 MHZ 13C-NMR spectrum of compound 67……………………………….
Figure 21.
300 MHz 1H-NMR spectrum of compound 69………………………………. 177
Figure 22.
75 MHZ 13C-NMR spectrum of compound 69……………………………….
Figure 23.
300 MHz 1H-NMR spectrum of compound 70………………………………. 179
Figure 24.
75 MHZ 13C-NMR spectrum of compound 70……………………………….
Figure 25.
300 MHz 1H-NMR spectrum of compound 72………………………………. 181
Figure 26.
75 MHZ 13C-NMR spectrum of compound 72……………………………….
Figure 27.
300 MHz 1H-NMR spectrum of compound 77………………………………. 183
Figure 28.
75 MHZ 13C-NMR spectrum of compound 77……………………………….
Figure 29.
300 MHz 1H-NMR spectrum of compound 80………………………………. 185
Figure 30.
75 MHZ 13C-NMR spectrum of compound 80……………………………….
Figure 31.
300 MHz 1H-NMR spectrum of compound 81………………………………. 187
Figure 32.
75 MHZ 13C-NMR spectrum of compound 81……………………………….
Figure 33.
300 MHz 1H-NMR spectrum of compound 84………………………………. 189
Figure 34.
75 MHZ 13C-NMR spectrum of compound 84……………………………….
Figure 35.
300 MHz 1H-NMR spectrum of compound 87………………………………. 191
Figure 36.
75 MHZ 13C-NMR spectrum of compound 87……………………………….
Figure 37.
300 MHz 1H-NMR spectrum of compound 82………………………………. 193
Figure 38.
75 MHZ 13C-NMR spectrum of compound 82……………………………….
Figure 39.
300 MHz 1H-NMR spectrum of compound 88………………………………. 195
Figure 40.
75 MHZ 13C-NMR spectrum of compound 88……………………………….
Figure 41.
300 MHz 1H-NMR spectrum of compound 89………………………………. 197
Figure 42.
75 MHZ 13C-NMR spectrum of compound 89……………………………….
x
176
178
180
182
184
186
188
190
192
194
196
198
Figure 43.
300 MHz 1H-NMR spectrum of compound 90………………………………. 199
Figure 44.
75 MHZ 13C-NMR spectrum of compound 90……………………………….
Figure 45.
300 MHz 1H-NMR spectrum of compound 91………………………………. 201
Figure 46.
75 MHZ 13C-NMR spectrum of compound 91……………………………….
Figure 47.
300 MHz 1H-NMR spectrum of compound 92………………………………. 203
Figure 48.
75 MHZ 13C-NMR spectrum of compound 92……………………………….
Figure 49.
300 MHz 1H-NMR spectrum of compound 93………………………………. 205
Figure 50.
75 MHZ 13C-NMR spectrum of compound 93……………………………….
Figure 51.
300 MHz 1H-NMR spectrum of compound 95………………………………. 207
Figure 52.
75 MHZ 13C-NMR spectrum of compound 95……………………………….
Figure 53.
300 MHz 1H-NMR spectrum of compound 96………………………………. 209
Figure 54.
75 MHZ 13C-NMR spectrum of compound 96……………………………….
Figure 55.
300 MHz 1H-NMR spectrum of compound 97………………………………. 211
Figure 56.
75 MHZ 13C-NMR spectrum of compound 97……………………………….
Figure 57.
300 MHz 1H-NMR spectrum of compound 98………………………………. 213
Figure 58.
75 MHZ 13C-NMR spectrum of compound 98……………………………….
Figure 59.
300 MHz 1H-NMR spectrum of compound 99………………………………. 215
Figure 60.
75 MHZ 13C-NMR spectrum of compound 99……………………………….
Figure 61.
300 MHz 1H-NMR spectrum of compound 100……………………………... 217
Figure 62.
75 MHZ 13C-NMR spectrum of compound 100……………………………...
Figure 63.
300 MHz 1H-NMR spectrum of compound 101……………………………... 219
Figure 64.
75 MHZ 13C-NMR spectrum of compound 101……………………………...
Figure 65.
300 MHz 1H-NMR spectrum of compound 102……………………………... 221
xi
200
202
204
206
208
210
212
214
216
218
220
Figure 66.
75 MHZ 13C-NMR spectrum of compound 102……………………………...
Figure 67.
300 MHz 1H-NMR spectrum of compound 103……………………………... 223
Figure 68.
75 MHZ 13C-NMR spectrum of compound 103……………………………...
Figure 69.
300 MHz 1H-NMR spectrum of compound 104……………………………... 225
Figure 70.
75 MHZ 13C-NMR spectrum of compound 104……………………………...
Figure 71.
300 MHz 1H-NMR spectrum of compound 109……………………………... 227
Figure 72.
75 MHZ 13C-NMR spectrum of compound 109……………………………...
Figure 73.
300 MHz 1H-NMR spectrum of compound 110……………………………... 229
Figure 74.
75 MHZ 13C-NMR spectrum of compound 110……………………………...
Figure 75.
300 MHz 1H-NMR spectrum of compound 111……………………………... 231
Figure 76.
75 MHZ 13C-NMR spectrum of compound 111……………………………...
Figure 77.
300 MHz 1H-NMR spectrum of compound 112……………………………... 233
Figure 78.
75 MHZ 13C-NMR spectrum of compound 112……………………………...
Figure 79.
300 MHz 1H-NMR spectrum of compound 113……………………………... 235
Figure 80.
300 MHz 1H-NMR spectrum of compound 116……………………………... 236
Figure 81.
75 MHZ 13C-NMR spectrum of compound 116……………………………...
Figure 82.
300 MHz 1H-NMR spectrum of compound 117……………………………... 238
Figure 83.
75 MHZ 13C-NMR spectrum of compound 117……………………………...
Figure 84.
300 MHz 1H-NMR spectrum of compound 118……………………………... 240
Figure 85.
75 MHZ 13C-NMR spectrum of compound 118……………………………...
Figure 86.
300 MHz 1H-NMR spectrum of compound 119……………………………... 242
Figure 87.
75 MHZ 13C-NMR spectrum of compound 119……………………………...
Figure 88.
300 MHz 1H-NMR spectrum of compound 120……………………………... 244
xii
222
224
226
228
230
232
234
237
239
241
243
Figure 89.
75 MHZ 13C-NMR spectrum of compound 120……………………………...
Figure 90.
300 MHz 1H-NMR spectrum of compound 121……………………………... 246
Figure 91.
75 MHZ 13C-NMR spectrum of compound 121……………………………...
Figure 92.
300 MHz 1H-NMR spectrum of compound 122……………………………... 248
Figure 93.
75 MHZ 13C-NMR spectrum of compound 122……………………………...
Figure 94.
300 MHz 1H-NMR spectrum of compound 115……………………………... 250
Figure 95.
300 MHz 1H-NMR spectrum of compound 123……………………………... 251
Figure 96.
75 MHZ 13C-NMR spectrum of compound 123……………………………...
Figure 97.
Assignment of protons of 72 based on the data from the decoupling
experiment……………………………………………………………………. 253
Figure 98.
Through space interactions in 72 by nOe experiment………………………..
254
Figure 99.
Through space interactions in 72 by nOe experiment………………………..
255
Figure 100.
Assignment of protons of 93 based on the data from the decoupling
experiment……………………………………………………………………. 256
Figure 101.
Through space interactions in 93 by nOe experiment………………………..
Figure 102.
COSY spectrum of 123………………………………………………………. 258
Figure 103.
Assignment of protons in structure 123, according to the data on proton
coupling from COSY experiment (Figure 102)………………………………
259
Through space interactions in 123 by nOe experiment………………………
260
Figure 104.
xiii
245
247
249
252
257
LIST OF ABBREVIATIONS
Å
Angstrom
Ac
acetyl
acac
acetylacetonate
AIBN
2,2’-azobisisobutyronitrile
Anhyd
anhydrous
aq
aqueous
Ar
aryl
Atm
atmosphere(s)
9-BBN
9-borabicyclo[3.3.1]nonyl
BINAP
(2R, 3S)-2,2’-bis(diphenylphosphino)-1,1’-binaphthyl
Bn
benzyl
BOC
tert-butoxycarbonyl
b.p.
boiling point
br
broad (spectral)
brsm
based on recovered starting material
Bu
butyl
i-Bu
iso-butyl
n-Bu
normal butyl
s-Bu
sec-butyl
t-Bu
tert-butyl
°C
degrees Celsius
calc
calculated
cat
catalytic
Cbz
benzyloxycarbonyl
CI
chemical ionization (in mass spectrometry)
cm
centimeter(s)
cod
cyclooctadiene
COSY
correlation spectroscopy
xiv
Cp
cyclopentadienyl
Cy-hexyl
cyclohexyl
δ
chemical shift in parts per million downfield from tetramethylsilane
Δ
heat
d
day(s); doublet (spectral)
D
deuterium
DA
Diels-Alder (reaction)
DABCO
1,4-diazabicyclo[2.2.2]octane
DBN
1,5-diazabicyclo[4.3.0]non-5-ene
DBU
1,8-diazabicyclo[5.4.0]undec-7-ene
DCC
N,N-dicyclohexylcarbodiimide
DCM
dichloromethane
DDQ
2,3-dichloro-5,6-dicyano-1,4,benzoquinone
DEAD
diethyl azodicarboxylate
DEPT
distortionless enhancement by polarization transfer
DIBALH
diisobutylaluminum hydride
DMAP
4-(dimethylamino)pyridine
DME
1,2-dimethoxyethane
DMF
dimethylformamide
DMPU
dimethylpropylene urea
DMSO
dimethyl sulfoxide
dr
diastereomeric ratio
E+
electrophile
ee
enantiomeric excess
EI
electron impact (in mass spectrometry)
E or E(O)
entgegen or opposite (alkene stereochemistry)
Equiv
equivalents
Et
ethyl
EWG
electron withdrawing group
FAB
fast action bombardment (in mass spectrometry)
FT
Fourier transform
xv
FTIR
Fourier transformed infrared
g
gram(s)
GC
gas chromatography
h
hours(s)
HMO
Hückel molecular orbital
HMPA
hexamethylphosphoric triamide
HOMO
highest occupied molecular orbital
HPLC
high-performance liquid chromatography
HRMS
high-resolution mass spectrometry
Hz
hertz
IMDA
intramolecular Diels-Alder (reaction)
IMPDA
intramolecular pyrone Diels-Alder (reaction)
Imid.
imidazole
IP
ionization potential
IR
infrared
J
coupling constant (in NMR)
k
kilo
KOH
potassium hydroxide
L
liter(s)
LAH
lithium aluminum hydride
LDA
lithium diisopropylamide
LHMDS
lithium hexamethyldisilazane
LTMP
lithium 2,2,6,6-tetramethylpiperidide
LUMO
lowest unoccupied molecular orbital
μ
micro
m
multiplet (spectral), meter(s), milli
M
moles per liter
m-CPBA
m-chloroperoxybenzoic acid
m/e
mass to charge ratio (in mass spectrometry)
Me
methyl
MEM
(2-methoxyethoxy)methyl
xvi
Mes
mesityl, 2,4,6-trimethylphenyl
MHz
megahertz
min
minute(s)
MO
molecular orbital
mol
mole(s)
MOM
methoxymethyl
m.p.
melting point
Ms
Methanesulfonyl (mesyl)
MS
mass spectrometry
MVK
methyl vinyl ketone
m/z
mass to charge ratio (in mass spectrometry)
Naphth
naphthalene
NBS
N-bromosuccinimide
NCS
N-chlorosuccinimide
NMO
N-methylmorpholine-N-oxide
NMR
nuclear magnetic resonance
NOE
nuclear Overhauser effect
Nuc
nucleophile
OD
optical density
ORD
optical rotary dispersion
Oxid’n
oxidation
p-
para
PCC
pyridinium chlorochromate
PDC
pyridinium dichromate
PEG
polyethylene glycol
Ph
phenyl
PMB
p-methoxybenzyl
PSB
p-siletanylbenzyl
PPA
polyphosphoric acid
ppm
parts per million (in NMR)
PPTS
pyridinium p-toluenesulfonate
xvii
Pr
propyl
i-Pr
isopropyl
q
quartet (spectral)
RDS
rate determining step
re
rectus (stereochemistry)
Rf
retention factor (in chromatography)
r.t.
room temperature
s
singlet (spectral); second(s)
SN1
unimolecular nucleophilic substitution
SN2
bimolecular nucleophilic substitution
t
triplet (spectral)
TBAF
tetrabutylammonium fluoride
TBAT
tetrabutylammonium difluorotriphenylsilicate
TBDMS
tert-butyldimethylsilyl
TBDPS
tert-butyldiphenylsilyl
TEA
triethylamine
Tf
trifluoromethanesulfonyl (triflyl)
TFA
trifluoroacetic acid
TFAA
trifluoroacetic anhydride
THF
tetrahydrofuran
THP
tetrahydropyran
TIPS
triisopropylsilyl
TLC
thin layer chromatography
TMEDA
N,N,N’,N’-tetramethyl-1,2-ethylenediamine
TMS
trimethysilyl, tetramethylsilane
Tol
toluene
Ts
tosyl, p-toluenesulfonyl
TS
transition state
UV
ultraviolet
Z or Z(O)
zusammen or together (alkene stereochemistry)
xviii
ABSTRACT
This dissertation is composed of two independent research projects. The first part
describes the synthesis and reactivity of siletanylmethyllithium, and includes a thorough review
of the chemistry of siletanes. Siletanylmethyllithium was successfully generated by
transmetallation of 1-(tributyltin)methyl-1-methylsiletane, which was produced on multi-gram
scale. The title compound demonstrates ambiphilic character and was employed for the
olefination of benzophenone. It also holds potential as a hydroxymethyllithium equivalent.
The second part focuses on the total synthesis of basiliolide B, a natural product with
promising biomedical potential. A key intramolecular 5-iodopyrone Diels-Alder cycloaddition
assembles the bridged decalin skeleton of basiliolide B. The reaction was firstly examined on
model systems and then successfully employed to construct the framework of the natural
product. The convenient functionalities were installed in the system which can be further
elaborated into dihydrooxepin ring to complete the structure of basiliolide B.
H
8
Me
Si+
δ
Li
5
9
CO2Me
4
O
O
10
δ–
O
20
19
O
OCH3
siletanylmethylllithium
basiliolide B
xix
29
Part I. SILETANYLMETHYLLITHIUM, AN AMBIPHILIC SILANE
CHAPTER I
SILACYCLOBUTANES AND DERIVATIVES
I.1 Introduction
Silacyclobutanes have become increasingly important in recent years. With respect to
routine storage and handling, silacyclobutanes are convenient and easy to use, much like
conventional organosilane reagents. However, the ring strain inherent to four-membered rings
can be exploited in various ring-opening reactions. Furthermore, this ring strain is attenuated
upon coordination with Lewis bases, thus imparting a degree of Lewis acidity to
silacyclobutanes.
Our research goal was to develop nucleophilic reagents based on electrophilic
silacyclobutanes (Figure 1). Such reagents would thus present ambiphilic character that provides
unique advantages in organic synthesis.
Goal:
nucleophilic
center
δ−
Si
δ+
Li
electrophilic
center
Figure 1. An ambiphilic siletanylmethyllithium
1
In order to develop new chemistry of silacylobutanes, it is valuable to have a thorough
understanding of what is known about silacyclobutane (siletane) reagents. This chapter draws
heavily on a review1 published earlier this year and provides a comprehensive review of siletane
chemistry.
I.2 Structure of Silacyclobutanes
The structural characteristics of 1,1-dialkylsilacyclobutanes have been studied both
computationally and experimentally.
The internal C–Si–C bond angle (ca. 80°) deviates
significantly from the ideal tetrahedral bond angle of 109.5°. The propensity of silacyclobutanes
to form pentavalent “ate” complexes is generally linked to this distorted bond angle, which is a
function of the constrained four-membered ring. The relative ease by which silacyclobutanes
form hypervalent species by accepting additional ligands provides the foundation for many
applications in organic chemistry.
The structures of the simplest members of silacyclobutanes (silacyclobutane, and 4silaspiro[3.3]heptane) were determined by electron diffraction and microwave spectroscopy.
Naphthyl-substituted silacyclobutanes have been investigated by X-ray diffraction. The
molecular
structures
dimethylsilacyclobutane,
of
1,1-difluorosilacyclobutane,
1,1-dichlorosilacyclobutane,
silacyclobutane,
1,1-diethynylsilacyclobutane,
1,11,3-
disilacyclobutane (1a), 1,1,3,3-tetramethyl-1,3-disilacyclobutane (1b), among monosubstituted
1-fluorosilacyclobutane and 1-chlorosilacyclobutane have been studied by gas phase electron
diffraction with refinement of experimental data by means of ab initio calculations (Table 1).
The molecule exists in a puckered conformation. During the structural refinement it was assumed
that all of the structural parameters except the puckering angle for both the equatorial and axial
conformers are equal.
2
R1
R
Si R
R Si
R
R3
R2
R4
(1)
a) R = H
b) R = Me
M R1
R2
R5
Si
(2)
R6
(3)
(a) R1 = R3 = R4 = TMS; R2 = Ph;
R5,R6 = Ph(TMS)C=
(b) R1 = But; R2 =
[Pt(PEt3)2(H2O)]SbF6; R3 = R4 =
Ph; R5,R6 = ButCH=
(c) R1 = R2 = R6 = But, R3 = OMe,
R4 = Mes, R5 = TMS
(d) R1 = H, R2 = R4 = TMS, R3 =
Mes, R5 = TMS-O, R6 = Ad
(e) R1 = H, R2 = Ph, R3 = Mes, R4 =
TMS, R5 = TMS-O, R6 = Ad
(f) R1 = Me, R2 = Ph, R3 = R4 =
TMS, R5 = TMS-O, R6 = But
(g) R1 = TMS, R2 = Ph, R3 = R4 =
Cl, R5 = H, R6 = CH2But
Mes = 2,4,6-Me3C6H2, Ad = 1 –
adamantyl
(a) M = Si, R1 = Mes, R2 =
NHSiBut3
(b) M = Sn, R1 = 2,4,6-But3
C6H2, R2 =
CH2CMe2C6H3But2-3,5
Table 1. Geometric parameters of silacyclobutanes
benzometallacyclobutenes 3
Structure
R
1
r (Å)
R
H
2
H
-CH2CH2CH2Me
M-C(2)
M-C(4)
1.885(2)
H
But
SiPh2
H
(4)
SiR1R2
, silacyclobutenes 2 and
Angles (º)
C(2)-C(3)
C(3)-C(4)
1.571(3)
<M
<C-2
<C-3
77.2(9)
87.9(12)
97.0(15)
86.8
99.9
1.898(2)
1.579(3)
76.6
Me
1.885(2)
1.563(4)
79.2(11)
<C-4
Ref.
c
d
e
F
F
1.836(3)
1.574(8)
82.7(6)
86.8(8)
100.6(8)
f
Cl
Cl
1.860(3)
1.557(4)
81.1(10)
85.7(12)
102.0(15)
g
HC≡C
HC≡C
1.874(2)
1.563(6)
79.2(6)
86.8
99.6
h
F
H
1.855(1)
1.586
80.8(6)
85.3
98.6(19)
i
Cl
H
1.864(2)
1.591(5)
80.7(14)
85.0
98.7(22)
i
86.8(3)
Np
(1a)
1.888(2)
90.6(3)
(1b)
1.910(5)
92.2(4)
a
Npa
Np
a
f
j
1.894(4)
1.527(6)
81.3(2)
85.3(5)
107.9(3)
1.877(3)
1.881(2)
1.475(5)
1.507(8)
78.8(1)
87.8(3)
106.2(4)
86.7(2)
d
1.863(2)
1.863(2)
1.537(3)
1.562(4)
79.5(1)
86.8(2)
100.5(2)
86.1(2)
d
2a
1.906(8)
1.915(8)
1.367(11)
1.500(11)
74.0(4)
91.9(5)
106.6(7)
87.5(5)
k
2b
1.86(1)
1.88(1)
1.40(1)
1.51(1)
75.3(4)
92.8(6)
103.1(7)
88.7(5)
k
2c
1.837(3)
1.928(3)
1.367(4)
1.599(4)
78.6(3)
91.7(2)
106.9(2)
81.8(2)
k
Si(CH2)3
d
│
Npa
Npa
OSi(CH2)3
│
Npa
3
Table 1 − continued
Structure
a
r (Å)
Angles (º)
2d
1.972(7)
71.4(3)
97.7(5)
103.8(5)
86.6(4)
k
2e
1.991(13)
73.8(6)
96.3(4)
106.0(11)
83.9(8)
k
2fb
1.981(18)
74.4(8)
95.5(14)
103.9(15)
82.8(10)
k
2g
1.828(1)
1.864(1)
3a
1.885(1)
1.938(1)
3b
2.185(5)
2.204(6)
1.417(9)
1.558(8)
4
1.884(1)
1.880(1)
1.564(1)
1.589(1)
b
1.354(1)
1.554(1)
c
d
80.7(1)
87.8(1)
110.4(1)
77.3(5)
89.9(8)
107.3(10)
85.4(7)
67.5(2)
93.5(4)
110.0(6)
89.0(4)
l
79.45(5)
86.44(7)
99.46(9)
85.88(7)
m
e
k
f
l
g
1-Naphthyl. For two independent molecules. Reference [2]. Reference [3]. Reference [4]. Reference [5].
h
i
j
k
Reference [6]. Reference [7]. Reference [8]. Reference [9]. Reference [10], reference [11], reference [12],
l
m
reference [13], reference[14]. Reference [15], reference [16]. Reference [17].
X-ray techniques have been used to examine the molecular structure of some
silacyclobutenes 2,10,11,12,13,14 benzosilacyclobutanes,16 benzostannacyclobutanes 3,16 and fused
silacyclobutane 4.17 The geometric parameters of metallacyclobutanes with the corresponding
literature reference are presented in Table 1.
The study of IR spectra of silacyclobutanes has shown that there are six ring vibrations
revealed for a four-membered ring, one of which, ring puckering, has a frequency below 200 cm1
. Three of the silacyclobutane ring modes occur between 850 cm-1 and 950 cm-1. Two
absorption bands near 1120 cm-1 and 1180 cm-1 result from vibrations involving methylene
groups of the ring.18 IR spectra of silacyclobutane, 1,1-dimethylsilacyclobutane, 1-methyl-1chlorosilacyclobutane, and 1,1-dichlorosilacyclobutane in inert gas matrixes at 10 K have been
previously reported.19 For 1-silacyclobutane-1 –d1, in the Si—H stretching region, in addition to
the fundamental Si—H band at 2148.3 cm-1, a second weaker band at 2151.3 cm-1 is observed.
These two bands arise from the Si—H stretching for the molecule in two different
conformations.20
Microwave studies have been accomplished on 1-fluorosilacyclobutane21 and 1chlorosilacyclobutane.22
Conformational analysis of 1-chlorosilacyclobutane employing microwave spectroscopy
data has shown that the equatorial conformer is more stable than the axial one by 185(40) cm-1.
The potential energy function of the ring puckering motion has been determined for that
molecule (Figure 2).
4
Figure 2. Ring puckering potential energy and wave functions of the first six vibrational states of
1-chlorosilacyclobutane.22
The
electron
24,25,26
dialkylsilacyclobutanes,
impact
fragmentation
of
1-alkyl-l-aryl-l-silacyclobutanes,
silacyclobutane,18,23
1,1-
and
with
silacyclobutanes
functional substituents on the silicon atom23,27 or the methyl group in the 2 or 3 position of the
ring25,28,27 has been investigated. With rare exceptions, silacyclobutanes show intense molecular
ion peaks. The main feature of the fragmentation process for the molecular ion of
silacyclobutanes is the elimination of ethylene from the heterocycle. The loss of ethylene from
these compounds also occurs when they are pyrolyzed in the gas phase.
I.3 Preparation of Silacyclobutanes and Derivatives from the Acyclic as well
as Cyclic Compounds
One of the most commonly used approaches to prepare silacyclobutanes is by cyclization
of halopropylsilyl halides with magnesium (eq. 1).18,29,30,31
5
Mg
X3-nMenSi
Cl
X
X
RM
Si
X
R
RM
Si
and
(2)
Si
R
R
1,1-Dihalosilacyclobutanes
(1)
X2-nMenSi
Et2O or THF
1-alkyl-1-chlorosilacyclobutanes
can
be
further
derivatized by substitution of the halide with different nucleophiles (eq. 3 and 4).32
Another convenient method for the synthesis of metallacyclobutanes is the reaction of diGrignard reagents with Me2MCl2 (M=Si, Ge, Sn)33,34 (eq. 3).35
Me2MCl2
+
R
R
R
MgBr
Me2M
MgBr
(3)
R
I.4 Pyrolysis and Photolysis
Pyrolysis of silacyclobutanes at 500-700 ºC yields silenes en route to 1,3disilacyclobutanes, ethylene being the predominant component of the gaseous reaction products
(Scheme 1). Gas phase and laser pulsed photolysis proceed in the same way.
R2Si
Δ or hυ
- CH2=CH2
R2Si
CH2
x2
R2Si
SiR2
Scheme 1
Copyrolysis of two different silacyclobutanes produces a mixture of three possible 1,3disilacyclobutanes.
Photochemical silene formation proceeds with useful efficiencies from silacyclobutanes
that bear alkyl, vinyl, ethynyl, silyl, and phenyl substituents at silicon.36 In contrast, alkoxy
substitution either directly at silicon or on the aromatic rings of phenylated derivatives makes the
silacyclobutane moiety inert to photocycloreversion.37,38
6
The photochemical cycloreversion of silacyclobutanes is known to be initiated from the
lowest (σ,σ*) excited singlet state by cleavage of one of the ring Si-C(2) bonds to form a
biradicaloid intermediate. This excited state intermediate cleaves to silene and alkene, recloses
to starting material, or undergoes an intramolecular disproportionation if an alkyl substituent is
present at C-2.39,36
In contrast, the mechanism of the thermal cleavage of silacyclobutanes is shown to
proceed by a stepwise mechanism involving initial C(2)-C(3) bond cleavage.40,41,42,43,36
Pyrolysis of 1,1-dimethyl-2-phenyl-1-silacyclobutane cleaves regioselectively through
the Si–C(4) bond to give dimethylsilylphenylmethylene, which dimerizes to afford cis/trans1,1,3,3-tetramethyl-2,4-diphenyl-1,3-disilacyclobutane. Photolysis of the same species cleaves
regioselectively through Si–C(2) bond (as shown on the Scheme 2).40 The ring-opening
regioselectivity in the photolysis of 1,1,2-triphenylsilacyclobutane proceeds similarly (Scheme
2),44,45 as do photolysis reactions of 2-alkyl substituted silacyclobutanes.39
Ph
D H
Si
OCH3
CH3OD
Ph
Ph2Si
500oC
hυ
Si
+
Si
Si
Si
Ph
Ph
hυ
Ph
Ph
Ph
Ph
MeOH
Si
Ph
Ph
Ph Si CH3
OMe
Scheme 2
Ph
R2Si
R2Si
PhHC CH2
+
R2Si CH2
Ph
OMe
R2Si CH3
R = Me
R = Ph
R2 H
Si
Scheme 3
7
MeOH
OMe
R2Si
Ph
Parallel with cycloreversion, [1,3]-silyl migration proceeds to give a bicyclic isotoluene
analogue that undergoes rapid desilylation in methanol solution to give ring-opened products
(Scheme 3).45 Previously, formation of these species was believed to occur by trapping of the
1,4-biradical/zwitterion formed upon Si-C bond cleavage of silacyclobutane.
Photolysis of 1-benzyl-1-methylsilacyclobutane and 1-benzyl-1-phenylsilacyclobutane
also leads to formation of isotoluene derivatives as the major primary products (Scheme 4). The
primary photolysis in both cases is dominated by reactivity specific to the benzyl chromophore
rather than the silacyclobutane moiety, unlike the case with other silacyclobutanes.
Si
Ph
R
Si
R
H
Si
hν
R=Me
98 %
hν
R=Me
R=Ph
R=Ph
Ph
complicated mixture
of products
Ph CH2 +
Scheme 4
Ph
Ph
Si
Ph
hν
MeOH
Ph CH3
+
Si
O
Ph
Si
+
other products
19 %
43 %
92 %
Scheme 5
Photolysis of 1-benzyl-1-methylsilacyclobutane, which proceeds via rearrangement to an
isotoluene
intermediate
followed
by
ring
opening,
produces
1-propyl-1-methyl-2,3-
45
benzosilacyclobutene in quantitative yield.
Photochemistry of the isotoluene derivatived of 1-benzyl-1-phenylsilacyclobutane is
initiated by preferential cleavage of the weaker of the exocyclic silacyclobutyl Si-C bonds,
yielding benzyl- and phenylsilacyclobutyl radicals. This fact is supported by steady photolysis of
1-benzyl-1-phenylsilacyclobutane in deoxygenated methanol solution, which leads to the
formation of two main products, toluene and disiloxane. In the absence of methanol, photolysis
of this species produces a complicated mixture of products (Scheme 5)
8
Thermally induced rearrangements of silacyclobutane are known as well. 1-Methyl-1phenylsilacyclobutane undergoes a [4→2+2] thermocyclodecomposition to give silene, which
undergoes a sigmatropic 1,3-hydrogen shift through the resulting 1,4-diradical. Ring-closing
gives 3,4-benzo-1-methyl-1-hydro-1-silacyclobutene (Scheme 6).46
4
Si
2+2
Si
CH3
- CH2=CH2
4
RC
1,3-H
CH2
Si
H
CH3
1,4-H
2+2
Si H
CH3
CH2
RC
- CH2=CH2
Si CH3
H2 C
Si
Si H
CH3
H2C Si H
CH3
CH3
Scheme 6
1-Methyl-1-naphthyl-1-silacyclobutane undergoes a similar transformation via a
thermolytic [4→2+2] cyclodecomposition and 1,4-hydrogen shift to yield 1-methyl-1-hydro-1silaacenaphthene (Scheme 6).
Surprisingly, 2-methylene-1-silacyclobutane at high temperatures does not undergo
cycloreversion to produce silene and allene, but it undergoes rearrangement to 2- and 3silacyclopentenes via the intermediacy of carbene formed by 1,2-silyl shift (Scheme 7).47
Me2Si
Δ
Me2Si
420 oC
salt bath
Me2Si
> 95%
Me2Si
+ Me2Si
Scheme 7
When deuterium-labeled 2-methylene-1-silacyclobutane was investigated, scrambling of
deuterium between the allylic methylene and the terminal vinyl was observed. This fact has been
explained by ring opening to the 1,4-diradical at temperatures below those required for the
rearrangement to the carbene.48
9
I.5 Ring-Opening Reactions of Silacyclobutanes
I.5.1 Ring-opening reactions leading to polymerization
Ring-opening polymerization is one of the most important applications of
silacyclobutanes in organic chemistry. Polymerization of silacyclobutanes, which gives rise to
carbosilane polymers, has been carried out thermally, by transition metal catalysis, or, most
commonly, by anionic initiation.
The strain-release Lewis acidity of silacyclobutanes makes them ideal monomers for
anionic polymerization. For example, n-butyllithium reacts with silacyclobutanes by attack on
the central silicon atom to generate a pentavalent silicate complex (Scheme 8). Although this
initiation process is reversible in principle, the intermediate silicate breaks down with selective
cleavage of a strained endocyclic bond to produce a new, silylpropyl carbanion.
Chain
propagation occurs as the silylpropyllithium species reacts with another molecule of the
silacyclobutane monomer. Likewise, initiation may be achieved with oxyanion salts of Group I
metals, with potassium being the preferred counterion.49,50,51
Scheme 8
Anionic
ring-opening
polymerization
of
Si-disubstituted
and
monosubstituted
silacyclobutanes (bearing alkyl, vinyl, or phenyl groups) thus provides the corresponding
poly(carbosilanes).52,53 In the case of 1,1-dimethyl-1-silacyclobutene, polymerization proceeds
with retention of alkene stereochemistry and yields predominantly poly(1,1-dimethyl-1-sila-cisbut-2-ene).54
10
Butyllithium-induced polymerization of dialkylsilacyclobutanes, typically conducted in
THF–hexanes mixed solvent systems, displays characteristics consistent with a living
polymerization process.
The living nature of polymerization — the ability to reinitiate
polymerization upon addition of a fresh supply of monomer — was investigated by addition of a
second portion of monomer, followed by end-capping the resulting polymer with an
electrophile.55,56 The end-capping efficiency, when poly(1,1-dimethylsilacyclobutane), was
treated with chlorodimethylphenylsilane was 0.9.56 The living nature of silacyclobutane
polymerization means that the synthesis of polysilabutanes can be incorporated into block
copolymers. Living polymerization can also translate into higher molecular weight polymers
and narrower polydispersity (Mw/Mn).
Application for the synthesis of block-copolymers. Addition of styrene to the living
poly(1,1-dialkylsilabutane)s provided a poly(1,1-dialkylsilabutane-b-styrene) block copolymers
in 99% yield with Mw/Mn =1.19.55,56 Amphiphilic block copolymers of silacyclobutane and
methacrylic acid (and methacrylic acid derivatives) with narrow molecular weight distribution
can be synthesized by sequential addition of 1,1-diphenylethylene and methacrylate or its
derivatives to living poly(silacyclobutane) in the presence of lithium chloride (Scheme 9).57,58,59
Scheme 9
It is important to end-cap the living carbosilane polymer with 1,1-diphenylethylene to
decrease the reactivity of the living center in order to obtain the block copolymer successfully.
The diphenylethylene thus provides a milder carbanion for initiation of the methacrylate
monomer. With this modification, efficiency of the end-capping by an electrophile (quenching)
has reached 0.95.57,59
11
Concept of “anionic pump.” Silacyclobutanes play an important role in the formation
of other block co-polymers. For example, the relatively less nucleophilic poly(ethylene oxide)
oxyanion can not initiate the polymerization of styrene, which needs a more nucleophilic
alkyllithium initiator.
To enable the synthesis of multi-block copolymers from various
combinations of monomers by anionic mechanisms, it is important to modify the reactivity of the
growing anionic chain end of each polymer so as to attack the co-monomer. There have only
been a few reports on the polymerization of styrene initiated by an oxyanion (see reference 60
and references cited). Thus, there exists a need for a transitional species that is capable of
converting oxyanions into carbanions. In 2000, Kawakami came up with the concept of the
“carbanion pump”, in which the ring-strain energy of the silacyclobutane is harnessed to convert
an oxyanion into a carbanion (Scheme 10).61
Concept of a carbanion pump
Scheme 10
The initially low efficiency of dimethylsilacyclobutane as a “carbanion pump” was
significantly improved by including 1,1-diphenylethylene to end-cap the initially formed
carbanion.60 Apparently, the reactivity of the resulting diphenylpentyl anion toward
dimethylsilacyclobutane is low, which helps to suppress side processes such as unwanted
polymerization of the silacyclobutane.
The effect of different counterions was investigated. Potassium counterions provide
improved efficiency as compared to lithium or sodium counterions. The most efficient system in
12
terms of formation of carbanions was achieved with diphenylsilacyclobutane in combination
with potassium tert-butoxide and diphenylethylene. Di-block copolymers from ethylene oxide
and methyl methacrylate (or styrene) was synthesized by this method in 85% efficiency (Scheme
11).
Stepwise formation of block co-polymer
Scheme 11
The “carbanion pump” method has been successfully applied for the preparation of
different block co-polymers including poly(ethylene oxide)-block-polystyrene, poly(ethylene
oxide)-block-polystyrene-block-poly(ethylene oxide), poly(ethylene oxide)-block-poly(methyl
methacrylate), poly(ethylene oxide)-block-poly(methylmethacrylate)-block-poly(ethylene oxide)
(shown in Scheme 11), and poly(ferrocenyldimethylsilane)-block-(methyl methacrylate).62,63,64
Transition
metal
catalyzed
polymerization.
Polymerization
of
1,1-
dimethylsilacyclobutane occurs with up to quantitative yield in the presence of catalytic
platinum(0) complexes, whereas dimerization is the predominant process in the presence of
phosphine-platinum(0) complexes (Scheme 12)65,66,67,68 Dimerization and polymerization
apparently have the same intermediate, 2,2-dimethyl-1-platina-2-silacyclopentane, which can be
isolated in moderate yield (45%).68
13
Scheme 12
In the case of 1,1-diphenyl-1-silacyclobutane, the corresponding platinum insertion
product (2,2-diphenyl-1-platina-2-silacyclopentane) can be isolated in 84% yield.
Irradiation of 1,1,3,3-tetramethyl-1,3-disilacyclobutane or 1,1-dimethyl-silacyclobutane
in the presence of Pt(acac)2 induces the same type of polymerization (Scheme 13).69, 70
Scheme 13
As Weber has shown, polymers bearing reactive Si-H bonds can be formed by ringopening polymerization of 1-silacyclobutane.53 These polymers can be further converted into Sifunctionally substituted polycarbosilanes by Pt-catalyzed hydrosilylation reaction of Si-H
functionality with alkenes (Scheme 14).71
n-BuLi, HMPA
Si
H
THF, -78oC
CN
Si
H
n
Si
H2PtCl6
n
CN
Scheme 14
14
Weber also has shown that simultaneous hydrosilylation-polymerization can be
accomplished with a Pt-catalyst72 as shown in Scheme 15.
Ph
Si
OPh
Si Ph
H
H2PtCl6
n
OPh
Scheme 15
Tanaka has shown that conditions for dehydro-coupling of silanes, which employs
Pt(cod)2 in case of silacyclobutane, lead mostly to formation of polymers via ring-opening
(Scheme 16).73 In contrast, larger ring homologues gave polysilacyclic polymers via
dehydrocoupling.
SiH2
x
x = 1, 2
Pt(cod)2
toluene
Si
n
x
x = 1 P1 (60 %) + P3 (40 %)
x = 2 P2 (80 %)
x=1
Me2Pt(cod), toluene
H
Si
H
n
P3 (95 %)
Scheme 16
Stereoselectivity in polymerization via ring-opening. Since data on the polymerization
of 1,1-dimethylsilacyclobutane (DMSB) do not tell anything about the ring-opening, a methyl
group was introduced at the 2-position of the ring to probe the regioselectivity in the ring
opening. Polymerization of 1,1,2-trimethylsilacyclobutane were carried out with PhLi and Pt
complexes74 (Scheme 17). The 1,4-bond of the monomer was selectively cleaved in the anionic
polymerization by phenyllithium. In case of the Pt-catalyzed polymerization, the propagation
reaction proceeded via a Pt-complex insertion in either the 1,2- or the 1,4-bond of the
silacyclobutane (Scheme 17).
15
PhLi
Si
n
1,4-cleavage
Si
Pt-cat
Si
n
1,4-insertion
+
Si
n
1,2-insertion
Scheme 17
Stereoregular polymerization with a Pt-catalyst has been achieved for 1-methyl-1-(1naphthyl)-2,3-benzosilacyclobut-2-ene75 (Scheme 18). When this type of polymerization was
attempted on optically pure (+)-1-methyl-1-(1-naphthyl)-2,3-benzosilacyclobut-2-ene, an
optically active polymer was formed. The proposed mechanism is shown in Scheme 18.
Pt-cat
Si* CH3
* CH3
Si
Pt
m
reductive
elimination
CH3
Si *
Pt
Si *
H3C
Si* CH3
HSi(C2H5)3
m
(C2H5)3Si
cyclic polymer
H3 C
*
Si
H
m
Scheme 18
Oxidative-addition of the Si-aryl carbon bond in the silacyclobutene ring to Pt gives the
optically active intermediate Pt complex. Further coordination of (+)-1-methyl-1-(1-naphthyl)2,3-benzosilacyclobut-2-ene to the complex and σ-bond metathesis will provide the cyclic dimer
Pt complex. Reductive elimination from the intermediate platinum complex gives cyclic
16
polymers and oligomers. Preference of σ-bond metathesis over reductive-elimination gives
polymers of higher molecular weight. The presence of Et3SiH in the system results in the
formation of linear products via σ-bond metathesis.
I.5.2 Ring-opening reactions leading to activated silanes for other reactions
Certain organosilane reactions require an activated silicon species in order to proceed
under synthetically useful conditions. For example, Hiyama couplings76 of vinyl- and arylsilanes
with electrophiles require a heteroatom activating group on the silicon in addition to the
Similarly, Tamao oxidation77 of carbon–silicon bonds relies on
palladium catalyst.
electronegative heteroatom substituents to promote formation of the active silicate intermediate
en route to the alcohol product.
Ring opening of silacyclobutanes can provide labile, heteroatom-activated silane species
in situ as reactive intermediates for such transformations.
Aqueous fluoride is frequently
employed towards this end.
Denmark’s group showed that alkenylsilacyclobutanes 5 can undergo facile palladiumcatalyzed Hiyama-type cross-coupling78,79,80,81 with aryl and vinyl iodides 6 to give the alkenes 7
(Scheme 19).
R1
Si
5
+
R3
R2
TBAF (3 eq),
Pd(dba)2 (5 mol %),
I
THF, rt, 10 min
6
R1
R3
7 R2
n-C5H11
C5H11
n-C5H11
91% (E/Z 99.9/0.1)
90% (E/Z 0.9/99.1)
COCH3
OMe
n-C5H11
94% (E/Z 99.0/1.0)
75% [(Z,E)/(Z,Z)+(E,E) 97.2/2.8]
n-C5H11
84% (E/Z 99.7/0.3)
Scheme 19
17
The reaction proceeds rapidly (10 min at ambient temperature) in the presence of 3
equivalents of TBAF and 5 mol% of Pd(dba)2 in THF.78,79,80 In cases when the reaction times
were longer, triphenylarsine was utilized as a ligand. Reactions showed excellent
stereospecificity with respect to alkene geometry for coupling with aryl halides and alkenyl
iodides as well.
Halo(aryl)silacyclobutanes were employed to achieve biaryl coupling (Scheme 20).82
R
+
Aryl
TBAF (3 eq),
[π-allylPdCl2] (2.5 mol %),
I
Si
(t-Bu)3P (20 mol %),
THF, reflux, 1-5 h
(9)
(8)
MeO
CH3
Aryl
R
(10)
MeO
CO2Et
83%
92%
H3C
O 2N
CH3
CH3
77%
85%
Scheme 20
The enhanced reactivity of alkenylsiletanes towards palladium-catalyzed cross-coupling
was first explained by strain-release Lewis acidity of the silicon center, which promoted
formation of a pentacoordinate fluorosilicate that was the active species for transmetallation.
However, further mechanistic elucidation by spectroscopic and kinetic analysis showed that
siletanes
undergo
fast
ring-opening
under
the
reaction
conditions
to
form
alkenyl(propyl)(methyl)silanols and disiloxane (11 and 12).83 As shown in Scheme 21, the
species formed in situ exists in equilibrium with silanol 15, a low energy resting state along the
reaction pathway.
Silicate 16 was postulated to be the active species that undergoes
transmetallation with palladium. Thus, the silacyclobutane serves as a stable precursor to the
active transmetallating reagent.
18
These couplings usually proceed slowly at room temperature; therefore, they were
conducted in THF at reflux. Addition of tri-(tert-butyl)phosphine was needed to suppress
competing homocoupling of the aryl iodide.
Me
n-C5H11 TBAF 3H2O
Si
(1 eq)
nC5H11
Si
+
OH
(10)
R
Me
Si
n-C5H11
Si
Si
O
Me Me
n-C5H11
(12) (45%)
(11) (42%)
R
R
OH
Si
n-C5H11
RR R
Si
O
(14)
(13)
R
n-C5H11
- Bu4NF
2 Bu4NF
+ H2O
R
2x
n-C5H11
RR R
Si
Si
O
F
(16)
n-C5H11
Bu4N
R
Si
n-C5H11
n-C5H11
O H F
Bu4N
(15)
Scheme 21
Another useful transformation of silacyclobutanes that involves active ring-opened
species was reported by Dudley’s group.84,85,86 Alkyl- and arylsilacyclobutanes can be oxidized
under the mild oxidative conditions recommended by Tamao for the oxidation of heteroatomactivated silanes: aqueous hydrogen peroxide and potassium fluoride as a fluoride source at room
temperature. This procedure was used to form a number of aliphatic alcohols and phenols
(Scheme 22).84
19
+
Si Cl
(17)
OH
R MgX
OSiMe2t-Bu
OH
H2O2, KF, KHCO3
Si R
(18)
THF/MeOH, rt
R OH
Me
OH
Me
Me
73%
OH
OH
Ph
84%
71%
76%
88%
Scheme 22
By analogy to Denmark’s proposed mechanism, silacyclobutane oxidation is believed to
proceeds via initial (and rapid) fluoride-promoted ring opening of the silacyclobutane, which
generates in situ a heteroatom-activated organosilane for subsequent oxidation. Because ring
opening is much faster than the typical Tamao oxidation (minutes vs. hours), silacyclobutane
oxidations occur under the typical Tamao conditions and within a similar duration. However,
silacyclobutanes are stable to standard purification and handling, and silacyclobutanes can be
carried through a wide range of organic reaction protocols, including acidic hydrolysis of silyl
ethers.85
The fact that oxidation of carbon–silicon bond is possible in the presence of a silyl ether
increases the attractiveness of siletanes as masked hydroxyl groups.
Siletane oxidation can be used as a trigger to promote cleavage of p-siletanylbenzyl
(PSB) ethers.85 Mild oxidation of the arylsiletane yields the p-hydroxybenzyl ether, which can be
easily hydrolyzed to release the alcohol. This methodology appears to be most efficient for the
protection and deprotection of phenols and primary alcohols (Scheme 23).
20
Br
Si
O
Si
R
2) FeCl3 (if needed)
OH
Ph
O
1) H2O2, K2CO3, KF;
Si
R
O
R OH
R
R OH
HO
Ph
OH
MeO
89%
OH
OH
86%
86%
OH
81%
80%
Scheme 23
Though direct reaction of secondary alcohols with PSB bromide appeared to be
inefficient, PSB-protected secondary alcohols can still be approached via a two step procedure85
or via regioselective reduction of p-siletanylbenzylidene acetals with DIBAL.86
Easy removal under mild oxidative conditions makes the p-siletanylbenzyl group
compatible with a wide range of functional groups. Another important advantage of this
protecting group is its orthogonality with PMB protecting groups.
R1 OH
82%
+
R2 OPMB
96%
H2O2, KF
K2CO3
R1 =
R1 OPSB + R2 OPMB
(1:1 mixture)
Ph
DDQ
CH2Cl2
R1 OPSB + R2 OH
94%
96%
R2=
OMe
Scheme 24
As shown in Scheme 24, the PSB group can be removed selectively in the presence of the
PMB ether by peroxide oxidation, while the PMB group can be cleaved without affecting the
PSB ether using DDQ.
21
I.6 Ring-Expansion Reactions
I.6.1 Ring expansions of silacyclobutanes using nucleophilic or carbenoid
reagents. Ring expansions with electrophilic carbenes
Examples of carbene insertions into the carbon–silicon bond of silacyclobutanes have
been known since 1967, when Seyferth studied the behavior of silacyclobutanes exposed to
dichlorocarbene,
which
was
generated
by
thermolytic
activation
of
phenyl(bromodichloromethyl)mercury.87 The reaction produces a mixture of products arising
from Si–C and C–H bond insertions, with the major products being the ring-expanded
silacyclopentanes that results from Si–C bond insertions (Scheme 25).
Scheme 25
Seyferth’s results were the first reported cases of carbene insertions into Si–C bonds. In
the case of silacyclopentanes or silacyclohexanes, carbene insertions occur exclusively into C-H
bonds, with no observed insertion into the endocyclic Si–C bonds. Therefore, the ring strain of
sila- and 1,3-disilacyclobutanes must enhance the reactivity of the Si–C bond so as to favor Si–C
bond insertion. In terms of atomic orbitals, the “ring strain” of a silacyclobutane is a result of an
increase in the p-character of the endocyclic Si–C bonds and the high degree of s-character in the
exocyclic Si–C and Si–H bonds relative to the analogous silacyclopentane. The greater pcharacter in the endocyclic Si–C bonds leads to poorer orbital overlap and weaker Si–C bonds.88
This difference can be observed in the IR stretching frequencies: ν(Si-H) for 1-methyl-1silacyclobutane is 2130 cm-1, whereas the analogous frequency for triethylsilane is observed at
2097 cm-1.
22
Me
Me
H
+
Cl
Cl
C
PhHg
Si
Me
Cl
Si
Br
Me
C
Cl
Me
+
Cl
Cl
Me C
H
Si
Me
Me
Me
39%
23%
Cl
+
Si
Me
H
Cl
Cl
C
PhHg
+
Si
Br
Me
CCl2H
68%
Cl
Si
Me
CCl2H
6%
Scheme 26
The reaction of several other silacyclobutanes with dichlorocarbenes generated from
phenyl(bromodichloromethyl)mercury were examined.
In the case of 1,1,3-trimethyl-1-
silacyclobutane bearing a tertiary C-H bond, which is more reactive toward carbene insertions,
the C-H insertion was favored over Si-C bond insertion. The competing C–H and Si–C insertion
products were obtained in 39% and 23% yields, respectively (Scheme 26).87,88 Also of interest
was 1-methyl-1-silacyclobutane, since the Si-H bond is highly reactive as a carbene trap.
Insertion into the Si–H bond proved to be more facile; the product distribution comprised 68% of
the Si–H insertion product and 6% of material in which insertion had occurred into both the Si–H
and Si–C bonds (Scheme 26).88
Ring expansions with nucleophilic reagents. The Oshima group has worked
extensively on ring-expansion reactions of silacyclobutanes promoted by various nucleophiles
and nucleophilic carbenoid reagents. Intramolecular and intermolecular insertions of lithium
carbenoids have been investigated; treatment of 1,1-dimethyl-1-silacyclobutane with lithium
carbenoids provided silacyclopentanes smoothly with good yields (Table 2).89,90
23
Table 2. Ring expansion reactions of 1,1-dimethyl-1-silacyclobutane with lithium carbenoinds
R
Si
R2
R1 R 2
+
X
R
Li
R
Si
R
R1
Entry
R
R1
R2
X
Yield (%)
1
Me
H
I
I
83
2
Me
H
Br
Br
57
3
Me
H
Cl
Cl
49
4
Me
Bun
I
I
59
6
Me
H
Me3Si
I
56
8
Ph
H
Br
Br
74
H
Br
Br
79
H
I
I
88
n
11
Bu
12
BunC≡C
Substitution on silicon did not appear to affect the reaction pathway. These reactions are
proposed to proceed via a pentacoordinate silicate intermediate (Scheme 27).
Me
Si
H R
+
Me
I
Me Si
Li
I
Me
R
Me
Si
R
Me
Scheme 27
Based on the presumed mechanism (Scheme 27), it was expected that 1-(1-iodoalkyl)-1silacyclobutanes should also undergo ring-expansions under the action of a nucleophile.
Although methyllithium and other carbanionic nucleophiles provided ring expansion products in
only low yields, potassium tert-butoxide-induced ring-enlargement reactions of these species
afforded silacyclopentanes in good yields.91
24
Scheme 28
Ring expansion in conjunction with Tamao-type oxidation of carbon–silicon bonds
provides access to 1,4-diols.
The 1-(1-iodoalkyl)-1-silacyclobutanes are available from 1-
chlorosilacyclobutanes (addition of vinyl, Scheme 28).91 The utility of silacyclopentanes formed
by the ring expansion of silacyclobutane for the synthesis of triols has been reported.92,93
Another way to activate 1-(1-iodoalkyl)-1-silacyclobutanes toward ring-expansion is to
use silver acetate in acetic acid. In this case the reaction is believed to proceed via formation of a
carbocation α to the silicon. The acetate counterion acts as a nucleophile, attacking the activated
silacyclobutane with C–Si bond migration (Scheme 29).91 Silver tetrafluoroborate in
dichloromethane induces ring-enlargement as well, but shows much lower efficiency (30% yield
upon treatment with MeLi).94
Scheme 29
The stereoselectivity of ring-expansion reactions of substituted silacyclobutanes has been
explored. Silacyclobutanes having a methyl substituent at the 3-position generally formed the
corresponding silacyclopentanes upon treatment with lithium carbenoids with stereoselectivity
favoring the cis-diastereomer (up to 93:7 ratio, Table 3).90 One notable exception is the triphenyl
system (entry 6, Table 3).
25
Table 3. Stereoselectivity in ring-expansion reactions of substituted silacyclobutanes
entry
R
R1
X
Yield (%)
Dr
1
Me
I
I
80
90:10
2
Me
Br
Br
58
89:11
3
Me
Ph
Br
40
90:10
4
Ph
I
I
97
93:7
5
Ph
Br
Br
88
93:7
6
Ph
Ph
Br
58
33:67
Similar ring-expansion reactions were observed for silacyclobutanes and oxiranyl anions
bearing the silyl group.95,94
Me
Si
Li
Me
SiPh3
O
A
SiPh3
SiPh3
Si
Me2 O
Me
Si
SiPh3
Si
Me2
MeLi
OLi
Me
Me Si
HO
SiPh3
44% from A
84% from B
O
B
Scheme 30
Reaction of 1,1-dimethylsilacyclobutane with triphenylsilyl-substituted oxiranyllithium
leads to the formation of an olefinic silanol via sequential (a) coordination to the silicon, (b) Si–
C bond migration, and (c) Peterson type Si–O-elimination to furnish the alkene.
A
pentacoordinate siliconate intermediate is presumably involved in this transformation. Therefore,
it was reasonable to expect that addition of a nucleophile (methyllithium or lithium isoprolyloxide) to an oxiranyl-substituted silacyclobutane, which could generate a similar
26
intermediate, would induce the C–Si bond migration to form the same silacyclopentane. Indeed,
this alternative order of addition sequence provides the corresponding silanol with better
efficiency (84% yield vs. 44%, Scheme 30).
The series of reactions leading to the 5-silyl-1-pentene — epoxidation, ring expansion,
and Peterson elimination — are all stereospecific. Therefore, epoxides with different geometry
can be transformed into the corresponding (E)- or (Z)-olefinic silanols.96,94 Subsequent Tamao
oxidation affords stereodefined pentenols.
Scheme 31
The divergent epoxide stereoisomers are available via epoxidation of the (E)- or (Z)vinylsilanes, which in turn are prepared by (1) addition of an E-vinyl Grignard reagent to the
chlorosilacyclobutane, or (2) partial hydrogenation of an alkynylsilacyclobutane, respectively
(Scheme 31).
One can also take advantage of the complementary methods for effecting the Peterson
elimination
to
prepare
either
the
(E)-
or
(Z)-
olefinic
silanols
from
a
single
oxiranylsilacyclobutane via ring expansion followed by a syn or anti elimination (Scheme
32).96,94
27
Scheme 32
In the presence of catalytic amounts of potassium t-butoxide, different silacyclobutanes
undergo reaction with aldehydes to yield six-membered cyclic silyl ethers (Scheme 33).95
Aldehyde insertion into the benzosilacyclobutene was regioselective.
Scheme 33
Other unsymmetrically substituted silacyclobutanes were examined. In the case of 1,1dimethyl-2-phenyl-1-silacyclobutane, aldehyde insertion occurred with essentially complete
regioselectively for migration of the benzylic carbon (Scheme 34). On the other hand, 1,1,2trimethyl-1-silacyclobutane displayed opposite (though not complete) regioselectivity, with
insertion taking place on the less substituted side. The phenyl-substituted silacyclobutane also
appeared to be more reactive. These data are consistent with the migrating group being the one
that is best able to support a developing negative charge.
28
Scheme 34
3-Methylene-1,1-diphenyl-1-silacyclobutane, which incorporates an allylsilane moiety,
reacts with ketones and aldehydes to afford insertion products even in the absence of catalytic
potassium tert-butoxide (Scheme 35). The methylene unit may enhance the Lewis acidity of the
silacyclobutane.97
Scheme 35
The resulting 5-methylene-2-oxa-1-silacyclohexanes are insufficiently Lewis acidic to
react with a second equivalent of the carbonyl compound. However, the incipient allylsilane does
react with dimethyl acetals in decent yields in the presence of external Lewis acids including
BF3·Et2O or AlCl3. Based on these results, double-allylation of dicarbonyl compounds with 3methylene-1,1-diphenyl-1-silacyclobutane was examined, leading to the formation of 3methylene-oxabicyclo[3.2.1]octanes. This transformation proceeded in one pot and in the
presence of BF3·Et2O (Scheme 36).
Scheme 36
29
I.6.2 Ring expansions triggered by transition metal catalysis. Mechanistic
aspects of transition metal insertion into siletanes
Silacyclobutanes
and
disilacyclobutanes
are
known
to
undergo
ring-opening
polymerization catalyzed by transition metal complexes including those of platinum, palladium,
and rhodium.65 Lappert suggested that an initial insertion of the metal catalyst into the strained
Si–C endocyclic bond leads to a ring expanded metallasilacycle, although no direct evidence was
available at the time.67 According to the proposed mechanism, polymerization involves several
steps (Scheme 37):
- oxidative addition of the transition metal complex to the silacyclobutane (ring
expansion);
- halogen or alkyl transfer from the metal to silicon (reductive elimination) leading to
ring-opening;
- polymer growth by insertion of the alkyl-metal species into an additional molar
equivalent of the silacyclobutane monomer.
Si
LxM–Cl
LxM
Si
Cl M
Lx
Si
LxM–H
LxM
SiCl
Si
M
Lx
Si
ClSi
SiCl
+
Si
Si
LxM
Si
Si
SiCl
n+1
n+1
SiCl
Scheme 37
The first insertion of a transition metal complex, such as pentacarbonyliron, into
silacyclobutanes was described by Lappert’s group and they isolated 2,2-dimethyl-1,1,1,1-ferra2-silacyclopentane (Scheme 38).98
30
Scheme 38
In 1995, Tanaka and co-workers isolated 2,2-diphenyl-1-platina-2-silacyclopentane
(Scheme 39) and showed that such a complex is a viable intermediate for both dimerization and
polymerization of silacyclobutanes.68 The reactivity of 1,1-disubstituted silacyclobutanes
towards oxidative addition of transition metals increases in the series of methyl < phenyl <
chloro.
Scheme 39
As shown in Scheme 39, 1,1-dimethylsilacyclobutane can undergo polymerization or
dimerization in the presence of similar platinum catalysts in good to excellent yields. The course
of the reaction is apparently linked to the presence or absence of phosphine ligands: platinum
complexes that include added phosphines lead to dimerization, whereas polymerization usually
occurred under “ligandless” conditions. Divinyltetramethyldisiloxane also serves as a ligand for
the platinum-catalyzed dimerization of silacyclobutanes and disilacyclobutanes as reported by
Chu and Frye.99
One of the first transition metal-catalyzed ring-expansion reactions of silacyclobutanes
with the formation of new C–C bonds involved the insertion of acetylenes catalyzed by Pdcomplexes to furnish silacyclohexenes (Scheme 40).100,101 In addition to the acetylene-insertion
products (silacyclohexenes), ring-opened allylvinylsilane products that also incorporate the
31
acetylene moieties were observed. The ratio of two types of the products depends heavily on the
nature of acetylenic compounds.
Scheme 40
The acetylene insertion reaction presumably occurs by the following mechanistic
sequence: (a) insertion of Pd(0) into the silacyclobutane, (b) regioselective syn-silylpalladation
of the acetylenic compounds to provide seven-membered 1-pallada-4-silacyclic intermediate, and
(c) reductive elimination of Pd(0) to afford silacyclohexene. Alternatively, β-hydride elimination
would open the palladacycle, generating a vinylpalladium hydride species that would undergo
reductive elimination to yield the ring-opened allylvinylsilane.
Isotopic labeling studies
provided evidence in support of this mechanistic hypothesis (Scheme 41).
Scheme 41
Under
similar
conditions,
silabenzocyclobutane
provided
the
corresponding
dihydrosilanaphthalenes. Phenylallene also inserted into the silabenzocyclobutane in the
32
presence of PdCl2(PPh3)2 to give the ring-expanded exo-methylene product in which the internal
alkene of phenylallene reacted (Scheme 42).
Scheme 42
Tanaka and coworkers102 observed the insertion of acid chlorides into silacyclobutanes in
the presence of palladium or platinum catalysts. When an excess of amine was employed,
silacyclobutanes undergo ring-expansion reactions to afford cyclic silyl enol ethers in good to
excellent yields (Scheme 43).
Scheme 43
When only 0.1 equivalent of triethylamine was used, 3-(chlorosilyl)propyl ketone was
formed as the major product in 86% estimated yield (based on NMR analysis). According to the
authors’ mechanistic hypothesis, oxidative insertion of the transition metal catalyst occurs into
33
the acid chloride, which is followed by ring insertion of the acylpalladium (or platinum) species
into the silacyclobutane ring. Amine-assisted cyclization then yields the observed silyl enol
ethers. In the absence of excess amine, reductive elimination of the catalyst affords an acyclic
chlorosilane. Although palladium can undergo oxidative addition to silacyclobutanes, addition
to acid chlorides proceeds faster.
Insertion of acyl chlorides into appropriately substituted silacyclobutanes, followed by
Tamao-type oxidation, has been used to prepare γ-lactones.103
Palladium-catalyzed three-component coupling of dimethylsilacyclobutane, carbon
monoxide, and aromatic iodides also yields cyclic silyl enol ethers via a ring expansion/insertion
process.104 Electron-rich and electron-deficient aromatic iodides are suitable substrates, giving
rise to the corresponding cyclic silyl enol ethers in excellent yields (Scheme 44).
Scheme 44
The mechanism of this three-component coupling reaction is probably analogous to the
aforementioned insertion of acyl chlorides (above). One can imagine assembling an intermediate
acylpalladium species either by oxidative addition to an acyl chloride or, in this case, by
oxidative addition to the aromatic iodide followed by migratory insertion into carbon monoxide.
Once formed, the acylpalladium intermediate can insert into the silacyclobutane to furnish a γ(chlorosilyl)propyl ketone, which cyclizes in the presence of the amine to afford cyclic enol
ethers.
Both ring expansion reactions proceed via a putative pallada(sila)cyclopentane
intermediate. In the course of the mechanistic elucidation studies, Tanaka succeeded in preparing
a 1-pallada-2-silacyclopentane complex with quantitative conversion (Scheme 45).105 Formation
of the complex is reversible, and the starting silacyclobutane can be released by addition of an
acetylene (which acts as a ligand for palladium, displacing the silacyclobutane).
34
Scheme 45
The formed 5-palladasilacyclopentane complex was examined as a model for the already
known Pd-catalyzed ring-opening reaction of silacyclobutanes with hydrosilanes and
dimerization of silacyclobutanes. Indeed it provided the expected products suggesting that the 5pallada-silacyclopentane complex represents an active intermediate in these reactions (Scheme
46).
PhMeSiH2
+
(4 equiv)
+
Si
Me
Me
Me2
P
Pd
P Si
Me2 Ph2
room temp
HPh2Si
SiPhMeH
70 %
Me2
P
Pd
P Si
Me2 Ph2
100 oC
Ph2Si
SiMe2
44 %
(4 equiv)
Scheme 46
Following work on the palladium-catalyzed ring expansions of silacyclobutane
substrates, Tanaka extended the list of substrates to aryl iodides in the absence of carbon
monoxide. Rather than obtaining 3-(iodosilyl)propylarenes, however, Tanaka observed an
unexpected regioselectivity that provided 1- and 2-propenyl(triaryl)silanes, in good yields
(Scheme 47).106 This outcome can be explained by phenyl group migration from palladium to
silicon (rather than a halide migration) en route to the ring-opened species.
35
I
Ph
Si
+
Ph
X
via:
Ph Ph Ln
Ar Si Pd I
Ph2
Si
PdCl2(PhCN)2
Et3N, toluene
120 °C, 24 h
X=H
X = OMe
X = Me
X=F
X
63% (77:23)
53% (22:78)
83% (47:53)
95% (4:96)
Ph2
Si
+
X
H2O
(X = H)
78%
Ph3Si OH
Scheme 47
The resulting mixture of allyl- and vinylsilanes can be hydrolyzed to afford triarylsilanols
(Scheme 47).
Silacyclobutanes will also undergo palladium-catalyzed cross-metathesis reactions with
disilanes (Scheme 48).107
Scheme 48
Nickel-catalyzed transformations of silacyclobutanes have been studied by Oshima,
Yorimitsu and Hirano.108 Nickel-catalyzed ring opening of silacyclobutanes with aldehydes
affords the corresponding alkoxyallylsilanes (Scheme 49). This transformation represents a
hydrosilane-free reductive silylation of aldehydes. A wide range of aldehydes — aliphatic,
aromatic, electron-rich and electron-deficient — can be converted to akoxyallylsilanes.
36
Scheme 49
In contrast, under identical conditions, benzosilacyclobutene reacted with aldehydes in a
highly regioselective ring-expansion to give oxasilacyclohexenes (50–75% yields) (Scheme 49).
I.7 Reactions of substituents attached to the ring carbon atoms
It was mentioned in previous sections that the reaction of siletanes with thermolytically
generated carbenes produces mixture of products arising from competing Si-C and C-H bond
insertions. For siletanes with tertiary carbons, insertion into a C-H is favored over a Si-C
insertion.87
When carbenes are generated from haloforms with potassium hydroxide exclusive
insertion of carbene into a β-C-H bond has been reported109 (Scheme 50).
But2Si
CHX3/KOH
Scheme 50
37
But2Si
X
X
Regioselective introduction of an ester functionality into the β-position of
silacyclobutanes can be accomplished by means of a Rh2(OAc)4-catalyzed C-H insertion
reactions of α-diazo esters110,103 (Scheme 51). The reaction proceeds cleanly to give the products
in excellent yields.
Rh2(OAc)4
Me2Si
+
Me2Si
CO2R
N2
CO2R
R = But: 90 %
R = Et: 97 %
Scheme 51
The formed 3-[(alkoxycarbonyl)methyl]-1,1-dimethyl-1-silacyclobutanes undergo a
palladium-catalyzed ring-opening coupling reaction with acid chlorides to give quantitative
yields of cyclic silyl enol ethers (see section 2.11.3.3.2). Under Tamao-oxidation conditions, the
produced silyl enol ethers furnish the corresponding γ-lactones bearing a ketone functionality at
the C-3 position in good to excellent overall yields (Scheme 52).103
Ph
Me2Si
CO2Et
+
O
R
PdCl2(PhCN)2 (5 mol%)
Cl
Et3N or i-Pr2EtN,
toluene, 80 oC, 4 h
O
n-C5H11
SiMe2
O
SiMe2
or
CO2Et
CO2Et
H2O2, KF,
KHCO3, MeOH/THF
rt, 16 - 48 h
O
O
O
R
R = Ph:
R = n-C6H11
94 %
97 %
Scheme 52
Silacyclobutanes with an ester functionality at the α-position can undergo an uncatalyzed
thermal rearrangement to give O-silyl ketene acetals in moderate yields. This ring expansion of
silacyclobutane-2-carboxylate by a 1,3(C→O) silyl shift proceeds largely due to the relief of
ring-strain from the four-membered ring (Scheme 53).111
38
hν, pentane
Si
CO2Et
X N2
Si
X CO2Et
- N2
A
O
+
X
Si
EtO
heat
B
A
X = Cl:
100 %
X = N3:
46 %
X = NCO: 100 %
X = NCS: 26 %
0%
54 %
0%
74 %
B
36 %
45 %
39 %
67 %
Scheme 53
2-Alkoxycarbonyl-1-silacyclobutanes, the starting materials for thermal rearrangements,
can be accessed via a novel intramolecular 1,4-insertion of a carbene into the C-H bond of a Si-tBu group.
An alternative way to functionalize the silacyclobutane would be through a bromination.
Bromination of 1,1-di(t-butyl)-2,3-benzo-1-silacyclobutane with NBS gives the 4-bromo
derivative (Scheme 54). Metalation with Bu2CuLi, followed by alkylation or acylation, generated
the corresponding 4-alkyl or acyl compounds. The replacement of the bromine atom with an
alkoxy group was achieved by treatment with an alcohol in the presence of AgBF4.112,32
Br
NBS
SiBut2
SiBut2
i) Bu2CuLi
ii) RX
R
SiBut2
ROH
AgBF4
OR
SiBut2
Scheme 54
Bromination of 2-phenylsilacyclobutanes followed by dehydrohalogenation provides
access to 1,1-disubstituted 2-phenyl-1-silacyclobut-2-enes (Scheme 55).32
39
N
NBS
SiR2
Ph
Ph
SiR2
SiR2
Br
Ph
Scheme 55
The attack of silacyclobutanes by the oxyl (CF3)2NO leads to 3-substituted products; 2,3disubstituted compounds were obtained as minor products (Scheme 56).113,32
Cl
Si
(CF3)2NO
R
Cl
(F3C)2NO
Si
R
Scheme 56
I.8 Reactivity of substituents attached to the ring silicon
In this type of reactions the silacyclobutane ring remains intact: most commonly,
substitution reactions at silicon. Nonetheless, the strained four-membered ring plays a key role
in the reactivity profile of silacyclobutane substitution reactions. 1-Halosilacyclobutanes are
common substrates for the installation of different substituents on silicon such as alkyls or aryls
(by reaction with Grignard reagents), as well as alkoxides, amines or even hydrogen (by
reduction with alkylaluminum hydrides). Displacement of a hydrogen substituent on the silicon
of silacyclobutanes through hydrosilylation of alkenes or by substitution with halogens, amines
or alkoxides is covered in the review.32 With any of these reactions, ring opening72 of the
silacyclobutane competes and in many cases cannot be avoided. Under dehydrocoupling
polymerization conditions – ring-opening polymerization predominates.73
O-(Silacyclobutyl)ketene acetals derived from esters, thioesters, and amides undergo
facile aldol addition with a variety of aldehydes without catalyst at ambient or low temperatures
(Scheme 57).114,115,116
Such reactivity stands in contrast to traditional silyl enol ethers,
suggesting that the silacyclobutane ring strain plays a role in promoting transfer of the enolate
substructure.
40
Scheme 57
For example, methylsilacyclobutyl O,O-ketene acetal (Y = OMe) reacted completely and
cleanly with benzaldehyde in benzene solution within 4 hours at 27 °C to afford the
corresponding aldol adduct quantitatively (Scheme 58).114 In contrast, the analogous Otrimethylsilyl ketene acetal reacts with benzaldehyde only at 150 °C without solvent, and the
reaction requires 18 hours for completion. The dramatically enhanced reactivity has been
attributed to the effect of the strained silacyclobutane ring. Prior to this report, N,O-ketene
acetals were the only trialkylsilyl enol ethers known to undergo uncatalyzed aldol addition with
aromatic aldehydes117,114 without heating or use of any activating agents like the fluoride ion.
Scheme 58
The enhanced reactivity of silacyclobutane-derived enol ethers is attributed to the
combination of ring strain and the potential for silicon to expand its coordination number form
penta- to hexacoordinate compounds.
Specifically, for silacyclobutanes, the reaction with
nucleophiles allows for relief of the strain energy via rehybridization of the geometry at silicon
from tetrahedral to trigonal bipyramidal (tbp) upon formation of a pentacoordinate species.
Although no complexation between aldehydes and a variety of silacyclobutanes was
spectroscopically detectable, the proposed mechanism for allylation of aldehydes using
allylsilacyclobutanes involves a closed transition state (in analogy to allylboration of aldehydes)
with intramolecular silicon group transfer via a pentacoordinate trigonal bipyramidal silicate.116
41
A double-label crossover experiment provided evidence in support of the intramolecular silicon
group transfer.114,116
Denmark115,116 and Myers114 led independent studies on the uncatalyzed aldol addition
reactions of silacyclobutyl ketene acetals with a variety of aliphatic and aromatic aldehydes.
Ester-derived silacyclobutyl O,O-ketene acetals are highlighted in Table 4. Interestingly, the silyl
enol ether with an E-configuration furnishes the syn aldol products with high diastereoselectivity;
in some cases, the stereoselectivity of the aldol product exceeded the purity of the starting silyl
enol ethers. In contrast, the Z-isomer reacted sluggishly with opposite, albeit weak, anti
selectivity (Table 4). Kinetic studies showed that the reaction rate for the E-isomer is
significantly higher than it is for the Z-isomer.116
Table 4. Uncatalyzed aldol addition reactions of silacyclobutyl ketene acetals to aliphatic and
aromatic aldehydes
But
Si
O
1. RCHO
CDCl3, 20 °C
O
MeO
MeO
OH
R
O
+
MeO
OH
R
2. HF, THF
syn
anti
E/Z
R
t1/2 (h)
yield (%)
syn/anti
95:5
Ph
2.2
94
95:5
89:11
cinnamyl
6.7
95
93:7
89:11
n-pentyl
17.0
91
93:7
89:11
cyclohexyl
38.3
85
>99:1
0:100
Ph
28.3
80
42:58
O-Silacyclobutyl S,O-ketene acetals (derived from thioesters) reacted more slowly with
aldehydes than did their ester counterparts (Table 5).115,116 The higher reactivity of the (1phenyl)silacyclobutyl derivatives enabled the uncatalyzed aldols to proceed at a reasonable rate,
affording the corresponding products after 50 hours at room temperature. In these series, the syn-
42
product formed stereoselectively from the Z-ketene acetal; the E-ketene acetal also yielded
predominantly the syn products, albeit with reduced selectivity (Table 5).
Table 5. Reaction of O-silacyclobutyl S,O-ketene acetals (derived from thioesters) with
aldehydes
Ph
Si
RCHO, 20 °C
O
solvent
ButS
O
O
ButS
Si
Ph
O
+
O
ButS
R
syn
Si
Ph
R
anti
E/Z
R
solvent
t (h)
conv. (%)
syn/anti
4:96
Ph
CDCl3
50.5
84
98:2
4:96
cinnamyl
CDCl3
51
91
70:30
4:96
n-pentyl
CDCl3
50.5
42
90:10
4:96
cyclohexyl
CDCl3
50
0
—
4:96
Ph
neat
99:1
100:0
Ph
neat
85:15
O-Silacyclobutyl N,O-ketene acetals (derived from amides) demonstrated high reactivity
towards aldehydes.114,115,116 Mixtures of syn and anti aldol products were obtained, with a slight
preference for the anti diastereoisomers in most cases (Table 6).
Table 6. Reaction of O-silacyclobutyl N,O-ketene acetals with aldehydes
Ph
Si
O
Me2N
RCHO, 20 °C
solvent
O
Me2N
O
Si
tBu
R
syn
O
+
O
Me2N
Si
R
anti
R
Solvent
t1/2 (h)
syn/anti
Ph
CDCl3
0.67
9:91
cinnamyl
C6D6
3.6
31:69
43
tBu
Table 6 − continued
R
Solvent
t1/2 (h)
syn/anti
n-pentyl
C6D6
4.6
40:60
cyclohexyl
C6D6
12.8
50:50
The unusual syn diastereoselectivity of (E)-silyl ketene acetals for ester and amide
derived species stands in contrast to the normal anti selectivity of geometry-independent Lewisacid promoted aldol additions, which are believed to involve open transition states. The
preponderance of syn-diastereomer products is also at odds with the Zimmerman–Traxler
predictive model that presumes a closed transition states with a chair-like geometry. Thus, on the
basis of the stereochemical outcome and computational studies it has been suggested that these
reactions proceed via a closed boat transition state with pentacoordinate silicon. Indeed,
computational modeling revealed that the boat conformation is slightly preferred over the
chair.116
The fundamental difference between the boat and chair systems of strained
silacyclobutanes and those of group І, ІІ and ІІІ metal enolates (e.g., lithium enolates) is that the
group IV silicon enolates contain a pentacoordinate silicate center, rather than the traditional
four-coordinate metal center. Thus, in the group IV systems, unfavorable eclipsing interactions
in conventional boat transition states are apparently less important than other steric interactions.
Aldol reactions of both (E)- and (Z)-ketene acetals are highly susceptible to KOBut
catalysis. In the presence of 5 mol% of KOBut, aldol reactions proceeded to completion within
minutes at –78 ºC.116 A double-label crossover experiment, devised to probe the nature of the
silicon group transfer in the alkoxide-catalyzed aldol reaction, suggested that free metal enolates
are the true reactive species adding to the aldehydes.
Asymmetric
aldol
additions
have
been
examined.
Chirally
modified
S,O-
(alkoxysilacyclobutyl) ketene acetals react with aromatic aldehydes to afford the corresponding
β-hydroxy thioesters in high enantiomeric excess (91–94% ee).118
Allylsilacyclobutanes react with carbonyl compounds in an uncatalyzed, stereoselective
allyl transfer process.
A reaction mechanism involving a closed transition state with
coordination of the aldehyde to silicon, similar to that advanced for the aldol reactions, has been
44
proposed.119 (E)-1-(2-Hexenyl)-1-phenylsilacyclobutane provided anti homoallylic alcohols with
high regio- and stereoselectivity upon treatment with various aldehydes at 130 ºC for 24–48 h. In
contrast, (Z)-1-(2-Hexenyl)-1-phenylsilacyclobutane gave rise to the syn allylation products
selectively (Table 7). The stereoselectivity of these reactions suggests that a closed, chair-like
transition state is in effect for these transformations. Ab initio calculations support the presumed
role of a pentacoordinate silicon transition state.120
Table 7. Reaction 1-(2-hexenyl)-1-phenylsilacyclobutanes with aldehydes
R1
R2
R
yield (%)
anti/syn
H
Prn
Ph
68
95:5
H
Prn
Hexn
59
90:10
Prn
H
Ph
66
5:95
60
20:80
Pr
n
H
Hex
n
The reaction of 1-allyl-1-(cyclohexyloxy)silacyclobutane with α-hydroxy carbonyl
compounds proceeded at a lower reaction temperature. The alkoxy group on silicon enhances the
Lewis acidity of the allylsilacyclobutane and presents the possibility for ligand exchange to
preceed the allylation event, which then occurs intramolecularly (Scheme 59).
45
major
OH
Si
+
O
R1
HCl/H2O
O
R1 = Ph
R1 = Bun
R1 = Ph
HO
OH
100 °C;
R2
R2 = Ph
R2 = Ph
R2 = Me
Si
H
R2
R1
R2
OH
R2
R1
+
HO
R1
O
O
H
Si
R2
O
Scheme 59
46
R2
R1
HO
84%, >99:1
85%, 98:2
84%, 85:15
R1
O
minor
O
O
Si
CHAPTER II
SILETANYLMETHYLLITHIUM
II.1 Introduction
As it has been broadly discussed in the previous chapter, the electrophilicity of
silacyclobutane and its strong inclination to form a pentacoordinated silicon center dramatically
enhances the reactivity of the species in aldol114,115,116,118 and allylation reactions,119 Hiyama-type
metal catalyzed coupling,78,79,80,81 as well as in carbosilane oxidation,84,85 compared to unstrained
silanes.
Electrophilic siletane reagents are intermediate in reactivity between conventional
unstrained silanes and boranes, which are conventional metalloid Lewis acids.
Much of the chemistry of organosilanes is similar with organoboranes, with boron
reagents being more reactive and silanes being generally more stable. In many ways, siletanes
combine attractive features of organoboranes (mild reaction conditions, inherent Lewis acidity)
and conventional organosilanes (stability in multi-step reaction sequences, ease of purification
and handling). The similarities notwithstanding, silicon and boron chemistries diverge when it
comes to metalloid-derived nucleophiles. For example, the boron analog121 of the Peterson
olefination122 is limited to highly hindered organoborane reagents. Presumably, it is difficult to
integrate the Lewis acidity of boranes with nucleophilic functionality. Siletane reagents, which
incorporate features reminiscent of boranes but with enhanced stability, may be particularly
attractive in this context.
In our studies we aimed to generate a nucleophilic center next to the electrophilic
siletane.
In this way one can form an ambiphilic species with potentially unprecedented
reactivity. Siletanylmethyllithium 20 was envisioned as the desired ambiphilic structure which
possibly can be generated from 1-(tributyltin)methyl-1-methylsiletane 19.
47
Me
Si
SnBu3
19
Me
Si+
δ
Li
δ–
20
As the project was evolving one could see two conceptual concerns. The first concern is
whether or not it is possible to generate siletanylmethyllithium by transmetallation employing
alkyllithium reagents, which are prone to attacking silacyclobutanes.49,52,55 The second concern is
whether or not siletanylmethyllithium is a viable structure which can exist in solution.
Conceivably it may react with itself and degrade.
Organometallic reagent 20, if successfully produced, may be considered as a “pseudoylide”. Whereas a traditional ylide contains positive and negative formal charges on adjacent
atoms, siletanylmethyl nucleophiles (e.g. 20) present adjacent nucleophilic and electrophilic
centers. In analogy with Wittig reaction, which involves phosphine ylides to olefinate carbonyl
group in one step, we can expect organometallic reagent 20 to perform one-step Peterson-type
olefination.122 Usually Peterson olefination proceeds over two steps. In the first step addition of
traditional silicon reagent leads to the formation of the stable intermediate. As a result an
additional basic or acidic step is required to promote the elimination to the alkene.
II.2 Results and Discussion
II.2.1 Generation of siletanylmethyllithium
In our approach to the desired siletanylmethyltin we started with 1-chloro-1methylsiletane 21,123 commonly used to generate silacyclobutane derivatives by nucleophilic
displacement of chloride. The goal was to displace the chloride of 21 using an α-stannyl
nucleophile (e.g. 23a or 23b).
48
SiMe3
M
Me
Si
Cl
21
Me
THF
M = MgCl: 91%
Si
M
SiMe3
22
M = Li: 0%
SnR3
M = MgCl, R = Me: 23a
M = Li, R = Bu: 23b
Scheme 60
We first examined α-silyl nucleophiles as models (Scheme 60). The results are fully
consistent with past experience: Grignard reagents react efficiently with 21, whereas
alkyllithiums78 afford little or none of the desired product.
In the case of stannyl-based nucleophiles attempts to couple 23a124 with 21 failed to
provide significant amounts of stannane product analogous to 22. Surprisingly, alkyllithium
reagent 23b125 (generated from 24126 by halogen–metal exchange) couples with 21 efficiently,
providing good yields of 19 after distillation in multi-gram scale reaction (Eq. 4). This example
demonstrates how subtle difference between silane and stannane can dramatically change the
reactivity.
I
SnBu3
2.4 equiv t-BuLi
Et2O, –78 °C;
24
1.4 equiv 21
–78 to 0 °C
Me
Si
SnBu3 (4)
19, 80%
The next phase our research focused on synthesis and applications of 20. It was unclear
whether nBuLi or any other alkyllithium would react faster with the siletane or stannane
functionality of 19. Attack at silicon would likely result in ring-opening of silacyclobutane and
anionic polymerization49,50,52 (as described above), leading to polymer-bound stannane.127,60 On the
other hand, stannanes can react quite fast with nBuLi to form “ate” complexes (e.g., A, Scheme
61), which in the case of A would formally release siletanylmethyllithium 20.
It turned out that transmetallation predominates over polymerization in the case of 1(tributyltin)methyl-1-methylsiletane 19.
49
19
n-BuLi
Me
Si
Li
SnBu4
Me
A
Si+
δ
Li + SnBu4
δ–
25
20
Scheme 61
Therefore the target siletanylmethyllithium reagent was successfully formed and
survived without extensive decomposition in solution at low temperature as evidenced by
trapping experiments with tribenzylsilyl chloride (Bn3SiCl, Table 8).
Table 8. Formation and trapping of silylmethyllithium 20
Ph
n-BuLi
Me
Si
SnBu3
19
a
–78 °C
THF, 0.5 h
Bn3SiCl
Me
Si+
δ
Li
δ
20
–
–78 °C Me
2–2.5 h
Si
Si
Ph
Ph
26
Entry
Equiv. 19/n-BuLi
Equiv. Bn3SiCl
Yielda (%)
1
1.0
1.2
52
2
1.2
1.0
57
3
1.5
1.0
59
4
2.0
1.0
26
Isolated yield of 26 following chromatographic purification.
Treating 19 with an equimolar amount of nBuLi at –78 °C for 30 min, followed by
addition of Bn3SiCl, provides 26 in 52% yield based on 19 (entry 1) or 57–59% based on
Bn3SiCl (entries 2 and 3). This chemical reactivity is consistent with that expected for
siletanylmethyllithium intermediate 20. Increasing the amount of 19 (and n-BuLi) relative to
Bn3SiCl is detrimental (entry 4), probably due to alkyllithium-induced decomposition of the
product (26). It thus appears that the carbanionic nature of 20 shields the siletane ring against
nucleophilic attack and species 20 can exist as a solution in ether at low temperature without
significant self-annihilation.
50
II.2.2 Reactivity of silethanylmethyllithium, reaction with benzophenone
Having concluded that siletane 20 is a viable chemical species, we next examined its
ambiphilic character and behavior as a pseudo-ylide species. The Peterson olefination with
silylmethyl anions is a well-known complementary method to the Wittig olefination, but this is a
two-step process in which β-hydroxysilanes are isolated and then eliminated regioselectively.122
Silylmethyl anions are more reactive toward a range of ketones than are phosphorus
ylides, but they require an extra elimination step, often involving acid or strong base, to complete
the olefination process. We expected: (1) that ambiphilic siletane 20 would maintain the high
nucleophilicity associated with silylmethyl anions, and (2) that the siletane electrophilicity would
promote elimination under mild conditions. Table 9 summarizes our observations on the reaction
of pseudo-ylide 20 (generated from 19 as described above) with benzophenone (Ph2CO).
Table 9. Reaction of 20 with benzophenone
Ph2CO
n-BuLi
Me
Si
19
SnBu3
–78 °C
THF
Me
Si+
δ
20
H
H
Li
δ–
–78 °C
to rt
Ph
Ph
27
Entry
Equiv. 19/n-BuLi
Equiv. Ph2CO
Yielda (%)
1
1.0
1.0
33
2a
1.0
1.0
36
3
1.0
1.5
40c
4
1.2
1.0
0 → 42d
a
Isolated yield of 27 following chromatographic purification. b In entry 2, MeLi was used in place of n-BuLi for
generating 20. c Bu4Sn (25) was isolated and quantified in this experiment. It was obtained in 74% yield. d None of
the expected product (27) was observed in the crude reaction mixture by TLC or 1H NMR analysis. Alkene 27 was
obtained after stirring the crude product with silica gel in methylene chloride overnight.
Addition of benzophenone to 20 affords 1,1-diphenylethylene, 27, which is obtained
along with 25 as the sole identifiable products in entries 1 and 3 (tributylmethyltin was produced
in the experiment described in entry 2). This one-step olefination stands in contrast to the
traditional Peterson process.128 When pentylphenylketone was treated with silylmethyllithium
51
under the similar reaction conditions the corresponding alkene was formed with 30-40% yield.
Modest yields may be caused by inefficiencies in the transmetallation event (19 → 20).
Nonetheless, this reaction is interesting from a mechanistic perspective and for the insight it
provides into the ambiphilic nature of 20.
The reaction described in entry 4 (with an excess of siletanylmethyllithium 20) takes a
different course: 27 was not observed in the crude reaction mixture, but forms gradually upon
treatment with acidic silica gel. This result, surprising at first, is consistent with the following
mechanistic hypothesis, which emphasizes the importance of the siletane ring (Scheme 62):
(polymer)
HO
Si
Me
28
Ph
Ph
excess 20
warm;
Li
quench
(entry 4)
Ph
Ph
warm;
O Si
Me
B
H
quench
Ph
(entries 1–3)
H
Ph
27
Scheme 62
We interpret these results as follows: nucleophilic attack of 20 on the carbonyl generates
a lithium alkoxide, which, although inert to most vicinal silanes, coordinates with the
electrophilic siletane. This intermediate (B) eventually decomposes into alkene 27. In entry 4, the
residual 20 likely promotes anionic polymerization127 of silicate B. The resulting polymer-bound
β-hydroxysilane (28) is no longer activated by the silacycle strain-release Lewis acidity, and
therefore requires further treatment with acidic silica gel overnight to promote elimination.
Besides interesting reactivity of siletanylmethyllithium displayed in its reaction with
benzophenone, the title reagent can also serve as a synthetic equivalent of hydroxymethyllithium.
Taking into account the ongoing research in Dudley’s lab on Tamao oxidation of siletanes,84 we
explored siletane derivative 26 as a substrate for Tamao reaction.
Si
26
SiBn3
KF(2.6 equiv.),
K2CO3 (2.5 equiv.),
THF/MeOH/H2O
45 oC (6.5 h)
32%
Scheme 63
52
HO
SiBn3
28
Though the initial experiment produced the product in a low yield, this result indicates
the potential of siletanylmethyllithium as a hydroxymethyllithium equivalent.
In conclusion. Stannane 19 was prepared conveniently and in high yield on a multigram
scale. The reactivity of 19 with nBuLi suggests that the presence of the stannyl moiety suppresses
polymerization of the siletane ring. The ambiphilic properties of 20 present new avenues for
organosilicon chemistry that warrant further investigation. Potential applications include the use
of 20 for olefination or as a synthetic equivalent of hydroxymethyllithium (in conjunction with
the siletane oxidation reported previously84). However, an improved synthesis of 20, particularly
one that avoids the use of stoichiometric tin, would be necessary before the reagent can be
developed to its full potential.
53
CHAPTER III
EXPERIMENTAL
General information
All the 1H and
13
C NMR spectra were recorded on a Mercury Varian 300 MHz using
CDCl3 as deuterated solvent. 1H NMR spectra are reported in ppm (δ) relative to the CHCl3 peak
at 7.26 ppm..
13
C NMR spectra are reported in ppm (δ) relative to the CDCl3 peak at 77.0 ppm.
The IR spectra were recorded on a Perkin Elmer Paragon 1000 FTIR spectrometer on NaCl
discs. Low and high resolution mass spectra were performed on a JEOL JMS600 apparatus. The
melting points were determined on a Köfler melting point apparatus. Yields refer to isolated
material judged to be 95% pure by 1H NMR spectroscopy.
Synthetic procedures
Me
Si
SnBu3
1-(Tributyltin)methyl-1-methylsiletane (19). A solution of tributyltinmethyl iodide (24, 5.63
g, 13.1 mmol, 1.0 equiv) in 10 mL of ethyl ether (Et2O) was added dropwise to a solution of tBuLi (24 mL, 1.3 M in pentane, 31.4 mmol, 2.4 equiv) in 20 mL of ether at –78 ºC. The reaction
mixture was maintained at this temperature for 90 min, warmed to 0ºC over 30 min, and then
recooled to –78 ºC. The resulting solution was added via canula (in portions over 15 min) to a
solution of 1-chloro-1-methylsiletane (21, 2.29 g, 18.9 mmol, 1.45 eq) in 12 mL of THF at –78
ºC. The resulting mixture was stirred for an additional 20 min and then allowed to warm to room
temperature over 1 h. The crude product mixture was quenched with 70 mL of saturated NH4Cl
solution and extracted with two portions of hexanes (70 mL and 40 mL). The combined organic
phases were washed (70 mL of saturated NaHCO3 solution and 70 mL of saturated NaCl
54
solution), dried over MgSO4, filtered, and concentrated under reduced pressure to leave a crude
oil, which was distilled under vacuum (bp 100–104 C, 0.1 mmHg) to afford 4.10 g (80%) of 19
as a colorless liquid.
1
H NMR (CDCl3, 300 MHz) δ 2.12-1.89 (m, 2H), 1.52-1.41 (m, 6H), 1.37-1.25 (m, 6H), 0.96
(apparent t, 4H), 0.90 (t, J = 7.3 Hz, 9H), 0.84 (t, J = 8.0 Hz, J(119Sn-1H) = 50.6 Hz, 6H), 0.25 (s,
3H), –0.02 (s, J(119Sn-1H) = 64.5 Hz, 2H);
13
13
C NMR (CDCl3, 75 MHz) δ 29.2 (J(119Sn-
C)=19.8 Hz), 27.4 (J(119Sn-13C)=56.5 Hz), 17.5, 17.0 (J(119Sn-13C)=16.5 Hz), 13.7, 10.3
(J(119Sn-13C)=327.0 Hz), 0.5, -6.3; IR (neat film) 2957, 2926, 1464, 1249, 1119 cm-1; HRMS
(CI+): Calc’d for C17H38SiSn [M+1]+: 391.1843; Found: 391.1841±0.0005.
Ph
Me
Si
Si
Ph
Ph
1-(Tribenzylsilyl)methyl-1-methylsiletane (26). A solution of n-BuLi (0.50 mL, 1.0 M in
hexane, 0.50 mmol, 1.2 eq) was added over 1 min to a solution of 1-(tributyltin)methyl-1methylsiletane (19, 200 mg, 0.50 mmol, 1.2 eq) in 1 mL of THF at -78°C. The reaction mixture
was stirred at –78 °C for 30 min, and then a solution of tribenzylsilyl chloride (8, 140 mg, 0.42
mmol, 1.0 eq) in 2 mL of THF was added dropwise over 10 min. The resulting mixture was kept
at –78 °C for 2 hours, quenched with water at –78 °C and allowed to warm to room temperature.
The quenched reaction mixture was extracted with 10 mL of ethyl ether, and the organics were
washed with 10 mL of saturated NH4Cl solution. The aqueous phase was extracted with 3 mL of
ethyl ether. The combined organic phases were washed (10 mL of saturated NaHCO3 solution
and 10 mL of saturated NaCl solution), dried over MgSO4, filtered and concentrated under
reduced pressure to give 332 mg of the crude oil.
The product (26) was purified by
chromatography 25 g of silica gel (gradient elution with hexane and then 10% toluene/hexane) to
afford 95 mg (57% yield) of a white solid: M.p.=39–41 °C.
1
H NMR (CDCl3, 300 MHz) δ 7.22 (t, J = 7.6 Hz, 6H), 7.10 (t, J = 7.4 Hz, 3H), 6.96 (d, J = 7.2
Hz, 6H), 2.14 (s, 6H), 2.14-1.92 (m, 2H), 0.97 (apparent t, 4H), 0.23 (s, 3H), –0.03 (s, 2H);
13
C
NMR (CDCl3, 75 MHz) δ 139.3, 128.6, 128.3, 124.3, 23.6, 18.0, 16.5, 0.76, –0.35; IR (neat
film) 3026, 2926, 1550, 1493 cm-1; HRMS (CI+): Calc’d for C26H32Si2 [M+1]+: 401.2121;
Found: 401.2118±0.0007.
55
Ph
HO
Ph
Si
Ph
Tribenzylsilylmethanol (28). To the mixture of 40 mg of 1-(tribenzylsilyl)methyl-1methylsiletane (26, 0.1 mmol, 1 equiv.) with KF·H2O (25 mg, 0.26 mmol, 2.6 equiv.) in 0.6 mL
of THF/MeOH (1:1) excess of H2O2 (30% in water, 0.3 mL, 30 mmol) was added at 0 oC. After
stirring for 10 min at 0 oC the reaction mixture was heated to 45 oC for 6.5 hours. The reaction
mixture was then diluted with EtOAc (7 mL) and the aqueous layer removed. The organic phase
was sequentially washed with a 1 M aqueous Na2S2O3 (3 mL) and brine (3 mL). The combined
aqueous phases were extracted with CH2Cl2 (3x3 mL). The combined organic phases were dried
over MgSO4, filtered and concentrated. Purification by flash column chromatography on silica
gel furnished 11 mg of product 10 (32% yield) as a white solid. M.p.=71-73 °C.
1
H NMR (CDCl3, 300 MHz) δ 7.25-7.19 (m, 6H), 7.14-7.06 (m, 3H), 7.03-6.97 (m, 6H), 3.34-
3.28 (m, 2H), 2.19 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 138.7, 128.5, 128.3, 124.5, 51.9, 20.4;
IR (neat film) 3400, 3023, 1598, 1493, 1452, 1206, 778, 698 cm-1; HRMS Calc for C22H25OSi
[M+1]+: 333.1677; Found: 333.1675±0.0008.
56
Spectra
Figure 3. 300 MHz 1H-NMR spectrum of compound 19
57
Figure 4. 75 MHz 13C-NMR spectrum of compound 19
58
Figure 5. 300 MHz 1H-NMR spectrum of compound 26
59
Figure 6. 75 MHz 13C-NMR spectrum of compound 26
60
Figure 7. 300 MHz 1H-NMR spectrum of compound 28
61
Figure 8. 75 MHz 13C-NMR spectrum of compound 28
62
Part II. SYNTHETIC APPROACH TO BASILIOLIDE B
CHAPTER I
BASILIOLIDE B, LITERATURE REVIEW
I.1 Introduction
Basiliolide B was isolated in 2005 by Appendino and Sterner.129 It demonstrates
inhibiting activity of sarcoendoplasmic reticulum Ca-pumps and holds potential as a leading
compound for treatment of neurodegenerative diseases. Besides promising biological activity,
basiliolide B is an attractive synthetic target. Its bridged structure incorporates four cycles and
six adjacent stereogenic centers.
Recent decades have witnessed the development of new and powerful synthetic methods
and strategies both for C-C bond formation130,131,132 and for stereocontrol.133,134 Consequently,
complex synthetic targets like spongistatin 1135 and discodermolide136 can now be prepared in
significant quantities. Likewise, targets with highly congested skeletal frameworks such as
chartellamide A,137 (-)-okilactomycin,138 haouamine139 and ageliferin140 remain in focus for the
synthetic community (Fig. 9).
63
(-)-haouamine
(-)-okilactomycin
(+)-spongistatin 1
Figure 9. Structures of (-)-haouamine, (-)-okilactomycin, and spongistatin 1
New methods to assemble the number of stereocenters in one step are of great interest
and are being actively developed.141,140 On the other hand the new variations of well known and
widely used Diels-Alder cycloaddition can be highly rewarding and give new ways for
generation of complex structural motifs. For instance, recently developed halopyrone variation of
Diels-Alder cycloaddition, when performed intramolecularly, was shown to provide an efficient
way to generate bridged decalin fragment.142,143
The proposed synthetic approach to basiliolide B (29) employs intramolecular
iodopyrone Diels-Alder reaction to construct bridged framework of the molecule (Scheme 64).
In case of successful application of the reaction, basiliolide B can be synthesized in a highly
efficient way, and the iodopyrone Diels-Alder cycloaddition will be recognized as an efficient
tool for the construction of bridged fragments in natural products.
H
8
5
9
R
4
19
H
O
O
O
O
10
R'O
Key intramolecular
Diels-Alder reaction
I
MeO2C
8
9
64
O
19
O
29
OCH3
basiliolide B
Scheme 64
4
O
10
OR'
O
I
5
CO2Me
In the course of exploring the synthetic route towards basiliolide B the key
intramolecular iodopyrone Diels-Alder cycloaddition was tested. The viable functionalities were
installed in the system which can be further elaborated into the natural product in a number of
ways.
I.2 Isolation, Biological Activity and Structure of Basiliolide B
Isolation and biological activity. Basiliolide B (29), first reported in 2005,129 is a
prominent member of a new class of terpenolide natural products isolated from Thapsia
Garganica L. This plant, distributed in the Mediterranean area and on the Iberian peninsula, was
known and used for medicinal needs since times of Hippocrates (400 B. C.),144 who first reported
on its skin irritating effects. Further accounts on the plant qualities are attributed to Thephrastos
(372-287 B. C.), Dioscorides (approximately A.D. 50), and Plinius (A.D. 24-79).144b
Resin from the root of Thapsia garganica L. for centuries has been used in Arabian and
European medicine for treatment of pulmonary diseases, catarrh, and as counterirritants for relief
of rheumatic pains.144 Drugs prepared from the plant have been recorded in several
pharmacopoeias, most recently in the French pharmacopoeia in 1937.144
Medicinal and biological qualities of Thapsia genus were mainly attributed to the two
principle active components: thapsigargin (THG) and thapsigargicin (Scheme 65).145,144b
R
O
O
O
O
O
H
O
O
C3H7
OH O
OH
O
O
R = C7H15: thapsigargin (30)
R = C5H11: thapsigargicin (31)
Scheme 65
These compounds trigger a host of biochemical response, including activity as histamine
liberators, general stimulants of the immune system and non-12-O-tetradecanoylphorbol-1365
acetate (TPA) tumor promoters.145,144,146 Most importantly, thapsigargin selectively inhibits the
calcium pumps in the sarco- and endoplasmic reticulum (SERCA).147,148
Thapsigargin earned widespread recognition as a powerful tool in cell physiology. It was
tested on all of the known intracellular-type Ca-pumps of SERCA-family. Thapsigargin, in subnanomolar concentrations,149 inhibits all of the SERCA isozymes with equal potency,
demonstrating rapid, stoichiometric, and essentially irreversible interaction with SERCAATPases.149 Interestingly, thapsigargin had no observable effect on Ca-pumps either in the
plasma membrane or in the mitochondrial membrane. Thus, thapsigargin specifically interacts
with a recognition site found only in members of sarco- and endoplasmic reticulum Ca-pump
family.148
The high cost of the compound prompted the studies on improvement of its isolation as
well as search for the biological analogues. Quite recently, these efforts resulted in isolation of
six new metabolites,150 referred as basiliolides/transtaganolides (Scheme 66). The absolute
stereochemistry of basiliolides/transtaganolides is still unknown. Basiliolides A1 and A2 are
identical to transtaganolides D and C, which were also first described in 2005.129,150
H
CO2CH3
OAc
H
O
O
O
O
OCH3
basiliolide B
O
O
O
8
O
O
O
O
H
O
OCH3
C-8 α−methyl, β−vinyl:
transtaganolide A
H
O
O
O
O
O
OCH3
basiliolide C
H
O
O
O
OCH3
transtaganolide C
(basiliolide A1)
O
OCH3
transtaganolide D
(basiliolide A2)
C-8 β−methyl, α−vinyl :
transtaganolide B
Scheme 66
Despite no obvious structural homology, the basiliolides and thapsigargin, which are all
produced by T. garganica L., exhibit similar selective inhibiting activity of SERCA-ATPases.
Basiliolides A1 and B, despite minor structural difference, displayed the same biological activity
profile, while basiliolide C, where C-15 is oxidized to an acetoxymethine, was much less active.
The SERCA-pumps play an important role in regulating levels of Ca2+ in the cells. In the
resting state of the cells, cytosolic Ca2+-concentration is maintained at a low level by active
transport of Ca2+ either into the endo- or sarcoplasmic reticulum or to the extracellular medium.
66
Inhibition of SERCA-ATPases by basiliolides or thapsigargin is accompanied by a leak of the
membranes surrounding the microsomal Ca2+-pools, which causes an increase in cytosolic Ca2+concentration, in other words influences Ca2+-homeostasis.144b
Because Ca2+ signal transduction regulates diverse cellular processes like fertilization,
cell growth, muscle contraction, neuronal signal transduction, mediator release and even
programmed death of the cell (apoptosis), any compound selectively affecting a step in the Ca2+homeostasis is an interesting tool for cell physiology studies as well as of potential therapeutic
use.
For instance, irreversible inhibition of SERCA-pumps by thapsigargin induces apoptosis,
causing the death of the cell. This type of activity makes thapsigargin a potential lead compound
for cancer treatment. Prodrugs based on thapsigargin are currently undergoing clinical trials as
treatments for prostate cancer.151
The initial report129 on the isolation and biological activity of the basiliolides highlights
similarities in biological activity between the basiliolides and their co-metabolite, thapsigargin,
but subsequent studies revealed important distinctions.152 In contrast to thapsigargin, the
basiliolides appear to inhibit SERCA reversibly; reversible inhibition of SERCA leads not to
apoptosis but rather is associated with cell homeostasis. These new data point to potential roles
for the basiliolides (transtaganolides) in the treatment of degenerative disorders such as
Alzheimer’s or Parkinson’s disease.
Structure of basiliolide B. The molecular connectivity and relative stereochemistry of
basiliolide B (Scheme 67) were solved largely through NMR spectroscopy.
The absolute
stereochemistry is unknown. The complex, densely functionalized architecture of the natural
product poses a significant challenge to the current state-of-the-art organic synthesis.
Nevertheless, the compact nature of the target suggests the possibility of identifying highly
efficient synthetic strategies.
67
15
14
CO2CH3
H
7
11
6
4
5
8
9
12
10
13
O
19
3
16
O
2
O
1
17
O
29
18
OCH3
basiliolide B
Scheme 67
Synthetic entry into the basiliolides requires adressing several challenges, including
installation of three distinct ester/lactone linkages, six stereogenic centers, three quaternary
carbon atoms (two of which are all-carbon quaternary stereocenters), and a cyclic O-acyl ketene
acetal moiety within the unique tetracyclic framework. A unified strategy that can access the
various basiliolides would be most attractive.
One biosynthesis hypothesis involves a cascade of pericyclic reactions culminating in
intramolecular Diels–Alder (IMDA) reactions to deliver the various basiliolides and
transtaganolides.129,150 Analogous approaches may be suitable in a laboratory setting. The
intramolecular Diels-Alder reaction of iodo-α-pyrones serves as a cornerstone of the present
synthetic approach towards basiliolide B. The whole bridged decalin framework of the molecule
will be assembled in this one step.
I.3 Retrosynthetic Plan
The key transformation of the proposed synthetic approach is an intramolecular Diels–
Alder (IMDA) reaction of an iodo-α-pyrone to install the carbon dioxide-bridged cyclohexene
complete with its two quaternary and two tertiary carbon stereocenters (Scheme 68).
68
R
H
O
19
O
H
9
R'O
19
9
1
O
29
4
O
O
19
OH
18
32
OMe
Key intramolecular
Diels-Alder reaction
R
4
1
18
basiliolide B OCH3
(R = CO2Me)
R
H
O
9
O
4
O
O
O
O
O
OR'
R
O
MeO2C
I
33
I
R'O
34
I
iodopyrone:
ambiphilic diene
34a
Scheme 68
The first disconnection involves the seven-membered dihydrooxepin ring, which is to be
crafted late in the sequence by cycloisomerization of carboxylic acid and methoxyacetylene
groups. An analysis that focuses narrowly on the O-acyl ketene acetal may result in concerns
relating to stability of this sub-structure.153 The rigid natural product skeleton, however, is
expected to promote formation of (and stabilize) this otherwise delicate moiety. An alternative
approach to the dihydrooxepin ring involves formation of a 7-membered cyclic anhydride first,
followed by methylation-induced enolization of the anhydride C-18 carbonyl oxygen.
Bridged tricycle 33 is to arise from the key IMDA reaction of iodopyrone 34 (Scheme
68). The illustrated conformation (34a) favors formation of the desired product.
Rossi154 and Larock155 describe iodocyclization reactions for preparing halopyrones such
as 34 (Scheme 69) from yne-enoates of type 35. The quaternary stereogenic center at C8 will be
constructed diastereoselectively by serial enolate alkylation to reach 36, using the stereochemical
information from C9 as a guide.
69
CO2Me
OR
4
8
I
8
1
9
1
9
3
RO
3
RO
O
O
34
35
OR
O
OR
O
O
8
O
O
9
36
37
1
Scheme 69
In summary, we propose to synthesize basiliolide B in an efficient, stereocontrolled, and
flexible manner using novel IMDA cycloaddition chemistry of halopyrones.
I.4 Diels-Alder Reactions of Pyrones
I.4.1 Diels-Alder cycloadditions of pyrones and halopyrones
Since the first application of pyrone as a diene in cycloaddition reactions by Kurt Alder
in 1931,156 these species have become a powerful tool for synthetic chemists. Due to a certain
degree of aromaticity inherent in 2-pyrones, these species undergo Diels-Alder [4+2]
cycloaddition not as easy as most cyclic conjugated dienes do. The reactions usually require high
temperatures, around 110-150 oC. Cycloaddition is frequently accompanied by loss of carbon
dioxide through cycloreversion; in certain reactions the initial cycloadduct may not be
observed.157
In case of pyrone cycloaddition to alkynes, first reported by Alder and Rickert in 1937,158
strained bicyclooctadienes are initially formed. These unstable species readily undergo extrusion
of carbon dioxide to form substituted aromatic products (Scheme 70).
70
O
R
O
+
O
Δ
O
R
-CO2
R
R
R
R
Scheme 70
The process has been broadly utilized for the synthesis of a wide variety of substituted
aromatic systems.157
The bicycloadducts generated from 2-pyrones and dienophilic alkenes are generally more
stable than the diene cycloadducts formed from alkyne dienophiles. However, they are still
thermally labile and CO2-extrusion can occur at temperatures as low as 60 oC.159 This process
furnishes cyclohexadiene products, as displayed in Scheme 71.
O
O
R
O
O
O
R
Δ
sealed tube
PhMe
66-72%
O
-CO2
R
O
O
O
O
Scheme 71
Isolation of the bridged cyclooctene intermediates is of great interest as it provides the
source of highly congested building blocks for the synthesis of natural products. There are
several ways to generate isolable bicycloadducts and suppress CO2-elimination:
1. Geometric constrains that accelerate the initial cycloaddition on either the pyrone or
dienophile can be imposed. For instance, 2-pyrone undergoes efficient Diels-Alder
cycloaddition
with
reactive
1,4-dihydronaphthalene-1,4-endo-oxide
at
room
temperature160 (Scheme 72). The obtained cycloadduct in a few additional steps was
converted into (+/-)-7-deoxydaunomycinone.
71
O
25 oC, 83%
MeO
O
O
OH
O
OH
OO
O
OMe
OMe O
O
OH
(+/-) - 7-deoxydaunomycinone
Scheme 72
2. The application of high pressure accelerates Diels-Alder cycloadditions (Scheme 73).161
The [4+2] Diels-Alder cycloaddition has a highly negative (-30 to -40 cm3/mol) volume
of activation.159 The application of pressure to such systems accelerates the rate of
chemical reaction. Conversely, high pressure retards the rates of chemical reactions with
positive volume of activation, such as extrusion of CO2.
O
O
O
O
O
OR*
+
13 kbar
7 days, 56-84%
O
O
O
OR
R* = acyclic group, camphor-derived chiral group, or
cyclohexane-related chiral group
Scheme 73
3. Electronic activation of the pyrone ring through substituent effects to match electronics of
the dienophile partner provides significant rate enhancement (Scheme 74).162 Thus, an
electron-rich dienophile should be used with pyrones bearing electron-withdrawing group
at the 3- or 5- position (inverse-electron-demand Diels-Alder reaction). Electron deficient
dienophiles should be used with pyrones bearing electron-releasing groups (normalelectron-demand fashion).
72
O
MeO2C
O
30 oC
N
+
O
92%
CF3
N
O
F3C
O
STol
85-90 oC
4 days
O
O
MeO2C
+
O
O
STol
70 %
O
Scheme 74
Posner and Afarinkia163 and others164 have reported on the advantages of employing
halopyrones as Diels–Alder dienes. The halopyrones are more reactive in both normal and
inverse electron-demand Diels–Alder reactions.165 This reactivity enhancement facilitates
isolation of the initial [4 + 2] adduct without cycloreversion. 5-Bromopyrones are shown to be
more reactive then 3-bromopyrones. In competition reaction with methyl vinyl ketone, the
reactivity of 5-bromopyrone exceeded the reactivity of its 3-bromoanalogue by the factor of
five.165 Ambiphilic nature of the starting pyrones and the fact that halide-bearing cycloadducts
can be further functionalized by palladium-catalyzed coupling make these reactions highly
attractive for the synthetic chemist.
Recently, Afarinkia’s group described extensive research on the cyloadditions of
different 3- and 5-halosubstituted pyrones. For the first time they examined 5-iodopyrones as
substrates (Table 10); this work inspired us to incorporate 5-iodopyran-2-ones in our synthetic
approach toward basiliolide B.
\
73
Table 10. Diels-Alder cycloaddition of 3- and 5- halosubstituted α-pyrones
O
R
O
+
90 - 100 oC
X
O
+
X
X
X
R
O
+
R
O
O
5-endo
6-endo
O
+
O
O
O
R
R
X
Dienophile
Pyrone Diene
Yield
(conditions)
CO2Me
o
(100 C, 3 days)
CN
o
(100 C, 3 days)
n-C4H9
(100 oC, 3 days)
O
O
O
(100 oC, 3 days)
O
Cl
(100 oC, 3 days)
5-exo
6-exo
Ratio of cycloadductsa
(%)
5-endo
6-endo
5-exo
6-exo
5-Chloro-2(H)-pyran-2-one
83b
63(58)
20(20)
17(22)
0
5-Bromo-2(H)-pyran-2-one
94
70(65)
20(20)
10(15)
0
5-Iodo-2(H)-pyran-2-one
90
70(65)
20(27)
10(8)
0
5-Chloro-2(H)-pyran-2-one
100b
41(42)
12(11)
41(41)
6(6)
5-Bromo-2(H)-pyran-2-one
96
42(40)
10(11)
42(42)
6(7)
5-Iodo-2(H)-pyran-2-one
55
46(40)
9(4)
37(53)
8(3)
5-Chloro-2(H)-pyran-2-one
68b
44(41)
8(13)
44(38)
4(8)
5-Bromo-2(H)-pyran-2-one
80
42(39)
10(17)
41(38)
7(6)
5-Iodo-2(H)-pyran-2-one
85
46(49)
10(6)
36(38)
8(7)
5-Chloro-2(H)-pyran-2-one
45
77(60)
23(40)
5-Bromo-2(H)-pyran-2-one
43
70(80)
30(20)
5-Iodo-2(H)-pyran-2-one
39
45(71)
55(29)
5-Chloro-2(H)-pyran-2-one
70b
65(73)
0
35(27)
0
5-Bromo-2(H)-pyran-2-one
81
70(72)
0
30(28)
0
5-Iodo-2(H)-pyran-2-one
92
70(72)
0
30(28)
0
a
Ratios of cycloadducts are normalized so as to total 100%. Values in parentheses are the ratios from isolated
cycloadducts. b Reaction was carried out for 4 days at 90 °C.
The authors have demonstrated that the reactivity pattern does not significantly change
between the halogens (Table 10). The reactions were carried out at 90 – 100 oC. It has been
shown that at these temperatures cycloadduct products are not equilibrating and there is no
cycloreversion.165 So, the observed product is a kinetically preferred product. All 5- and 3-
74
halopyrones show ambiphilic reactivity. Endo-products were highly preferred over exo-products
in most cases.
Afarinkia and co-workers screened 4-halosubstituted pyrones as substrates for the DielsAlder reaction. These species undergo efficient cycloadditions only with electron-deficient
dienophiles, and the cycloadducts are significantly more prone to CO2-elimination. Therefore,
the reactions must be maintained at 50-70 oC to minimize formation of barrelenes and aromatic
byproducts. The reaction time at lower temperatures reaches fourteen to seventeen days.
In conclusion, 5- and 3-halopyrones display unique and interesting ability to undergo
both normal and inverse electron demand Diels-Alder reactions.
I.4.2 Intramolecular Diels-Alder cycloadditions of pyrones
Intramolecular Diels–Alder (IMDA) reactions of halopyrones for making macrocycles
have been reported.166
It has been shown that 5-bromo-2-pyrones attached to acrylate or
acrylamide dienophiles through alkynyl tether undergo facile IMDA cycloaddition reactions to
provide tricyclolactones in good to fair yields, as shown in the Table 11.166 The starting materials
for the listed reactions were easily generated by regioselective Stille coupling at C3-Br position
of 3,5-dibromo-2-pyrones.166
Table 11. Intramolecular cycloadditions of 5-bromo-2-pyrones
n
O
O
O
n
A
Br
O
PhMe
o
110 C
Br
A
O
O
38
39
Entry
A
n
time (h)
endo:exo
Yield (%)
1
O
2
41
100:0
51
2
O
3
13
100:0
55
3
O
4
13
100:0
66
4
N
2
13
47:53
46
75
Table 11 − continued
Entry
A
n
time (h)
endo:exo
Yield (%)
5
N
3
13
100:0
53
6
N
4
11
100:0
69
The examples in Table 11 display that tethering pyrone to dienophile significantly
reduces the time of the reaction: eleven to thirteen hours (on average) versus three days for
intermolecular reactions of halopyrones described in the previous section.
At the time when we designed our synthesis there were no examples of intramolecular
Diels-Alder reactions of halopyrones furnishing bridged decalin or similar tricyclic systems.
Thus, for the synthesis of compact tricycles one must make inferences from IMDA
reactions of other classes of α-pyrones. One notable example is the temporary boronate ester
tether that Nicolaou and co-workers described for their synthesis of taxol (Scheme 75).167 In
original efforts to effect the fusion between the Diels-Alder partners, without use of tether, the
undesired regioisomer was formed as the major product in about 40% yield (after 24 h at 150
o
C).
39
38
41
40
42
Scheme 75
76
43
Therefore, they examined the Diels-Alder reaction of pyrone 38 tethered to dienophile
39 by phenylboronic acid under dehydrating conditions (to generate intermediate 40), which
provided intermediate endo-diastereomeric adduct 41. Upon decomplexation with neopentyl
glycol, lactone migration occured to give 43167 (Scheme 75). With phenylboronic acid as a
temporary tether, the desired IMDA reaction proceeded under conditions that were sufficiently
mild so as to avoid cycloreversion with loss of carbon dioxide.
The key IMDA reaction in our synthetic approach to basiliolide B shares features in
common with Nicolaou’s example. We employ a permanent tether en route to the tricyclic core
of the basiliolides/transtaganolides. Importantly, use of a halopyrone provides a handle for
further functionalization of the core to complete the synthesis.
I.5 Formation of Oxepine Ring via Cycloisomerization of Methoxyacetylene or
Alternative Routes
Close to the end of the total synthesis we plan to assemble the dihydrooxepin ring by
intramolecular addition of the carboxylic acid to a methoxyacetylene moiety (Scheme 76).
Methoxyacetylene can be installed in the system employing a known Stille-type coupling of tin
alkoxyacetylides with vinyl iodides.168
Figure 10. Structure 32 after
Molecular Mechanics conformational
minimization
O
O
O
O
O
O
CO2Me
HO
MeO
CO2Me
O
MeO
29
32
Scheme 76
COOH
OMe
77
Intermolecular addition of carboxylic acids to ethoxyacetylene catalyzed with ruthenium
has been thoroughly examined because the O-acyl ketene acetal is a good acyl-transfer reagent.
Originally, activation of carboxylic acids by ethoxyvinyl ester formation was explored by
Wasserman in 1960,169 but it did not find much synthetic application as the procedure involved
toxic stoichiometric mercury. Later in 1986, Dixneuf170 showed that ruthenium efficiently
catalyzes addition of carboxylic acids to acetylenes to produce the corresponding vinyl ethers.
Application of [RuCl2(p-cymene)]2 was found to give the best yields in acid additions to
alkoxyacetylenes.153
O
R
OH
O
Ru-cat.
+
R
O
R'OH
O
OEt
H
OEt
+
R
O
O
O
OH
OH
OEt
Ru-cat.
(5)
R'
O
O
OEt
cat. CSA
O
(6)
OH
With the convenient methodology for ruthenium catalyzed formation of ethoxyvinyl
esters available, Y. Kita153 further explored their potential as preactivated acylating reagent and
elaborated methodology for intermolecular formation of esters (eq. 5) and amides. He found that
(trimethylsilyl)ethoxyacetylene is an excellent dehydrating reagent for the synthesis of
carboxylic anhydrides (as well as amides) from the corresponding dicarboxylic acids under mild
conditions with quantitative yields.171
Recently Trost investigated ethoxyvinyl esters derived from the hydroxy acids for
macrolactonization purposes.172 The reaction procedures involve catalytic camphorsulfonic acid
to activate ethoxyvinyl ester toward macrolactonization, which in case of fourteen- or higher
membered rings produces macrocycles in 60 to 70% yields (eq. 6).
In the case of basiliolide B we look at intramolecular addition of carboxylic acid to
methoxyacetylene that proceeds in endo-fashion. Examples of intramolecular ruthenium
cycloisomerization are known in literature as well. So, Valerga’s group173 has shown that with
certain type of Ru-catalyst these reactions produce exclusively endo-cyclized product (Table 12).
78
Table 12. Cycloisomerization of carboxylic acid with terminal alkyne
n
O
TpRu{PhC=C(Ph)C=CPh}(PMei-Pr2)
O
O
+
O
OH
O
n
Tp = hydrotris(pyrazolyl)borate(-1)
n
a
b
Entry
n
a:b
Yield (%)
1
1
0 : 100
97
2
2
0 : 100
95
3
3
0 : 100
45
4
4
0 : 100
84
Generally speaking, it has been shown that intermolecular addition of carboxylic acids to
terminal alkynes in the presence of certain ruthenium complexes proceeds regioselectively in
anti-Markovnikov fashion to give Z-alkene derivatives.174
In our case regioselectivity of the desired endo-cyclization to the great extent will be
controlled electronically. Molecular models as well as optimization of the conformation by
molecular mechanics method (MM2, Scheme 76) suggests that carboxylic acid and alkyne in
structure 32 are situated very close in space (Fig. 10) and may even undergo cycloisomerisation
spontaneously (Scheme 77).
79
CO2CH3
H
CO2CH3
H
O
O
O
O
PO2C
I
PO2C
45
44
OMe
O
O
O
O
O
O
CO2Me
O
CO2Me
HO
MeO
MeO
29
32
Scheme 77
As shown in Scheme 77, upon deprotection carboxylic acid 32 may undergo
cycloisomerization in situ to furnish the natural product.
Alternatively, dihydrooxepin ring can be generated from a 7-membered cyclic anhydride
by reaction with methylating reagent in the presence of the base (route I, Scheme 78), or by
cyclization reaction of methyl ester with acid chloride functionality in the presence of the base
(route II).
Route I
H
Route II
CO2Me
H
O
O
H
base
O
O
O
O
OMe
Me
CO2Me
O
O
O
46
H
O
O
O
CO2Me
H
Cl
O
base
OMe
47
29
Scheme 78
Though O-acyl ketene acetals are not generally very stable, it was shown that ethoxy
vinyl esters can survive rapid column chromatography.172 The isolation of basiliolide B
involving column chromatography129 suggests a certain degree of stability inherent in the
molecule, as the rigid carbon skeleton probably stabilizes the otherwise delicate O-acyl ketene
acetal.
80
I.6 Generation of 5-Iodopyrones by Iodocyclization
5-Halopyrones can be generated in a number of ways. The methods known since 1969175
or 1992163,176 as well as more recent ones177,164 tend to elaborate 5-halo-pyrone from α-pyrone or
dihydropyrone
functionality
by
treatment
with
brominating
reagents
(bromine,
bromosuccinimide) usually in the presence of base as it shown in Eq. 7-13.175,177,176,164,178
O
O
Br2, Δ
Br
80%
Br
O
26%
(7)175
52%
(8)175
60%
(9)177
36%
(10)176
O
65-
(11)164
Br
76%
O
Et3N
Br
33%
Br
O
Br
O
O
O
Br2, Δ
O
57%
O
Br
O
O
O
Br
O
Br
O
O
Br
1) NBS (x 2), Ph(CO)2,
CCl4, reflux
O
O
2) Et3N
O
O
(PhCO2)2
R
O
O
NBS, LiOAc, Bu4NBr
Br
O
Br
CCl4 / MeCN (2:1)
HO2C
O
NEt3
Br
O
Br
Et3N
93%
99%
Br
Br2, hν
Br
Br2, hν
O
O
O
Br
O
Et3N
O
Br
Br
59%
(12)178
59%
(13)178
NBS
O
Br
Br2
O
Br
O
Et3N
O
O
Br
Br
Br
81
N-
These methods have a number of the inherent drawbacks. For instance, many
functionalities, like multiple bonds, allylic methylene or methylene α to carbonyl group, won’t
be tolerated under the harsh reaction conditions. On the other hand, a prior installation of the
prerequisite moiety, such as pyrone or dihydropyrone ring, is required, which is not a simple
synthetic task itself and implies several additional steps.
Also, the reactions shown above furnish 5-halo-pyrones with only moderate efficiency.
Thus, before the new methodology has been reported by Renzo Rossi154,179 and Richard
Larock,180 the installment of halopyrone moiety into complex molecule was a synthetic
challenge.
Over the past decades considerable efforts have been directed towards the synthesis of
substituted 2-pyrones either by traditional approaches (mainly lactonization/condensation
reactions)181 or by processes involving transition metal-catalyzed reactions,182 including
palladium-catalyzed couplings of internal alkynes.183 These efforts are highly rewarding as 2pyrones are useful synthetic intermediates and occur as structural fragments in a wide variety of
natural products.184
Recently, Rossi’s and Larock’s groups154,179,180 reported new methodology for generation
of α-pyrones or substituted isocoumarins by electrophilic cyclization of (Z)-2-alken-4-ynoates or
o-(1-alkynyl)benzoates, or the corresponding acids (Scheme 79). The reported methodology has
several advantages over the previous approaches.
O
O
OR1
E+
O
O
O
+
R2
R2
E
E
R2
R1= H, Alk
Scheme 79
At first the reactions of 5-substituted (Z)-2-alken-4-ynoic acids were explored,154a It
appears that when exposed to the iodination conditions, the acids afford mixtures of iodopyrones
and iodofuranones in high combined yields, with pyrone formation being favored. Some
examples are presented in the Table 13.
82
Table 13.154a Iodocyclization of alkenynoic acids
I
COOH
+
R1
R1
48a-e
Entry
Starting
48a
O
O
R1
49a-e
R1
material
1
O
O
I
Method for
50a-e
Products
iodocyclization
CH3
I2 (x3), NaHCO3
49a+50a(E/Z)
Yield
Yield
(%) of
(%) of
49
50
64
27 (E)
(x3),
5 (Z)
CH3CN, 1.5 h at r. t.
2
48b
C6H13
I2 (x3), NaHCO3
49b+50b
65
31 (E)
49c+50c
60a
27(E)a
49d+50d
3a
75a
49e+50e
72
19 (E)
(x3),
CH3CN, 1.5 h at r. t.
3
48c
C6H13
ICl (x1), CH2Cl2,
1 h at r. t.
4
48d
C6H13
NIS (x1.1), KHCO3
(x1), CH3CN,
2.5 h at r.t.
5
48e
(E)-CH=CH-
I2 (x3), NaHCO3
C3H7
(x3),
3 (Z)
CH3CN, 1.5 h at r. t.
a
The yields are referred to GLC analysis
The ratio of the formed pyrones and furanones usually is around 2 : 1. The reactions with
a stronger electrophile, such as iodine monochloride, proceed and reach completion faster.
This iodocyclization approach was extended over methyl and ethyl esters of (Z)-2alkene-4-ynoic acids.179,154b,180a,180b Interestingly, the regioselectivity of iodocyclization shifted
significantly towards the pyrone products for the ester substrates versus acids, while the products
were generally formed in good to excellent yields (Table 13). Different electrophilic reagents
83
such as I2, ICl, p-O2NC6H4SCl, PhSeCl and HI were tested in the cyclization (some examples are
presented in the Table 14). Though reactions with iodine as the electrophile generally afford
mixtures of the products, reactions with iodine monochloride furnish 5-iodopyrones with better
yields and higher ratios or even exclusively. Those reactions also demonstrate the highest
reaction rate, followed by iodine, p-O2NC6HSCl and PhSeCl (entries 1, 2, 3, 5, 6), while reaction
with hydrogen iodide is the longest and takes up to 96 hours.
Table 14.179, 154b, 180a, 180b Iodocyclization of alkynenoates
Entry
Starting
Reagent
material
1
CO2Me
time
Products
(h)
ICl
Yield
(%)
0.5
94
O
O
Ph
Ph
I
2
O
p-O2NC6H4SCl
O
1
80
Ph
S
NO2
3
O
PhSeCl
O
1
97
Ph
SePh
4
O
CO2Me
ICl
O
0.5
80
n-C4H9
n-C4H9
I
5
CO2Et
O
ICl
O
0.5
Ph
59
Ph
I
84
Table 14 − continued
Entry
Starting
Reagent
material
6
time
Products
Yield
(h)
(%)
CO2Et
O
I2
O
1
Ph
84
Ph
I
7
CO2Et
O
ICl
Ph
O
0.5 h
84
Ph
Ph
Ph
I
8
Me
CO2Me
I2
Ph
O
O
Me
1
Ph
Me
O
Ph
Ph
Ph
Ph
I
9
Ph
CO2Et
I
O
O
I2
Ph
Ph
1
Ph
Ph
O
Ph
Ph
Ph
Ph
I
O
O
ICl
0.5
Ph
Ph
O
Ph
+
Ph
17 + 55
O
Ph
Ph
I
I
11
6 + 71
O
+
I
10
17 + 76
O
+
O
CO2Et
ICl
0.5
55
O
Ph
Ph
I
12
O
PhSeCl
1
Ph
PhSe
13
60
O
O
CO2Et
ICl
O
0.5
0
Ph
Ph
I
85
Table 14 − continued
Entry
Starting
Reagent
material
14
time
Products
(h)
Yield
(%)
O
CO2Et
I2
O
16
85
Ph
Ph
I
When 2,3-disubstituted (Z)-2-alkene-4-ynoates are employed, mixtures of five- and sixmembered-ring products are obtained no matter whether I2, ICl or PhSeCl is employed as the
electrophile (entries 8, 9, 10, Table 14). The authors180b propose that steric effects play an
important role in the regioselectivity of cyclization. The bulkier the substituents are in position 2
or 3 of the (Z)-2-alkene-4-ynoates, the lower the yield of the six-membered-ring product.
Compared with I2, the stronger electrophilic reagent ICl affords a higher yield of the sixmembered-ring product, although the five-membered ring lactone still predominates (entry 9, 10,
Table 14).
When ring-containing esters are explored, esters containing six-membered ring result in
formation of furanones only (entries 11, 12, Table 14). Interestingly, the five-membered-ring
containing esters give only products of addition of ICl across the triple bond (entry 13, Table 14).
However, when I2 is used instead of ICl, the examined substrates afford the desired bicyclic αpyrones as the only products in good yields (entry 14 as an example, Table 14 as an example).
The latter reactions also take longer time to reach completion. The decrease in the
reaction rate can be explained by new orientation of the carbonyl group: oxygen atom is now
further away from the triple bond as a result of the rigid geometry of five-membered cyclic
system.
Taking into account the described observations together with the fact that different esters
(methyl, ethyl and t-butyl esters) undergo iodocyclization and demonstrate similar reactivity the
mechanistic rational shown in Scheme 80 was proposed.180b
86
ClO
O
OR
OR
51
1
R
ICl
R1
52
I
O
O
O
2
O
1
R2
R2
R
I
I
53
2
55
Cl-
O R
O
1
O
O
54
I
R2
56
I
R2
Scheme 80
Activation of the triple bond by coordination of the iodonium cation is followed by
nucleophilic attack of carbonyl group oxygen on one of the two carbons of the original triple
bond (52, Scheme 80). The attack on different carbons in structure 52 leads to formation of either
pyrone or furanone product. The formed cations 53 or 54 undergo SN2 type substitution with the
chloride, or in case of tert-butyl ester – SN1 cleavage to afford the product.
Among advantages of the methods described above, like mild reaction condition, it is
worth noting that the (Z)-2-alkene-4-ynoate functionality, required for the cyclization step, can
be easily installed in the complex molecule by Sonogashira coupling of terminal alkyne with the
corresponding (Z)-3-iodo-2-propenoates.154a, 180b
In conclusion, the efficient synthesis of a broad variety of substituted α-pyrones as well
as isocoumarins can be accomplished under mild conditions employing Rossi-Larock
methodology. The required (Z)-4-alkene-2-enoate functionality can be easily introduced into the
molecule and the resulting iodine-containing products are readily elaborated by Pd-catalyzed
couplings164 to the more complex compounds. Thus, the described approach represents an
attractive tool for the synthetic chemist as it provides solution for 5-iodopyrone generation in
quite complex systems at the later stages of the synthesis.
87
CHAPTER II
RESULTS AND DISCUSSION
II.1 Model Studies toward Bridged Decalin System and on Diastereoselectivity
of Intramolecular Pyrone Diels-Alder Reaction (IMPDA)
Entry into the basiliolides through chemical synthesis requires that several challenges be
addressed, including installation of three distinct ester/lactone linkages, six stereogenic centers,
two quaternary carbon atoms, and a cyclic O-acyl ketene acetal moiety.
The retrosynthetic analysis shown in Scheme 81 calls for an intramolecular pyrone
Diels–Alder (IMPDA) reaction of 34, which features an ambipihilic 5-iodo-2-pyrone185 diene, to
assemble bridged decalin framework and to introduce four out of six stereogenic centers.
Halogen substitution on 2-pyrones159 increases their reactivity in both normal and inverse
electron-demand Diels–Alder reactions, thereby providing the flexibility needed to prepare other
basiliolides and their analogues.
88
CO2Me
H
4
8
O
9
3
O
10
O
O
basiliolide B
8
5
9
10
4
O
O
note:
R = Me provides
basiliolide A1
MeO2C
I
I
iodopyrone:
ambiphilic diene
equatorial
H
I
chair
O
H
chair
32
O
H
flagpole
interaction
O
endo
O
OR'
R
MeO2C
I
OR
MeOO
2C
O
O
34
exo
OR
endo
1
OCH3
R'O
equatorial
O
3
O
R'O
29
preferred O
CO2Me
H
RO
axial
I
I
CO2Me
A1,3 strain
MeO2C
IH
H
OR
endo
O
O
H boat
34a
Scheme 81
To establish the feasibility of the IMPDA approach to basiliolide using 5-halo-2-pyrones,
two main concerns must be addressed: (1) reactivity with respect to cycloaddition versus carbon
dioxide (CO2) cycloreversion159 and (2) diastereoselectivity.
The diastereoselectivity of the key IMDA step was analyzed. Molecular models of
tricycle 32 reveal the C4 methoxycarbonyl group to be endo on the oxabicyclo[2.2.2]octene, and
the C9 alkoxymethyl group to be equatorial on the cyclohexane ring. The IMDA transition state
leading to 32 is reached from a conformation of 34 that reflects these features (Scheme 81). If the
tether adopts a chair-like conformation with the C9 substituent in a pseudo-equatorial alignment,
then endo cyclization of the dienophile sets the stereochemistry of carbons C3, C4, C5, and C10
in accord with the natural product target. Alternative conformations lead to transition states that
suffer either from additional steric interactions or lack the kinetic advantage of endo approach as
shown on the Scheme 81.
When we started our studies on intramolecular pyrone Diels-Alder approach to
basiliolide B there were no examples of halopyrone cycloadditions to construct bridged dcecalin
system. Recently Nelson and Stoltz reported progress towards the synthesis of the basiliolides
and transtaganolides,143 including an encouraging IMPDA reaction of a 3-bromo-2-pyrone
(Scheme 82).
89
CO2Me
1) PhH, 90 oC
3 days, 76%
H
CO2Me
O
MeO2C
MeO2C
O
2) Bu3SnH, 50%
MeO2C
Br
O
O
57
CO2Me
58
Scheme 82
However, their system lacks an appropriate handle at the 5-position of the pyrone for
further elaboration, and the bromine atom inserted late in the sequence to activate the key
IMPDA reaction had to be removed in a subsequent step.
This chapter focuses on new IMPDA reactions relevant to our approach to basiliolide
186
B.
These studies provide data specific to the challenges of the basiliolides, and, in general
terms, provide insight into the application of IMPDA reactions in natural products synthesis. In
particular, we establish that halogen substitution at the 5-position of the pyrone (cf. 34) is
suitable for the IMPDA reaction that is central to our synthetic design.
Model study toward bridged decalin system. The first model study addresses the
feasibility of the IMPDA reaction in simplest terms, establishing that the desired cycloadducts of
5-iodo-2-pyrones can be obtained free from cycloreversion products (Scheme 84).
The first test substrate, 5-iodo-2-pyrone 64, was synthesized as shown in the Scheme 83.
90
1. (COCl)2, DMSO,
CH2Cl2, -78 oC;
Et3N, -78 oC to rt
1. LiAlH4, THF, 0 oC
HOOC
HO
2.
I
59
60
2.
CO2Me
cat PdCl2(PPh3)2,
cat CuI, Et3N,
rt (6.5 h)
62
PhCH3, rt (1 day),
35 oC (4 h)
MeO2C
61
CO2Et
Ph3P
81%
82%
CO2Et
ICl, CH2Cl2,
rt (5 h)
CO2Et
I
57%
O
MeO2C
63
64
O
Scheme 83
Heptynoic acid (59) was reduced to heptyn-7-ol following the known procedure187 and coupled
with iodide 60 under Sonogashira conditions to give alcohol 61. Homologation of alcohol 61 was
achieved using the Swern oxidation and Wittig olefination to furnish dienyne 63. Finally, Rossi–
Larock iodocyclization154,155 employing Larock’s protocol155 provided iodopyrone 64.
CO2Et
PhCH3, 100 oC
3 days
H
I
O
39%
(46% brsm)
64
CO2Et
O
O
65
I
O
Scheme 84
5-Iodo-2-pyrone
64
provides
insight
into
cycloaddition
reactivity
vis-à-vis
decarboxylation (Eq 1). Heating 64 at 100 °C for three days provided cycloadduct 65 as a single
diastereomer and free from cycloreversion products. Extrusion of CO2 becomes dominant at
higher temperatures, illustrating the delicate balance of pyrone Diels–Alder reactions.
91
Model studies on diastereoselectivity. The second model study focuses on the
diastereoselectivity of a strategic IMPDA reaction of a readily available and chiral 5-iodo2-pyrone (70, Schemes 85 and 86). IMPDA substrate 70 (Scheme 87) includes a stereogenic
center to influence the diastereoselectivity of the reaction. Also, the omission of one methylene
unit in the tether between diene and dienophile in 70 lowers the entropic barrier of the key
IMPDA reaction. (A similar effect for intermediate 34 will be associated with Thorpe-Ingold
conformational biases due to the presence of substituents at C8).
Scheme 85 illustrates the synthesis of IMPDA substrate 70. Corey-Fuchs homologation
of citronellal (66),188 followed by Sonogashira coupling with iodide 60 provided dienyne 67.
O
OMe
m -CPBA, CH2Cl2,
-78 oC (4 h)
O
1. PPh3, CBr4
2. n-BuLi
(30%, 2 steps)
CHO
79%
OMe
67a
60
CO2Me
3. I
cat. PdCl2(PPh3)2,
cat. CuI, Et3N,
50 oC (1.5 h)
66
O
67
O
87%
X
X
1. HIO4, THF:H2O (2:1),
0 oC (2.5 h)
2.
Ph3P
62
CO2Et
CH2Cl2, rt (1 d), 32 oC (4 h)
OMe
O
CO2Et
68
OMe
69
75%, 2 steps
Scheme 85
When dienyne 67 was exposed directly to iodocyclization conditions, the more
substituted double bond reacted, selectively providing undesired halogenated products consistent
with 68 without any impact on alkenoate functionality. The observed selectivity suggested that
chemoselective epoxidation of the more electron-rich double bond of 67 should be efficient.
92
Epoxidation of 67 with m-CPBA at -78 oC cleanly produced 67a in 79% yield. Epoxide
67a, which was quite unstable for storage, was involved in the next step immediately. Hydration
of 67a in situ furnished diol, which was cleaved with periodic acid. Crude aldehyde was
involved in olefination with stabilized Wittig reagent to furnish enyne 69 in 59% over three steps
from dienyne 67 (Scheme 85).
Iodocyclization of 69 provided iodopyrone 70 along with the iodobutenolide product of
5-exo cyclization (71) in a 2.5 : 1 ratio (Scheme 86).
O
OMe
Rossi–Larock
iodocyclization
CO2Et
I
ICl, CH2Cl2
rt, 4 h, 61%
+
O
EtO2C
I
EtO2C
O
O
69
70
O
(2.5 : 1)
71
Scheme 86
The IMPDA reaction of pyrone 70 (70 → 72, Scheme 87) was much faster than that of
pyrone 35 with the four-methylene tether (64 → 65, Scheme 84): complete conversion of 70
occurred within 12 h at 100 °C. Furthermore, the desired cycloadduct 72 was formed as a single
diastereomer along with a minor by-product 73 (≤9%) arising from decarboxylation.
As shown on the Scheme 87 the desired cycloadduct 72 is generated from pyrone 70 by
adopting conformation A. In case of conformation B, another diastereomer (epi-72) would be
produced. However, conformation B is highly unfavored due to 1,3-allylic strain between an
iodide and a pseudo-axial methyl substituent. Apparently, the reaction proceeds exclusively via
conformation A resulting in formation of only one diastereomer (72). The geometry of
cycloadduct 72 was confirmed by nOe experiment.
93
A
O
O
I
100 °C, 12 h
I
PhCH3
O
O
EtO2C
H
I
H
H
72
nOe
O
EtO2C
CH3
60%
MeO2C
O
O
H
70
B
O
O
O
CH3
I
not
formed
CO2Me
EtO2C
H
A1,3 strain
I
epi-72
Scheme 87
When cycloadduct 72 was exposed to high temperature for longer time we observed
formation of the product 73 (Scheme 88), which we have observed before as a byproduct while
performing cycloaddition of 70 (Scheme 87).
O
EtO2C
O
100 °C, 24 h
EtO2C
I
H
H
I
PhCH3
73
72
Scheme 88
The above reaction demonstrates a sensitive balance between cycloaddition and CO2extrusion that depends on both time and temperature of the reaction.
The cycloaddition reactions of 64 and 70 illustrate the utility of 5-iodo-2-pyrones in
intramolecular Diels–Alder reactions, building on promising initial data from related
intermolecular processes.185d It is worth noting that similar IMPDA reactions are completely
intractable in the absence of halogen activation.143
Conclusions. These initial studies provide a solid foundation for the synthesis of the
basiliolides and transtaganolides. Importantly, these studies afforded preliminary experimental
support — in the form of a diastereoselective IMPDA reaction (70 → 72, Scheme 87) controlled
by a stereogenic center on the tether — for the hypothesis that the C9 stereochemistry can be
94
used to impart diastereocontrol over construction of the basiliolides and transtaganolides. What
remained is to prepare, following the general approach outlined in Scheme 69, an IMPDA
substrate (cf. 34) with appropriate functional group handles for further elaboration.
II.2 Synthetic Approach to Basiliolide B
II.2.1 Conjugate addition to butenolide 37
En route to basiliolide B our first target was to install the stereocenter at the γ-carbon of
butyrolactone. If a bulky substituent (R in 37a, Scheme 89) blocks one side of the fivemembered ring, then serial enolate alkylations at the α-carbon will furnish the quaternary center
of intermediate 36 (Scheme 89) with high diastereoselectivity.
O
O
O
O
O
OR
O
R
37
37a
36
Scheme 89
Initially, we envisaged 1,4-addition of triisopropylsilylacetylene to butenolide as the first
step of the synthesis. The large triisopropylsilyl group was chosen to maximize the following
alkylations. Though alkynylation of α,β-enones still represents a challenging transformation,
nowadays several methodologies have been reported.
Conjugate alkynylation of enones. The conjugate addition of alkynyl groups to α,βunsaturated ketones for a long time has remained an elusive synthetic challenge. Organocuprate
reagents, most commonly used for 1,4-addition of alkyl, alkenyl or aryl groups to α,β-enones, in
case of acetylides reveal strong complexation between sp-carbon and copper (I), which limits
their effectiveness as nucleophiles.
95
Until recently alkynyl ligands have been considered unreactive in copper-promoted
conjugate additions. In fact, the stability of copper acetylides has allowed alkynyl groups to serve
as nontransferable ligands in mixed cuprate reagents as shown by Corey.189 The use of mixed
cuprates of the formula (RC≡C)RtCuLi helps to avoid wasting one equivalent of the valuable
group Rt, designed for the installment by conjugate addition, while the acetylide (RC≡C−) serves
as the second cheap nontransferrable ligand.
Interestingly, bis(acetylido)cuprates do undergo addition to α,β-unsaturated aldehydes,
but exclusively in 1,2-addition fashion.190
Alternatively, acetylides of aluminum,191,192,193 boron,194,195,196 zinc197 or even rhodium198
were examined as reagents for 1,4-addition. The binding between alkyne and the metals listed
above is weaker; thus, the alkynyl moiety can be successfully transferred to form new C−C
bonds.
There is an important limitation in some of the latter methods. Alkynyldialkylalanes191
and alkynylboron194,195 reagents undergo addition only to α,β-enones that can achieve an s-cis
conformation (Scheme 90). Cyclic systems that cannot adopt an s-cis conformation thus present
even greater challenge.
O
M
R
O
ML2
O
ML2
H3O+
R
R
O
R
s-cis
Scheme 90
For aluminum acetylides, Schwartz successfully expanded the method to cyclic enones
with the rigid transoid geometry by using nickel(I) as a catalyst.192 Active nickel(I) species are
generated in situ by reduction of Ni(acac)2 with DIBALH (entry 1, Table 15).
96
Table 15. Conjugate addition of acetylides
entry
Reagents and conditions
Yield, %
author
and year
O
(i) Me2Al
t-Bu
Ni(acac)2, DIBALH
1
O
60%
(ii) H3O+
1978
t-Bu
O
OTBS
BrZn
R
TBSOTf
2
THF, -40 oC
R
O
R=Ph 78%
S. Kim
R=n-Bu 77%
1990
M. Nilsson
O
(i) n-Bu
Cu LiI-TMSI
THF, -30 oC
3
68%
(ii) NH4Cl / NH3 (aq.)
(i) TMS
Cu LiI-TMSI
O
OTMS
H 3O +
THF, -30 oC
(ii) Et3N
4
& T. Olsson
1993
n-Bu
O
J. Schwartz
TMS
TMS
92%
M. Nilsson
(overall)
1997
86%
E. J. Corey
82-88% ee
2004
67%
T.Nishimura
88% ee
and
(78% Y, if isolated)
O
Me2Al
5
6
Ni-cat*:
O
TMS
Ni-cat.* (5 mol%),
t-BuOMe, 0 oC
O
N
N
Ni
O
O
Ph
TMS
Si(i-Pr)3
[Rh(μ−OAc)(C2H4)2]2
(2.5 mol%),
(R)-DTBM-segphos
(5.5 mol%),
1,4-dioxane, 40 oC
Ph
(R)-DTBM-segphos:
O
H
O
O
R
O
O
O
TIPS
PAr2
PAr2
2008
O
t-Bu
Ar =
OMe
t-Bu
97
T. Hayashi
Though zinc acetylides do not react with α,β-enones at room temperature, Kim197
demonstrated that conjugate addition of these reagents proceed cleanly and rapidly in the
presence of t-butyldimethylsilyl triflate (TBSOTf) at -40 oC (entry 2, Table 15).
Nilsson and Olsson199 have reported that reactivity of copper(I) acetylides toward
alkynylation also can be enhanced by addition of iodotrimethylsilane or trimethylsilyl triflate to
the reaction mixture. They found that otherwise unreactive copper acetylides successfully
undergo conjugate addition to α,β-enones present as s-trans conformers to provide good yields of
the silyl enol ethers of β-acetylido carbonyl compounds (entry 4, Table 15).199a
The methodology for 1,4-additions of alkynes is still actively developing. Many current
methods hold potential for evolving into enantioselective reactions, for instance, by introduction
of asymmetric ligands on the metal atoms.
Obviously, the possibility to accomplish the first step in the total synthesis of basiliolide
B enantioselectively is highly advantageous for us as potentially enantiomeric product can be
synthesized without a significant loss of material.
Enantioselective conjugate alkynylations. To date there have been only few reports on
asymmetric conjugate alkynylations by Chong,196 Corey200 and Nishimura and Hayashi.198
Firstly, Chong and collaborators demonstrated that asymmetric conjugate additions of
alkynylboronates196 can be accomplished. The method is still limited to acyclic enones capable to
achieve s-cis conformation.
Later, inspired by Schwartz’s studies on nickel-catalyzed addition of alanes, Corey200
successfully extended the method to enantioselective conjugate addition of aluminum
trimethylsilylacetylide to cyclohexenone in the presence of a chiral complex of nickel (II) as a
catalyst (entry 5, Table 15).
In 2008, 1,4-additions of triisopropylsilylacetylene to cyclic enones in the presence of
catalytic complexes of rhodium with chiral bulky phosphine ligands were accomplished by
Nishimura and Hayashi198 (entry 6, Table 15). Previously, rhodium-catalyzed asymmetric
conjugate addition of alkynes was not efficient due to high reactivity of terminal acetylene
toward the alkynyl-rhodium intermediate, which results in the predominant formation of
acetylene dimers rather than β-alkynyl ketones. The problem was solved by employing sterically
98
bulky substituents on silicon and DTBM-SEGPHOS as a chiral phosphine ligand to hinder the
acetylene from approaching the alkynyl-rhodium intermediate.
These studies on addition of alkynes to α,β-enones provide encouraging support for our
goal, but extension of these methods to butenolide electrophiles is not assured. Butenolides differ
from cyclic α,β-enones in at least two significant ways.
O
O
vs.
O
Firstly, butenolides are less electrophilic than α,β-enones owing to resonance effects of the
lactone oxygen. This effect is generally cited for the greater stability/poorer reactivity of esters as
compared to ketones.132 Secondly, γ-deprotonation of butenolides generates an aromatic
dienolate anion. Consequently deprotonation of butenolides is a significant concern.
Mindful of these potential pitfalls, we began our studies on the conjugate addition of
alkynes to butenolide. Ultimately, our best solution involved conjugate addition of a propenyl
group, which was subsequently converted into the requisite alkyne (vide infra).
Attempts of alkynylation of butenolide. Upon extensive literature search of reported
methods for conjugate alkynylation, we examined some of the described methods with our
starting material, commercially available butenolide 37, en route to basiliolide B (as represented
in the Table 16).
When we followed the procedure reported by Schwartz’s group,192b employing aluminum
acetylide in the presence of nickel (I) (entry 1, Table 16), the reaction provided a complex
mixture of unidentified products with no desired alkynylbutyrolactone observed. None of the
desired product was formed when zinc trimethylsilylacetylide199a was tested as a reagent (entry
2, Table 16). Interestingly, there was one major product observed in 1H-NMR of the crude
reaction mixture for the latter experiment. This product was isolated in 22% yield after the
column and identified as 2-(tert-butyldimethylsiloxy)furan.201 This result reflects an inherent
problem of conjugate addition to unsubstituted butenolide associated with acidity of the γ-proton.
99
Table 16. Results on conjugate addition to butenolide 37
O
OR'
O
M
A
R
A
A
OR
A = O, CH2
R
R
Entry
Starting
Reaction conditions
Product
material
O
1
O
Yield
(%)
Ni(acac)2 (25-mol%), DIBALH,
TMS (2.5
Me2Al
no
equiv.),
o
Et2O, -5 C
O
2a
TMS (1.25
BrZn
equiv.),
TBSOTf (1.25 equiv.), Et2O, -40 oC
O
OTB S
22
O
74
O
3
TIPS (1.5
(i) Li
equiv.),
O
≤ 64b
CuI (1.65 equiv.), TMSI (1.5 equiv.),
-78 oC to -25 oC, THF;
(ii) NH4Cl – to quench
O
4
TIPS (1.5
(i) Li
equiv.),
75
TIPS
OTMS
≤ 98b
CuI (1.65 equiv.), TMSI (1.5 equiv.),
-78 oC to -25 oC, THF;
76
TIPS
(ii) Et3N – to quench
O
5
TIPS (1.5
(i) Li
equiv.),
CuI (1.65 equiv.), TMSI (1.5 equiv.),
O
no
-78 oC to -25 oC, THF;
(ii) NH4Cl/NH3-buffer – to quench
O
6
O
(i) Li
TIPS (1.5
equiv.),
CuI (1.65 equiv.), TMSI (1.5 equiv.),
o
o
-78 C to -25 C, THF;
(ii) Et3N – to quench
100
no
Table 16 − continued
Entry
Starting
Reaction conditions
Product
material
O
7
O
Yield
(%)
(i) Li
TIPS (1.5
equiv.),
CuI (1.65 equiv.), TMSI (1.5 equiv.),
no
-78 oC to -25 oC, Et2O;
(ii) Et3N – to quench
a
Tributylsilyloxyfuran was formed as the major product and was isolated by chromatography (≥ 22% yield).
isolated product contained impurity.
b
The
At this point we examined addition of copper acetylides in the presence of
iodotrimethylsilane to cyclopentenone as a model substrate (entries 3, 4, Table 16). When the
reaction was quenched with buffered ammonium chloride (entry 3, Table 16), 3(triisopropylsilylalkynyl)cyclopentanone was isolated as a major product contaminated with
inseparable byproduct. The characteristic peaks of the product were consistent with data reported
in literature.198a A different work up procedure, quench of the reaction mixture by addition of
triethylamine at low temperature (entry 4, Table 16), allowed isolation of the corresponding
TMS enol ether in high yield (still contaminated with the byproduct). Any attempt to purify
product 76 by distillation or column chromatography lead to the loss of the trimethylsilyl group
with formation of ketone 75.
After successful alkynylation of cyclopentenone with trimethylsilylalkynyl cuprate we
proceeded with butenolide as a substrate. We tested different work up procedures (entries 5 and
6) and examined both THF and ether as solvents (entries 6 and 7), but none of the desired
product was formed.
We concluded that difficulty in alkynylation of butenolide is associated with its
heterocyclic nature and high acidity of γ-proton. In case of the reactions with
iodotrimethylsilane, ring-opening of lactone can be involved as similar transformations are
known for butyrolactone.202
Consequently, we focused our attempts on conjugate addition of an alkenyl moiety which
can serve as a prerequisite for the generation of terminal alkyne.
101
Conjugate addition of vinylcuprates to butenolide. Though there are many known
examples of conjugate addition to γ-substituted butenolides,203,204 addition to the parent,
unsubstituted butenolide is harder to accomplish due to the ease of deprotonation to form
alkoxyfuran as we discussed above (entry 2, Table 16). Nonetheless, we found examples of 1,4addition to unsubstituted or α-substituted butenolides. The first report involves addition of
lithium di-2-trans-butenylcuprate to butenolide,205 but only limited experimental detail was
provided. Another example demonstrates conjugate addition of 2-propenylmagnesium bromide
in the presence of catalytic CuBr·SMe2 complex.206
We tried to apply the latter procedure to butenolide, as well as slightly modified
conditions. However, we obtained only poor yields of the desired product 77 (entry 1, 2, 3, Table
17).
Then we attempted to use vinyllithiums for the generation of cuprates.204 In entry 4 we
prepared vinyllithium from transmetallation of tetravinylstannane. Upon addition to butenolide
we obtained the product with the yield even lower than in previous cases (entry 4, Table 17).
However, when we tried addition of propenyllithium produced by halogen-metal
exchange between 2-bromopropene and n-butyllithium (the same method is used in all of the
following examples), the yield of 1,4-addition increased to 32% (entry 5, Table 17). Use of
tetrahydrofuran instead of ether was detrimental for the reaction (entries 5 and 6, Table 17). The
increase of the load of the cuprate – from 1.2 equivalents to 2 equivalents – provided the product
with almost 47% yield after bulb to bulb distillation (entry 7, Table 17).
Table 17. Conjugate addition of vinylcuprates to butenolide
O
O
M
CuX +
O
R
O
37
Entry
77 : R = CH3
78 : R = H
R
Conditions
1
MgBr
(i)
+
(1.5 equiv.)
Yield, %
CuBr SMe2
(20 mol%),
THF, -40 oC (20 min);
(ii) addition of furanone, -78 oC (25 min)
102
20%
Table 17 − continued
Entry
Conditions
2
MgBr
(i)
+
CuBr SMe2
(20 mol%),
(3 equiv.)
Yield, %
THF, -20 oC (20 min);
13%
(ii) addition of furanone, -20 oC (1 h)
3
+
MgBr
(i)
(2.2 equiv.)
CuI SMe2
(1 equiv.) ,
THF, -40 oC (5 min), -78 oC (15 min);
25%
(ii) addition of furanone, -78 oC (1 h)
4
Sn
+
4
n-BuLi
(i) (2 equiv.)
+
CuI
(1 equiv.) ,
(4 equiv.)
Et2O, -20 oC (20 min);
<13%
(ii) addition of furanone, -78 oC (1 h)
5
Li
(i)
+
(2.4 equiv.)
CuI
(1.2 equiv.),
Et2O, -20 oC (20 min);
32%
(ii) addition of furanone, -78 oC (1 h); + NH4Cl(aq.)
6
Li
(i)
+
CuI
(1 equiv.),
(2 equiv.)
THF, -78 oC (2.5 h), -40 oC (20 min);
0%
(ii) addition of furanone, -78 oC (1 h) to rt; + NH4Cl(aq.)
7
Li
(i)
(4 equiv.)
+
CuI
(2 equiv.),
Et2O, -25 oC (0.5 h);
47%
(ii) addition of furanone, -78 oC (1 h); + NH4Cl(aq.)
We have noticed that at the stage of cuprate formation the reaction mixture never
becomes homogeneous (enries 5-7, Table 17), though the dark green color of the slurry indicates
the formation of cuprate. This stage of the procedure thus became the target for further
optimization (Table 18).
First we tried to decrease the time from 30 to 15 min while producing cuprate at -30 oC.
In this way we obtained 59% yield for 0.5 g scale and 42% yield for 1 g scale reactions (entries
3, 4 vs. 1).
103
Then, we reduced the temperature of the step to -45 oC. That allowed formation of a clear
green solution of cuprate on 40 mg scale reaction. On bigger scale with 0.9 g load of starting
material the desired product was formed in 59% yield, though the reaction mixture stayed as a
slurry (entry 5, Table 18).
While trying to scale up the reaction we faced difficulty with the reproducibility of the
yields. This was attributed to inefficient stirring of the slurry and was addressed by using an
overhead mechanical stirrer instead of stirring plates (entries 5 and 6, Table 18).
Table 18. Further optimization of the conjugate addition step and scaling up
O
O
CuI
+
Li
O
O
37
Entry
Conditions
Li
1
77
(i)
+
Yield, %
0.6
47%
1.5
34%
0.5
59%
1
42%
0.9
54%
CuI
(2 equiv.),
(4 equiv.)
Scale, g
Et2O, -25 oC (0.5 h);
(ii) addition of furanone, -78 oC (1 h); + NH4Cl(aq.)
Li
2
(i)
+
CuI
(2 equiv.),
(4 equiv.)
Et2O, -30 oC (0.5 h);
(ii) addition of furanone, -78 oC (1 h ) to rt; + NH4Cl(aq.)
Li
3
(i)
+
CuI
(2 equiv.),
(4 equiv.)
Et2O, -30 oC (15 min);
(ii) addition of furanone, -78 oC (1 h); + NH4Cl(aq.)
Li
4
(i)
+
CuI
(2 equiv.),
(4 equiv.)
Et2O, -30 oC (15 min);
(ii) addition of furanone, -78 oC (1 h); + NH4Cl(aq.)
Li
5
a
(i)
(4 equiv.)
+
CuI
(2 equiv.),
Et2O, -45 oC (20 min);
(ii) addition of furanone, -78 oC (1 h); + NH4Cl(aq.)
104
Table 18 − continued
Entry
Conditions
Li
a
6
(i)
+
(3.4 equiv.)
Scale, g
Yield, %
1.5
61%
CuI
(1.7 equiv.),
Et2O, -45 oC (45 min);
(ii) addition of furanone, -78 oC (1 h); + NH4Cl(aq.)
a
mechanical stirrer was used to ensure reproducibility
After a few more minor modifications of the method we managed to prepare the desired
product 77 in 61% yield after distillation on 1.5 g scale with the slightly reduced load of cuprate
(entry 6, Table 18).
II.2.2 Stereoselective alkylations of butyrolactone 77
Installation of the first stereogenic center at the β-position of butyrolactone by addition of
the 2-propenyl moiety provided starting material 77 for the following alkylations and ensures
diastereocontrol in the system.
According to our synthetic approach to basiliolide B, the construction of the quaternary
center at C8 will be guided by stereochemical information at C9 of the butyrolactone. From this
perspective, a 2-propenyl group is an excellent choice of substituent. Due to its bulkiness,
propenyl hinders the β-face of the ring and efficiently directs alkylation to furnish the products
with trans-geometry.205 It is worth noting that even in case of γ-substituted butyrolactones an
electrophilic attack on the enolates is controlled exclusively by the β-substituent.207,208
Firstly, we attempted alkylation of butyrolactone 77 employing the following procedure:
20 mg of butyrolactone solution in THF was added dropwise to an LDA solution at low
temperature. Upon stirring for 1 hour to form the enolate, an excess of iodide 79 with HMPA as
a solution in THF was added. The reaction was kept at -78 oC, followed by 0 oC and eventually
105
warmed to room temperature. The alkylated product was isolated in 53% yield (entry 1, Table
19).
Table 19. Alkylation of butyrolactone 77
79
O
I
entry
O
OTBS
O
O
77
80
Conditions
OTBS
scale, mg
yield, %
20 mg
53%
400 mg
54%
30 mg
34%
30 mg
68%
645 mg
77%
1g
80%
(i) LDA (1.05 equiv.), THF, -78 oC (1 h);
1
(ii) iodide 79 (3 equiv.), HMPA (3 equiv.),
-78 oC (5 h), 0 oC (4.5 h), 0 oC to r.t. (over 16 h)
(i) LDA (1.05 equiv.), THF, -78 oC (2 h);
2
(ii) iodide 79 (2.5 equiv.), HMPA (5 equiv.),
-78 oC (2 h), 0 oC to r.t. (over 16 h)
(i) LDA (1.2 equiv.), Et2O, -78 oC (1.5 h);
3
(ii) iodide 79 (3 equiv.), HMPA (5 equiv.),
-78 oC (6 h), 0 oC to r.t. (over 14 h)
(i) LDA (1.2 equiv.), THF, -78 oC (0.5 h);
4
ZnMe2 (1.2 equiv.), -78 oC (1 h);
(ii) iodide 79 (3 equiv.), HMPA (5 equiv.), -78 oC (1.5 h)
(i) LDA (1.2 equiv.), THF, -78 oC (1 h);
5
ZnMe2 (1.2 equiv.), -78 oC (1 h);
(ii) iodide 79 (2.5 equiv.), HMPA (5 equiv.), -78 oC (3 h)
(i) LDA (1.2 equiv.), THF, -78 oC (1 h);
6
ZnMe2 (1.2 equiv.), -78 oC (1 h);
(ii) iodide 79 (3 equiv.), HMPA (5 equiv.), -78 oC (4 h)
106
Then, we tested the described procedure starting with 400 mg of the starting material
(entry 2, Table 19). The product was formed with the same yield. Together with desired transmonoalkylated lactone 80 (54% yield), dialkylated and cis-monoalkylated butyrolactones were
isolated with 3.6% and 4% yield correspondently (entry 2, Table 19). Formation of the latter
compounds can be attributed to α-proton exchange between enolates and lactones.209
Use of ether as a solvent for alkylation (entry 3, Table 19) did not help; instead, the yield
of 80 dropped to 34%. The explanation of the result can be a lower solubility of the enolate:
formation of the precipitate was observed upon addition of lactone to LDA solution in ether.
Noyori210 demonstrated that the use of dimethyl- or diethylzinc as an additive for enolate
alkylations effectively suppresses proton exchange and highly favors monoalkylation. This
approach proved to be efficient for monoalkylation of cyclopentanes and even fulvene-type
enolates of 4-alkylidenecyclopentenones.211 The monoalkylated product was formed with
excellent diastereoselectivity providing more than 99 to 1 ratio versus dialkylated product.
This convenient procedure earlier proved to be an indispensable tool for the synthesis of
(+)-dihydro-epi-deoxyarteannuin B.212
When the described method was applied to our system it furnished alkylated product 80
with significantly improved efficiency (68% yield, entry 4, Table 19). The reaction mixture was
quenched at low temperature upon stirring for an hour and a half after addition of the iodide. We
increased the time for alkylation to three hours, and the product was isolated in 77% yield (entry
5, Table 19). The increase of time for alkylation to four hours did not significantly change the
efficiency of the reaction (entry 6, Table 19).
Methylation. The methylation of lactone 80 was explored. The reaction involving slight
excess of LDA (1.1 equivalent) in the presence of HMPA with THF as a solvent (entry 1, Table
20) provides product 81 in 71% yield (estimated by 1H-NMR) as an inseparable mixture with the
starting material (14% of recovery). When two equivalents of LDA were employed, the
methylated product was formed in almost quantitative yield (entry 2, Table 20).
107
Table 20. Stereoselective methylation of 80
O
O
OTBS
O
O
80
entry
1
OTBS
81
Conditions
scale,
yield,
mg (g)
%
70 mg
71%
1g
97%
(i) LDA (1.1 equiv.), THF, -78 oC (1 h 20 min), 0 oC (0.5 h);
(ii) MeI (5 equiv.), HMPA (5 equiv.),
-78 oC (1.5 h), -78 oC to r. t. (over 16 h)
2
(i) LDA (2 equiv.), THF, -78 oC (0.5 h), 0 oC (0.5 h);
(ii) MeI (5 equiv.), HMPA (5 equiv.),
-78 oC (5 h), -78 oC to r. t. (over 16 h)
This observation is consistent with the studies reported over the past decade by Collum’s
group on aggregation of lithium reagents213 including lithium dialkylamides.214,215 LDA exists
predominantly as a dimer in THF solution. Addition of HMPA does not cause deaggregation as it
was believed before, but leads to the substitution of THF ligands on lithium with molecules of
HMPA.215 Further research revealed that metalation/enolization of the esters in the presence of
LDA proceeds in “an aggregate-based pathway”.215 Though the sequence of equilibria that
transform the observable disolvated lithium dialkylamide dimer to the rate-limiting transition
structure is complicated, the supposedly active species involved in metallation, so called
“putative triple ions,” still require two molecules of LDA to form.213,215 These two molecules of
LDA perform, in effect, separate functions. The 1st equivalent generates the enolate and the
second forms heterodimeric complex with the enolate.
Thus, the presence of at least 2 equivalents of LDA while generating enolate can be
crucial for complete formation of the enolate at a reasonable rate.
108
In conclusion, one of two quaternary centers at C8 of the target natural product was
successfully installed by sequential alkylations with high diastereoselectivity controlled by a 2propenyl substituent at the β-carbon of the γ-furanone.
II.2.3 Generation of terminal alkyne
The next synthetic challenge in the proposed synthesis of basiliolide B is to install the
terminal alkyne functionality in the system (82), which will be further functionalized by
Sonogashira coupling into alkynenoate 83.
OR
O
OR
O
OR
O
8
O
O
O
9
CO2R
36
83
82
Scheme 91
Methyl ketone is a versatile building block that can be transformed into a number of
functional groups. Thus, the propenyl moiety of compound 81 was oxidized into methylketone in
84 by ozonolysis in almost quantitative yield, employing triphenylphosphine to reduce an
intermediate ozonide (Scheme 92). It is worth noting that a vigorous stirring of the reaction
mixture upon addition of PPh3 powder was necessary to obtain a high yield of product.
O
OTBS
O
O3, CH2Cl2, -78 oC;
PPh3, -78 oC to r.t. (2 h),
r. t. (16 h)
98%
O
OTBS
O
O
84
81
Scheme 92
109
With ketone 84 available we envisioned an enol ester of 85 as a potential intermediate on
the way to alkyne. For instance, phosphate enol esters are known to undergo β-elimination in the
presence of hard base like lithium diisopropylamide (Scheme 93).216
O
O
OTBS
O
O
85
O
LDA (2 equiv.)
THF
P
EtO
OTBS
O
82
OEt
Scheme 93
This transformation is commonly used by the synthetic community to elaborate terminal
(and even internal) alkynes.217,218 The reaction requires at least two equivalents of the base: one
equivalent is needed for phosphate elimination, while another equivalent is consumed by
deprotonation of the formed alkyne to give acetylide, which gets protonated upon aqueous work
up.
The lactone functionality present in the starting material 85 can significantly complicate
the reaction as it is a potential target for nucleophilic attack by intermediate acetylide. The
quaternary center at α-carbon may serve to our advantage by hindering the lactone and
decreasing the reaction rate of 1,2-addition of acetylide. The use of milder bases can also be a
potential solution.
Phosphate enol esters as precursors for alkynes. Phosphate 85 can be generated from
ketone 84 by quenching the “kinetic” enolate with diethyl chlorophosphate in ≤54% yield (entry
1, Table 21). The phosphate was usually contaminated with a minor inseparable unidentified
impurity and was involved in the next step as it is.
We were concerned about the use of LDA in this reaction, which generates a terminal
alkyne. Specifically, metallation of the terminal alkyne could lead to competing, undesired
reactions of the resulting acetylide anion. Therefore, we took precautions aimed at minimizing
such processes.
Generated phosphate 85 was treated with LDA (6 equivalents) in a dilute (0.05 M) THF
solution (entry 1, Table 21). We expected that low concentration of the starting material together
with six-fold access of LDA will kinetically favor phosphate elimination over the intramolecular
110
addition of acetylide to furanone leading to self-annihilation of the material. The desired alkyne
was produced in 56-60% yield on 25 mg scale, or in 30% combined yield from ketone 84.
Table 21. Generation of alkyne 82 via phosphate enol ester functionality
O
O
O
OTBS
OTBS
OTBS
O
O
O
OPO(OEt)2
O
84
82
85
entry
Conditions of the first step/stage
yield, %
Conditions of the second
yield, %
overall
(scale, mg)
step/stage
(scale,
yield,
mg)
%
(scale,
mg)
1. (i) LDA (1.3 equiv.), THF,
2. 0.05 M in THF,
o
LDA (6 equiv.), -78 oC (45
56–60%
30–
min)
(25 mg)
32%
a) (i)LDA (1.2 equiv.) THF, -78 oC, 1 h;
b) 0.05 M in THF, LDA (6 equiv.), -78
24–
(ii) ClPO(OEt)2 (1.5 equiv.),
o
26%
54%
-78 C, 1-1.5 h;
1
(150 mg)
(ii) ClPO(OEt)2 (1.5 equiv.),
-78 oC (4.5 h), -78 oC to rt (over 16 h)
2
C (1 h)
-78 oC (1 h), -78 oC to rt (over 16 h)
(40
mg)
O
O
O
OTBS
OTBS
O
OPO(OEt)2
O
84
-78 oC, 1-1.5 h;
TMS
2. 0.1 M in THF,
50%
(ii) ClPO(OEt)2 (1.2 equiv.),
o
86
85
1. (i) LDA (1.3 equiv.), THF,
3
OTBS
O
O
(50 mg)
o
LDA (3 equiv.),
TMSCl (5 eqiuv.), THF,
o
-78 C (2 h), -78 C to r.t. (over 16 h)
-78 C (2 h)
111
61%
(36 mg)
30%
Table 21 − continued
entry
Conditions of the first step/stage
yield, %
Conditions of the second
yield, %
overall
(scale, mg)
step/stage
(scale,
yield,
mg)
%
(scale,
mg)
a) (i) LDA (1.4 equiv.), THF, -78 oC (1 h)
4
b) 0.06 M in THF,
o
(ii) ClPO(OEt)2 (1.5 equiv.), -78 C (1.5 h),
LDA (3 equiv.), TMSCl (5 equiv.), -78
o
o
-78 C to r.t. (over 16 h)
C (2 h)
50%
(40
mg)
5
a) (i) LDA (1.05 equiv.), THF, -78 oC (1 h)
b) 0.1 M in THF,
(ii) ClPO(OEt)2 (1.25 equiv.),
LDA (3 equiv.), TMSCl (5 equiv.),
o
o
o
-78 C (2.5 h), -78 C to r.t. (over 16 h)
-78 C (2 h)
10%
(100
mg)
O
O
OTBS
OTBS
O
O
O
84
6.
OPO(OEt)2
85
(i) LDA (1.05 equiv.), THF
-78 oC (1 h);
(ii) ClPO(OEt)2, -78 oC (2.5 h),
24%
(400 mg)
o
-78 C to r.t.
Further, we attempted to perform two-step transformation represented in entry 1 of 22 as
“one-pot” reaction (entry 2, Table 21) by transferring the prepared phosphate solution to LDA
solution via cannula. This procedure provided product 82 in only 24-26% yield.
As we mentioned above, the low efficiency of alkyne generation can be attributed to selfannihilation of the material. We tried to solve the problem by in situ quench of reactive acetylide
with chlorotrimethylsilane (TMSCl) by transferring the phosphate into the solution containing
both LDA, needed for the elimination, and an excess amount of TMSCl to protect acetylide. It is
112
important to mention that TMSCl can react with LDA; still, we hoped that by using excess
amounts of the reagents we will be able to approach the product. Thus, protected alkyne 86 was
produced in 61% with 36 mg –load of the starting material, or 30% combined yield from ketone
84 (entry 3, Table 21).
The yields of the two-steps transformation presented in entry 1 and in entry 2 are
basically the same (Table 21); however TMS-acetylene derivative 86 requires the subsequent
deprotection step. The TMS-group was removed in methanol solution in the presence of
potassium carbonate to give acetylene in a 70% yield (Scheme 94).
O
O
OTBS
OTBS
O
K2CO3, MeOH
O
r.t. (3 h)
70%
86
82
TMS
Scheme 94
We were not satisfied with a low overall efficiency of the latter method modification
(entry 3, Table 21). We attempted to combine the two-steps sequence into “one pot” procedure –
entry 4, Table 21. Interestingly, the obtained yield increased to 50% when 40 mg of the starting
material was used.
However, our attempts to scale up the latter modification failed. So, when reaction was
attempted with 100 mg load of the starting material, the product was formed in only 10% yield
(entry 5, Table 21).
It turned out that even scaling up the phosphate forming step to 400 mg of starting
material lead to the dramatic loss in efficiency – 24% yield of isolated product (entry 6, Table
21).
A different approach was needed to convert methylketone 84 into terminal alkyne in the
presence of lactone ring.
One way to avoid the formation of the acetylide species while forming alkyne is to use
mild base, which would not affect the terminal acetylene. Phosphate 85 was treated by DBU with
heating to 35 oC or 100 oC (Scheme 95) However, no product was observed in either of two
reactions, the starting material remained unchanged.
113
O
O
OTBS
DBU (2 equiv.)
O
OTBS
O
OPO(OEt)2
82
85
CH2Cl2, 35 oC (3 h)
0%
Tol, 100 oC (4 h)
0%
Scheme 95
Though phosphate could not be eliminated in the presence of mild base DBU, the better
leaving group such as triflate might be suitable for these conditions.
Enol triflates as precursors for alkynes. Methods involving enol triflates in generation
of terminal219 or internal alkynes220 by triflate elimination in the presence of base, usually LDA,
are also well-described and widely used in the synthesis. Mindful of these examples we hoped
that, in contrast to phosphate 85, exposure of the enol triflate derivative of 84 to mild base like
DBU may provide access to the desired alkyne.
As presented in Table 22, we tested both Comins’ reagent221 and N-phenylbis(trifluoromethanesulfonimide)222 to form enol triflate 87 (which turned out not be very stable
for storage). When ketone 84 was treated with KHMDS solution first, followed by addition of
Comins’ reagent, (N-(5-chloro-2-pyridyl)-triflimide), the product was formed in 64% yield
(entry 1, Table 22). We also attempted addition of KHMDS solution to the reaction mixture
containing ketone 84 and Comins’ reagent, this procedure afforded enol triflate 87 in 45% yield
together with the recovered starting material (50%). When the enolate produced by exposure of
ketone
84
to
KHMDS
solution
in
THF
was
treated
with
N-phenyl-
bis(trifluoromethanesulfonimide) the product 87 was produced in a high yield (84%, entry 3,
Table 22). Gratifyingly, the scaling up of the latter procedure to 1 gram and more did not affect
the yield (entry 4, Table 22). Thus, the desired enol triflate can be produced with high efficiency
on multigram scale.
114
Table 22. Generation of triflate enol ester 87
O
O
OTBS
OTBS
O
O
OTf
O
87
84
entry
Conditions
scale, mg (g)
yield, %
30 mg
64%
30 mg
45%
(i) KHMDS (1.2 equiv.), -78 oC (1 h), THF;
1
(ii) Comins’ reagent (1.2 equiv.), -78 oC (2 h),
-25 oC to -15 oC (over 3 h)
(i) Comins’ reagent (1.25 equiv.), KHMDS (1.25 equiv.),
2
THF, -78 oC (2 h), -78 oC to -15 oC
(90% brsm)a
3
(i) KHMDS (1.2 equiv.), -78 oC (1 h), THF;
100 mg
84%
1 g − 1.1 g
79 − 81%
(ii) PhNTf2 (1.3 equiv.), -78 oC (1 h), -25 oC (0.5 h)
4
(i) KHMDS (1.2 equiv.), -78 oC (1 h), THF;
(ii) PhNTf2 (1.3 equiv.), -78 oC (2 h), -25 oC (0.5 h)
a
90% yield of product based on recovery of starting material
With the convenient method to produce enol triflate 87 in hand, we searched the
literature specifically for the examples of triflate elimination in the presence of mild bases. There
was a highly encouraging report on alkyne generation by treatment of enol triflate with DBU
solution at elevated temperature (60 oC) which tolerated an epoxide moiety present in the
molecule.223
115
Table 23. Generation of terminal alkyne 82 from enol triflate 87
O
O
OTBS
O
DBU
OTBS
O
OTf
87
82
entry
Conditions
scale, mg (g)
yield, %
1.
DBU (1.4 equiv.), THF, 60 oC (14 h)
120 mg
78%a
2.
DBU (1.5 equiv.), THF, 45 oC (6 h)
2.5 g
76%
3.
DBU (1.5 equiv.), THF, 45 oC (12 h)
1.1
91%
a
TBS-deprotected product was isolated in 6% yield
Thus, upon heating to 60 oC the solution of triflate 87 and DBU in THF for fourteen
hours, the desired alkyne 82 was formed in 78% yield together with minor amounts of alcohol
(6% yield), resulting from TBS-deprotection of 82. When the reaction was performed on 2.5
gram scale with heating to 45 oC for six hours, the product was isolated in 76% yield (entry 2,
Table 23). Heating 1.1 gram of the starting material together with DBU (freshly distilled) to 45
o
C for twelve hours produced 82 in 91% yield (entry 3, Table 23), and no TBS-deprotection was
observed.
In conclusion, phosphate enol ester 85, formed from ketone 84 with modest efficiency,
can be converted into the desired alkyne 82 only in moderate yields. On the other hand, enol
triflate 87 is a far superior intermediate in the synthesis of terminal alkyne 82. Compound 87 can
be easily generated from 84 and in the presence of DBU smoothly transformed into alkyne 82
with high efficiency.
116
II.2.4 Synthesis of the lactone intermediates 91, 96 and lactol intermediates 102,
103 and their Diels-Alder cycloaddition reactions
Generated alkyne 82 provides access to the corresponding alkynenoate species for
iodocyclization, which furnishes iodo-α-pyrones as a starting material for Diels-Alder
cycloaddition.
Upon heating to 50 oC in triethylamine for three and a half hours in the presence of one
equivalent of methyl (Z)-3-iodoprop-2-enoate (60),224 alkyne 82 undergoes Sonogashira coupling
to furnish alkenynoate 88 in 82% yield (Scheme 96). TBS-deprotection of 88 gives alcohol 89 in
88% yield upon treatment with the mixture of acetic acid, water and THF225 (3:1:1) at room
temperature (Scheme 29).
60
O
OTBS
O
I
CO2Me
(1.1 equiv.)
OTBS
O
O
cat. PdCl2(PPh3)2,
cat. CuI, Et3N,
50 oC (3.5 h)
CO2Me
82
2.
O
CO2Me
Ph3P
62
PhCH3, 35 oC (25 h)
CO2Et
O
CO2Et
90
O
OH
O
CO2Me
88%
89
88
82%
1. (COCl)2, DMSO,
CH2Cl2, -78 oC;
Et3N, -78 oC to rt
0.1 M,
AcOH:H2O:THF
(3:1:1)
ICl (1.1 equiv.)
-25 oC (2.5 h)
-25 oC to 10 oC
(over 3.5 h)
85%
CO2Et
O
CO2Et
O
O
O
I
+
I
O
O
91
O
O
92
(36 : 64)
93%
Scheme 96
Swern oxidation of 89 provides crude aldehyde in almost quantitative yield. Without
further purification, the aldehyde was involved in subsequent olefination with commercially
available (carbethoxyethylidene)triphenylphosphorane (62) to provide the olefinated product 90
in 93% yield. Though the natural product bears methyl ester functionality, we employed
(carbethoxyethylidene)triphenylphosphorane first due to its availability.
When alkynenoate 90 was exposed to iodine monochloride solution in methylene
chloride at -25 oC followed by warming up to 10 oC the mixture of products was produced with
117
~65% yield. Surprisingly, 5-iodopyrone 91 was formed only as a minor constituent in the
mixture with iodobutenolide 92 with the ratio of 36 : 64 (Scheme 96).
The observed change in regioselectivity (see Chapter II.1 on model studies for
comparison with other systems) can be associated with the electronic effect due to the presence
of the lactone moiety. Thus, the closer to the alkyne the lactone functionality (or any other
electronegative group) is located, the more polarized the triple bond will be and the stronger
preference for exo-cyclization will be demonstrated. Consequently, a less electronegative group
next or close to the alkyne should increase the content of 5-iodopyrone in the reaction mixture.
This hypothesis is now supported by additional data, as discussed on the following pages.
With 91 in hand we can test one more variation on the key IMPDA reaction. Heating 91
in toluene provided complete conversion to a single product identified as cycloadduct 93
(Scheme 97) by nOe studies and by analogy to data gathered in support of cycloadducts prepared
during our earlier model studies. Although the amount of starting material (ca. 3 mg of 91)
employed for this experiment was insufficient for a quantitative conclusion as to the yield of the
reaction, qualitatively the reaction appears to be clean and efficient (1.5 mg of 93 isolated as the
sole identifiable reaction product).
O
CO2Et
O
H
o
O
100 C, 23.5 h,
PhCH3
I
O
O
91
(3 mg)
93
(1.5 mg)
O
9
4
O
O
10
I
O
O
8
EtO2C
5
CO2Me
O
19
O
OCH3
basiliolide B
Scheme 97
The key cycloaddition assembles the bridged decalin framework of the natural product
and introduces four new stereogenic centers stereospecifically. The six stereocenters in structure
93 are analogous to the six stereogenic centers present in the natural product (at C3, C4, C5, C8,
C9 and C10, Scheme 97). However, bridged lactone 93 presents an ethyl ester where the natural
product incorporates a methyl ester. With the viability of the key IMPDA reaction established on
small scale, we then embarked on the synthesis of the corresponding methyl ester by the most
efficient route possible.
118
The efficiency of iodocyclization, which was low in the case of alkynenoate 90 (in the
range of 20−30%, Scheme 96), dropped even lower (to 9% yield of 5-iodopyrone product) in
case of alkynenoate 95 (Scheme 98). Alkynenoate 95 can be synthesized from alcohol 89
following our previously described two-step procedure.
O
OH
O
CO2Me
89
1. (COCl)2, DMSO,
CH2Cl2, -78 oC;
Et3N, -78 oC to rt
2.
ICl (1.1 equiv.),
r.t. (4.5 h), CH2Cl2
O
CO2Me
CO2Me
Ph3P
94
PhCH3, 40 oC (30 h)
CO2Me
O
CO2Me
O
9%
O
I
O
96
95
O
74%
Scheme 98
Taking into account the poor yield of the iodocyclization (Scheme 96 and 98) in our
attempt to generate 5-iodopyrone 96, we switched to the longer, but overall more efficient
synthetic pathway (Scheme 99). As the electronegative lactone group is problematic for the
electrophile-induced iodocyclization reaction, reduction and protection of the lactone as a lactol
acetal may result in a substrate that provides a higher yield of the desired iodocyclization.
Lactone 82 can be easily reduced by DIBAL at low temperature to produce the mixture
of diastereomeric lactols 97 in almost quantitative yield (Scheme 99). After screening a number
of conditions for methyl lactol formation we found that methyl orthoformate solution in
methylene chloride in the presence of pyridinium p-toluenesulfonate converts mixture of lactols
97 into protected epimeric lactols 98 in 92% yield. Further, the mixture of formed epimers was
taken through the number of synthetic steps.
119
O
O
OTBS
O
99%
82
TBAF (2.4 equiv.)
THF, 0 oC (6 h)
OH
DIBAL (2 equiv.),
0.1 M in PhCH3,
-78 oC (0.5 h)
OTBS
OH
O
2.
85%
60
I
CO2Me
(1.1 equiv.)
O
CO2Me
Ph3P
99
98
CO2Me
OMe
1. Swern oxid'n
OTBS
O
92%
97
OMe
OMe
(MeO)3CH,
PPTS (10-mol%),
CH2Cl2, r.t. (3 h)
OMe
O
cat. PdCl2(PPh3)2,
cat. CuI, Et3N,
35 oC (1.5 h)
100
94
PhCH3, 35 oC (10 h)
CO2Me
CO2Me
101
91%
89%
Scheme 99
For TBS-deprotection to form alcohol 99 we switched from the acidic conditions used
earlier (AcOH:H2O:THF (3:1:1)) to TBAF solution in THF to avoid hydrolysis of the methyl
acetal functionality. Alcohol 99 was obtained in 85% yield as a mixture of diastereomers.
Following the routine procedure of Swern oxidation followed by Wittig olefination, α,βunsaturated esters 100 were obtained in 89% yield. Sonogashira coupling of terminal alkyne of
100 furnished alkynenoates 101 with high efficiency (Scheme 99).
Obtained alkynenoates 101 were treated with iodine monochloride at 0 oC for seven
hours (Scheme 100).
OMe
CO2Me
ICl (1.1 equiv.)
O
O
CH2Cl2, 0 oC (7 h)
CO2Me
101
CO2Me
OMe
62%
O
I
O
102
Scheme 100
In agreement with our hypothesis, the less electronegative lactol substituent at acetylene
(versus lactone in 90, Scheme 96) favors endo-cyclization. 5-Iodopyrones 102 were formed as
major products in 62% yield. Minor amounts of butenolide byproducts were observed by proton
NMR of the crude mixture.
120
O
60% AcOH
I
O
cat. H2SO4,
60 oC (5 h)
O
CO2Me
OH
CO2Me
OMe
102
I
(COCl)2, DMSO,
CH2Cl2, -78 oC;
Et3N, -78 oC to rt
87%
O
O
I
O
103
73%
CO2Me
O
O
O
96
O
Scheme 101
Deprotection of lactol acetal 102 was performed in aqueous acetic acid with a catalytic
amount of sulfuric acid (Scheme 101). Swern oxidation of lactol 103 provides the desired 5iodopyrone in 87% yield. Though the new pathway involves 9 steps from 82 to pyrone 96, it
brings the material with better efficiency (25% overall yield for 82 → 96).
Following the new route we prepared 24 mg of lactone 96 to examine Diels-Alder
cycloaddition (Scheme 102).
O
CO2Me
O
o
O
100 C, 26 h,
PhCH3
I
O
MeO2C
I
79%
O
O
bridged lactone
O
96
(24 mg)
O
104
(19 mg)
butyrolactone
moiety
Scheme 102
Cycloaddition of 96 proved to be highly efficient, providing a single product 104 with
the the yield of 79%. The structure was identified by nOe studies and by analogy to data
collected for the cycloadduct 93.
Both examples of IMPDA cycloadditions (Schemes 97 and 102) described above
demonstrate a dramatic enhancement of the reaction rate and efficiency by the presence of
substituted butyrolactone tether, which lowers the entropic barrier of the reaction. In contrast, the
reactivity of our model system 64 lacking any substitution at four-methylene tether was
significantly lower (39% yield over 3 days at 100 oC, Scheme 84).
In summary, we generated cycloadduct 104 bearing methyl ester functionality and
butyrolactone tether. The structure contains six stereogenic centers in analogy with the natural
121
product. The next synthetic goal would be to elaborate an oxepin ring. In case of compound 104,
it would be problematic to distinguish between two lactones moieties present in the system.
Therefore, the alternative system was necessary.
At this point two potential IMPDA substrates looked most attractive as alternatives to 96
en route to basiliolide B: the first in which lactone is replaced by a protected lactol (102 or 103,
Scheme 103) and the other (34) in which the C8 quaternary center has been fully elaborated.
CO2Me
O
O
CO2Me
OR
PO
O
I
O
O
O
O
I
96
102 : R = Me
103 : R = H
CO2Me
8
I
9
O
O
34
P - protecting group
Scheme 103
Intramolecular pyrone Diels-Alder reaction of protected lactol. Out of the two new
IMPDA substrate choices, the lactol was explored first because it was already in hand (see
Scheme 100).
Protected lactol 105 was heated in toluene at 100 oC in a sealed tube (Scheme 104). After
two days, an aliquot for 1H-NMR analysis was taken. Together with formation of the product
105 (corresponding peaks in the 1H-NMR spectrum were tentatively assigned based on the
spectra previously obtained for lactone 104), we observed formation of new byproducts, whose
characteristic peaks in 1H-NMR spectrum were analogous with the NMR data for the earlier
observed products of CO2-elimination in the model systems.
122
O
OMe
Me
CO2Me
O
MeO2C
o
I
100 C, Tol
O
I
O
O
O
Me
MeO
102
105
Prd : St.m. : Bpr1 : Bpr2
48 h:
0.42 : 0.30 : 0.10 : 0.18
Scheme 104
The reaction mixture presumably contains four major components (Scheme 104)
including starting material. Unfortunately all our attempts to separate cycloadduct 105 from the
byproducts by silica gel chromatography failed.
Then, we attempted to perform the Diels-Alder reaction on deprotected lactols 103
(Scheme 105), allowing the epimers of 103 to equilibrate at elevated temperature. In this way if
one epimer can adopt a lower energy conformation and undergo cycloaddition with the higher
reaction rate (via a lower energy transition state), then equilibration of the epimers will result in a
faster conversion of all starting material (103) into the cycloadduct (107).
O
O
OH
o
100 C, Tol
I
Me
Me
O
MeO2C
CO2Me
O
Ph3P CH2
I
O
Me
HO
103
O
14 h:
26 h:
MeO2C
X
I
Me
O
106
O
OH
107
Prd : St.m. : Bpr1 : Bpr2
0.48 : 0.45 : 0.07
0.51 : 0.13 : 0.13 : 0.23
Scheme 105
Indeed, more than 50% conversion of the starting material was observed already after
heating the reaction mixture for 14 hours (Scheme 105). However, increasing the time of the
reaction did not increase the content of the desired product. Instead, the content of byproducts
increases. This observation complies with our assumption that observed byproducts are formed
by CO2-elimination from cycloadduct 106.
123
Again the purification of the components of the mixture was problematic. We expected
that methylenation can be a solution for isolation of the desired cycloadduct 107. However, our
attempts to perform Wittig olefination on the mixture of lactols did not afford any product
though starting compounds were consumed (Scheme 105).
Apparently, the change of the substituted lactone tether between diene and dienophile in
structures 90 and 95 for the lactol in compounds 102 and 103, or in other words change in
hybridization of C11 from sp2 to sp3, had a dramatic effect on IMDA reactions of these
substrates. The lactols (102, 103) were less reactive toward cycloaddition and the reaction time
increased (reaction was not complete after 26 h, Scheme 104 and 105) when compared to IMDA
of lactones (reaction is complete within 26 h, Schemes 97 and 102). There was a drop in
efficiency, too: the lactol cycloadducts (105, 106) were formed together with significant amounts
of byproducts resulted from competing CO2-loss from the cycloadducts.
II.2.5 Synthesis of the alkene intermediates for Diels-Alder reaction and their
further synthetic elaboration. Iodocyclization
Inefficiency of cycloadditions of the lactol intermediates discussed in the previous
chapter convinced us to consider structure 34 as a viable substrate for the Diels-Alder step and as
our new synthetic goal (Scheme 106). In contrast with model system 64 containing an
unsubstituted four-methylene tether, the proposed intermediate 34 has fully elaborated
quaternary center at C8, which might accelerate cycloaddition due to the Tharpe-Ingold effect.
O
12
11
PO
CO2Me
8
IMPDA
I
9
O
MeO2C
8
O
O
34
33
P - protecting group
Scheme 106
124
I
9
OP
Furthermore, olefination of the lactols in the presence of the bridged lactone was
problematic (as shown in Scheme 105). By installment of the methylene fragment C11-C12
before the key IMPDA we will avoid difficulties related to methylenation of bridged
cycloadducts.
Our initial attempts were to olefinate already elaborated lactol 103 (Scheme 107).
However, methylenation of 103 did not afford any of the desired product 108.
OH
CO2Me
O
O
103
CO2Me
HO
I
I
X
Ph3P CH2
O
108
O
O
Scheme 107
We decided to change our synthetic pathway and introduce the vinyl group earlier in the
route. We started with lactol 97 (Scheme 108), the preparation of which is discussed previously.
Our initial attempts of Wittig methylenation (97→109) at room temperature furnished the
product in modest 37% yield. The quaternary center at C8 next to the hemiacetal carbon can be
responsible for the difficulty in olefination. Heating the reaction mixture to 60 oC for 2 hours to
ensure alkene elimination from the intervening oxaphosphetane adduct improved the yield up to
94%.
125
OH
OTBS
O
Ph3PCH3Br (3 equiv.),
t-BuOK (2.9 equiv.), THF
OTBS
HO
109
97
r.t. for 28 h
r.t. for 17 h, 60 oC for 2-2.5 h
PMB-imidate
(1.8 equiv.),
CSA (10-mol%),
OTBS
PMBO
r.t. (8.5 h)
60
I
CO2Me
(1.05 equiv.)
37%
81-94%
OTBS
cat. PdCl2(PPh3)2,
cat. CuI, Et3N,
35 oC (2 h)
110
72%
AcOH:THF:H2O
(3:1:1)
PMBO
CO2Me
111
96%
75%
OH
PMBO
112
CO2Me
1. Swern oxid'n
2.
CO2Me
Ph3P
94
PhCH3, 35 oC (13 h)
CO2Me
PMBO
CO2Me
113
85%
Scheme 108
Alcohol 109 was protected as a PMB-ether using PMB-trichloroacetimidate.226
Sonogashira coupling of alkyne 110, TBS-deprotection, Swern oxidation and Wittig olefination
proceeded uneventfully with high yields to provide alkynenoate 113.
When 113 was treated with ICl, however, no formation of α-pyrone was observed.
Instead, a different product was formed (Scheme 109). After column chromatography, the new
compound still was contaminated with minor impurities. Analysis of proton NMR data revealed
that the alkynenoate functionality as well as α,β-unsaturated methyl ester remained unchanged.
On the other hand there was no PMB-group or terminal vinyl group present in the new product.
Taking into account the proton NMR data we propose the following explanation
(Scheme 109): PMB-ether reacts with the alkene-iodonium cation to form tetrahydrofuran 115
upon loss of PMB-group.
126
I+
CO2Me
O
ICl
PMBO
I
CO2Me
CO2Me
O
CO2Me
CO2Me
MeO
CO2Me
114
113
115
Scheme 109
Mass spectrometric analysis of our undesired product supports this conclusion by
providing a molecular ion consistent with the proposed structure 115 for the newly formed
product.
Assuming that formation of the cyclic iodonium salt is reversible, we expected that the
encountered difficulty can be addressed by changing the protecting group to something less
nucleophilic. Therefore, the large and electron-withdrawing t-butyldiphenylsilyl group (TBDPS)
was chosen to substitute electron-rich PMB protecting group. Interaction between low-lying
empty orbitals on the silicon atom with the lone pairs of electrons on oxygen, known as dp-πbonding,227 should reduce nucleophilicity of the protected oxygen atom. Consequently, the
oxygen atom will be less prone to react with any transient electrophilic alkene-iodonium cation.
Alcohol 109 was successfully protected with the TBDPS-group in the presence of
imidazole in DMF solution (Scheme 110). To deprotect the t-butyldimethylsilyl (TBS) group in
the presence of TBDPS protecting group, we employed the method we used previously of
treating the compound with the mixture of acetic acid, THF and water. The deprotection step
provided alcohol 117 in the almost quantitative yield (Scheme 110). Swern oxidation furnished
aldehyde,
which
without
further
purification
was
olefinated
with
[1-
(methoxycarbonyl)ethyl]triphenylphosphorane 94 to provide 118 in 84% yield over two steps.
Sonogashira coupling of alkyne 118 with methyl 3-iodo-2-propenoate (61) produces 119 in 90%
while coupling with isobutyl 3-iodo-2-propenoate (120) produces 121 in 87% yield. In this way
we prepared two alkynenoates 119 and 121 to examine iodocyclization on both of them.
127
OTBS
TBDPSCl (1.3 equiv.),
imidazole (2.5 equiv.),
DMF, r.t. (24 h)
HO
OH
OTBS
0.05 M AcOH:H2O:THF
(3:1:1)
TBDPSO
0
93%
109
oC,
TBDPSO
r. t. (3 h)
117
99%
116
CO2Me
60
I
CO2Me
(1.1 equiv.)
CO2Me
cat. PdCl2(PPh3)2,
cat. CuI, Et3N,
40 oC (2.5 h)
90%
1. Swern Oxid'n
TBDPSO
2.
CO2Me
Ph3P
94
TBDPSO
CO2Me
119
CO2Me
118
PhCH3, 40 oC (14 h)
120
I
CO2i-Bu
(1.1 equiv.)
84%
TBDPSO
O
cat. PdCl2(PPh3)2,
cat. CuI, Et3N,
40 oC (4 h)
87%
O
121
Scheme 110
When methyl alkynenoate 119 was treated with iodine monochloride in methylene
chloride at 0 oC, the desired α-iodopyrone 122 was isolated in 27% yield (Table 24). The major
observed byproduct (≤23% yield) was consistent with the structure 115 (the product with this
structure has been isolated before as a major product in iodocyclization of PMB-protected
intermediate 113, Scheme 109).
Table 24. Iodocyclization of TBDPS protected alkynenoates
CO2Me
CO2Me
ICl
TBDPSO
+
TBDPSO
O
CO2R
I
R= Me (119)
i-Bu (121)
CO2Me
I
O
O
CO2Me
122
115
entry
R
Conditions
yield of 122, %
yield of 115, %
1.
Me
0.2 M in CH2Cl2, ICl (1.1 equiv.),
27%
23%
0 oC (6 h)
128
Table 24 − continued
entry
R
Conditions
yield of 122, %
2.
Me
0.2 M in CH2Cl2, t-BuOH (5 equiv.),
yield of 115, %
39%
o
ICl (1.3 equiv.), 0 C (4 h)
3.
Me
0.2 M in CH2Cl2,
32%
t-BuOH (5 equiv., dried),
ICl (1.3 equiv.), 0 oC (4 h)
4.
i-Bu
0.2 M in CH2Cl2, ICl (1.2 equiv.),
≥ 36%
0 oC (9.5 h)
Thus, TBDPS-protection of the alcohol allowed us to obtain some desired product 122,
though it was formed with a low efficiency.
We explored the influence of protic compounds present in the reaction mixture by adding
5 equivalents of tert-butyl alcohol to the reaction mixture (entry 2 and 3, Table 24). In the initial
experiment (entry 2, Table 24) the obtained yield improved to 39%, and the reaction reached
completion in a shorter period of time (while monitored by TLC). The second time, when we
used tert-butanol (t-BuOH) stored over molecular sieves to remove moisture, the obtained yield
dropped to 32%. These preliminary results deserve further investigation and suggest that, though,
t-BuOH additive has a minor effect on the reaction, the presence of the residual amounts of
moisture in the solvent can be advantageous.
When 90 mg of isobutyl alkynenoate 121 was exposed to iodine monochloride for 9
hours at 0 oC, 36 mg (36% yield) of the desired iodopyrone 122 was produced after purification
by column chromatography, together with 8 mg of the product containing impurities. In other
words the yield of the latter reaction is at least 36%.
Further, Diels-Alder cycloaddition of accessed iodopyrone 122 was investigated (Scheme
111). Pyrone 122 was heated to 100 oC as a solution in toluene in a sealed tube.
129
CO2Me
O
PhCH3, 100 oC
TBDPSO
O
I
O
MeO2C
I
sealed tube
O
OTBDPS
122
123
Scheme 111
Despite our expectations, the substitution at C8 did not accelerate the cycloaddition
(compared with the related model studies, discussed before). Upon heating for eleven days the
reaction was not complete and the product was isolated together with the starting material in the
ratio of 92 : 8 estimated by 1H-NMR. Gratifyingly, presumably due to the increased stability of
the starting material (compared to the model system) the desired product 123 was formed in
acceptable yield of 67%.
In summary, key Diels-Alder reaction efficiently produced cycloadduct 123. The bridged
tricyclic framework of 123 contains all six stereogenic centers of basiliolide B and appropriate
functionality for further elaboration into the natural product.
130
CHAPTER III
SUMMARY AND FUTURE CHALENGES
According to the results presented in the previous chapter, the original hypothesis of
constructing the skeletone of basiliolide B employing IMPDA cycloaddition was confirmed.
Three out of four rings in the structure of natural product were constructed with total
stereocontrol. All six stereogenic centers of the natural product were successfully installed.
What still remained is to annulate the final (oxepin) ring using TBDPS-ether and iodide
functionalities. Preliminary results on further elaboration of 123 into natural product 29 are
described below.
Preliminary results. TBDPS-deprotection of 123 turned out to be quite challenging due
to the hindrance of the targeted functionality. It is located next to the quaternary center at C8,
while the iodine atom blocks the access to the group from the other side (Table 25).
Table 25. Removal of the TBDPS protecting group from 123
O
O
O
O
MeO2C
MeO2C
I
I
OTBDPS
OH
107
123
entry
Conditions
Comments or yield, %
1.
TBAF, THF, r. t.
decomposed
2.
o
HF·Et3N, THF, 0 C, r. t. (1 day)
131
no product
Table 25 − continued
entry
Conditions
Comments or yield, %
3.
70% HF·Py : Py : THF (1 : 1 : 1),
minor amount of product
o
4.
0 C, r.t. (12 h)
was formed
70% HF·Py : Py : THF (1 : 1 : 1),
~55%
0 oC, r.t. (3 days)
TBAT (2.5 equiv.), THF, 60 oC (16 h)
5.
minor amount of product
was formed
6.
7.
TBAF + HOAc (1 equiv.),
minor amount of product
THF, r. t. (10 h), 45 oC (48 h)
was formed
70% HF·Py : Py : THF (1 : 1 : 1),
64%
40 oC, (27 h)
As shown in the Table 25, when 123 was treated with TBAF solution in THF at room
temperature the material decomposed (entry 1, Table 25). Hydrofluoric acid buffered with
triethylamine did not produce any product either (entry 2, Table 25). When 123 was treated with
hydrofluoric acid buffered with pyridine at ambient temperature for 12 hours, a minor amount of
the product was formed (entry 3, Table 25). Letting the reaction proceed for three days produced
the product in about 55% yield (9 mg scale; entry 4, Table 25). Tetrabutylammonium
difluorotriphenylsilicate (TBAT),228 or tetrabutylammonium fluoride (TBAF) buffered with
acetic failed to provide the product in reasonable yield (entry 5 and 6, Table 25). Finally, heating
compound 123 to 40 oC with hydrofluoric acid buffered with pyridine in THF over 27 hours
produced alcohol 107 in 64% yield (entry 7, Table 25).
Alcohol 107 was easily oxidized into the corresponding aldehyde with Dess-Martin
periodinane,229 and further to the acid in the presence of excess of sodium chlorite230 (Scheme
112). 1H-NMR data for the obtained material was consistent with the structure 125. The yield of
the crude product constituted 98%. The column purification with silica gel or aluminum oxide
was problematic due to the affinity of the carboxylic acid, which does not come out from the
column.
Our attempts to perform Stille coupling with tributyltin ethoxyacetylide or (β-E-
132
ethoxyvinyl)tributyltin (128) brought inferior results. The interpretation of the experimental data
was complicated by the lack of an efficient purification technique. At this stage we considered
that protection of carboxylate prior to the Pd-catalyzed coupling step may resolve the difficulties.
AcO OAc
I OAc
O
1.
O
MeO2C
OH
O
MeO2C
I
I
107
124
O
(2.3 equiv.)
O
O
CH2Cl2 (6.5 h)
2. NaClO2, NaH2PO4, H2O,
t-BuOH, 2-methyl-2-butene
125
HO
O
~98%
O
O
126
SnBu3
BnO
N
TfO
O
MeO2C
EtO
I
PhCF3, 83 oC (24 h)
80%
127
BnO
O
128
cat. PdCl2(PPh3)2,
Bu4NCl (1 equiv.),
DMF, 80 oC (2.5 h)
O
MeO2C
OEt
129
BnO
O
Scheme 112
The initial experiments on benzylating acid 125 in the presence of DCC and DMAP did
not afford any product. The steric hindrance of carboxylate may explain its low reactivity. When
Dudley’s reagent (126)231 was used for benzylation,232 the desired product 127, was formed
cleanly (as evidenced by 1H-NMR analysis).
Ester 127 undergoes Stille coupling under Hibino’s conditions.233 Although (β-Eethoxyvinyl)tributyltin, 128, used for the reaction was contaminated with its α-isomer (with 1:0.6
ratio as produced by hydrostannation of ethoxyacetylene in the presence of Pd-catalyst),234 only
the β-isomer 128 reacts with the vinyl iodide to furnish product 129. This chemoselectivity of the
Stille coupling was first reported by Ohyun Kwon.235 The reaction was accomplished on less than
1 mg scale. Mass-spec analysis identified a molecular ion consistent with structure 129.
Ethoxyvinyl functionality in 129 provides flexibility for further elaboration of the oxepin
ring in the natural product. Thus, electrophilic cyclization (with X2) of the carboxylate with the
electron rich alkene upon removal of the benzyl group will construct the seven-membered ring
directly (130), final product 131 can be reached upon subsequent elimination of HX (in this case
133
the ethoxyvinyl functionality serves as a model, and methoxyvinyl has to be installed to
construct basiliolide B, Scheme 113).
O
O
O
MeO2C
X2
O
base
X
O
O
O
MeO2C
OEt
O
130
O
OEt
(+/-)-131
O
MeO2C
OEt
BnO
O
O
129
O
O
O
MeO2C
MeO2C
O
O
O
O
O
OMe
(+/-)-29
132
basiliolide B
Scheme 113
Alternatively, the ethoxyvinyl group can be converted into the methylene carboxylic acid
moiety. Dehydration of a diacid will assemble seven-membered ring anhydride 132, which can
provide access to the racemic natural product 29 (Scheme 113).
The preliminary results discussed above lay the foundation for future work on synthetic
approach to the natural product. The studies toward completion of the total synthesis of
basiliolide B will continue in Dudley lab.
134
CHAPTER IV
EXPERIMENTAL
General information
Solvents were reagent grade and in most cases dried prior to use. All other commercially
available reagents were used as received unless otherwise specified. Tetrahydrofuran (THF),
methylene chloride (CH2Cl2), ethyl ether (Et2O) and toluene (PhCH3) were purified by passing
through a column of activated alumina.
1
H NMR and
13
C NMR spectra were recorded on a Mercury Varian 300 (300 MHz)
spectrometer or Brüker AC300 (300 MHz) spectrometer using CDCl3 as a solvent. The chemical
shifts (δ) are reported in parts per million (ppm) relative to the chloroform peak (7.26 ppm for 1H
NMR, 77.0 ppm for
13
C NMR). The coupling constants (J) were reported in Hertz (Hz). IR
spectra were recorded on a Perkin-Elmer FTIR Paragon 1000 spectrometer on NaCl discs. Mass
spectra were recorded on a JEOL JMS600H spectrometer. Mass spectra were recorded using
chemical ionization (CI) or electron ionization (EI) techniques. Yields refer to isolated material
judged to be ≥95% pure by 1H NMR spectroscopy. All chemicals were used as received unless
otherwise stated. The purifications were performed by flash chromatography using silica gel F254 (230-499 mesh particle size).
135
Synthetic procedures
1. LiAlH4
HOOC
2.
HO
I
CO2Me
cat PdCl2(PPh3)2,
cat CuI
MeO2C
Methyl 10-hydroxydec-1-en-3-yneoate 61. Heptyn-7-ol was prepared from 6-heptynoic acid by
reduction
with
lithium
aluminum
hydride
following
the
known
procedure.236
To
dichlorobis(triphenylphosphine)palladium (II) (250 mg, 0.36 mmol, 4-mol%) and copper iodide
(34 mg, 0.18 mmol, 2-mol%) in 25 mL of triethylamine under argon neat iodide 60237 (2.1 g, 9.8
mmol, 1.1 equiv.) was added dropwise, followed by addition of heptyn-7-ol (1.00 g, 9.8 mmol,
1.1 equiv.) dissolved in 10 mL of triethylamine. After 6.5 hours of stirring at room temperature,
the reaction mixture was diluted with 100 mL of ethyl ether and 50 mL of water. The phases
were separated and the water layer was extracted with 3x50 mL of ethyl ether. The organic phase
was washed with water (2x50 mL), saturated NH4Cl (aq) (50 mL) and brine (50 mL), dried over
MgSO4, filtered and concentrated by rotary evaporation. The crude oil was purified by
chromatography (20% ethyl acetate/hexanes) to give 1.44 g (82% yield) of methyl ester 32 as a
colorless oil.
1
H-NMR (CDCl3) δ 6.16 (dt, J=11.4, 2.3 Hz, 1H), 6.05 (d, J=11.4 Hz, 1H), 3.75 (s, 3H), 3.67
(q, J=5.6 Hz, 2H), 2.44-2.52 (m, 2H), 1.73 (t, J=5.7 Hz, 1H), 1.55-1.69 (m, 6H);
13
C-NMR
(CDCl3) δ 165.4, 127.0, 124.4, 104.1, 78.0, 62.6, 51.4, 32.1, 27.9, 24.7, 20.0; IR (neat film)
3415, 2936, 2860, 2206, 1727, 1609, 1438, 1235, 1197, 1176, 1045, 817 cm-1; HRMS Calc for
C11H16O3 [M+Na]+ 219.0997, found 219.1003.
1. Swern oxid'n
HO
2.
CO2Et
Ph3P
CO2Et
MeO2C
MeO2C
Ethyl α,β-unsaturated ester 63. To a solution of oxalyl chloride (388 mg, 3.1 mmol, 1.2 equiv.)
in 7 mL of methylene chloride neat DMSO (478 mg, 6.1 mmol, 2.4 equiv.) was added at -78 ºC.
After stirring for 15 minutes 500 mg of methyl 10-hydroxydec-2-en-4-yneoate (61) (2.55 mmol,
1 equiv.) in 2 mL of methylene chloride was added over 8 minutes. The reaction mixture was
136
stirred for 20 min, then quenched with 1.8 mL of triethylamine (12.7 mmol, 5 equiv.) at -78 ºC
and warmed to room temperature. After 1.5 hour the reaction mixture was poured into water (50
mL), the phases were separated and water layer was extracted with methylene chloride (2x40
mL). The organic phase was washed with aqueous NH4Cl (30 mL), 0.3 M solution of HCl (30
mL), aqueous NaHCO3 (30 mL) and brine (30 mL), dried over MgSO4 and concentrated by
rotary evaporation to give 504 mg of crude aldehyde. Obtained aldehyde without further
purification was involved in Wittig-olefination step.
To a solution of 400 mg of obtained aldehyde (2.1 mmol, 1 equiv.) in 10 mL of toluene 1.12 g of
(carbethoxyethylidene)triphenylphosphorane (62, 3.1 mmol, 1.5 equiv.) was added in one
portion. After stirring for 4 hours at 35 ºC the reaction mixture was diluted with 50 mL of
hexanes, washed with water (30 mL), water layer was extracted with ethyl ether (30 mL), the
organic phases were combined and washed with aqueous NH4Cl, aqueous NaHCO3 and brine,
filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography
(gradient elution, 10%–20% ethyl acetate/hexanes) and 466 mg of olefinated product 63 was
obtained as a colorless oil with 81% overall yield.
1
H-NMR (CDCl3) δ 6.76 (br t, 1H), 6.15 (dt, J=11.4, 2.3 Hz, 1H), 6.05 (d, J=11.4 Hz, 1H), 4.18
(q, J=7.1 Hz, 2H), 3.75 (s, 3H), 2.44-2.52 (m, 2H), 2.21 (q, J=6.8 Hz, 2H), 1.83 (broad s, 3H),
1.58-1.67 (m, 4H), 1.29 (t, J=7.1 Hz, 3H);
13
C-NMR (CDCl3) δ 167.8, 164.9, 141.3, 127.8,
126.8, 123.8, 103.3, 77.7, 60.0, 51.0, 27.8, 27.7, 27.4, 19.5, 14.0, 12.0; IR (neat film) 2943,
2205, 1709,1610, 1438, 1264, 1195, 1176, 1116, 817 cm-1; HRMS calc for C16H22O4 [M+Na]+
301.1416, found 301.1404.
CO2Et
ICl
I
CO2Et
MeO2C
O
O
5-Iodopyrone 64. The reaction was carried out in the dark under argon atmosphere using
degassed methylene chloride. To a solution of 290 mg of ethyl α,β-unsaturated ester (63) (1.1
mmol, 1 equiv.) in methylene chloride 1.2 mL of 1 M solution of iodine monochloride in
methylene chloride (1.2 mmol, 1.1 equiv.) was added dropwise at room temperature. Upon
137
stirring for 5 hours at room temperature the reaction mixture was first quenched with 3 mL of
aqueous Na2SO3, diluted with 30 mL of methylene chloride and washed with 10 mL of aqueous
Na2SO3. The water layer was extracted with 10 mL of methylene chloride, the combined organic
phases were washed with aqueous NaHCO3, brine and dried over MgSO4. After evaporation of
the solvent the crude oil was purified by chromatography (gradient elution, 10-20% ethyl
acetate/hexane) to yield 242 mg (57% yield) of 5-iodopyrone as a yellow oil.
1
H-NMR (CDCl3) δ 7.43 (d, J=9.7 Hz, 1H), 6.67-6.76 (m, 1H), 5.99 (d, J=9.7 Hz, 1H), 4.18 (q,
J=7.1 Hz, 2H), 2.73 (q, J=7.55 Hz, 2H), 2.22 (q, J=7.4 Hz, 2H), 1.83 (s, 3H), 1.66-1.80 (m, 2H),
1.46-1.59 (m, 2H), 1.29 (t, J=7.1 Hz, 3H);
13
C-NMR (CDCl3) δ 167.8, 164.9, 160.9, 151.5,
140.9, 128.1, 114.6, 67.7, 60.2, 36.1, 28.0, 27.6, 26.4, 14.1, 12.2; IR (neat film) 2932, 1736,
1541, 1261, 1011 cm-1; HRMS Calc for C15H19IO4 [M+Na]+ 413.0219, found 413.0220.
CO2Et
100 oC, PhCH3
I
H
CO2Et
O
O
I
O
O
Bridged decalin cycloadduct 65. In the sealed tube under argon 105 mg of 5-iodopyrone 64
(0.27 mmol, 1 equiv.) in 15 mL of toluene was heated to 100 ºC. After 3 days the reaction
mixture was cooled down to room temperature and concentrated in vacuo. The brown crude
residue was purified by chromatography to give 41 mg (39% yield) of the desired cycloadduct (a
single observed diastereomer) as a viscous yellow oil, 15 mg of starting material was recovered
(46% yield based on recovery of starting material).
1
H-NMR (CDCl3) δ 6.98 (d, J=6.5 Hz, 1H), 4.06-4.30 (m, 2H), 3.51 (d, J=6.5 Hz, 1H), 2.31-2.41
(m, 1H), 2.07-2.18 (m, 1H), 1.31-1.95 (m, 7H), 126 (s, 1H); 13C-NMR (CDCl3) δ 174.7, 171.3,
140.7, 101.8, 83.6, 61.6, 53.6, 47.8, 43.8, 37.7, 25.0, 24.9, 21.2, 20.7, 14.1; IR (neat film) 2941,
2862, 1758, 1729, 1251, 1225, 1200, 1179, 1094, 946, 934, 882 cm-1; HRMS Calc for C15H19IO4
[M+Na]+ 413.0226, found 413.0226.
138
O
1. Corey-Fuchs
homologation
CHO
OMe
2.
I
CO2Me
cat. PdCl2(PPh3)2,
cat. CuI
Methyl dienynoate 67. Racemic citronellal (66) was converted into the corresponding alkyne
(66a) according to the Corey-Fuchs protocol as it has been reported before.238
In a 25 mL round bottom flask under argon atmosphere 550 mg of iodide (60)237 (2.6 mmol, 1
equiv.) was added to 10 mg of copper iodide (0.052 mmol, 2-mol%) and 73 mg of
dichlorobis(triphenylphosphine)palladium (II) (0.104 mmol, 4-mol%) in 7 mL of dry
triethylamine. Alkyne 66a (466 mg, 2.86 mmol, 1.1 equiv.) prepared as deacribed above was
added to the reaction mixture at room temperature followed by heating to 50 ºC for 1.5 hours
(completion of the reaction was monitored by TLC). The reaction mixture was diluted with 50
mL of diethyl ether, then 25 mL of water was added. The phases were separated and aqueous
phase was extracted with diethyl ether (2x15 mL). The combined organic layers were washed
with water (30 mL), aqueous Na2SO3 (30 mL) and brine (30 mL). The organic phase was dried
over MgSO4, filtered and evaporated. The crude residue was purified by silica gel
chromatography (using 3% ethyl acetate/hexane) to yield 500 mg (87% yield) of product 67 as a
colorless oil.
1
H-NMR (CDCl3) δ 6.16 (dd, 1H), 6.02 (dd, 1H), 5.10 (br t, 1H), 3.74 (s, 3H), 2.62-2.76 (m,
1H), 2.07-2.23 (m, 2H), 1.68 (s, 3H), 1.62 (s, 3H), 1.42-1.60 (m, 2H), 1.23 (d, J=6.9 Hz, 3H);
13
C-NMR (CDCl3) δ 165.3, 132.08, 126.9, 124.0, 123.8, 108.3, 77.9, 51.2, 36.7, 26.7, 25.8, 25.7,
20.5, 17.6; IR (neat film) 2968, 2208, 1730, 1609, 1437, 1376, 1290, 1194, 1175, 817 cm-1.
O
1. m -CPBA
2. HIO4
OMe
3.
O
OMe
Ph3P
CO2Et
CO2Et
Ethyl α,β-unsaturated ester 69. To 370 mg of prepared dienyne 67 (1.68 mmol, 1 equiv.)
dissolved in 12 mL of methylene chloride 638 mg of m-CPBA (50-wt%, 1.85 mmol, 1.1 equiv.)
was added at -78 ºC. The reaction mixture was stirred at -78 ºC for 4 hours, then additional 0.4
equivalents of m-CPBA were added and the mixture was kept for additional 16 hours at -30 ºC.
The reaction mixture without warming up was filtered quickly from excess of m-CPBA into the
139
flask with 20 mL of aqueous Na2S2O3 and diluted with 25 mL of ethyl ether. The phases were
separated and aqueous layer was extracted with 10 mL of ethyl ether, combined organic phases
were washed once again with aqueous Na2S2O3 (20 mL), then with aqueous NaHCO3 (20 mL)
and brine (20 mL). The ether layer was dried over MgSO4, filtered and evaporated in vacuo. The
crude product was purified by flash chromatography using silica gel neutralized by washing with
triethylamine (3% Et3N in 10% ethyl acetate/hexanes) to give 313 mg of the desired epoxide
(67a) as a colorless oil (79%).
To 179 mg of epoxide (67a, 0.76 mmol, 1 equiv.) prepared in the way as described above was
dissolved in 3 mL of THF:water (2:1) 259 mg of periodic acid (1.14 mmol, 1.5 equiv) in 1 mL of
THF:water was added at 0 ºC. The reaction mixture was stirred at 0 ºC for 2.5 hours with
monitoring of the completion by TLC. The reaction mixture was quenched with 7 mL of aqueous
solution of Na2S2O3 and diluted with 15 mL of ethyl ether to dilute organic phase. The phases
were separated and aqueous layer was extracted with 2x7 mL of ethyl ether. The combined
organic phases were washed with 10 mL of aqueous NaHCO3 (7 mL) and brine (7 mL). The
ether layer was dried over MgSO4, filtered and concentrated in vacuo to give 177 mg of crude
aldehyde (67b) as a yellow oil which was involved in the olefination step without further
purification.
Prepared aldehyde (67b) was dissolved in 4 mL of methylene chloride then 411 mg of
(carbethoxyethylidene)triphenylphosphorane (62, 1.14 mmol, 1.5 equiv.) was added at ambient
temperature. The reaction mixture was stirred for one day then heated to 32 ºC and stirred for
four hours to ensure completion of the reaction. Then solvent was evaporated and the crude
residue was purified by column chromatography (10% ethyl acetate/hexanes) to yield 160 mg of
product 69 as a viscous yellow oil containing an unseparatable unidentified minor impurity (75%
yield of product from epoxide (69) together with minor impurity).
1
H-NMR (CDCl3) δ 6.76 (br t, 1H), 6.16 (dd, 1H), 6.05 (d, J=11.4 Hz, 1H), 4.18 (q, J=7.1 Hz,
2H), 3.75 (s, 3H), 2.65-2.80 (m, 1H), 2.3-2.48 (m, 2H), 1.86 (s, 3H), 1.59-1.71 (m, 2H), 1.29 (t,
J=7.1 Hz, 3H), 1.26 (d, J=6.9 Hz, 3H); IR (neat film) 2974, 1736, 1599, 1540, 1460, 1366, 1261,
1186, 1104, 1026, 821 cm-1; HRMS Calc for C16H22O4 [M+Na]+ 301.1416, found 301.1417.
140
O
I
OMe
I
ICl
+
O
EtO2C
O
CO2Et
EtO2C
O
O
5-Iodopyrone 70. The reaction was carried out in the dark under argon atmosphere using
degassed methylene chloride. In 5 mL round bottom flask under argon to 30 mg of ethyl α,βunsaturated ester 69 (0.11 mmol, 1 equiv) in 0.8 mL of methylene chloride 18 mg of iodine
monochloride (0.11 mmol, 1.05 equiv.) in 0.3 mL of methylene chloride was added dropwise at
-25 ºC (ice/acetone bath). After four hours of stirring and monitoring by TLC reaction was
quenched with aqueous Na2SO3 (some amount of the starting material still was present in the
reaction mixture), 7 mL of ethyl ether was added and the phases were separated, aqueous layer
was extracted with 2 mL of ethyl ether. The combined ether layers were washed with brine (5
mL). Product was purified by column chromatography (using 10% ethyl acetate/hexanes) to give
17 mg (44%) of the desired 5-iodopyrone as a viscous yellow oil. A mixture of diastereomeric 5exo cyclization byproducts (71) was also obtained, along with minor impurities, in an amount
estimated by 1H NMR to be 7 mg (17%).
1
H-NMR (CDCl3) δ 7.44 (d, J=9.7 Hz, 1H), 6.70 (br t, 1H), 5.99 (d, J=9.7 Hz, 1H), 4.175 (q,
J=7.1 Hz, 2H), 3.05-3.19 (m, 1H), 2.09-2.24 (m, 2H), 1.87-2.06 (m, 1H), 1.80 (s, 3H), 1.62-1.75
(m, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.235 (d, J=6.9 Hz, 3H);
13
C-NMR (CDCl3) δ 167.9, 167.4,
161.1, 151.8, 140.6, 128.7, 115.0, 67.8, 60.5, 40.7, 33.2, 26.4, 18.1, 14.3, 12.5; IR (neat film)
3650, 1734, 1540, 1262 cm-1; HRMS Calc for C15H19IO4 [M+Na]+ 413.0215, found 413.0219.
O
I
O
100 °C
O
O
EtO2C
PhCH3
+
EtO2C
EtO2C
H
I
H
H
Bridged lactone 72. A solution of 5-iodopyrone (70, 15 mg, 0.038 mmol, 1 equiv.) in 1.5 mL of
toluene in the scintillation vial under argon was heated to 100 ºC for 12.5 hours. The reaction
mixture was cooled down to room temperature and concentrated in vacuo. The crude residue
containing cycloadduct 72 as a single diastereomer was chromatographed to afford 9 mg of the
141
desired cycloadduct as a colorless oil (60% yield). See Figures 97 and 98 for nOe correlations in
support of structure of 72.
1
H-NMR (CDCl3) δ 6.88 (d, J=6.2, 1H), 4.08-4.23 (m, 2H), 3.60 (d, J=6.2, 1H), 2.67 (dd J=11.2,
8.8, 1H), 2.43-2.58 (m, 1H), 2.09-2.23 (m, 1H), 1.86-2.00 (m, 1H), 1.59-1.82 (m, 2H), 1.30 (s,
3H), 1.26 (t, J=7.1, 3H), 1.19 (d, J=6.8, 3H);
13
C-NMR (CDCl3) δ 174.7, 171.3, 140.0, 96.8,
94.4, 61.7, 54.4, 50.4, 45.5, 41.2, 30.4, 23.7, 21.3, 14.1, 12.8; IR (neat film) 2974, 2877, 1763,
1730, 1458, 1381, 1260, 1220, 1189, 1168, 1104, 1024, 944, 892 cm-1; HRMS Calc for
C15H19IO4 [M+Na]+ 413.0226, found 413.0232.
The characteristic signals of the single observed impurity were consistent with the structure of 73
(product of CO2-extrusion): 1H-NMR (CDCl3) δ 6.81 (d, J=9.8, 1H), 6.27 (d, J=9.8, 1H).
O
O
2 CuLi
O
O
4-(2-Propenyl)furan-2-one 77. 2-Propenyl lithium was prepared under argon in 500 mL two
neck round bottom flask equipped with addition funnel. t-BuLi solution (1.7 M solution in
pentane, 71 mL, 121 mmol, 6.8 equiv.) was added dropwise over 30 min to 2-bromopropene
(7.34 g, 61 mmol, 3.4 equiv.) in 250 mL of ethyl ether at -78 ºC. The solution was stirred at -78
ºC for 30 min and for additional 30 min at -25 ºC, cooled back to -78 ºC. Copper iodide (5.78 g,
30.3 mmol, 1.7 equiv.) was placed in 1 L three neck round bottom flask equipped with the
mechanical stirrer, 50 mL of ethyl ether was added to form a suspension which was cooled down
to -78 ºC. Prepared 2-propenyl lithium solution in ethyl ether/pentane was transferred via
cannula to the slurry of copper iodide over 15-20 min while stirring vigorously. Upon
transferring the reaction mixture was stirred at -45 ºC for 45 min (after 30 min grey suspension
becomes dark green) and cooled back to -78 ºC. A solution of butenolide (1.5 g, 17.8 mmol, 1
equiv.) in 35 mL of ethyl ether was added dropwise over 10-15 min. The mixture was stirred for
1 hour at -78 ºC and quenched at low temperature with 100 mL of saturated NH4Cl solution
poured into the flask slowly. The two phases mixture was allowed to warm up to room
temperature over 1 hour and 100 mL of ammonium chloride/ammonia buffer (9:1, pH=9) was
added, the mixture was stirred for additional 30-40 min (over this time most of the precipitate
dissolves), then phases were separated, the water layer was extracted with ethyl ether (2x70 mL).
142
The combined organic layers were washed with ammonium chloride/ammonia buffer (3x100
mL) and brine (100 mL), dried over MgSO4, filtered and concentrated by rotary evaporation. The
obtained crude oil was purified by bulb to bulb distillation to give 1.37 g of furanone 77239 (61%
yield) as a colorless oil.
1
H-NMR (CDCl3) δ 4.89 (s, 1H), 4.82 (s, 1H), 4.45 (dd, J=8.9, 7.8, 1H), 4.11 (dd, J=8.9, 7.7 Hz,
1H), 3.20 (p, J=8.1 Hz, 1H), 2.65 (dd, J=17.4, 8.5 Hz, 1H), 2.47 (dd, J=17.4, 8.8 Hz, 1H), 1.77
(s, 3H). 13C-NMR (CDCl3) δ 176.6, 142,2, 112.1, 71.6, 42.2, 32.9, 20.2.
O
O
i) LDA, THF
O
OTBS
O
ii)
I
OTBS
Lactone 80. A solution of 4-(2-propenyl)furan-2-one 77 (645 mg, 5.1 mmol, 1 equiv.) in 11 mL
of tetrahydrofuran was added to the prepared solution of LDA (6.14 mmol of LDA in 11 mL of
tetrahydrofuran, 1.2 equiv.) dropwise at -78 ºC over 10 min. Upon stirring for 50 min 3.1 mL of
Me2Zn solution (2 M solution in toluene, 1.2 equiv.) was added. The reaction mixture was stirred
for 1 hour at -78 ºC and mixture of TBS-protected 3-iodopropanol240 (79, 4.6 g, 15.3 mmol, 3
equiv.) in 8 mL of tetrahydrofuran and 4.5 mL of HMPA was added dropwise at -78 ºC over 10
min. The reaction mixture was stirred for 3 hours at -78 ºC, 20 mL of saturated NH4Cl solution
was added and two layers mixture was allowed to warm to room temperature. The mixture was
poured into 100 mL of saturated NH4Cl solution with ice, diluted with 150 mL of ethyl ether.
The water layer was extracted with 3x50 mL of ethyl ether, the organic phases were combined
and washed with aqueous NH4Cl, aqueous NaHCO3 and brine, dried over MgSO4, filtered and
concentrated in vacuo. The crude oil was purified by chromatography to yield 1.18 g (77% yield)
of the alkylated lactone as a colorless oil.
1
H-NMR (CDCl3) δ 4.90-4.94 (broad s, 1H), 4.34 (dd, J=8.1, 8.9 Hz, 1H), 3.95 (t, J=9.2, 1H),
3.62 (t, J=5.8, 1H), 2.9-3.0 (m, 1H), 2.49-2.59 (m, 1H), 1.58-1.86 (m, 4H), 1.75 (s, 3H), 0.88 (s,
9H), 0.04 (s, 6H); 13C-NMR (CDCl3) δ 178.5, 141.2, 114.0, 69.5, 62.7, 49.0, 42.6, 29.6, 25.9,
25.8, 19.4, 18.3, -5.35; IR (neat film) 2953, 2928, 2856, 1777, 1647, 1472, 1386, 1254, 1161,
1097, 1012, 899, 836, 776 cm-1;
HRMS Calc for C16H30O3Si [M+Na]+ 321.1855, found
321.1857.
143
O
O
OTBS
O
i) LDA, THF
OTBS
O
ii) MeI, HMPA
Lactone 81. To a prepared solution of LDA (1 M solution in THF, 6.7 mL, 2 equiv.) lactone 80
(1 g, 3.35 mmol, 1 equiv.) in 7 mL of THF was added dropwise at -78 ºC over 5 min. The
solution was stirred for 30 min at -78 ºC and 30 min at 0 ºC, 2.38 g of methyl iodide (16.7 mmol,
5 equiv.) in 7 mL of THF and 2.9 mL of HMPA was added dropwise. The reaction mixture was
stirred for 3 hours and then was allowed to warm to room temperature overnight. The reaction
mixture was poured into 100 mL of saturated solution of NH4Cl with ice, diluted with 100 mL of
ethyl ether, the phases were separated and organic layer was extracted with ethyl ether (3x35
mL). The combined organic layers were washed with aqueous NH4Cl, aqueous NaHCO3 and
brine. The crude residue was dissolved in 10% ethyl acetate/hexane and filtered through the plug
of SiO2, 1.03 g of pure methylated lactone 81 was obtained as a yellow solid (98%).
1
H-NMR (CDCl3) δ 5.0 (broad s, 1H), 4.76 (broad s, 1H), 4.32 (dd, J=9.2, 7.2 Hz, 1H), 4.21 (t,
J=7.95, 1H), 1.79 (s, 3H); 13C-NMR (CDCl3) δ 180.7, 140.2, 114.3, 67.6, 63.0, 53.3, 44,4, 28.7,
27.1, 25.9, 22,8, 22.5, 18.3, -5.34; IR (neat film) 2926, 1774, 1459, 1098, 836, 775 cm-1; HRMS
Calc for C17H32O3Si [M+Na]+ 335.2018, found 335.2016.
O
OTBS
O
O3, CH2Cl2;
Ph3P
O
OTBS
O
O
Ketone 84. Alkene 81 (1 g, 3.2 mmol, 1 equiv.) in 50 mL pear bottom flask was dissolved in 32
mL of CH2Cl2:MeOH (4:1). The solution was cooled down to -78 ºC and ozone was bubbled
through for 15 minutes until the color changes for light blue, air was bubbled through the
solution till the color disappeared, 2.5 g of triphenylphosphine (9.6 mmol, 3 equiv.) was added in
one portion while stirring vigorously. The mixture was allowed to warm to room temperature
over 1 hour. The solvent was removed by rotary evaporation and the crude residue containing
excess of triphenylphosphine was purified by chromatography to yield 0.98 g of ketone 84 (98%
yield).
1
H-NMR (CDCl3) δ 4.52 (t, J=7.95 Hz, 1H), 4.27 (dd, J=9.7, 7.9, 1H), 3.5-3.6 (m, 2H), 3.32 (dd,
J=9.9, 7.9, 1H), 2.25 (s, 3H), 1.52 (s, 3H), 1.33-1.68 (m, 4H), 0.87 (s, 1H), 0.016 (s, 6H);
144
13
C-
NMR (CDCl3) δ 203.9, 178.7, 65.2, 62.5, 59.0, 44.6, 30.9, 29.9, 27.2, 25.8, 23.1, 18.2, -5.42; IR
(neat film) 2954, 2929, 2885, 2856, 1770, 1711, 1472, 1462, 1384, 1360, 1256, 1176, 1099,
1032, 941, 837, 776, 660 cm-1; HRMS Calc for C16H30O4Si [M+Na]+ 337.1804, found 337.1804.
O
O
OTBS
O
OTBS
KHMDS, THF;
PhNTf2
O
OTf
O
Triflate 87. A solution of ketone 84 (100 mg, 0.32 mmol, 1 equiv.) in 0.8 mL of THF was added
dropwise at -78 ºC to the solution of KHMDS (0.76 mL, 0.5 M in toluene, 0.38 mmol, 1.2
equiv.)
diluted
with
0.8
mL
of
THF.
After
1
hour
of
stirring
N-phenyl-
bis(trifluoromethanesulfonimide) (148 mg, 0.41 mmol, 1.3 equiv.) in 0.8 mL of THF was added
dropwise. The reaction mixture was stirred for 1 hour at -78 ºC and 30 min at -25 ºC, then was
quenched with 1 mL of aqueous NH4Cl, diluted with ethyl ether (10 mL), washed with 5 mL of
aqueous NH4Cl, the water layer was extracted with ethyl ether (2x3 mL). The combined organic
phases were washed with aqueous NH4Cl, aqueous NaHCO3 and brine, dried over MgSO4,
filtered and concentrated by rotary evaporation. The crude residue was purified by
chromatography on triethylamine-deactivated silica gel (gradient elution, 5–15% ethyl
acetate/hexanes) to yield 120 mg of triflate 57 (84% yield).
1
H-NMR (CDCl3) δ 5.41 (dd, J1=7.6 Hz, J2=9.2 Hz, 1H), 5.02 (dd, J1=0.9 Hz, J2=4.6 Hz, 1H),
4.44 (dd, J1=1.3 Hz, J2=5.6 Hz, 2H), 4.16 (t, J=9.4 Hz, 1H), 3.59 (dd, J1=1.3 Hz, J2=5.6 Hz,
2H), 3.24 (m, 1H), 1.73-1.44 (m, 4H), 1.40 (s, 3H), 0.87 (s, 9H), 0.03 (s, 6H);
13
C-NMR
(CDCl3) δ 178.4, 151.3, 120.5, 116.2, 106.9, 65.2, 62.6, 51.2, 44.6, 29.1, 27.0, 25.8, 22.0, 18.2, 5.4; IR (neat film) 2956, 2931, 2859, 1780, 1666, 1464, 1422, 1251, 1216, 1139, 1099, 1038,
924, 836, 776, 715, 610 cm-1; HRMS Calc for C17H29F3O6SSi [M+Na]+ 469.13039, found
469.1320.
O
OTBS
O
O
DBU, THF
OTBS
O
OTf
Alkyne 82. Obtained triflate 87 (1.1 g, 2.46 mmol, 1 equiv.) was dissolved in 16 mL of THF,
562 mg of neat DBU (3.7 mmol, 1.5 equiv.) was added and the reaction mixture was heated to 45
145
ºC. After 12 hours the solution was cooled down to room temperature, diluted with 40 mL of
methylene chloride, washed with 20 mL of water. The water layer was extracted with methylene
chloride (2x15 mL), washed with brine, dried over MgSO4, filtered and concentrated in vacuo.
The crude residue was purified by chromatography to yield 667 mg of alkyne as a white solid
with 91% yield.
1
H-NMR (CDCl3) δ 4.41 (m, 1H), 4.10 (t, J=9.3 Hz, 1H), 3.62 (t, J=6.0 Hz, 2H), 3.14-3.23 (m,
1H), 2.28 (d, J=2.53, 1H), 1.56-1.81 (m, 4H), 1.29 (s, 3H), 0.89 (s, 3H), 0.04 (s, 3H). 13C-NMR
(CDCl3) δ 179.1, 78.0, 74.2, 68.1, 62.8, 44.6, 39.4, 30.3, 27.2, 25.8, 21.4, 18.2, -5.4; IR (neat
film) 3275, 2927, 2855, 1760, 1460, 1382, 1256, 1188, 1093, 1050, 1007, 834, 774 cm-1; HRMS
Calc for C16H28O3Si [M+Na]+ 319.1698, found 319.1698.
O
OTBS
O
O
I
CO2Me
cat. PdCl2(PPh3)2,
cat. CuI
OTBS
O
CO2Me
Enyne 88. To a mixture of dichlorobis(triphenylphosphine)palladium (II) (2.5 mg, 0.0035 mmol,
4-mol%) and copper iodide (0.33 mg, 0.0017 mmol, 2-mol%) in 0.3 mL of triethylamine 20.5
mg of neat iodide 60237 (0.096 mmol, 1.1 equiv.) was added at room temperature, followed by
alkyne 52 (26 mg, 0.087 mmol, 1 equiv.) in 0.2 mL of triethylamine. The reaction mixture was
stirred at 50 ºC for 3.5 hours, the mixture was diluted with 5 mL of ethyl ether, washed with
3 mL of water, extracted with 3x2 mL of ethyl ether; combined organic phases were washed with
water (3 mL), aqueous NH4Cl and brine, dried over MgSO4, filtered and concentrated in vacuo.
The crude oil was purified by chromatography to yield 27 mg of enyne product 88 as a yellow oil
with 82% yield.
1
H-NMR (CDCl3) δ 6.14 (dd, 2H), 4.46 (t, J=8.5 Hz, 1H), 4.18 (t, J=9.1 Hz, 1H), 3.75 (s, 3H),
3.61 (t, J=6.0, 2H), 3.43 (dd, J=9.1, 8.5 Hz, 1H), 1.56-1.83 (m, 4H), 1.33 (s, 3H), 0.87 (s, 3H),
0.025 (s. 6H); 13C-NMR (CDCl3) δ 179.2, 164.7, 129.2, 122.3, 95.9, 82.5, 68.1, 63.0, 51.5, 45.3,
40.9, 30.5, 27.4, 25.9, 21.6, 18.3, -5.33; IR (neat film) 2952, 2856, 1778, 1729, 1614; 1438;
1382; 1255; 1197; 1176; 1096; 1027; 836; 776 cm-1; HRMS Calc for C20H32O5Si [M+Na]+
403.1917, found 403.1912.
146
O
OTBS
O
AcOH:H2O:THF
(3:1:1)
O
OH
O
CO2Me
CO2Me
Alcohol 89. Enyne 88 (37 mg, 0.097 mmol, 1 equiv.) was treated with 1 mL of the mixture of
AcOH:H2O:THF (3:1:1) for 5 hours at room temperature. The reaction mixture was poured into
5 mL of methylene chloride with solid NaHCO3, after 5 min 3mL of water was added, phases
were separated and water layer was extracted (with 2 mL of methylene chloride), the combined
organic layer was washed with aqueous NaHCO3 and brine, dried over MgSO4, filtered and
concentrated in vacuo. The crude oil was purified by chromatography to yield 23 mg (88% yield)
of product 89 as a colorless oil. 1H-NMR (CDCl3) δ 6.16 (broad s, 2H), 4.46 (t, J=8.6 Hz, 1H),
4.17 (t, J=9.1 Hz, 1H), 3.74 (s, 3H), 3.66 (q, J=5.1 Hz, 2H), 3.43 (t, J=8.7 Hz, 1H), 2.36 (broad s,
1H), 1.59-2.04 (m, 4H), 1.33 (s, 9H);
13
C-NMR (CDCl3) δ 179.3, 165.2, 128.9, 122.9, 96.3,
82.4, 68.1, 62.9, 51.7, 45.4, 40.8, 31.1, 27.4, 21.8; IR (neat film) 3446, 2952, 1772, 1718, 1616,
1438, 1201, 1022, 819 cm-1; HRMS Calc for C14H18O5 [M+Na]+ 289.1052, found 289.1049.
CO2Et
O
O
OH
O
CO2Me
1. Swern oxid'n
2.
O
CO2Et
CO2Me
Ph3P
Dienyne 90. Oxalyl chloride (29 mg, 0.225 mmol, 2 equiv.) was added to the solution of DMSO
(35 mg, 0.45 mmol, 4 equiv.) in 0.45 mL of methylene chloride at -78 ºC. After stirring the
mixture for 15 min alcohol 89 (30 mg, 0.113 mmol, 1 equiv.) in 0.35 mL of methylene chloride
was added dropwise. The solution was stirred for 10 min at -78 ºC and for 10 min at -25 ºC, then
57 mg of triethylamine was added (0.56 mmol, 5 equiv.) at -78 ºC and the reaction mixture was
allowed to warm to room temperature over 1 hour. The mixture was diluted with 3 mL of ethyl
ether, washed with 3 mL of water, water phase was extracted with 3 mL of ether, combined
organic layers were washed with water (3 mL) and brine (3 mL), dried over MgSO4, filtered, and
concentrated in vacuo. Obtained 25.5 mg (85%) of the crude aldehyde as a yellow oil was
involved in the next step without further purification.
Prepared aldehyde (25 mg, 0.095 mmol, 1 equiv.) was dissolved in 0.8 mL of toluene,
(carbethoxyethylidene)triphenylphosphorane (52.5 mg, 0.143 mmol, 1.5 equiv.) was added in
147
one portion and the reaction mixture was heated to 35 ºC for 25 hours. Solvent was evaporated
and crude residue was purified by silica gel chromatography to yield 32 mg (93% yield) of the
final product 90 as a colorless oil.
1
H-NMR (CDCl3) δ 6.68 (br t, 1H), 6.18 (d, J=11.5 Hz, 1H), 6.13 (d, J=11.5 Hz, 1H), 4.49 (t,
J=8.5 Hz, 1H), 3.74 (s, 3H), 3.41-3.51 (m, 1H), 2.19-2.44 (m, 2H), 1.77-1.95 (m, 2H), 1.82 (s,
3H), 1.37 (s, 3H), 1.28 (t, J=7.1, 3H);
13
C-NMR (CDCl3) δ 178.9, 168.0, 164.7, 140.4, 129.5,
128.7, 122.2, 95.4, 82.7, 68.2, 60.5, 51.5, 45.4, 40.7, 32.7, 23.5, 21.6, 14.3, 12.4; IR (neat film)
1774, 1709, 1438, 1175, 1027 cm-1; HRMS Calc for C19H24O6 [M+Na]+ 371.1471, found
371.1456.
O
O
ICl
O
O
I
I
+
CO2Me
CO2Et
O
CO2Et
O
CO2Et
O
O
O
O
5-Iodopyrone 91. The reaction was carried out in the dark under argon atmosphere using
degassed methylene chloride. Dienyne 90 (15 mg, 0.041 mmol, 1 equiv.) was dissolved in 0.8
mL of methylene chloride. Solution of 7.4 mg of iodine monochloride (0.046 mmol, 1.1 equiv.)
in 0.1 mL of methylene chloride was added dropwise at -25 ºC. After 5 hours 1 mL of aqueous
Na2S2O3 was added and the mixture was diluted with 3 mL of ethyl ether, water layer was
extracted with ether (2x2 mL), combined organic phases were washed with 3 mL of sodium
thiosulphate and 3 mL of brine, dried over MgSO4, filtered and concentrated in vacuo. The crude
brown oil was purified by chromatography to yield 6.5 mg (35%) of the desired 5-iodopyrone 91
as a yellow oil together with 9.5 mg of 5-exocyclized byproduct 92 (50%). Characterization of
91: 1H-NMR (CDCl3) δ 7.49 (d, J=9.7 Hz, 1H), 6.60 (br t, 1H), 6.09 (d, J=9.75 Hz, 1H), 4.57
(dd, J=9.4, 7.2, 1H), 4.46 (dd, J=9.45, 7.6, 1H), 4.17 (q, J=7.1, 2H), 3.89 (t, J=7.3, 1H), 2.3-2.47
(m, 1H), 2.07-2.23 (m, 1H), 1.83-1.97 (m, 1H), 1.80 (s, 3H), 1.5 (s, 3H), 1.39-1.54 (m, 1H), 1.28
(t, J=7.1 Hz, 3H);
13
C-NMR (CDCl3) δ 178.4, 168.1, 159.9, 159.3, 151.5, 140.1, 129.1, 116.9,
71.3, 66.4, 60.8, 52.9, 47.5, 31.8, 23.5, 23.1, 14.5, 12.7; IR (neat film) 1740, 1541, 1027 cm-1;
HRMS Calc for C18H21IO6 [M+Na]+ 483.0269, found 483.0262.
Characterization of 92: 1H-NMR (CDCl3) δ 7.74 (d, J=5.6 Hz, 1H), 6.73 (br t, 1H), 6.41 (d,
J=5.6, 1H), 4.48 (dd, J1=6.6 Hz, J2=10.1 Hz, 1H), 4.30, J1=2.9 Hz, J2=10.1 Hz, 1H), 4.30 (dd,
148
J1=2.9 Hz, J2=10.1 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.88 (dd, J1=2.9 Hz, J2=6.6 Hz, 1H), 2.542.37 (m, 1H), 2.19-2.00 (m, 1H), 1.98−1.82 (m, 1H), 1.70-1.57 (m, 1H), 1.42 (s, 3H), 1.28 (t,
J=7.1 Hz, 3H). Characteristic peaks by 13C-NMR (CDCl3) δ 179.05, 168.4, 168.0, 151.5, 144.9,
140.3, 128.6, 124.2, 88.3, 70.0, 60.6, 48.6, 46.4, 31.1, 23.0, 22.25, 14.3, 12.3. IR (neat film)
3500, 2924, 1773, 1703, 1556, 1462, 1366, 1284, 1171, 1097, 1039, 952, 873, 815 cm-1; HRMS
Calc for C18H21IO6 [M+Na]+ 483.0281, found 483.0301.
O
1. Swern oxid'n
O
CO2Me
CO2Me
O
OH
2.
O
CO2Me
CO2Me
Ph3P
PhCH3, 40 oC
Alkynenoate 95. Oxalyl chloride (17 mg, 0.135 mmol, 2 equiv.) was added to the solution of
DMSO (21 mg, 0.27 mmol, 4 equiv.) in 0.27 mL of methylene chloride at -78 ºC. After stirring
the mixture for 15 min at -78 ºC alcohol 59 (18 mg, 0.0676 mmol, 1 equiv.) in 0.2 mL of
methylene chloride was added dropwise. The solution was stirred for 10 min at -78 ºC and for 10
min at -25 ºC, then 34 mg of triethylamine was added (0.338 mmol, 5 equiv.) at -78 ºC and the
reaction mixture was allowed to warm to room temperature over 1 hour. The mixture was diluted
with 10 mL of ethyl ether, washed with 5 mL of water, water phase was extracted with 2x5 mL
of ether, combined organic layers were washed with water (5 mL) and brine (5 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Obtained crude aldehyde was involved in the next
step without further purification. Prepared aldehyde (~0.0676 mmol, 1 equiv.) was dissolved in
0.5 mL of toluene, [1-(methoxycarbonyl)ethyl]triphenylphosphorane 94241 (35 mg, 0.1014 mmol,
1.5 equiv.) was added in one portion and the reaction mixture was heated to 40 ºC for 30 hours.
Solvent was evaporated and crude residue was purified by silica gel chromatography to yield 17
mg (74% yield) of product 95 as a colorless oil.
1
H-NMR (CDCl3) δ 6.72 (br t, 1H), 6.20-6.09 (m, 2H), 4.48 (t, J=8.6 Hz, 1H), 4.18 (t, J=9.2 Hz,
1H), 3.74 (s, 3H), 3.71 (s, 3H), 3.50-3.41 (m, 1H), 2.44-2.19 (m, 2H), 1.95-1.75 (m, 2H).
13
C-
NMR (CDCl3) δ 178.3, 168.45, 164.7, 140.8, 129.5, 128.3, 122.2, 95.4, 82.7, 68.1, 51.7, 51.5,
45.4, 40.7, 32.7, 23.5, 21.5, 12.4. IR (neat film) 2918, 1770, 1714, 1197 cm.-1
HRMS Calc for C18H22O6 [M+Na]+ 357.1314, found 357.1315.
149
O
O
CO2Me
O
ICl
CO2Me
O
I
O
O
MeO2C
Iodocyclization of 95 to approach 96. The reaction was carried out in the dark under argon
atmosphere using degassed methylene chloride. Dienyne 95 (17 mg, 0.051 mmol, 1 equiv.) was
dissolved in 0.5 mL of methylene chloride. Solution of iodine monochloride (56 μL, 1 M in
CH2Cl2, 0.056 mmol, 1.1 equiv.) was added dropwise at ambient temperature. After 4.5 hours 1
mL of aqueous Na2S2O3 was added and the mixture was diluted with 5 mL of methylene
chloride, water layer was extracted with methylene chloride (3 mL), combined organic phases
were washed with 5 mL of aqueous Na2S2O3 and 3 mL of brine, dried over MgSO4, filtered and
concentrated in vacuo. The crude brown oil was purified by column chromatography to yield
only 2 mg (9%) of 5-iodopyrone 96. (The alternative reaction that provides 96 with better
efficiency is described further).
1
H-NMR (CDCl3) δ 7.49 (d, J=9.8 Hz, 1H), 6.60 (br t, 1H), 6.10 (d, J=9.8 Hz, 1H), 4.57 (dd,
J1=7.3 Hz, J2=9.4 Hz), 4.50 (dd, J1=7.6 Hz, J2=9.4 Hz, 1H), 3.89 (t, J=7.4, 1H), 3.72 (s, 3H),
2.48-2.30 (m, 1H), 2.24-2.07 (m, 1H), 1.96-1.82 (m, 1H), 1.80 (s, 3H), 1.50 (s, 3H), 1.50-1.38
(m, 1H); 13C-NMR (CDCl3) δ 178.1, 168.3, 159.7, 159.0, 151.3, 140.3, 128.5, 116.6, 71.1, 66.2,
52.6, 51.7, 47.3, 31.5, 23.3, 23.2, 22.8, 12.5; IR (neat film) 2921, 1739, 1542, 1286, 1024 cm-1;
HRMS Calc for C17H19IO6 [M+Na]+ 469.0124, found 469.0140.
O
CO2Et
O
O
I
O
100 oC
PhCH3
O
CO2Et
I
O
O
O
Cycloadduct bearing lactone tether (93). A solution of 5-iodopyrone 91 (3 mg, 0.0065 mmol,
1 equiv.) in 1 mL of toluene in a scintillation vial under argon was heated to 100 ºC for 23.5
hours. Solvent was evaporated and crude oil containing cycloadduct 93 as the only present
diastereomer was purified by silica gel chromatography (using 20% and 30% ethyl
150
acetate/hexanes) to give 1.5 mg of pure product. See Figure 100 and 100 for nOe correlations in
support of structure of 93.
1
H-NMR (CDCl3) δ 7.1 (d, J=6.5, 1H), 4.51 (dd, J=9.9, 6.2 Hz, 1H), 4.28 (d, J=9.9 Hz, 1H),
4.1-4.25 (m, 2H), 3.55 (d, J=6.6 Hz, 1H), 2.94 (d, J=6.0 Hz, 1H), 2.45-2.54 (m, 1H), 2.33-2.44
(m, 1H), 1.41-1.72 (m, 3H), 1.39 (s, 3H), 1.28 (s, 3H), 1.26 (t, J=7.1 Hz, 3H); 13C-NMR (CDCl3)
δ 179.0, 174.1, 169.1, 143.2, 98.7, 84.2, 65.5, 62.0, 53.7, 50.9, 48.6, 43.5, 40.9, 30.4, 26.1, 21.2,
20.8, 14.1; IR (neat film) 2970, 1768, 1727, 1205, 1106, 1012 cm-1; HRMS Calc for C18H21IO6
[M+Na]+ 483.0281, found 483.0290.
O
OH
OTBS
O
DIBAL, CH2Cl2
OTBS
O
-78 oC
Lactol 97. A solution of 500 mg of lactone 82 (1.686 mmol, 1 equiv.) in 17 mL of methylene
chloride was cooled down to -78 oC. DIBAL solution (3.4 mL, 1 M in toluene, 3.4 mmol, 1
equiv.) was added dropwise at low temperature, followed by stirring for 30 min. Methanol (2
mL) was added to quench the reaction, after 5 min 10 mL of potassium tartrate solution (1 M)
were added. The reaction mixture was allowed to warm to room temperature and to stir for 2
hours until slurry becomes a clear solution. Then 30 mL of methylene chloride and additional 30
mL of potassium tartrate were added, the phases were separated in separational funnel, water
phase was extracted with methylene chloride (3x50 mL). Combined organic phases were washed
with potassium tartrate solution (50 mL), aqueous NH4Cl (50 mL), aqueous sodium bicarbonate
(30 mL), brine (30 mL) and dried over MgSO4. The crude product was dissolved in 30% ethyl
acetate /hexanes and filtered through the plug of silica. After concentration in vacuo 507 mg of
lactol 97 were obtained, 99% yield.
1
H-NMR (CDCl3) δ 5.13 (d, J1=3.1 Hz, 0.65H), 4.89 (d, J=8.31 Hz, 0.36H); 4.28-4.14 (m,
1.46H), 3.77 (dd, J1=8.2 Hz, J2=9.2 Hz, 0.69H), 3.68-3.57 (m, 2H), 3.10 (dt, J1=2.5, J2=9.1,
0.56H), 2.94 (d, J=8.3, 0.33H), 2.71 (ddd, J1=2.7, J2=3.8, J3=6.6, 0.34H), 2.58-2.53 (m, 0.58H),
2.27 (d, J=2.6, 0.3H), 2.15 (d, J=2.52, 0.53H), 1.80-1.16 (m, 4.5H), 1.10 (s, 2H), 1.03 (s, 1.1H),
0.89 and 0.88 (s, 9H), 0.05 (s, 1.8H), 0.039 (s, 3.12H); 13C-NMR (CDCl3) δ 105.1, 101.8, 84.25,
80.8, 72.3, 73.4, 72.3, 70.6, 63.7, 63.6, 48.7, 48.35, 39.35, 38.6, 29.6, 29.0, 28.2, 27.9, 76.0,
25.95, 22.9, 18.4, 18.3, 17.7, -5.3; IR (neat film) 3312, 2954, 2857, 1463, 1255, 1099, 939, 836,
151
775, 635 cm-1; HRMS Calc for C16H30O3Si [M+H-H2O]+ 281.1931, found 281.1942; calc for
C16H30O3Si [M+Na]+ 321.1856, found 321.1864.
OH
OTBS
O
OMe
(MeO)3CH,
PPTS
OTBS
O
Methyl acetal 98. To 473 mg of lactol 97 (1.58 mmol, 1 equiv.) in 26 mL of methylene chloride
and 2.1 mL of trimethylorthoformate (19 mmol, 12 equiv.) under argon atmosphere PPTS (40
mg, 0.158 mmol, 0.1 equiv.) was added in one portion. The reaction mixture was stirred at
ambient temperature and monitored by TLC. After 3 hours the reaction mixture was quenched
with 15 mL aqueous NaHCO3, 20 mL of methylene chloride were added, the phases were
separated and water phase was extracted with DCM (2x10 mL), combined organic phase was
washed with NaHCO3 aqueous solution (2x20 mL), then with brine (20 mL). The organic phase
was dried over MgSO4, filtered and concentrated by rotary evaporation. The crude product was
purified by silica gel chromatography to furnish 452 mg of 98 (92% yield).
1
H-NMR (CDCl3) δ 4.60 (s, 0.84H), 4.45 (s, 0.12H), 4.3-4.12 (m, 0.21H), 4.14 (dd, J=8.3 Hz,
J=8.85 Hz, 1H), 4.00-3.93 (m, 0.11H), 3.79 (dd, J1=8.18, J2-9.19, 1H), 3.68-3.55 Hz (m, 2H),
3.34 and 3.32 (s, 3H), 3.04 (dt, J1=2.6 Hz, J2=9.2 Hz, 0.83H), 2.74-2.68 (m, 0.04H), 2.18 (d,
J=2.6, 0.12H), 2.15 (d, J=2.6 Hz, 0.88H), 1.74-1.21 (m, 4H), 1.06 and 1.04 (s, 3H), 0.90 (s, 9H),
0.053 (s, 6H); characteristic peaks of two diastereomers 70 by 13C-NMR (CDCl3) δ 110.9, 108.4,
81.3, 72.8, 70.6, 63.8, 55.1, 48.5, 39.9, 30.1, 28.2, 26.2, 18.6, 17.9, -5.05; IR (neat film) 3312,
2954, 2857, 1463, 1384, 1256, 1098, 1011, 836, 775 cm-1; HRMS Calc for C17H32O3Si [M+Na]+
335.2013, found 335.199.
OMe
OMe
OTBS
O
TBAF
THF
OH
O
Alcohol 99. To 68 mg of methyl acetal 98 (0.218 mmol, 1 equiv.) in 1.1 mL of THF at 0 oC 0.52
mL of 1 M TBAF solution in THF was added dropwise. The reaction mixture was kept at 0 oC
for 7.5 hours, while monitored by TLC. Then it was quenched with 3 mL of aqueous NH4Cl,
diluted with 15 mL of ether, 5 more mL of DCM were added, phases were separated, water
152
phase was extracted with etgher (3x5mL). The organic phase was washed with NH4Cl(aq.) (10
mL), NaHCO3(aq.) (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated.
Purification of the product by column chromatography provided 118 mg of product 99 with 90%
yield.
1
H-NMR (CDCl3) δ 4.61 (s, 0.69H), 4.48 (s, 0.23H), 4.27 (t, J=8.5 Hz, 0.26 H), 4.15 (dd, J1=8.2
Hz, J2=8.9 Hz, 0.77H), 3.97 (dd, J1=5.05, J2=8.5 Hz, 0.25H), 3.80 (dd, J1=8.3 Hz, J2=9.05 Hz,
0.77H), 3.72-3.61 (m, 2H), 3.80 (dd, J1=8.3 Hz, J2=9.05 Hz, 0.77H), 3.72-3.61 (m, 2H), 3.35 (s,
0.76H), 3.33 (s, 2.14H), 3.06 (dt, J1=2.6 Hz, J2=9.1 Hz, J3=9.1 Hz, 0.68), 2.77-2.70 (m, 0.22H),
2.20 (d, J-2.65, 0.2H), 2.17 (d, J=2.6 Hz, 0.56H), 1.84-1.25 (m, 5H), 1.08 (s, 2.15H), 1.054 (s,
0.75H); characteristic peaks of two diastereomers 99 by 13C-NMR (CDCl3) δ 110.5, 108.2, 81.0,
72.7, 72.0, 71.6, 70.4, 63.45, 63.4, 55.0, 54.9, 48.3, 39.6, 39.4, 29.9, 28.5, 28.4, 28.0, 24.40,
17.7; IR (neat film) 3292, 2917, 1100, 1053 cm-1; HRMS Calc for C11H18O13 [M+Na]+
221.1148, found 242.2814.
OMe
CO2Me
OMe
OH
1. Swern oxid'n
O
O
2.
CO2Me
Ph3P
Methyl alkenoate 100. Oxalyl chloride (310 mg, 2.44 mmol, 2 equiv.) was added to the solution
of DMSO (381 mg, 4.88 mmol, 4 equiv.) in 5 mL of methylene chloride at -78 ºC. After stirring
the mixture for 15 min alcohol 99 (242 mg, 1.22 mmol, 1 equiv.) in 3 mL of methylene chloride
was added dropwise. The solution was stirred for 10 min at -78 ºC and for 10 min at -25 ºC, then
617 mg of triethylamine was added (6.1 mmol, 5 equiv.) at -78 ºC and the reaction mixture was
allowed to warm to room temperature over 1 hour. The mixture was diluted with 30 mL of ethyl
ether, washed with 15 mL of water, water phase was extracted with 10 mL of ether, combined
organic layers were washed with water (15 mL) and brine (15 mL), dried over MgSO4, filtered,
and concentrated in vacuo. Obtained crude aldehyde as a yellow oil was involved in the next step
without further purification.
Aldehyde
(1.22
mmol,
1
equiv.)
was
dissolved
in
6
mL
of
toluene,
[1-
(methoxycarbonyl)ethyl]triphenylphosphorane 94241 (637 mg, 1.83 mmol, 1.5 equiv.) was added
in one portion and the reaction mixture was heated to 35 ºC for 10-12 hours. Solvent was
153
evaporated and crude residue was purified by silica gel chromatography to yield 288 mg (93%
yield) of olefinated product 100.
1
H-NMR (CDCl3) δ 6.75 (br t, 1H), 4.63 (s, 0.87H), 4.47 (s, 0.11H), 4.30-4.22 (m, 0.14H), 4.15
(dd, J1=3.3 Hz, J2=9.0 Hz, 1H), 3.99-3.93 (m, 0.14H), 3.79 (dd, J1=8.2 Hz, J2= 9.0 Hz, 1H),
3.73 (s, 3H), 3.34 and 3.33 (s, 3H), 3.06 (dt, J1=2.5 Hz, J2=9.0 Hz, J3=9.1 Hz, 0.82H), 2.73
(ddd, J1=2.7 Hz, J2=5.2 Hz, J3=8.1 Hz, 0.07H), 2.36-2.06 (m, 2H), 2.17 (d, J=2.5, 1H), 1.84 (s,
3H), 1.75-1.60 (m, 1H), 1.57-1.42 (m, 1H), 1.09 and 1.07 (s, 3H); major diastereomer of 100 by
13
C-NMR (CDCl3) δ 168.6, 141.9, 127.7, 108.0, 80.8, 72.9, 70.4, 54.95, 51.7, 48.4, 39.5, 32.8,
24.0, 17.7, 12.4; IR (neat film) 3291, 2951, 1716, 1651, 1436, 1384, 1282, 1194, 1155, 1096,
1052, 1011, 967, 748 cm-1; HRMS Calc for C15H22O4 [M+Na]+ 289.1410, found 289.1392.
OMe
CO2Me
CO2Me
OMe
I
CO2Me
O
O
cat. PdCl2(PPh3)2,
cat. CuI
CO2Me
Alkenynoate 101. To the mixture of alkyne 100 (268 mg, 1.006 mmol, 1 equiv.) and iodide 60
(224 mg, 1.05 equiv.) in 10 mL of triethylamine dichlorobis(triphenylphosphine)palladium (II)
(28 mg, 0.04 mmol, 4-mol%) was added, followed by copper iodide (4 mg, 0.02 mmol, 2-mol%).
The reaction mixture was heated to 35 oC for 1.5 hour, then crude material evaporated with silica
and purified by chromatography column to 322 mg of material 101 in 92% yield.
1
H-NMR (CDCl3) δ 6.67 (br t, 1H), 6.20-6.12 (m, 1H), 6.08 (d, J=11.5 Hz, 1H), 4.66 (s, 0.97H),
4.50 (s, 0.11H), 4.24-4.23 (m, 1H), 3.91-3.82 ()m, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.35 (s, 3H),
3.35-3.28 (m, 0.55H), 2.37-2.10 (m, 2H), 1.84 (s, 3H), 1.81-1.69 (m, 1H), 1.61-1.46 (m, 1H),
13
1.15 (s, 3H); major diastereomer of 101 by
C-NMR (CDCl3) δ 168.5, 164.9, 142.0, 128.0,
127.5, 123.1, 108.0, 99.4, 81.6, 70.1, 54.9, 51.6, 51.3, 49.2, 49.1, 40.9, 32.8, 23.9, 17.7, 12.2; IR
(neat film) 2951, 2213, 1715, 1611, 1437, 1285, 1233, 1196, 1096, 1031, 818 cm-1; HRMS Calc
for C19H26O6 [M+Na]+ 373.1627, found 373.1628.
OMe
ICl
O
CO2Me
OMe
CO2Me
O
O
CO2Me
I
154
O
5-Iodopyrone 102. The reaction was carried out in the dark under argon atmosphere using
degassed methylene chloride. Dienyne 101 (15 mg, 0.041 mmol, 1 equiv.) was dissolved in 2 mL
of methylene chloride. Solution of iodine monochloride in dichlromethane (0.47 mL, 1 M in
DCM, 0.47 mmol, 1.1 equiv.) was added dropwise at 0 ºC. After 7 hours 1 mL of aqueous
Na2S2O3 (3 mL) was added, the mixture was diluted with 30 mL of DCM, additional 15 mL of
aqueous Na2S2O3 were added, water layer was extracted with DCM (10 mL), combined organic
phases were washed with 15 mL of sodium thiosulphate and 15 mL of brine, dried over MgSO4,
filtered and concentrated in vacuo. The crude brown oil was purified by column chromatography
(gradient elution 5-30% ethyl acetate/hexane) to yield 123 mg (62%) of the desired 5-iodopyrone
75 as a yellow oil together
1
H-NMR (CDCl3) δ 7.48 (d, J=9.7 Hz, 0.62H), 7.44 (d, J=9.7 Hz, 0.33H), 6.66 (br t, 1H), 6.03
and 6.00 (d, J=9.7 Hz, 1H), 4.72 (s, 0.67H), 4.53 (s, 0.30H), 4.34-4.10 (m, 2.14H), 3.86-3.79 (m,
0.78H), 3.72 (s, 3H), 3.47 (dd, J1=6.9 Hz, J2=8.7 Hz, 0.4H), 3.40 (s, 2.1H), 3.37 (s, 0.93H),
2.23-2.02 (m, 2H), 1.80 (s, 3H), 1.76-1.57 (m, 1H), 1.36-1.2 (m, 1H), 1.32 and 1.25 (s, 3H);
Characteristic peaks of two diastereomers 102 by
13
C-NMR (CDCl3) δ 168.6, 168.4, 162.7,
162.2, 160.2, 151.9, 151.3, 142.1, 141.5, 127.8, 127.6, 115.5, 115.4, 109.4, 108.9, 71.2, 68.0,
67.5, 55.4, 55.2, 54.2, 53.8, 52.5, 52.3, 51.7, 32.8, 30.5, 26.2, 24.5, 24.2, 19.6, 12.4, 12.2; IR
(neat film) 2951, 1738, 1598, 1537, 1434, 1284, 1097, 1038, 1011, 820 cm-1; HRMS Calc for
C18H23IO6Si [M+Na]+ 485.0437, found 485.0432.
60% AcOH
O
O
I
CO2Me
OH
CO2Me
OMe
O
O
O
O
I
Lactol 103. A solution of mixed acetal 102 (76 mg, 0.164 mmol) in 1.7 mL of acetic acid (60%
in water) with catalytic amount of H2SO4 (1 drop) was heated to 60 oC for 5 hours. The reaction
mixture was cooled down to the room temperature poured into 25 mL of DCM with 10 mL of
NaHCO3(aq.), more of NaHCO3 was added in portions until no gas evolves. The phases were
separated in separatory funnel, water phase was extracted with DCM (3x10 mL. The combined
organic layers were washed with 10 mL of aqueous NaHCO3, brine (10 mL), dried over MgSO4,
155
filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography
to yield 54 mg of pure 103 (73% yield).
1
H-NMR (CDCl3) δ 7.49, 7.47 (d, J=9.7, 1H), 6.66 (br t, 1H), 6.04 (d, J=9.7, 1H), 5.29 (d, J=3.7
Hz, 0.66H), 5.07-5.00 (m, 0.36H), 4.36-4.17 (m, 2H), 3.87 (dd, J1=7.1 Hz, J2=8.5 Hz, 0.75H),
3.72 (s, 3H), 3.52 (dd, J1=4.9 Hz, J2=8.1 Hz, 0.38H), 3.18-3.10 (m, 0.28H), 2.61 (bs, 0.62H),
2.37-1.96 (m, 2.33H), 1.81 and 1.80 (s, 3H), 1.73-1.14 (m, 2H), 1.31 and 1.29 (s, 3H);
13
characteristic peaks of two diastereomers 103 by
C-NMR (CDCl3) δ 162.9, 162.2, 151.9,
151.6, 141.6, 141.4,128.0, 127.9, 115.6, 115.4, 104.7, 102.5, 71.1, 69.3, 67.6, 54.9, 53.6, 52.1,
51.8, 32.5, 31.1, 25.6, 24.2, 24.1, 19.3, 12.4; IR (neat film) 3431, 2919, 1714, 1598, 1538, 1435,
1286, 1012, 822, 751 cm-1; HRMS Calc for C17H21I1O6 [M+Na]+ 471.0281, found 471.0270.
O
I
O
O
CO2Me
O
CO2Me
OH
Swern oxid'n
O
I
O
O
5-Iodopyrone 96 via oxidation of 103. Oxalyl chloride (5 mg, 0.0385 mmol, 1.15 equiv.) was
added to the solution of DMSO (7.3 mg, 0.094 mmol, 4 equiv.) in 0.2 mL of methylene chloride
at -78 ºC. After stirring the mixture for 15 min at -78 ºC lactol 103 (15 mg, 0.0335 mmol, 1
equiv.) in 0.15 mL of methylene chloride was added dropwise. The solution was stirred for 10
min at -78 ºC and for 10 min at -25 ºC, then 24 μL of triethylamine was added (0.168 mmol, 5
equiv.) at -78 ºC and the reaction mixture was allowed to warm to room temperature over one
hour. The mixture was diluted with 10 mL of ethyl ether, washed with 5 mL of water, water
phase was extracted with 2x5 mL of ether, combined organic layers were washed with water (5
mL) and brine (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. Crude product
was dissolved in 25% ethyl acetate/hexane and filtered through a plug of silica gel. Solvent was
removed by rotary evaporation to give 13 mg of product 96 (87% yield).
The characterization data was reported earlier in this section.
156
O
CO2Me
O
O
O
100 oC
PhCH3
I
CO2Me
I
O
O
O
O
Cycloadduct bearing lactone tether 104. A solution of 5-iodopyrone 96 (24 mg, 0.0538 mmol,
1 equiv.) in 12 mL of toluene in a sealed tube under argon was heated to 100 ºC for 26 hours.
Solvent was evaporated and crude oil containing cycloadduct 104 as the only present
diastereomer was purified by silica gel chromatography (using 20% and 30% ethyl
acetate/hexanes) to give 19 mg of pure product (79% yield).
1
H-NMR (CDCl3) δ 7.09 (d, J=6.6 Hz, 1H), 4.48 (dd, J1=6.2 Hz, J2=9.9 Hz, 1H), 4.25 (d, J=9.9
Hz, 1H), 3.7 (s, 3H), 3.52 (d, J=6.6 Hz, 1H), 2.92 (d, J=6.0 Hz, 1H), 2.46 (dd, J1=3.8, J2=12.3
Hz, 1H), 2.40-2.29 (m, 1H), 1.77-1.39 (m, 3H), 1.36 (s, 3H), 1.25 (s, 3H); 13C-NMR (CDCl3) δ
179.1, 174.6, 169.1, 143.0, 98.8, 84.2, 85.5, 53.6, 53.1, 50.9, 48.5, 43.5, 40.9, 30.4, 26.1, 21.2,
20.8; IR (neat film) 3521, 2953, 2255, 1770, 1732, 1456, 1366, 1207, 1120, 1008, 917, 730 cm-1;
HRMS Calc for C17H19IO6 [M+Na]+ 469.0124, found 469.0121.
OH
OTBS
O
Ph3P
OTBS
HO
THF
Alcohol 109. To 1.15 g of methyl triphenylphosphonium bromide (3.216 mmol, 3 equiv.) in 6.5
mL of THF solution of t-BuOK (2.8 mL, 1 M in THF, 2.8 mmol, 2.6 equiv.) was added at 0 oC.
Upon stirring the reaction mixture for 30-40 min lactol 97 (323 mg, 1.072 mmol, 1 equiv.) in 3.2
mL of THF was added dropwise. The reaction mixture was allowed to warm up to room
temperature and was stirred for 16 hours, then heated to 60 oC for 2.5 hours. After the mixture
was cooled to room temperature 50 mL of aqueous NH4Cl were added, then the water phase was
extracted with 70 mL of ether, and then with ethyl acetate (3x20 mL). The organic phases were
combined and washed with aqueous HN4Cl (50 mL), NaHCO3(aq) (50 mL) and brine (50 mL),
then dried over MgSO4. The solvent was removed in vacuo and the crude product was
concentrated in vacuo and purified by column chromatography to provide 291 mg of alcohol 109
in 91% yield.
157
1
H-NMR (CDCl3) δ 5.86 (dd, J1=10.9 Hz, J2=17.6 Hz, 1H), 5.02 (ddd, J1=1.2, J2=14.2,
J3=18.8, 1H), 3.74-3.62 (m, 1H); 3.62-3.46 (m, 3H), 2.59-2.52 (m, 1H), 2.19 (d, J=2.5, 1H), 1.76
(dd, J1=3.91, J2=9.6, 1H), 1.57-1.32 (m, 4H), 1.049 (s, 3H), 0.865 (s, 9H), 0.018 (s, 6H);
13
C-
NMR (CDCl3) δ 143.3, 113.6, 83.3, 73.0, 63.4, 61.95, 45.1, 40.75, 34.95, 27.2, 25.9, 20.4, 18.2,
-5.35; IR (neat film) 3309, 2952, 1255, 1099, 835, 775 cm-1; HRMS Calc for C17H32O2Si
[M+H]+ 297.2244, found 297.2230; calc for C17H32O2Si [M+Na]+ 319.2064, found 319.2044.
OTBS
HO
PMB-trichloroacetimidate
OTBS
PMBO
CSA
PMB-protected alcohol 110. The reaction mixture containing alcohol 109 (47 mg, 0159 mmol,
1 equiv.) and PMB-trichloroacetoimidate (81 mg, 0.85 mmol, 1.8 equiv.) in 0.5 mL of
dichloromethane was cooled to 0 oC, catalytic CSA (4 mg, 10-mol% was added). The reaction
mixture was warmed to room temperature and stirred for 10 hours, then quenched by addition of
aqueous NaHCO3 (5 mL), diluted with ether 7 mL, the water phase was extracted with ether (2x4
mL), the combined organic layers were washed with aqueous NaHCO3 (5 mL), brine (5 mL) and
dried over MgSO4. After concentration in vacuo crude product was purified by column
chromatography to furnish 5.5 mg of pure product 110 (72% yield).
1
H-NMR (CDCl3) δ 7.29-7.24 (m, 3H), 6.91-6.84 (m, 2H), 5.85 (dd, J1=10.9 Hz, J2=17.5 Hz,
1H), 5.07 (dd, J1=1.2 Hz, J2=10.9 Hz, 1H), 4.96 (dd, J1=1.2 Hz, J2=17.6 Hz, 1H), 4.50 (d,
J=11.8 Hz, 1H), 4.45 (d, J=12.0 Hz, 1H), 3.80 (s, 3H), 3.60-3.53 (m, 3H), 3.46-3.38 (m, 1H),
2.64-2.57 (m, 1H), 2.14 (d, J=2.4 Hz, 1H), 2.64-2.57 (m, 1H), 2.14 (d, J=2.4 Hz, 1H), 1.56-1.36
(m, 4H), 1.06 (s, 3H), 0.89 (s, 9H), 0.04 (s, 6H). Characteristic peaks in
13
C-NMR (CDCl3) δ
143.5, 129.2, 113.7, 113.6, 72.7, 71.4, 70.0, 63.6, 55.3, 42.1, 41.1, 35.0, 26.0, -5.3. IR (neat film)
3309, 2928, 2856, 1613, 1514, 1463, 1360, 1248, 1173, 1100, 1038, 835, 775 cm.-1
HRMS Calc for C25H40O3Si [M+Na]+ 439.2644, found 439.2627.
OTBS
OTBS
PMBO
I
CO2Me
PMBO
cat. PdCl2(PPh3)2,
cat. CuI
CO2Me
158
Alkynenoate 111. Alkynenoate 111 was prepared from 110 following the same procedure as
reported for formation of 88.
1
H-NMR (CDCl3) δ 7.28-7.24 (m, 3H), 6.89-6.83 (m, 2H), 6.18 (dd, J1=2.3 Hz, J2=11.4 Hz,
1H), 6.03 (d, J=11.6 Hz, 1H), 5.93 (dd, J1=10.8 Hz, J2=17.5 Hz, 1H), 5.08 (dd, J1=1.2 Hz,
J2=10.9 Hz, 1H), 4.98 (dd, J1=1.2 Hz, J2=17.6 Hz, 1H) 4.50 (d, J=4.7 Hz, 1H), 4.45 (d, J=4.7
Hz, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.66-3.44 (m, 4H), 2.88-2.80 (m, 1H), , 1.63-1.37 (m, 4H),
1.11 (s, 3H), 0.88 (s, 9H), 0.03 (s, 6H); 13C-NMR (CDCl3) δ 143.8, 130.62, 129.4, 127.5, 123.9,
114.0, 113.8, 103.9, 80.8, 72.9, 70.3, 63.9, 55.5, 51.5, 43.9, 42.1, 35.3, 27.7, 26.2, 21.0, 18.6, 5.05; IR (neat film) 2951, 2856, 2209, 1731, 1612, 1514, 1463, 1438, 1249, 1194, 1174, 1098,
1037, 1006, 916, 835, 751 cm-1; HRMS Calc for C29H44O5S [M+Na]+ 523.2856, found
523.2849.
OH
OTBS
PMBO
PMBO
CO2Me
AcOH:THF:H2O
(3:1:1)
CO2Me
Alcohol 112. Compound 111 underwent TBS-deprotection according to the same procedure as
reported for 89.
1
H-NMR (CDCl3) δ 7.29-7.24 (m, 3H), 6.91-6.84 (m, 2H), 6.21 (dd, J1=1.2, J2=11.4, 1H), 6.07
(d, J1=11.5 Hz, 1H), 5.92 (dd, J1=10.9 Hz, J2=17.5 Hz, 1H), 5.09 (dd, J=1.2 Hz, J=10.9 Hz),
4.97 (dd, J=1.2 Hz, J2=17.6, 1H), 4.9 (d, J=11.6 Hz, 1H), 4.45 (d, J1=11.8 Hz, 1H), 3.8 (s, 3H),
3.73 (s, 3H), 3.71-3.58 (m, 3H), 3.52-3.43 (m, 1H), 2.89-2.82 (m, 1H), 2.31- 2.25 (m, 1H), 1.891.65 (m, 2H), 1.64-1.38 (m, 2H), 1.28-1.18 (m, 1H), 1.11 (s, 3H); characteristic peaks 13C-NMR
(CDCl3) δ 143.2, 129.2, 127.1, 124.4, 113.9, 113.7, 80.6, 72.7, 70.0, 63.3, 55.3, 51.5, 43.8, 41.9,
35.5, 27.3, 20.7; IR (neat film) 3500, 2919, 1713, 1610, 1513, 1172, 816 cm-1; HRMS Calc for
C23H30O5 [M+Na]+ 409.1991, found 409.1991.
CO2Me
OH
PMBO
CO2Me
1. Swern oxid'n
PMBO
CO2Me
2.
CO2Me
Ph3P
159
Methyl alkenoate 113. Compound 113 was prepared following the same standard procedure as
reported for 100.
1
H-NMR (CDCl3) δ 7.29-7.23 (m, 3H), 6.90-6.83 (m, 2H), 6.77 (br t, 1H), 6.18 (dd, J1=2.2 Hz,
J2=11.5 Hz, 1H), 6.05 (d, J=11.4, 1H), 5.60 (dd, J1=10.8 Hz, J2=17.6 Hz, 1H), 5.13 (dd, J1=1.1
Hz, J2=10.9 Hz, 1H), 5.01 (dd, J=1.14 Hz, J2=17.6 Hz, 1H), 4.50 (d, J=11.9, 1H), 4.45 (d,
J=11.5, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.63 (dd, J1=5.0, J2=9.4, 1H), 3.49 (dd, J1=7.8 Hz,
J2=9.3 Hz, 1H), 2.89-2.82 (m, 1H), 2.29-1.99 (m, 1H), 1.81 (s, 3H), 1.74-1.62 (m, 2H), 1.15 (s,
3H); characteristic peaks 13C-NMR δ .143.06, 129.2, 127.5, 123.5, 113.7, 72.8, 70.0, 55.3, 51.6,
51.3, 42.2, 37.6; IR (neat film) 2916, 1713, 1613, 1514, 1436, 1248, 1174, 1100, 818 cm-1;
HRMS Calc for C27H34O6 [M+Na]+ 477.2253, found 477.2239.
OTBS
HO
TBDPSCl
OTBS
TBDPSO
imidazole, DMF
TBDPS-protected alcohol 116. To 250 mg of alcohol 109 (0.843 mmol, 1 equiv.) and 143 mg
of imidazole (2.108 mmol, 2.5 equiv.) in DMF tert-butyldiphenylsilyl chloride (0.28 mL, 301
mg, 1.096 mmol, 1.3 equiv.) was added at ambient temperature. The reaction was worked up
after stirring for 24 hours at ambient temperature. The mixture was diluted with 50 mL of ether,
followed by 30 mL of water, the water phase was extracted with ether (2x25 mL). Combined
organic phases were washed with NH4Cl(aq.) (30 mL), NaHCO3(aq.) (30 mL) and brine (30
mL).The organic phase was dried over MgSO4 and concentrated. Product 116 (418 mg) was
isolated by column chromatography in 93% yield.
1
H-NMR (CDCl3) δ 7.72-7.66 (m, 4H), 7.46-7.36 (m, 6H), 5.80 (dd, J1=10.8 Hz, J2=17.6 Hz,
1H), 5.00 (dd, J1=1.3 Hz, J2=10.9, 1H), 4.88 (dd, J1=1.3 Hz, J2=17.5 Hz, 1H), 3.81-3.63 (m,
2H), 3.58-3.48 (m, 2H), 2.54-2.45 (m, 1H), 2.12 (d, J1=2.5 Hz, 1H), 1.52-1.2 (m, 4H), 1.05 (s,
9H), 0.98 (s, 3H), 0.88 (s, 3H); 13C-NMR (CDCl3) δ 143.6, 135.65, 135.6, 133.7, 133.5, 129.6,
129.55, 127.6, 113.3, 84.3, 71.5, 63.8, 63.6, 44.8, 41.0, 35.0, 27.4, 26.8, 26.0, 20.6, 19.2, 18.3, 5.3; IR (neat film) 3309, 2930, 2887, 2857, 1472, 1428, 1389, 1255, 1104, 1006, 835, 775, 738,
701, 614 cm-1; HRMS Calc for C33H50O2Si2 [M+Na]+ 557.3247, found 557.3244.
160
OH
OTBS
TBDPSO
AcOH:H2O:THF
(3:1:1)
0 oC, r.t.
TBDPSO
Alcohol 117. To 415 mg of compound 116 (0.776 mmol, 1 equiv.) cooled down to 0 oC in THF
(3 mL) and water (3 mL) 9 mL of glacial acetic acid was added fast. The reaction mixture was
warmed to room temperature and stirred for four hours. Methylene chloride (70 mL) was added
to the reaction mixture, followed by addition of solid potassium carbonate in portions until no
more gas evolves, 20 mL of water was added and the phases were separated in separatory funnel.
The water phase was extracted with methylene chloride (2x25 mL), the combined organic phases
were washed with aqueous NaHCO3 (25 mL) and brine (25 mL) and dried over MgSO4. The
solvent was removed by rotary evaporation under vacuum and the crude product was purified by
column chromatography to furnish 325 mg of pure product (99% yield).
1
H-NMR (CDCl3) δ 7.72-7.65 (m, 4H), 7.47-7.34 (m, 6H), 5.82 (dd, J1=10.9 Hz, J2=17.5 Hz,
1H), 5.02 (dd. J1=1.2 Hz, J2=10.8 Hz, 1H), 4.90 (dd, J1=1.2, J2=17.6, 1H), 3.82-3.64 (m, 2H),
3.63-3.53 (m, 2H), 2.50 (ddd, J1=2.44 Hz, J2= 5.2, J3=7.7 Hz, 1H), 2.13 (d, J1=2.5 Hz), 1.531.33 (m, 4H), 1.16 (t, J1=5.5 Hz, 1H), 1.05 (s, 9H), 1.0 (s, 3H);
13
C-NMR (CDCl3) δ 143.35,
135.6, 133.6, 133.4, 129.6, 129.5, 127.55, 111.4, 84.1, 71.6, 63.7, 63.3, 44.6, 40.9, 34.9, 27.2,
26.7, 20.4, 19.1; IR (neat film) 3306, 3071, 2932, 2857, 1472, 1428, 1390, 1257, 1112, 1006,
917, 824, 739, 702, 614 cm-1; HRMS Calc for C27H36O2Si [M+Na]+ 443.2382, found 443.2375.
CO2Me
OH
TBDPSO
1. Swern Oxid'n
TBDPSO
2.
CO2Me
Ph3P
PhCH3, 40 oC
Alkenoate 118. Oxalyl chloride (145 mg, 1.14 mmol, 2 equiv.) was added to the solution of
DMSO (179 mg, 2.29 mmol, 4 equiv.) in 2.5 mL of methylene chloride at -78 ºC. After stirring
the mixture for 15 min at -78 oC alcohol 117 (240 mg, 0.57 mmol, 1 equiv) in 2.0 mL of
methylene chloride was added dropwise. The solution was stirred for 15 min at -78 ºC and for 15
min at -25 ºC, then 0.4 mL of triethylamine (290 mg, 3.1 mmol, 5 equiv.) was added at -78 ºC
and the reaction mixture was allowed to warm up to room temperature over 1 hour. The mixture
was diluted with 50 mL of methylene chloride, washed with 30 mL of water, the water phase
161
was extracted with 2x15 mL of methylene chloride, the combined organic layers were washed
with NH4Cl(aq) (30 mL), NaHCO3(aq) (30 mL) and brine (30 mL), dried over MgSO4, filtered, and
concentrated in vacuo. Obtained 236 mg (>99%) of the crude aldehyde as a yellow oil was
involved in the next step without further purification.
Prepared aldehyde (0.57 mmol, 1 equiv.) was dissolved in 2.9 mL of toluene, [1(methoxycarbonyl)ethyl]triphenylphosphorane 94241 (278 mg, 0.799 mmol, 1.4 equiv.) was
added in one portion and the reaction mixture was heated to 40 ºC for 15 hours. Solvent was
evaporated and crude residue was purified by silica gel chromatography to yield 235 mg (84%
yield) of product 118 as a colorless oil.
1
H-NMR (CDCl3) δ 7.72-7.65 (m, 4H), 7.47-7.33 (m, 6H), 6.71 (br t, 1H), 5.82 (dd, J1=10.9 Hz,
J2=17.6 Hz, 1H), 5.05 (dd, J1=1.1 Hz, J2=10.8 Hz, 1H), 4.92 (dd, J1=1.0 Hz, J2=17.6 Hz, 1H),
3.73 (s, 3H), 3.79-3.64 (m, 2H), 2.50 (ddd, J1=2.5 Hz, J2=5.2 Hz, J3=7.6 Hz, 1H), 2.14 (d,
J1=2.5 Hz, 1H), 2.17-1.91 (m, 2H), 1.80 (s, 3H), 1.67-1.46 (m, 1H), 1.05 (s, 9H), 1.02 (s, 3H);
13
C-NMR (CDCl3) δ 168.7, 143.0, 142.5, 135.7, 133.6, 133.5, 129.7, 129.6, 127.6, 127.4,
113.85, 83.9, 71.8, 63.8, 51.7, 44.6, 41.3, 37.6, 26.8, 23.5, 20.4, 19.2, 12.3; IR (neat film) 2930,
1714, 1428, 1283, 1111, 824, 702 cm-1; HRMS Calc for C31H40O3Si [M+Na]+ 511.2644, found
511.2622.
CO2Me
CO2Me
I
TBDPSO
CO2Me
TBDPSO
cat. PdCl2(PPh3)2,
cat. CuI, Et3N
CO2Me
Alkynenoate 119. To the solution of alkyne 118 (110 mg, 0.225 mmol, 1 equiv.) and iodide 60
(53
mg,
0.248
mmol,
1.1
equiv.)
in
1
mL
of
triethylamine
6
mg
of
dichlorobis(triphenylphosphine)palladium (II) (0.009 mmol, 4-mol%) were added, followed by
addition of copper iodide (0.9 mg, 0.0045 mmol, 2-mol%) at room temperature. The reaction
mixture was stirred at 40 ºC for 2.5 hours then it was diluted with 10 mL of chloroform and
evaporated with silica. The crude product adsorbed on silica was put on the silica gel column.
The gradient elution with ethyl acetate/hexane solvent system furnished 116 mg of pure product
119 in 90% yield.
162
1
H-NMR (CDCl3) δ 7.7-7.65 (m, 4H), 7.46-7.33 (m, 6H), 6.76 (br t, 1H), 6.15 (dd, J1=2.15 Hz,
J2=11.5 Hz, 1H), 6.04 (d, J1=11.5 Hz, 1H), 5.91 (dd, J1=10.9 Hz, J2=17.6 Hz, 1H), 5.07 (d,
J1=10.8, 1H), 4.94 (d, J1=17.6 Hz, 1H), 3.86-3.72 (m, 2H), 3.71 (s, 3H), 3.69 (s, 3H), 2.80-2.73
(m, 1H), 2.19-1.93 (m, 2H), 1.80 (s, 3H), 1.72-1.61 (m, 2H), 1.56 (s, 9H), 1.09 (s, 3H), 1.04 (s,
3H); 13C-NMR (CDCl3) δ 168.7, 165.0, 143.2, 142.7, 135.7, 133.6, 133.5, 129.7, 129.6, 127.6,
127.35, 123.5, 113.9, 103.5, 81.1, 63.8, 51.6, 51.3, 46.2, 42.0, 37.6, 26.8, 23.6, 20.6, 19.2, 12.3;
IR (neat film) 2917, 1714, 1428, 1195, 1112, 702 cm-1; HRMS Calc for C35H44O5Si [M+Na]+
595.2856, found 595.2849.
HO
I
CO2H
I
DCC, DMAP
O
O
Isobutyl 3-iodo-2-propenoate 120. To the mixture of iodopropenoic acid242 (300 mg, 1.52
mmol, 1 equiv.) and DMAP (37 mg, 0.30 mmol, 20-mol%) in 3 mL of dichloromethane 344 mg
of DCC (1.67 mmol, 1.1 equiv.) were added.243 The reaction mixture was stirred at ambient
temperature for 2 hours. Then, the reaction mixture without work up was filtered through a plug
of silica. The obtained solution was concentrated by rotary evaporation. The crude mixture was
purified by column chromatography to furnish 329 mg of product 120 contaminated with minor
impurity (≤85%). It was used in the next steps without further purification.
1
H-NMR (CDCl3) δ 7.45 (d, J=9.0 Hz, 1H), 6.9 (d, J=8.9 Hz, 1H), 3.98 (d, J=6.7 Hz,
1H), 2.00 (sept, J=6.7 Hz, 1H), 1.57 (s, 3H); 13C-NMR (CDCl3) δ 164.7, 130.0, 94.4, 70.9, 27.7,
19.1; IR (neat film) 2961, 1728, 1600, 1470, 1323, 1197, 1163, 999, 807 cm-1; HRMS Calc for
C7H12O2I [M+H]+ 254.9882, found 254.9891.
CO2Me
CO2Me
I
TBDPSO
O
TBDPSO
O
cat. PdCl2(PPh3)2,
cat. CuI, Et3N
O
O
Alkenynoate 121. To a solution of alkyne 118 (110 mg, 0.225 mmol, 1 equiv.) and isobutyl 3iodo-2-propenoate 120 (53 mg, 0.248 mmol, 1.1 equiv.) in 1 mL of triethylamine 6 mg of
dichlorobis(triphenylphosphine)palladium (II) (0.009 mmol, 4-mol%) were added, followed by
163
addition of copper iodide (0.8 mg, 0.004 mmol, 2-mol%) at room temperature. The reaction
mixture was stirred at 40 ºC for 4 hours then it was diluted with 10 mL of chloroform and
evaporated with silica. The crude product adsorbed on silica was put on the silica gel column.
The gradient elution with ethyl acetate/hexane solvent system furnished 109 mg of pure product
121 in 87% yield.
1
H-NMR (CDCl3) δ 7.71-7.64 (m, 4H), 7.46-7.32 (m, 6H), 6.75 (br t, 1H), 6.14 (dd, J1=2.1 Hz,
J2=11.4 Hz, 1H), 6.05 (d, J1=11.6 Hz, 1H), 5.91 (dd, J1=10.7 Hz, J2=17.4 Hz, 1H), 5.06 (d,
J=10.8 Hz, 1H), 4.93 (d, J=17.3 Hz, 1H), 3.90 (d, J=6.7 Hz, 1H), 3.84-3.73 (m, 2H), 3.71 (s, 3H),
2.79-2.71 (m, 1H), 2.19-1.86 (m, 3H), 1.79 (s, 3H), 1.69-1.59 (m, 2H), 1.09 (s, 3H), 1.04 (s, 9H),
0.92 (d, J=6.73, 6H);
13
C-NMR (CDCl3) δ 168.6, 164.5, 143.2, 142.8, 135.6, 133.6, 133.4,
129.6, 129.55, 127.7, 127.6, 127.2, 123.3, 113.8, 103.25, 81.1, 70.3, 63.7, 51.6, 46.2, 42.1, 37.6,
27.7, 26.7, 23.6, 20.6, 19.2, 19.1, 12.2; IR (neat film) 2959, 1714, 1428, 1183, 1111 cm-1;
HRMS Calc for C38H50O5Si [M+Na]+ 637.3325, found 637.3318.
CO2Me
CO2Me
ICl
TBDPSO
TBDPSO
+
O
CO2Me
I
I
O
CO2Me
O
CO2Me
5-Iodopyrone 122 from alkenynoate 119. The reaction was carried out in the dark under argon
atmosphere using degassed dry methylene chloride. Dienyne 119 (154 mg, 0.269 mmol, 1
equiv.) was dissolved in 1.35 mL of methylene chloride. Solution of iodine monochloride (0.30
mL, 1 M solution in CH2Cl2, 0.296 mmol, 1.1 equiv.) was added dropwise at 0 ºC. After 6 hours
3 mL of aqueous Na2S2O3 was added and the mixture was diluted with 20 mL of methylene
chloride, additional 10 mL of aqueous Na2S2O3 was added, water layer was extracted with
methylene chloride (15 mL). The combined organic phases were washed with 15 mL of sodium
thiosulphate and 15 mL of brine, dried over MgSO4, filtered and concentrated in vacuo. The
crude brown oil was purified by chromatography to yield 49 mg of the desired 5-iodopyrone 122
(27%) as a yellow oil. The major byproduct was isolated as well (28 mg), the data from 1HNMR spectrum was consistent with structure 115, mass-spec analysis also identified the
molecular ion consistent with the proposed structure 86 (byproduct was produced in ≤23%
yield).
164
1
H-NMR (CDCl3) δ 7.69-7.62 (m, 2H), 7.58-7.53 (m, 2H), 7.49 (d, J1=9.7, 1H), 7.45-7.33 (m,
6H), 6.62 (m, 1H), 6.00 (d, J1=9.7 Hz, 1H), 5.84 (dd, J1=10.8 Hz, J2=17.4 Hz, 1H), 5.02 (dd,
J1=0.8 Hz, J2=10.8 Hz, 1H), 4.87 (dd, J1=0.8 Hz, J2=17.4 Hz, 1H), 4.04 (t, J=10.1 Hz), 3.80
(dd, J1=4.2 Hz, J2=10.0 Hz, 1H), 3.73 (s, 3H), 3.33 (dd, J1=42 Hz, J2=10.1 Hz), 2.06-1.87 (m,
2H), 1.75 (s, 3H), 1.55-1.45 (m, 1H), 1.34-1.20 (m, 1H), 1.05 (s, 3H), 0.96 (s, 3H); 13C-NMR
(CDCl3) δ 168.6, 165.5, 160.9, 151.7, 142.0, 141.8, 135.6, 133.3, 132.9, 129.8, 127.8, 127.75,
127.6, 114.8, 114.5, 72.9, 62.4, 57.6, 51.7, 43.0, 37.9, 31.1, 29.7, 23.4, 19.3, 191.1, 12.4; IR
(neat film) 2928, 1746, 1538, 1428, 1111, 702 cm.-1
HRMS (of 122) Calc for C34H41O5ISi [M+Na]+ 707.1666, found 707.1643.
HRMS (of 115) Calc for C19H25O5I [M+Na]+ 483.0644, found 483.0631.
CO2Me
CO2Me
ICl
TBDPSO
TBDPSO
O
CO2i-Bu
O
I
5-Iodopyrone 122 from alkenynoate 121. The reaction was carried out in the dark under argon
atmosphere using degassed dry methylene chloride. Dienyne 121 (90 mg, 0.146 mmol, 1 equiv.)
was dissolved in 0.73 mL of methylene chloride. Solution of iodine monochloride (0.176 mL, 1
M solution in CH2Cl2, 0.176 mmol, 1.2 equiv.) was added dropwise at 0 ºC. After 9.5 hours 3
mL of aqueous Na2S2O3 was added and the mixture was diluted with 20 mL of methylene
chloride, additional 7 mL of aqueous Na2S2O3 were added, the water layer was extracted with
methylene chloride (15 mL). The combined organic phases were washed with 10 mL of aqueous
Na2S2O3 and 10 mL of brine, dried over MgSO4, filtered and concentrated in vacuo. The crude
brown oil was purified by chromatography to yield 36 mg of the pure desired 5-iodopyrone 121
(≥36% yield) as a yellow oil. Additional 8 mg of the product in mixture with an unknown
impurity were isolated as well.
Characterization for 122 has been reported for the previous example.
.
165
O
CO2Me
PhCH3, 100 oC
O
CO2Me
TBDPSO
O
sealed tube
O
I
TBDPSO
I
Bridged cycloadduct 123. A solution of 36 mg of 5-iodopyrone 122 (0.0526 mmol, 1 equiv.) in
12 mL of toluene was heated to 100 ºC in the sealed tube under argon for 11 days. Then, the
reaction mixture was cooled down to room temperature and solvent was evaporated. The crude
oil contained cycloadduct 123 as a single diastereomer together with some amount of the
unreacted starting 5-iodopyrone 122. The crude mixture was purified by silica gel
chromatography (gradient elution, 5-20% ethyl acetate/hexanes) to provide 24 mg of product 123
(67% yield) as a mixture with 5-iodopyrone 122 (2 mg) in 92:8 ratio estimated by 1H-NMR.
See Figure 102 for nOe correlations in support of structure 95.
1
H-NMR (CDCl3) δ 7.71-7.61 (m, 4H), 7.44-7.29 (m, 6H), 6.83 (d, J1=6.5 Hz, 1H), 6.29 (dd,
J1=11.0, J2=17.4, 1H), 4.98 (dd, J1=1.4 Hz, J2=11.0, 1H), 4.85 (dd, J1=1.5 Hz, J2=17.4, 1H),
3.85 (dd, J1=7.4 Hz, J2=11.5 Hz, 1H), 3.71 (s, 3H), 3.74-3.66 (m, 1H), 3.46 (d, J=6.5 H, 1H),
2.29 (dd, J1=1.3 Hz, J2=7.3 Hz, 1H), 2.27-2.18 (m, 1H), 1.69-1.55 (m, 4H), 1.35 (s, 3H), 1.25 (s,
3H), 1.08 (s, 9H);
13
C-NMR (CDCl3) δ 175.0, 170.4, 142.1, 140.0, 136.3, 136.0, 133.4, 133.3,
129.6, 129.5, 127.5, 114.2, 100.9, 87.9, 63.4, 55.2, 52.9, 52.6, 47.9, 44.9, 40.3, 39.2, 28.4, 27.2,
21.0, 20.5, 19.2; IR (neat film) 2924, 2850, 1770, 1736, 1428, 1210, 1104, 926, 702 cm-1;
HRMS Calc for C34H41O5Si [M+Na]+ 707.1666, found 707.1655.
166
Spectra
Figure 11. 300 MHz 1H-NMR spectrum of compound 61
167
Figure 12. 75 MHz 13C-NMR spectrum of compound 61
168
Figure 13. 300 MHz 1H-NMR spectrum of compound 63
169
Figure 14. 75 MHz 13C-NMR spectrum of compound 63
170
Figure 15. 300 MHz 1H-NMR spectrum of compound 64
171
Figure 16. 75 MHz 13C-NMR spectrum of compound 64
172
Figure 17. 300 MHz 1H-NMR spectrum of compound 65
173
Figure 18. 75 MHz 13C-NMR spectrum of compound 65
174
Figure 19. 300 MHz 1H-NMR spectrum of compound 67
175
Figure 20. 75 MHz 13C-NMR spectrum of compound 67
176
Figure 21. 300 MHz 1H-NMR spectrum of compound 69
177
Figure 22. 75 MHz 13C-NMR spectrum of compound 69
178
Figure 23. 300 MHz 1H-NMR spectrum of compound 70
179
Figure 24. 75 MHz 13C-NMR spectrum of compound 70
180
Figure 25. 300 MHz 1H-NMR spectrum of compound 72
181
Figure 26. 75 MHz 13C-NMR spectrum of compound 72
182
Figure 27. 300 MHz 1H-NMR spectrum of compound 77
183
Figure 28. 75 MHz 13C-NMR spectrum of compound 77
184
Figure 29. 300 MHz 1H-NMR spectrum of compound 80
185
Figure 30. 75 MHz 13C-NMR spectrum of compound 80
186
Figure 31. 300 MHz 1H-NMR spectrum of compound 81
187
Figure 32. 75 MHz 13C-NMR spectrum of compound 81
188
Figure 33. 300 MHz 1H-NMR spectrum of compound 84
189
Figure 34. 75 MHz 13C-NMR spectrum of compound 84
190
Figure 35. 300 MHz 1H-NMR spectrum of compound 87
191
Figure 36. 75 MHz 13C-NMR spectrum of compound 87
192
Figure 37. 300 MHz 1H-NMR spectrum of compound 82
193
Figure 38. 75 MHz 13C-NMR spectrum of compound 82
194
Figure 39. 300 MHz 1H-NMR spectrum of compound 88
195
Figure 40. 75 MHz 13C-NMR spectrum of compound 88
196
Figure 41. 300 MHz 1H-NMR spectrum of compound 89
197
Figure 42. 75 MHz 13C-NMR spectrum of compound 89
198
Figure 43. 300 MHz 1H-NMR spectrum of compound 90
199
Figure 44. 75 MHz 13C-NMR spectrum of compound 90
200
Figure 45. 300 MHz 1H-NMR spectrum of compound 91
201
Figure 46. 75 MHz 13C-NMR spectrum of compound 91
202
Figure 47. 300 MHz 1H-NMR spectrum of compound 92
203
Figure 48. 75 MHz 13C-NMR spectrum of compound 92
204
Figure 49. 300 MHz 1H-NMR spectrum of compound 93
205
Figure 50. 75 MHz 13C-NMR spectrum of compound 93
206
Figure 51. 300 MHz 1H-NMR spectrum of compound 95
207
Figure 52. 75 MHz 13C-NMR spectrum of compound 95
208
Figure 53. 300 MHz 1H-NMR spectrum of compound 96
209
Figure 54. 75 MHz 13C-NMR spectrum of compound 96
210
Figure 55. 300 MHz 1H-NMR spectrum of compound 97
211
Figure 56. 75 MHz 13C-NMR spectrum of compound 97
212
Figure 57. 300 MHz 1H-NMR spectrum of compound 98
213
Figure 58. 75 MHz 13C-NMR spectrum of compound 98
214
Figure 59. 300 MHz 1H-NMR spectrum of compound 99
215
Figure 60. 75 MHz 13C-NMR spectrum of compound 99
216
Figure 61. 300 MHz 1H-NMR spectrum of compound 100
217
Figure 62. 75 MHz 13C-NMR spectrum of compound 100
218
Figure 63. 300 MHz 1H-NMR spectrum of compound 101
219
Figure 64. 75 MHz 13C-NMR spectrum of compound 101
220
Figure 65. 300 MHz 1H-NMR spectrum of compound 102
221
Figure 66. 75 MHz 13C-NMR spectrum of compound 102
222
Figure 67. 300 MHz 1H-NMR spectrum of compound 103
223
Figure 68. 75 MHz 13C-NMR spectrum of compound 103
224
Figure 69. 300 MHz 1H-NMR spectrum of compound 104
225
Figure 70. 75 MHz 13C-NMR spectrum of compound 104
226
Figure 71. 300 MHz 1H-NMR spectrum of compound 109
227
Figure 72. 75 MHz 13C-NMR spectrum of compound 109
228
Figure 73. 300 MHz 1H-NMR spectrum of compound 110
229
Figure 74. 75 MHz 13C-NMR spectrum of compound 110
230
Figure 75. 300 MHz 1H-NMR spectrum of compound 111
231
Figure 76. 75 MHz 13C-NMR spectrum of compound 111
232
Figure 77. 300 MHz 1H-NMR spectrum of compound 112
233
Figure 78. 75 MHz 13C-NMR spectrum of compound 112
234
Figure 79. 300 MHz 1H-NMR spectrum of compound 113
235
Figure 80. 300 MHz 1H-NMR spectrum of compound 116
236
Figure 81. 75 MHz 13C-NMR spectrum of compound 116
237
Figure 82. 300 MHz 1H-NMR spectrum of compound 117
238
Figure 83. 75 MHz 13C-NMR spectrum of compound 117
239
Figure 84. 300 MHz 1H-NMR spectrum of compound 118
240
Figure 85. 75 MHz 13C-NMR spectrum of compound 118
241
Figure 86. 300 MHz 1H-NMR spectrum of compound 119
242
Figure 87. 75 MHz 13C-NMR spectrum of compound 119
243
Figure 88. 300 MHz 1H-NMR spectrum of compound 120
244
Figure 89. 75 MHz 13C-NMR spectrum of compound 120
245
Figure 90. 300 MHz 1H-NMR spectrum of compound 122
246
Figure 91. 75 MHz 13C-NMR spectrum of compound 122
247
Figure 92. 300 MHz 1H-NMR spectrum of compound 122
248
Figure 93. 75 MHz 13C-NMR spectrum of compound 122
249
Figure 94. 300 MHz 1H-NMR spectrum of compound 115
250
Figure 95. 300 MHz 1H-NMR spectrum of compound 123
251
Figure 95. 75 MHz 13C-NMR spectrum of 123
252
Figure 97. Assignment of protons of 72 based on the data from the decoupling experiment
253
O
H
O
H
O
OH
I
H
Figure 98. Through space interactions in 72 by nOe experiment
254
O
H
O
H
O
OH
I
H
Figure 99. Through space interactions in 72 by nOe experiment
255
Figure 100. Assignment of protons of 93 based on the data from the decoupling experiment
256
O
O
H
H
O
O
O
H
H
O
I
Figure 101. Through space interactions in 93 by nOe experiment
257
Figure 102. COSY spectrum of 123
258
Figure 103. Assignment of protons in structure 123, according to the data on proton coupling
from COSY experiment (Figure 101).
259
O
O
CO2Me
I
TBDPSO
H
H
123
nOe
Figure 104. Through space interactions in 123 by nOe experiment.
260
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274
BIOGRAPHICAL SKETCH
Current position:
Postdoctoral Research Associate under supervision of Professor Amos B. Smith,
University of Pennsylvania, Department of Chemistry, September 2008
Education and work experience:
August 2002 –
August 2008
Doctor of Philosophy in Organic Chemistry
Florida State University, Tallahassee, FL
GPA = 3.93/4.00
Research Advisor: Professor Gregory B. Dudley
Dissertation:
I. Siletanylmethyllithium, an ambiphilic siletane
II. Synthetic approach to basiliolide B
June 2001 –
June 2002
Laboratory Assistant
Kharkiv Institute for Single Crystals of Academy of Science of Ukraine,
Kharkiv, Ukraine
Research advisor: Professor Lidia A. Kutulia
Research project: Studies on chiral components for liquid-crystal
systems and their electrooptic properties
September 1996 – Master of Science in Chemistry
July 2001
Kharkiv National University, Kharkiv, Ukraine
Cum Laude, GPA = 4.0/4.0
Research advisor: Professor Lidia A. Kutulia
Thesis: The new chiral esters with p-menthanone skeleton as
components for liquid crystal systems
275
Research experience:
•
Lab techniques include: synthesis of complex organic molecules, optimization and
scale up of intermediates, isolation and characterization of complex compounds.
•
Familiar with Varian NMR spectrometers (300 and 500 MHz), decoupling and nOeexperiments, GC, IR, and HPLC.
Honors and Awards:
2007 – ACS Young researcher Travel Award to attend the 234th ACS National Meeting in
Boston, MA (sponsored by Schering-Plough)
2001 – Master Degree with Honor Diploma – cum laude
Publications:
1. Kozytska, M. V.; Dudley, G. B. On the intramolecular pyrone Diels-Alder approach to
basiliolide B. Tetrahedron Lett. 2008, 49, pp 2899-2901.
2. Kozytska, M. V.; Dudley, G. B. Four-membered rings with one silicon, germanium, tin, or
lead atom. In “Comprehensive Heterocyclic Chemistry III”; Katritsky, A. R., Ramsden, C.
A., Scriven, E. F. V., Taylor, R. J. K., Eds., Elsevier: Oxford, 2008; vol 2, pp 513-554.
3. Kozytska, M. V.; Dudley, G. B. Siletanylmethyllithium: an ambiphilic organosilane.
Chem. Commun. 2005, pp 3047–3049.
276
Posters and presentations:
Synthetic approach toward basiliolide B. Kozytska, M. V.; Dudley, G. B., 56th Natural
Products Gordon Conference, Tilton School, NH, July 22-27 2007 (poster)
Synthetic approach toward basiliolide B. Kozytska M. V.; Dudley G. B., 234th ACS National
Meeting, Boston, MA, August 19-23 2007 (talk)
Synthetic approach towards basiliolide B. Kozytska, M. V.; Dudley, G. B., 40th National
Organic Symposium, Durham, NC, June 3-7 2007 (poster)
Synthetic approach towards basiliolide B. Kozytska, M. V.; Dudley, G. B., 58th SERMACS,
Augusta, GA, November 1-4 2006 (talk)
Siletanylmethyllithium: an ambiphilic organosilane. M. V. Kozytska and G. B. Dudley,
National Organic Chemistry Symposium, Salt Lake City, Utah, June 12-16 2005 (poster)
Studies on siletanylmethyllithium compounds as promising one-step methylenation reagents.
Kozytska, M.; Dudley, G., SERMACS, Atlanta, GA, November 16-19 2003 (poster)
277
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