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Walsh, Anthony
Novel Methods to Access Bioactive Molecules
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Walsh, Anthony (2015) Novel Methods to Access Bioactive Molecules. Doctoral thesis, University
of Huddersfield.
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NOVEL METHODS TO ACCESS BIOACTIVE
MOLECULES
ANTHONY EDMOND JUDE WALSH
A thesis submitted to the University of Huddersfield in partial fulfilment of the requirements
for the degree of Doctor of Philosophy
The University of Huddersfield
19th November 2015
Copyright statement
i.
ii.
iii.
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thesis) owns any copyright in it (the “Copyright”) and he has given The
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1
Acknowledgements
First I would like to thank my supervisor, Prof. Joe Sweeney. Joe has been a tremendous
advisor; he’s been my harshest critic and my best advocate and I’ve learned an incredible
amount under his mentorship. I’m grateful to him for believing in my potential and for
encouraging me throughout.
I'd also like to thank my secondary advisor during my time at Reading University, Dr. David
Lindsay. David wasn't just an excellent chemist and teacher, he was also a good friend who
introduced me to some of the finer restaurants in Reading as well as the excellent quality of
Tebay Farmshop services. I also have him to 'thank' for my subsequent black coffee
addiction.
I worked with a talented bunch of people in the Sweeney group so thanks to Jim, Scarlet,
James, Chris, Lucy, Kirsty, Sam, Ian, and Tes for making my PhD a little easier. I'd
especially like to thank Tes for proof reading the first draft of this thesis. Outside the group
I'd also like to thank Georgina and Kat for their infectious enthusiasm and many well earned
coffees.
There have been a lot of support staff without whom my research simply would not have
been possible, but I'd like to single out Jim Rooney for his can do attitude and superhuman
ability to problem solve whatever equipment issue I was having that day.
Finally I want to thank my parents. Without their endless love, support and encouragement
I would never have made it this far. So I’d like to dedicate this thesis to my Mum and Dad,
who are still my greatest inspiration.
2
Abstract
This thesis is divided into two chapters detailing research on applying microwave
methodology to access aminated nucleosides in significantly reduced time frames, and
applying the Belluš-Claisen reaction to produce non-proteogenic dipeptides.
1. Amination of Nucleosides Using Microwave Methodology
2,2’-Anhydrouridine undergoes a ring opening reaction with aliphatic amines to give the
corresponding aminated product. Under conventional heating reaction times are extremely
lengthy, taking at least 3 to 4 days and up to a month in the case of very hindered amines.
A modified procedure using microwave irradiation has proven to drastically reduce reaction
time and has allowed access to novel nucleosides on gram scale.
2. Functionalised Amino Acids via the Belluš-Claisen Rearrangement
The Belluš-Claisen reaction is a [3,3] sigmatropic rearrangement of allylic amines, ethers
and thioethers to give the corresponding amide, ester of thioester. A modified procedure of
the Belluš-Claisen rearrangement was used to prepare functionalised dipeptides by reaction
of a ketene prepared from N-phthaloylglycyl chloride in situ with allylic amino acid
derivatives in the presence of a Lewis Acid and diisopropylethylamine. Rearrangments were
successfully carried out using N,N-diallyl alanine and N-allyl proline. A range of N-allyl
proline derivatives are demonstrated. However, attempts to repeat the reaction with
structurally more complex amino acids did not result in successful reactions.
3
Table of Contents
List of Figures ........................................................................................................... 7
List of Schemes ........................................................................................................ 8
List of Tables .......................................................................................................... 10
List of Abbreviations ............................................................................................... 11
1. Amination of Nucleosides Using Microwave Methodology ................................... 12
1.1 Introduction ......................................................................................................12
1.1.1 Nucleoside Chemistry ....................................................................................12
1.1.2 Microwave Chemistry ....................................................................................17
1.1.2.1 Introduction to Microwaves ......................................................................17
1.1.2.2 Microwave Theory ...................................................................................17
1.1.2.3 Microwaves and the Effect on the Speed of Reaction. ...................................19
1.1.3 Aminated Nucleosides ...................................................................................20
1.1.4 Amination of 2,2'-anhydroarabinouridine (23) and its Derivatives .......................22
1.2 Results and Discussion ........................................................................................23
1.2.1 Optimization of Protection Step ......................................................................25
1.2.2 Amenity To Larger Scale Reactions .................................................................27
1.3 Conclusions and Future Work ...............................................................................28
1.4 Experimental .....................................................................................................28
1.4.1 Numbering of atoms in a nucleoside molecule ..................................................29
1.4.2 2,2’-Anhydrouridine 16 .................................................................................29
1.4.3 TBS Protection .............................................................................................30
1.4.4 5’-O-tert-Butyldimethylsilyl-2,2’-anhydrouridine 27 ..........................................30
1.4.5 3’,5’-Di-O-tert-butyldimethylsilyl-2,2’-anhydrouridine 28 ..................................31
1.4.6 5’-O-tert-Butyldiphenylsilyl-2,2’-anhydrouridine 29 ..........................................31
1.4.7 General Amination Procedure... ......................................................................30
1.4.8 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl) -3’, 4’dihydroxyoxolan-2’-yl)-2-(methylamino)pyrimidin-6(1H)-one 30a ..............................32
1.4.9 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan2’-yl)-2- (ethylamino)pyrimidin-6(1H)-one 30b ........................................................33
1.4.10 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan2’-yl)-2-(propylamino)pyrimidin-6(1H)-one 30c .......................................................34
1.4.11 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan2’-yl)-2-(butylamino)pyrimidin-6(1H)-one 30d .........................................................35
1.4.12 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl) -3’,4’dihydroxyoxolan-2’-yl)-2-(allylamino)pyrimidin-6(1H)-one 30f ...................................36
4
1.4.13 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl) -3’,4’dihydroxyoxolan-2’-yl)-2-(iso-butylamino)pyrimidin-6(1H)-one 30e
.........................36
1.4.14 3-((2’R,3’S,4’S,5’R)-5’-((tert-utyldiphenylsilyl)oxymethyl) -3’,4’dihydroxyoxolan-2’-yl)-2-(benzylamino)pyrimidin-6(1H)-one 30i ...............................38
1.4.15 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl) -3’,4’dihydroxyoxolan-2’-yl)-2-(cyclohexylamino)pyrimidin-6(1H)-one 30j ..........................39
1.4.16 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl) -3’,4’dihydroxyoxolan-2’-yl)-2-(pentylamino)pyrimidin-6(1H)-one 30g ...............................40
1.4.17 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’dihydroxyoxolan-2’-yl)-2-(hexylamino)pyrimidin-6(1H)-one 30h ................................41
1.4.18 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan2’-yl)-2-(iso-pentylamino)pyrimidin-6(1H)-one 30k .................................................42
2. Functionalised Amino Acids via the Belluš-Claisen Rearrangement .................... 43
2.1 Introduction ......................................................................................................43
2.1.1 Amino Acids and Peptides ..............................................................................43
2.1.2 The Claisen Rearrangement ...........................................................................44
2.1.3 Claisen Variants............................................................................................47
2.1.3.1 The Eschenmoser-Claisen Rearrangement. .................................................47
2.1.3.2 The Johnson Rearrangement. ...................................................................48
2.1.3.4 The Reformatsky-Claisen Rearrangement. ..................................................51
2.1.4 The Belluš-Claisen Rearrangement ..................................................................52
2.1.4.1 Enantioselective Claisen Rearrangements. ..................................................55
2.1.4.2 Enantioselective Acyl-Claisen Rearrangement. ............................................55
2.2 Results and Discussion ........................................................................................59
2.2.1 Application to Amino Acids .............................................................................63
2.2.2 Reaction Optimization ...................................................................................71
2.2.2.1 Solvent Screen .......................................................................................71
2.2.2.2 Base Screen ...........................................................................................72
2.2.2.3 Lewis Acid Screen ...................................................................................74
2.2.3 Temperature Control .....................................................................................76
2.2.3.1 Conventional Method ...............................................................................76
2.2.3.2 Microwave ..............................................................................................76
2.2.3.3 Ring Closing Metathesis ...........................................................................78
2.3 Conclusions and Future Work ...............................................................................79
2.4 Experimental .....................................................................................................79
2.4.1 N-Phthaloylglycyl Chloride 108 .....................................................................80
2.4.2 N-Tosylglycine 121 .......................................................................................80
5
2.4.3 N-Tosylglycyl Chloride 122 ............................................................................81
2.4.4 General Belluš-Claisen Procedure ....................................................................81
2.4.5 2-Phthaloyl-N,N-dimethylpent-4-enamide 110 .................................................82
2.4.6 General Diallylation Procedure ........................................................................82
2.4.7 N,N-Diallyl alanine methyl ester 123..............................................................83
2.4.8 N,N-Diallyl isoleucine methyl ester 111c ........................................................83
2.4.9 N,N-Diallyl valine methyl ester 111a ..............................................................84
2.4.10 N,N-Diallyl leucine methyl ester 111b ...........................................................84
2.4.11 General Mono Allylation Procedure ...............................................................84
2.4.12 N-Allyl proline methyl ester 129 ..................................................................85
2.4.13 (S)-Methyl 2-((R)-N-allyl-2-(1,3-dioxoisoindolin-2-yl)pent-4-enamido)propanoate
124 ....................................................................................................................86
2.4.14 (S)-Methyl 1-((R)-2-(1,3-dioxoisoindolin-2-yl)pent-4-enoyl)pyrrolidine-2carboxylate 131 ...................................................................................................87
2.4.15 (S)-Methyl 1-((S)-2-(1,3-dioxoisoindolin-2-yl)pent-4-enoyl)pyrrolidine-2carboxylate 132 ...................................................................................................88
2.4.16 N-Crotyl L-proline methyl ester 145a ............................................................88
2.4.17 N-(2-Methylprop-2-en-1-yl)-L-proline methyl ester 145c .................................89
2.4.18 N-(3-Methylbut-2-enyl)-L-proline methyl ester 145b .....................................90
2.4.19 N-Cinnamyl-L-proline methyl ester 145e ......................................................90
2.4.20 N-(4-Methoxy-4-oxobut-2-en-1-yl)-L-Proline methyl ester 145f .......................91
2.4.21 N-(Pent-2-enyl)-L-proline methyl ester 145d .................................................92
2.4.22 (S)-Methyl 1-((2R,3S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylpent-4enoyl)pyrrolidine-2-carboxylate 146a .....................................................................93
2.4.23 (S)-Methyl 1-((R)-2-(1,3-dioxoisoindolin-2-yl)-4-methylpent-4-enoyl)pyrrolidine2-carboxylate 146c ..............................................................................................93
2.4.24 (S)-Methyl 1-((R-2-(1,3-dioxoisoindolin-2-yl)-3,3-dimethylpent-4enoyl)pyrrolidine-2-carboxylate 146b .....................................................................94
2.4.25 (S)-Methyl 1-((2S,3S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpent-4enoyl)pyrrolidine-2-carboxylate 147e .....................................................................95
2.4.26 (S)-Methyl 1-((2R,3S)-2-(1,3-dioxoisoindolin-2-yl)-3-(methoxycarbonyl)pent-4enoyl)pyrrolidine-2-carboxylate 146f ......................................................................96
2.4.27 (S)-Methyl 1-((2S,3R)-2-(1,3-dioxoisoindolin-2-yl)-3-ethylpent-4enoyl)pyrrolidine-2-carboxylate 147d .....................................................................97
2.4.28 Methyl (2S)-2-(3-(1,3-dioxoisoindolin-2-yl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin1-yl)propanoate 159 .............................................................................................97
3. References...................................................................................................... ....99
6
List of Figures
1
Nucleoside Structure
13
2
Schematic model of the double helix
14
3
Arabino Nucleosides
15
4
Ara-CTP
15
5
F-Ara-ATP
15
6
Lysidine tRNA nucleobase
16
7
Amino Acid Structure
8
Enantiomers of Proline
44
9
A [3,3] sigmatropic rearrangement
45
10
A [1,5] sigmatropic rearrangement
45
11
Gelsemine
49
12
Dipole Accelerated Claisen Rearrangements
53
13
Chiral Lewis acid complex
56
14
1
61
43
H NMR of 2-phthaloyl-N,N-dimethylpent-4-enamide showing AB
splitting pattern at 2.76-3.21 ppm
15
N-phthaloylallylglycine
61
16
TMS Triflate
62
17
X-ray data of (S)-methyl 1-((S)-2-(1,3-dioxoisoindolin-2-yl)pent-4-
66
enoyl)pyrrolidine-2-carboxylate
18
147d
70
7
List of Schemes
1
Ring opening of 2,2’-O-anhydrouridine with ammonia
16
2
Azidation of 2,2’-anhydrouridine
20
3
Synthesis of 2’-amino-2’-deoxyuridine
21
4
Synthesis of 2-aminated nucleosides
21
5
2,2’-O-Anhydro-bridge opening with piperidine
22
6
Initial amination reaction conditions
22
7
Synthesis of 2,2’-anhydrouridine
24
8
TBS Protection of 2,2’-anhydrouridine
24
9
Synthesis of 5’-O protected 2,2-Anhydrouridine
25
10
Amination of TBDPS protected 2,2-Anhydrouridine
25
11
The Claisen Rearrangement
46
12
Highly ordered six-membered transition state
46
13
Rearrangement of ethyl -cinnamyloxycrotonate
14
The Eschenmoser–Claisen Rearrangement
47
15
The Eschenmoser–Claisen Rearrangement used in total synthesis of
48
46
stenine 51
16
The Johnson–Claisen Rearrangement
48
17
Synthesis of ,-unsaturated ester 60
18
Ireland-Claisen Rearrangement
50
19
Ireland-Claisen Rearrangement used in total synthesis of
50
49
aspidophytine 67
20
Reformatsky-Claisen Rearrangement
51
21
Synthesis of difluroacid 72
51
22
First Observation of the Belluš-Claisen Rearrangement
52
23
General Scheme for the first reported Belluš-Claisen Rearrangement
53
24
Generation of chlorocyanoketene
54
25
New Lewis Acid-Catalysed Claisen Rearrangement
54
26
The catalytic enantioselective Claisen Rearrangement of 2-
55
alkoxycarbonyl-substituted allyl vinyl ethers
27
Catalysed Acyl-Claisen Rearrangement
56
28
Mechanism of Belluš-Claisen Rearrangement
57
29
Proposed scheme for synthesis of 2-Phthaloyl-N,N-dimethylpent-4-
58
enamide
30
Proposed scheme for synthesis of non-proteogenic dipeptides
58
31
Proposed scheme for [3,3] Belluš Claisen Rearrangement performed on
59
generic peptide
32
Synthesis of N-phthaloylglycyl chloride
59
33
Synthesis of 2-phthaloyl-N,N-dimethylpent-4-enamide
60
34
Alternate Lewis acid catalyst
62
35
N-Tosyl glycyl chloride synthesis
63
36
Belluš-Claisen Rearrangement of N,N-diallyl alanine methyl ester
63
37
Synthesis of diallylated amino acid derivatives
64
38
First attempt of synthesis of N-allyl proline methyl ester
65
39
Belluš-Claisen Rearrangement of allyl proline methyl ester
65
40
Diastereoselective Ketene-Claisen Rearrangement
67
41
Preference for (Z)-enolate formation in addition to mono-substituted
67
ketene
42
Preference for R stereochemistry
68
43
Synthesis of N-Allyl Proline Methyl Ester derivatives
68
44
Belluš-Claisen Rearrangement with N-Allyl Proline Methyl Ester
69
derivatives
45
Syn/anti control in Clasien type reactions
71
46
Solvent Screen
71
47
Base Screen
72
48
Tertiary amine catalyzed formation of -lactone
49
Lewis Acid Screen
74
50
Catalyst Loading Screen
75
51
Microwave irradiation screen of reactions
77
52
Ring closing metathesis of dipeptides 114 and 115
78
9
73
List of Tables
1
Conventional amination reaction times
21
2
Initial Reactions investigated by Ochocińska
23
3
Amination of 5’-O-TBDPS-2,2’-Anhydrouridine
26
4
Amination of 5’-O-TBDPS-2,2’-Anhydrouridine (1g scale)
28
5
Effect of chiral acid loading
56
6
Synthesis of di-allylated amino acid derivatives
64
7
Synthesis of N-Allyl Proline Methyl Ester derivatives
69
8
Belluš-Claisen Rearrangement with N-Allyl Proline Methyl Ester
69
derivatives
9
Solvent Screens
72
10
Base Screens
73
11
Lewis Acid Screens
74
12
Catalyst Loading Screen
75
13
Microwave N-allyl proline methyl ester rearrangement
77
10
List of Abbreviations
app
apparent
aq
aqueous
b.p.
boiling point

chemical shift
d
doublet
DBU
1,8-Diazabicyclo[5.4.0]undec-7-ene
DCE
Dichloroethane
DCM
Dichloromethane
DMAP
4-Dimethylaminopyridine
ee
enantiomeric excess
eq
equivalents
g
gram
HOMO
highest occupied molecular orbital
HPLC
high performance liquid chromatography
Hz
Hertz
IR
infra red
J
coupling constant
LUMO
lowest unoccupied molecular orbital
m
multiplet
mg
milligram
MHz
megahertz
mL
millilitres
mp
melting point
mmol
millimoles
m/z
mass / charge ratio
NMR
nuclear magnetic resonance
q
quartet
s
singlet
t
triplet
TMS
trimethylsilyl
TBDPS
tert-butyldiphenylsilyl
TBS
tert-butyldimethylsilyl
TLC
thin layer chromatography
max
frequency maxima
11
1. Amination of Nucleosides Using Microwave
Methodology
1.1 Introduction
1.1.1 Nucleoside Chemistry
Nucleoside chemistry dates back to 1869 when Miescher discovered a substance that he
termed "nuclein".1
Twenty years later, Altmann isolated a protein-free nuclein which
was termed "nucleic acid".2 Studies in this area continued but since the 1950s,
nucleosides and nucleotides have been the subject of a wealth of research when their
role in cells was established, most famously as the chemical building blocks of
ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) chains.3
A nucleotide is comprised of three components (Figure 1): A nitrogen-containing base which is either:1.
a purine, 1-2, a six-membered pyrimidine ring fused to a five membered
imidazole ring
or
2.
a pyrimidine, 3-5, a six membered heterocyle with two nitrogens in the
ring.
 A pentose sugar. In RNA this is ribose 6 and in DNA it is deoxyribose 7.
Arabinose 8 and ribose 6 differ from the relative stereochemistry of the hydroxyl
group in the C2’ position.
 A phosphate group.4
12
Figure 1: Nucleoside Structure2
In 1953, using experimental data obtained by Wilkins and Franklin 5, Watson and Crick
determined that DNA exists as a double helix.6 DNA consists of two polynucleotide chains
that are held together by hydrogen bonds between the paired bases (Figures 1 and 2). A
(adenine 1) bases are paired with T (thymine 5) bases and C (Cytosine 3) are paired
with G (guanine 2). The nucleotides are linked by a phosphodiester bond whereby the 5’
phosphate group of one nucleotide is linked to the 3’-OH group of another.4,6
13
Figure 2: Schematic model of the double helix (Copied with permission from Pray (2008)7
Nucleoside molecules contain several functional groups within their structure that can be
easily modified by chemical transformations.8 These modified nucleosides have been
shown to possess a variety of biological and clinical properties. They mimic physiological
nucleosides and can inhibit DNA synthesis causing chain termination which results in cell
death.9
Over the years, numerous modified nucleosides have been used as antiviral,
antibiotic and antitumor drugs.3,9,10 De Clerq
affirms that several anti-viral drugs had
been developed including some used to treat HIV (human immunodeficiency virus).11,12
The majority of research pertaining to nucleoside drugs relates to modified heterocyclic
components but ribose core modification can lead to advanced biological activity.13
Examples include the arabino-configured nucleosides (or ara-nucleosides): Cytarabine
(1- -D-arabinofuranosylcytosine, ara-C)
9,
Fludarabine
(9-(β-D-Arabinofuranosyl)-2-
fluoro-9H-purin-6-amine) 10 and Clevudine (1-[2-deoxy-2-fluoro-β-arabinofuranosyl]
thymine) 11.
Cytarabine (Ara-C) 9 (Figure 3) consists of a cytosine base combined with an arabinose
sugar. Ara-C 9 was first synthesized in 1959 and since that time it has proven to be a
very effective drug in the treatment of non-Hodgkin lymphomas, acute myeloid
leukaemias and as an antiviral drug eg to treat the herpes virus.14,15,16
14
Cytarabine
15
Fludarabine
17
Clevudine
18
Figure 3: Arabino Nucleosides
Ara-nucleosides are isomeric with ribosyl derivatives but the 2’ position of the sugar
moiety is epimeric. Thus, they have similar chemical properties to deoxyribosyl
derivatives. This is a significant factor in their ability to inhibit DNA synthesis.15. In order
to be effective, after Ara-C 9 has entered a cell, it must be metabolised to Ara-CTP 12,
(1-β-D-arabinofuranosylcytosine triphosphate) (Figure 4) to become biologically active.14
Once incorporated into a DNA strands Ara-CTP 12 causes chain termination, resulting in
a block of DNA synthesis and subsequent cell death.19
Figure 4: Ara-CTP10
The success of Ara-C (cytarabine) 9 in treating acute leukaemias prompted the
development of further nucleoside analogues, such as fludarabine 10 (Figure 3).
Fludarabine 10 is widely used in the treatment of chronic lymphocytic leukaemia and
non-Hodgkins lymphoma.20,21 Fludarabine 10 must be converted to F-ara-ATP 13 once it
is in the cell if it is to be effective. Studies have shown that F-ara-ATP 13 inhibits DNA
synthesis and also stalls RNA translation.22
Figure 5: F-Ara-ATP
15
Clevudine 11 (Figure 3), a pyrimidine L-nucleoside analogue, has proven to have potent
activity against HBV.23 Hepatitis B virus (HBV) infection affects more than 350 million
people in the world. It is estimated that over half a million deaths per year are as a
result of HBV complications.24 In general, nucleoside inhibitors interfere with the viral
activities by incorporation into DNA chains and competitive inhibition. However, in
clinical trials, it was noted that Clevudine was not incorporated into DNA as anticipated.25
Clevudine inhibits DNA non-competitively by binding to the Hepatitis B Virus active site
and thus altering the viral structure.26,27
In addition to their therapeutic uses, modified nucleosides are useful as the chemical
starting points for functional polynucleotides.28 As part of an ongoing research program
on novel catalytic polynucleotides, a synthetic entry to isocytosines 14, arabinoconfigured analogues of the tRNA nucleoside Lysidine 15 (Figure 6), was required.
Polynucleotides, resulting from monomers that are similar to 14, have been shown to
form stable duplexes with DNA containing isoguanosine.29 Further, related isocytosines
have been reported to possess anti-tumour properties.30
Figure 6: Lysidine tRNA nucleobase
Existing methods to obtain compounds 14 have proven to be lengthy and often lowyielding. The ring-opening of 2,2’-O-anhydrouridine 16 by ammonia was first reported
by Todd et al31 (Scheme 1).
Scheme 1: Ring opening of 2,2’-O-anhydrouridine with ammonia31
The method was later refined and generalized to include higher amines.32 The time
required to give the aminated derivatives 14 is very slow, taking at least 3 to 4 days and
up to a month in the case of very hindered amines such as cyclohexyl amine. We hoped
to
produce
a
more
time
efficient
method
anhydrouridines by utilizing microwave technology.
16
of
accessing
aminated
arabinose-
1.1.2 Microwave Chemistry
1.1.2.1 Introduction to Microwaves
Microwave technology has been used in inorganic chemistry since the late 1970s.33
However, it did not gain widespread acceptance in organic laboratories until the late
1980s. The availability of microwave technology and its adoption in organic chemistry
has been relatively slow compared to other fields, for example computational and
combinatorial chemistry.34 This slow uptake could be attributed to safety aspects and
issues with control and reproducibility.35 Since the mid-1990s the number of publications
in this field has considerably increased.36 This development is mainly due to the shorter
reaction times afforded by microwave chemistry as well as the availability of improved
equipment which included redesigned microwave cavities to improve the heating
characteristics.34,33 A correctly designed cavity will enable uniform heating because cold
and hot spots will be eliminated. This is particularly important for organic chemistry
because it means that the heating of small samples can be accurately controlled. 37
Microwave heating possesses certain advantages over conventional heating:




Energy is imparted directly to the solvent and sample, rather than via
conduction through the reaction vessel; thus, heating is quicker.
A correctly designed reactor allows a uniform increase in temperature.
It is possible to increase the temperature above the boiling point of the
solvent, thus solvents with lower boiling points can be used if desired.
Microwave heating is more energy efficient.38,39
1.1.2.2 Microwave Theory
All electromagnetic radiation can be divided into two components: an electric field and a
magnetic field. The microwave electric field is responsible for the dielectric heating
phenomenon that allows microwave oven technology to function. Dielectric heating
occurs using two principal mechanisms, dipolar polarization and conduction.
The first mechanism is dipolar polarization. This is the mechanism most commonly
associated with microwave heating. Only substances that contain a dipole moment will
generate heat when irradiated with microwaves. Dipoles respond to external electric
fields and will rotate and try to align themselves with the electric field.34 When an
17
external electric field provides the energy for this rotation, any molecules that contain a
dipole will attempt to align themselves with it. The speed with which a molecule will do
so depends on the environment. Instantaneous alignment is hindered in liquids due to
the proximity of other molecules, causing a transfer of kinetic energy. Conversely,
molecules in gases will align rapidly because their molecules are not in such close
proximity and thus do not adversely affect the alignment. Gases are therefore not
heated as efficiently as liquids within the microwave environment. In most regions of the
electromagnetic spectrum, the ability to impart energy via the dielectric effect is limited.
Low frequency radiation will allow molecules to rotate in alignment with the field, but the
heating effect is small. In high frequency radiation there is insufficient time for the
molecules to rotate. As the heating is dependent on motion being parted into the
component molecules of a material, there is therefore no change in temperature.
Microwave radiation is unique in being between these two extremes. Microwave radiation
is not so high that dipoles do not have time to respond to the electric current. The
frequency is not, however, low enough for dipoles to fully align before the orientation of
the field changes. This creates a phase difference between the orientation of the field
and the dipole. This phase difference causes energy to be lost from the dipole by
molecular friction and collisions, giving rise to dielectric heating.34
If two samples, one containing water and the other dioxane, were irradiated for a fixed
time at a fixed power, the sample of water would have a higher temperature at the end
of the experiment. Dioxane, as a non-polar solvent, lacks the dipole characteristics
necessary for microwave dielectric heating so energy can not be transferred to the
sample. However, if two samples containing water, one with tap water, the other distilled
water, were used in the same experiment they would not heat uniformly. The sample
containing the tap water would be hotter which can be explained by conduction, the
second principal mechanism.34
When a solution is subjected to an electric field, any ions will be influenced by the field
and will move and collide. Due to the increased collision rate this causes, a greater
conversion of kinetic energy to heat will result. Heat generated via the conductivity is
much stronger than that generated solely by dielectric heating. This explains the
difference in temperature mentioned above. The sample containing tap water will reach
a higher temperature than pure water because the ions, influenced by conduction, will
add to the heat produced.
18
Dielectric heating is dependent on dipole rotation and therefore, it should follow that the
higher the solvent dielectric constant (i.e. the more polar a solvent is), the more
effective it will be as a solvent for microwave heating. It is possible for two solvents with
comparable dielectric constants to have significant differences as microwave solvents.
Factors that affect this are the efficiency of a solvent to convert energy into heat, the
volume of the reaction and the geometry of the reaction vessel. These latter two are
vital in order to create reproducible and uniform heating but volume is the more
significant factor.
It is important to follow manufacturer guidelines because over or
under loading the vessel can result in difficulty obtaining reproducible results.34
1.1.2.3 Microwaves and the Effect on the Speed of Reaction.
The major advantage in employing microwave methodology is a decrease in required
reaction time.40 How microwave irradiation alters the outcome of organic synthetic
reactions has been the subject of debate.41,42 Specifically, whether it is simply a thermal
effect or if there is something unique to microwave reactions and if any non-thermal
effects should also be considered. There is some controversy around the effects of the
magnetic field but in most cases of microwave reactions in the literature, the decrease in
reaction time can be attributed solely to thermal effects.34,43
In well-designed systems, microwave heating is efficient, uniform and rapid which can
lead to different reaction profiles when compared to conventional heating, even if the
final temperature is the same. The first published examples of microwave assisted
organic synthetic chemistry made use of domestic ovens and it is only recently that
purpose-built machines have become available. While domestic ovens have the
advantage that they are widely available and relatively cheap there are usually major
safety concerns with safety, especially when using pressurised vessels.34
A desire to increase safety led to the development of a number of reflux systems which
all broadly have the same advantages and disadvantages. These systems are safer to
use and there is minimal risk of an explosion because reactions are performed at
atmospheric pressure and flammable products cannot enter the cavity. However,
because the reactions are performed at atmospheric pressure, this means that the
temperature can only be increased a few degrees (13˚C to 26˚C),
above the boiling
point of the solvent being used. This higher temperature will speed up the reaction to
some degree but it does not utilise the full potential of microwave heating. 34 Ideally,
19
reactions will be performed under pressure in a microwave cavity so that they will
benefit both from rapid heating rates and remote dielectric microwave heating. Modern
apparatus, purpose built for running these reactions, are safe, have good temperature
control and accurate pressure measurement.43
We therefore planned to apply pressurized microwave system methodology to the
amination of anhydrouridine. We hoped that the reaction accelerating effects would
drastically reduce the reaction time without the need for harsh conditions. It was also
envisaged that this would ease the purification of the product because there would be
limited or no side reactions with the reagents and conditions employed.
1.1.3 Aminated Nucleosides
During the 1950s and 1960s, numerous studies were reported relating to the ring
opening of 2,2’-anhydronucleosides by nucleophiles but the procedures reported were
lengthy
and
sometimes
required
harsh
conditions.44,29,45,46
There
are
literature
investigations into nucleophilic attack of ammonia,31,32 sulfides31,47 and halides.48 Amines
attack at the 2-position (Scheme 1) giving the corresponding 2-aminated product.
Conversely, azides will ring open by attacking at the 2’ position. For example, azidation
of 2,2’-anhydrouridine 16 will give 2’-azido-2’-deoxyuridine 18 in one step (Scheme
2).49
Scheme 2: Azidation of 2,2-anhydrouridine49
It is possible to access 2’-aminated nucleosides by the formation of intermediate azides
that can be later reduced to the corresponding amine49,50. Wnuk et al.51 developed a
scheme to give the 2’-amino-2’-deoxyuridine 19 in a two-step process (Scheme 3).
20
Scheme 3: Synthesis of 2’-amino-2’-deoxyuridine51
Delia and Beranek44 reported the reaction of 2,2’-anhydrouridine 16 with ammonia,
primary aliphatic amines, secondary aliphatic amines and aromatic amines. Their work
proved successful with ammonia and primary amines, leading to the corresponding 2aminated nucleosides 20 (Scheme 4 and Table 1).
Scheme 4: Synthesis of 2-aminated nucleosides
Table 1: Conventional amination reaction times44
Entry
R
% Yield
Time of Reaction (Hours)
1
n-Bu
82
72
2
Allyl
86
96
3
Benzyl
90
360
4
Cyclohexyl
72
768
5
Ph
0
-
Aromatic amines (Scheme 4, Table 1, Entry 5) failed to aminate the nucleoside because
they were not sufficiently nucleophilic to effect the reaction under the conditions
employed. Secondary amines also only returned starting materials when used. It had
been assumed that these would successfully react as they had base strengths similar to
the primary amines. The lack of reactivity was presumably due to steric issues. Evidence
to support this was the relative rates of reaction of the various primary amines. Butyl
amine and allyl amine both reacted relatively quickly (three and four days respectively)
while the more bulky cyclohexylamine and benzylamine took considerably longer (almost
a month). These results demonstrate a significant steric dependence as the branching
21
increases. It was later reported that some secondary amines were successful in opening
the 2,2’-O-anhydo-bridge of compounds containing the 3’-O-mesyl group, for example
the mesyl protected compound 21 reacted with piperdine to give the 2-aminated product
22. However, this also resulted in an epoxide ring forming between the 2’ and 3’
positions (Scheme 5).52
Scheme 5: 2,2’-O-Anhydro-bridge opening with piperidine52
1.1.4 Amination of 2,2'-anhydroarabinouridine (23) and its
Derivatives
As part of a research program directed towards novel catalytic polynucleotides,
Ochocińska53 had attempted to apply microwave methodology to the same chemistry
(Scheme 6, Table 2) in the hope of cutting the time required to access C2-aminesubstituted nucleosides.
Scheme 6: Initial amination reaction conditions53
22
Table 2: Initial Reactions investigated by Ochocińska53
Entry
Reagents
Temp (˚C) Time
R
R1
R2
(mins)
1
Benzophenone
Product,
Yield %
120
60
C(Ph)2
TBS
OH
Trace
120
30
Me
TBS
OH
Partial 30,
imine
2
MeNH2
not isolated
3
MeNH2
80
60
Me
TBS
TBS
30, 65
4
MeNH2
80
60
Me
TBS
OH
30, 89
5
MeNH2
80
60
Me
TBS
TBS
0
6
1)Zinc
120
60
Me
TBS
TBS
0
80
30
Me
OH
OH
0
2)NH2Me
7
NH2Me
BF3.Et2O
When 5’-O-tert-butyldimethylsilyl-2,2’-anhydrouridine was reacted with methylamine
using microwave irradiation at 120˚C for 30 minutes, a mixture of products was
obtained. 1H NMR analysis of the crude mixture revealed that some of the expected
product 24 was present (Entry 2). Several different temperature and reaction times
were tried. It was found that 80˚C for 1 hour (Entry 4) gave the expected product 24 in
89% yield. Of particular satisfaction was that to isolate the product as a colourless solid,
only concentration of the reaction mixture followed by filtration was required. Addition of
a Lewis acid or other modifications of initial conditions failed to give the desired product.
The purpose of this research was to follow up this lead to devise a general protocol for 2amination of ara-uridines.
1.2 Results and Discussion
5’-O Protected 2,2'-anhydrouridine of general structure 23 (Scheme 6) are readily
prepared and have served as key intermediates in this research. It was necessary to
optimise the synthesis of the starting materials at this point. We wanted to conduct the
experiments on a gram scale reactions and the method used did not give sufficient
starting materials for the reaction.
23
The procedure outlined by Ochocinska53 was followed and this gave the desired 2,2’anhydrouridine 16. (Scheme 7)
Scheme 7: Synthesis of 2,2’-anhydrouridine53
Purification by recrystallization in methanol proved difficult because the product was only
sparingly soluble and a large excess of methanol was needed to completely dissolve the
solution. It was found that simply washing the crude product with cold methanol resulted
in a product that was found to be pure by 1H NMR analysis.
When attempting to repeat the TBS protection step a mixture of both the mono and diprotected compound 27 and 28 were obtained.
Scheme 8: TBS Protection of 2,2’-anhydrouridine53
Crude
1
H NMR analysis showed mono-protected compound was the major product
(20:80 ratio) but separation of the two compounds during the column chromatography
purification step proved challenging. This meant that the mono-protected compound was
isolated with yields of only 5-21%.
The di-TBS protected compound was also challenging to purify, giving a yield of 65%
(Table 2, Entry 3), therefore alternative silyl protecting groups were investigated to
determine if this would simplify the purification.
Silyl ethers are widely used protective groups for hydroxyl functional groups because
they are stable under a wide range of conditions and are removable with high
selectivity.54,55 Their reactivity can be modulated by carefully selecting the substituents
on the silicon atom.56,57 Originally TBS had been used because it is a very widely used
silyl protective group.58,59 It can be introduced with several reagents and can be easily
24
removed under conditions that do not affect other functional groups.57 It is sensitive
toward acid but is stable toward base and it can withstand temperatures up to 230˚C.60
The TBDPS group is far more stable than the TBS group toward acid but is less stable
than the TBS group towards base. The TBDPS group has also proven to have better
stability to many reagents which are not compatible with the TBS group. 57,61
1.2.1 Optimization of Protection Step
In order to improve the selectivity of the protection step of the starting material the TBS
protecting group was changed to the TBDPS group. Following a procedure by Sebesta et
al.62
(Scheme 9), the primary alcohol of 2,2’-anhydrouridine 16 was protected with
TBDPS-Cl to give the TBDPS protected compound 29.
Scheme 9: Synthesis of 5’-O protected 2,2’-Anhydrouridine
Analysis of the crude residue by
1
H NMR spectroscopy showed that only the mono-
protected compound 29 was obtained, which made the resulting purification by column
chromatography straightforward.
5’-O-TBDPS-2,2’-anhydrouridine 29 was reacted with a variety of amines on 100 mg
scale (Scheme 10) using the previously optimised microwave methodology conditions
(Scheme 6, Table 2, Entry 4). 5’-O-TBDPS-2,2’-anhydrouridine 29 was successfully
reacted with a range of primary amines to give compound 30 in yields of 73-51%
(Scheme 10 and Table 3). Secondary amines failed to give the desired product, returning
the amine and compound 29.
Scheme 10: Amination of TBDPS protected 2,2’-Anhydrouridine
25
Table 3. Amination of 5’-O-TBDPS-2,2’-Anhydrouridine
Entry
Compound
R
% Yield
1
30a
Me
73
2
30b
Et
65
3
30c
Pr
73
4
30d
n-Bu
68
5
30e
sec-Bu
64
6
30f
Allyl
66
7
30g
n-Pentyl
61
8
30h
n-Hexyl
52
9
30i
Benzyl
56
10
30j
Cyclohexyl
51
11
30k
iso-Pentyl
58
12*
30d
n-Bu
74
13
30l
iso-Pr
0
14
30m
iso-Bu
0
15
30n
tert-Bu
0
16
30o
2-Ethyl-hexyl
0
17
30p
Ph
0
18**
30b
Et
0
conditions: *rt, 4 days **reflux, 1 hr
This compares very favourably with amination using conventional methods. When using
primary aliphatic amines, this gave a very significant reduction in reaction time
compared to similar reactions reported in the literature (Compare Table 1, Entries 1-4
with Table 3, Entries 4, 6, 9 and 10). The reaction was repeated conventionally, being
left to stir at room temperature until the starting material was consumed as monitored
by TLC analysis (Table 3, Entry 12). This took four days to go to completion, compared
to 1 hour with microwave heating (Table 3, Entry 4). The reaction was also repeated
using a conventional hot plate for heating. After being refluxed in THF for one hour, TLC
analysis showed that there was no conversion of starting material (Table 3, Entry 18). It
took four days for unprotected 2,2'-anhydrouridine 16 to undergo the same reaction
(Table 1, Entry 1), thus the decrease in reaction time can be explained solely by the
application of microwave irradiation.
26
1.2.2 Amenity To Larger Scale Reactions
The reaction was repeated on a one gram scale using n-butyl amine in 10 ml of THF
using the standard conditions (1 hr, 80˚C, 300 W) but on a 1g scale. When first
attempted using butylamine the product had already started to precipitate at the end of
the reaction. A final yield was obtained of 90%. Gratifyingly, this was not only a better
yield than the 100 mg scale reaction, but also higher than when the reaction was carried
out conventionally.44
The reaction was then repeated on the same scale using the same amines that had
successfully given aminated product 30 (Scheme 10). When attempting the reaction
using cyclohexylamine on 1g scale, no improvement in yield was noted. This time the
reaction mixture was concentrated in vacuo at 1mm pressure. Analysis of the crude
residue by 1H NMR spectroscopy revealed that the reaction had not gone to completion.
The reaction was repeated on the same scale, with twice the amine loading and double
the reaction time. The reaction mixture was again concentrated under 1mm pressure
and analysis of the solid residue revealed the remaining material was the 2-aminated
product. The total yield obtained was 81%. Overall yields for 1g scale reactions ranged
from 70-90% (Table 4).
In summary, the reaction proceeded smoothly with simple and unhindered amines. As
observed when performing the reaction under conventional conditions, increasing steric
bulk had an adverse effect on the reaction. In the case of cyclo-hexylamine, twice the
usual amine load was required and it was also necessary to double the reaction time in
order to drive the reaction to completion. However, as the reaction is reported to take
one month using conventional methods this still represents a significant improvement.
27
Table 4. Amination of 5’-O-TBDPS-2,2’-Anhydrouridine (1g scale)
Entry
Compound
R
% Yield
1
30a
Me
85
2
30b
Et
86
3
30c
Pr
88
4
30d
n-Bu
89
5
30e
iso-Bu
80
6
30f
Allyl
87
7
30g
Pentyl
85
8
30h
Hexyl
79
9
30i
Benzyl
70
10
30j
Cyclo-hexyl
81
11
30k
iso-pentyl
81
1.3 Conclusions and Future Work
We have reported a new method of aminating 2,2’-anhydrouridine using a microwave
methodology. The presented methodology gave a new, effective, high yielding and neat
way of obtaining 2-aminated nucleosides. This discovery offers a means to increase the
capacity of these molecules and significantly decreases the required reaction time.
1.4 Experimental
Reagents were purchased from Sigma-Aldrich, Acros, Alfa Aesar or Fisher Scientific and
were not purified except where stated. Solvents were purchased anhydrous and stored
over molecular sieves, or distilled under nitrogen from an appropriate drying agent. THF
and diethyl ether were distilled from sodium benzophenone ketyl radical while DCM and
acetonitrile were distilled from calcium hydride. Thin layer chromatography was
performed on aluminium sheets coated with Merck silica gel 60 F254 with visualisation
using potassium permanganate solution and/or scrutinised under 254 nm UV light.
Column chromatography was performed using Silica gel 60 (35-70 microns) supplied by
Fisher.
Nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker Advance
400 NMR spectrometer (1H NMR at 400 MHz,
28
13
C NMR at 100 MHz) with the appropriate
deuterated solvent. Chemical shifts in 1H NMR spectra are expressed as ppm downfield
from TMS and in
13
C NMR, are relative to internal standard, and reported as singlet (s),
doublet (d), triplet (t), quartet (q) and combinations thereof, or multiplet (m). Coupling
constants (J) are quoted in Hz and are rounded to the nearest 0.5 Hz.
Mass
spectrometry was performed using a Bruker MicroTOF-Q instrument with electrospray
ionisation in the positive mode.
FT-IR data was acquired using Thermo Electron
Corporation Nicolet 380 FTIR with Smart Orbit diamond window instrument with
wavenumbers being reported in cm-1. All melting points were obtained using a Stuart
SMP10 melting point instrument. All non-microwave reactions were carried out under an
inert atmosphere of nitrogen that was dried by passage through phosphorus pentoxide.
Microwave reactions were performed using a Milestone MicroSYNTH reactor and SK10
vessel with or without three inserts that each contained one magnetic stirring bead
depending on volume. Twist control, rotor control, start parameters and continuous
power were all selected. T1 control was used with 60 % stirring.
1.4.1 Numbering of atoms in a nucleoside molecule
1.4.2 2,2’-Anhydrouridine 1663
Uridine (13.0 g, 53.0 mmol) and diphenyl carbonate (13.0 g, 60.0 mmol) were slurried
in DMF (30 mL) and the reaction was heated to 80 ˚C. After one hour the reagents had
29
dissolved and sodium hydrogen carbonate (0.53 g, 6.0 mmol) was added followed by
heating the reaction to 120 ˚C. After stirring for five hours the reaction was allowed to
cool to room temperature and the resulting precipitate was collected by filtration. The
product was washed with MeOH to give the crude as a colourless solid. (9.71g, 42.9
mmol, 81%), mp = 238-40 ˚C. lit 238-244 ˚C
H (400 MHz, DMSO-d6), 3.19 (1H, dd, J = 6.0, 11.5 Hz, C5’-H1), 3.28 (1H, dd, J = 5.0,
11.5 Hz, C5’-H2), 4.08 (1H, app t, J = 5.0 Hz, C4-H’), 4.38-4.41 (1H, m, C3’-H), 5.00
(1H, br s, C5’-OH), 5.20 (1H, app d, J = 6.0 Hz, C2’-H), 5.85 (1H, d, J = 7.5 Hz, C5-H),
5.91 (1H, br s, C3’-OH), 6.30 (1H, d, J = 6.0 Hz, C1’-H), 7.84 (1H, d, J = 7.5 Hz, C4-H);
C (100 MHz, DMSO-d6), 61.3 (C5’), 75.2 (C3’), 89.2 (C2’), 89.7(C4’), 90.5 (C1’), 109.1
(C5), 137.3 (C4), 160.3 (C2), 171.7 (C6); max (thin film), 1650 (C=O); m/z calculated
for C9H10N2O5 [M+Na]+, 249.0482, found 249.0482.
1.4.3 TBS Protection
2,2’-Anhydrouridine (3.00 g, 13.3 mmol) was dissolved in pyridine (15 mL) at 0
o
C.
TBDPS chloride (3.64 g, 13.3 mol) was added drop-wise in pyridine (5 mL). After stirring
for four days at room temperature, the reaction was treated with ether (30 mL) and the
pyridinium salt was removed by filtration. After evaporating the solvents, the crude
mixture was dissolved in DCM and washed with water to remove the remaining pyridine.
Purification
by
flash
chromatography
MeOH:DCM
(7.5:92.5)
gave
5’-O-tert-
butyldimethylsilyl-2,2’-anhydrouridine (601 mg, 2.50 mmol, 19%), mp = 137-140 ˚C
and 3’,5’-di-O-tert-butyldimethylsilyl-2,2’-anhydrouridine (611 mg, 1.34 mmol, 10%),
mp = 100-102 ˚C, obtained as colourless solids.
1.4.4 5’-O-tert-Butyldimethylsilyl-2,2’-anhydrouridine 27
H (400 MHz, DMSO-d6), -0.03 (3H, s, Si-CH3), -0.03 (3H, s, Si-CH3), 0.83 (9H, s, CCH3),
3.39-3.52 (m, 2H, C5’-H1, C5’-H2), 4.09-4.12 (1H, m, C4’-H), 4.37 (1H, m, C3’-H), 5.26
(1H, d, J = 5.5 Hz, C2’-H), 5.90 (1H, d, J = 7.5 Hz, C5-H), 6.00 (1H, d, J = 4.0 Hz, C3’-
OH), 6.33 (1H, d, J = 5.5 Hz, C1’-H), 7.47 (d, 1H, J = 7.5 Hz, C4-H); C (100 MHz,
30
DMSO-d6), -5.03 (Si-CH3), -5.01 (Si-CH3), 18.5 (SiC), 26.2 (Si(C)CH3), 62.7 (C5’), 74.5
(C3’), 88.4 (C2’), 89.1 (C4’), 90.1 (C1’), 109.2 (C5), 137.3 (C4), 160.0 (C2), 171.4
(C6); max (thin film), 1530 (C=N), 1651 (C=O), 2929 (C-H aliphatic); m/z calculated for
C15H24N2O5Si [M+H]+, 341.1527, found 341.1528.
1.4.5 3’,5’-Di-O-tert-butyldimethylsilyl-2,2’-anhydrouridine 28
H (400 MHz, DMSO-d6), -0.04 (3H, s, Si-CH3), -0.03 (3H, s, Si-CH3), 0.15 (3H, s, SiCH3), 0.17 (3H, s, Si-CH3), 0.81 (9H, s, CCH3), 092 (9H, s, CCH3), 3.43 (dd, 1H, J = 5.5,
11.5 Hz, C5’-H1), 3.55 (1H, dd, J = 5.0, 11.5 Hz, C5’-H2), 4.06 (1H, app dd, J = 5.0, 9.0
Hz, C4’-H) 4.53 (1H, m, C3’-H), 5.26 (1H, dd, J = 1.0, 5.0 Hz, C2’-H), 5.90 (1H, d, J =
7.5 Hz, C5-H), 6.33 (1H, d, J = 6.0 Hz, C1’-H), 7.47 (d, 1H, J = 7.5 Hz, C4-H); C (100
MHz, DMSO-d6), -5.10 (Si-CH3), -5.07 (Si-CH3), -4.66 (Si-CH3), -4.50 (Si-CH3), 18.2
(SiC), 18.4 (SiC), 26.0 (Si(C)CH3), 26.1 (Si(C)CH3), 61.7 (C5’), 76.0 (C3’), 87.4 (C4’),
89.1 (C2’), 89.6 (C1’), 109.3 (C5), 137.2 (C4), 160.0 (C2), 171.3 (C6); max (thin film),
1468 (C=N), 1656 (C=O), 2929 (C-H aliphatic); m/z
calculated for C21H38N2O5Si2
+
[M+H] , 455.2392, found 455.2393.
1.4.6 5’-O-tert-Butyldiphenylsilyl-2,2’-anhydrouridine 2962
2,2’-Anhydrouridine(3.00 g, 13.3 mmol) was dissolved in pyridine (26 mL) and DMF (12
mL) at 0 oC. TBDPS chloride (3.64 g, 13.3 mol) was added dropwise over five minutes.
After stirring for two days at room temperature DCM was added (70 mL) and washed
with saturated NaHCO3 solution (3 x 50 mL). The organic layer was dried over Na2SO4,
filtered and concentrated in vacuo to give the crude product. Purification by flash
chromatography MeOH:DCM (0:100 to 20:80) gave the desired product as colourless
crystals. (3.21g, 6.92 mmol, 52%), mp = 181-182˚C.
31
H (400 MHz, DMSO-d6), 0.92 (9H, s, CCH3), 3.47 (dd, 1H, J = 6.5, 11.5 Hz, C5’-H1),
3.59 (dd, 1H, J = 5.0, 11.5 Hz, C5’-H2), 4.15-4.20 (1H, m, C4’-H), 4.43-4.47 (1H, m,
C3’-H), 5.26 (1H, dd, J = 1.5, 5.5 Hz, C2’-H), 5.89 (1H, d, J = 7.5 Hz, C5’-H), 6.01 (1H,
d, J = 4.5 Hz, C3’-OH), 6.33 (1H, d, J = 5.5 Hz, C1’-H), 7.37-7.49 (6H, m, Ar-H), 7.50-
7.58 (4H, m, Ar-H), 7.93 (d, 1H, J = 7.5 Hz, C4-H); C (100 MHz, DMSO-d6), 19.2 (SiC),
26.9 (Si(C)CH3), 63.1 (C5’), 74.4 (C3’), 87.6 (C4’), 89.1 (C2’), 89.8 (C1’), 109.2 (C5),
128.4 (Ar-C), 128.4 (Ar-C), 130.4 (Ar-C), 130.4 (Ar-C), 132.8 (Quat. Ar-C), 133.0 (Quat
Ar-C), 135.4 (Ar-C), 135.4 (Ar-C), 137.3 (C4), 159.9 (C2), 171.4 (C6); max (thin film),
1533 (C=N), 1650 (C=O), 2157, 2929 (C-H aliphatic); m/z calculated for C25H28N2O5Si
[M+Na]+, 487.1660, found 487.1666.
1.4.7 General Amination Procedure
5’-O-TBDPS-2,2’-anhydrouridine (100 mg, 0.21 mmol, 1.0 eq) was dissolved in THF (0.5
ml) and primary amine (10.0 eq). The mixture was reacted at 80 ˚C for 1 hour at 300W.
After completion the reaction mixture was poured into a flask of ether (100 ml).
Filtration of the resulting precipitate gave the product.
1.4.8 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)
-3’, 4’-dihydroxyoxolan-2’-yl)-2-(methylamino)pyrimidin-6(1H)one 30a
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100 mg,
0.21 mmol, 1.0 eq) and methylamine in 2.0M THF solution (1.05 mL, 2.1 mmol, 10.0 eq)
3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’, 4’-dihydroxyoxolan-2’-yl)2-(methylamino)pyrimidin-6(1H)-one
was obtained as a colourless solid (76mg, 0.15
mmol, 73%), mp = 187-188 ˚C. A drop of D2O was added to the analytical sample
before the 1H NMR analysis.
H (400 MHz, DMSO-d6), 1.00 (9H, s, C(CH3)3), 2.71 (3H, s, N-CH3), 3.76-3.79 (1H, m,
C4’-H), 3.81-3.84 (1H, m, C5’-H1), 3.92 (1H, dd, J = 3.0, 11.5 Hz, C5’-H2), 4.07 (1H,
32
app t, J = 6.5 Hz, C3’-H), 4.25 (1H, app t, J = 6.0 Hz, C2’-H), 5.26 (1H, d, J = 7.5 Hz,
C5-H), 5.86 (1H, d, J = 6.0 Hz, C1’-H), 7.38-7.51 (6H, m, Ar-H), 7.58-7.68 (5H, m, Ar-
H, C4-H); C (100 MHz, DMSO-d6), 19.3 (Si-C(CH3)3), 27.0 (Si-C(CH3)3), 28.7 (N-CH3),
62.9 (C5’), 74.6 (C3’), 75.9 (C2’), 82.9 (C4’), 85.9 (C1’), 104.9 (C5), 128.4 (Ar-C),
128.4 (Ar-C), 130.4 (Ar-C), 130.5 (Ar-C), 132.9 (Quat. Ar-C), 133.2 (Quat Ar-C), 135.5
(Ar-C), 135.6 (Ar-C), 139.2 (C4), 153.6 (C2), 170.0 (C6); max (thin film), 3304 (N-H),
1650 (C=O); m/z calculated for C26H33N3O5Si [M+H]+, 496.2262, found 496.2267.
1.4.9 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)3’,4’-dihydroxyoxolan-2’-yl)-2- (ethylamino)pyrimidin-6(1H)-one
30b
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100mg,
0.21 mmol, 1.0 eq) and ethylamine in 2.0M THF solution (1.05 mL, 2.1 mmol, 10.0 eq)
3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)2-(ethylamino)pyrimidin-6(1H)-one was obtained as a colourless solid (71mg, 0.14
mmol, 65%), mp = 193-194 ˚C. A drop of D2O was added to the analytical sample
before the 1H NMR analysis.
H (400 MHz, DMSO-d6), 0.99 (9H, s, C(CH3)3), 1.06 (3H, t, J = 7.0 Hz, CH2CH3), 3.173.33 (2H, m, N-CH2), 3.76-3.79 (1H, m, C4’-H), 3.82 (1H, dd, J = 4.5, 11.5 Hz, C5’-H1),
3.91 (1H, dd, J = 3.0, 11.5 Hz, C5’-H2), 4.07 (1H, app t, J = 6.5 Hz, C3’-H), 4.26 (1H,
app t, J = 6.0 Hz, C2’-H), 5.26 (1H, d, J = 7.5 Hz, C5-H), 5.83 (1H, d, J = 6.0 Hz, C1’-
H), 7.38-7.49 (6H, m, Ar-H), 7.56-7.67 (5H, m, Ar-H, C4-H); C (100 MHz, DMSO-d6),
14.9 (CH2CH3), 19.3 (Si-C(CH3)3), 27.1 (Si-C(CH3)3), 36.2 (N-CH2), 62.9 (C5’), 74.7
(C3’), 76.0 (C2’), 82.9 (C4’), 85.8 (C1’), 104.4 (C5), 128.4 (Ar-C), 128.4 (Ar-C), 130.4
(Ar-C), 130.5 (Ar-C), 132.9 (Quat. Ar-C), 133.2 (Quat Ar-C), 135.5 (Ar-C), 135.6 (Ar-
C), 139.4 (C4), 153.1 (C2), 170.0 (C6); max (thin film), 3303 (N-H), 1637 (C=O); m/z
calculated for C27H35N3O5Si [M+H]+, 510.2419, found 510.2432.
33
1.4.10 3-((2’R,3’S,4’S,5’R)-5’-((tertButyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)-2(propylamino)pyrimidin-6(1H)-one 30c
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100 mg,
0.21 mmol, 1.0 eq) and propylamine (124 mg, 0.17 mL, 2.1 mmol, 10.0 eq) 3((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)-2(propylamino)pyrimidin-6(1H)-one was obtained as a colourless solid (80mg, 0.15 mmol,
73%), mp = 197-198˚C. A drop of D2O was added to the analytical sample before the 1H
NMR analysis.
H (400 MHz, DMSO-d6), 0.85 (3H, t, J = 7.5 Hz, CH2CH3), 1.01 (9H, s, C(CH3)3), 1.461.55 (2H, m, CH2CH3), 3.09-3.25 (2H, m, N-CH2), 3.76-3.79 (1H, m, C4’-H), 3.83 (1H,
dd, J = 4.5, 11.5 Hz, C5’-H1), 3.91 (1H, dd, J = 3.0, 11.5 Hz, C5’-H2), 4.06 (1H, app t, J
= 6.5 Hz, C3’-H), 4.24 (1H, app t, J = 6.0 Hz, C2’-H), 5.25 (1H, d, J = 7.5 Hz, C5-H),
5.87 (1H, d, J = 6.0 Hz, C1’-H), 7.41-7.50 (6H, m, Ar-H), 7.57 (1H, J = 7.5 Hz, C4-H),
7.61-7.65 (4H, m, Ar-H); C (100 MHz, DMSO-d6), 11.8 (CH2CH3), 19.3 (Si-C(CH3)3),
22.2 (CH2CH3), 27.1 (Si-C(CH3)3), 43.1 (N-CH2), 62.9 (C5’), 74.5 (C3’), 76.0 (C2’), 82.8
(C4’), 85.8 (C1’), 105.0 (C5), 128.4 (Ar-C), 128.4 (Ar-C), 130.4 (Ar-C), 130.5 (Ar-C),
132.9 (Quat. Ar-C), 133.2 (Quat Ar-C), 135.5 (Ar-C), 135.6 (Ar-C), 139.3 (C4), 153.2
(C2), 170.0 (C6); max (thin film), 3333 (N-H), 1636 (C=O); m/z calculated for
C28H37N3O5Si [M+H]+, 524.2575, found 524.2590.
34
1.4.11 3-((2’R,3’S,4’S,5’R)-5’-((tertButyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)-2(butylamino)pyrimidin-6(1H)-one 30d
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100mg,
0.21 mmol, 1.0 eq) and butylamine (154 mg, 0.21 mL, 2.1 mmol, 10.0 eq) 3((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)-2(butylamino)pyrimidin-6(1H)-one was obtained as a colourless solid (75mg, 0.14 mmol,
68%), mp = 199-200˚C. A drop of D2O was added to the analytical sample before the 1H
NMR analysis.
H (400 MHz, DMSO-d6), 0.87 (3H, t, J = 7.0 Hz, CH2CH3), 1.00 (9H, s, C(CH3)3), 1.231.32 (2H, m, CH2CH3), 1.43-1.51 (2H, m, CH2CH2CH3), 3.13-3.29 (2H, m, N-CH2), 3.763.79 (1H, m, C4’-H), 3.82 (1H, dd, J = 4.5, 11.5 Hz, C5’-H1), 3.91 (1H, dd, J = 3.0, 11.5
Hz, C5’-H2), 4.06 (1H, app t, J = 6.5 Hz, C3’-H), 4.24 (1H, app t, J = 6.0 Hz, C2’-H),
5.25 (1H, d, J = 7.5 Hz, C5-H), 5.85 (1H, d, J = 6.0 Hz, C1’-H), 7.40-7.50 (6H, m, Ar-
H), 7.56-7.66 (5H, m, Ar-H, C4-H); C (100 MHz, DMSO-d6), 14.3(CH2CH3), 19.3 (SiC(CH3)3), 20.1 (CH2CH3), 27.1 (Si-C(CH3)3), 31.2 (CH2CH2CH3), 41.1 (N-CH2), 62.9
(C5’), 74.7 (C3’), 76.0 (C2’), 82.9 (C4’), 85.9 (C1’), 105.0 (C5), 128.4 (Ar-C), 128.4
(Ar-C), 130.4 (Ar-C), 130.5 (Ar-C), 132.9 (Quat. Ar-C), 133.2 (Quat Ar-C), 135.5 (Ar-
C), 135.6 (Ar-C), 139.4 (C4), 153.2 (C2), 170.0 (C6); max (thin film), 3362 (N-H), 1636
(C=O); m/z calculated for C29H39N3O5Si [M+H]+, 538.2732, found 538.2735.
35
1.4.12 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)
-3’,4’-dihydroxyoxolan-2’-yl)-2-(allylamino)pyrimidin-6(1H)-one
30f
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100mg,
0.21 mmol, 1.0 eq) and allylamine (120 mg, 0.17mL, 2.1 mmol, 10.0 eq) 3((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)-2(allylamino)pyrimidin-6(1H)-one was obtained as a colourless solid (72mg, 0.14 mmol,
66%), mp 185-186˚C. A drop of D2O was added to the analytical sample before the 1H
NMR analysis.
H (400 MHz, DMSO-d6), 1.01 (9H, s, C(CH3)3), 3.78-3.93 (5H, m, C4’-H, C5’-H1, C5’-H2,
N-CH2), 4.08 (1H, app t, J = 6.5, C3’-H), 4.26 (1H, app t, J = 6.0 Hz, C2’-H), 5.06 (1H,
d, J = 10.0 Hz, cis CH=CH2), 5.17 (1H, d, J = 17.0 Hz, trans CH=CH2), 5.25 (1H, d, J =
7.5 Hz, C5-H), 5.82-5.89 (1H, m, CH2-CH=CH2), 5.91 (1H, d, J = 6.0 Hz, C1’-H), 7.41-
7.50 (6H, m, Ar-H), 7.58-7.67 (5H, m, Ar-H, C4-H); C (100 MHz, DMSO-d6), 19.3 (SiC(CH3)3), 27.1 (Si-C(CH3)3), 43.5 (N-CH2), 62.9 (C5’), 74.5 (C3’), 76.0 (C2’), 82.9 (C4’),
85.9 (C1’), 105.2 (C5), 115.6 (CH=CH2), 128.4 (Ar-C), 128.4 (Ar-C), 130.4 (Ar-C),
130.5 (Ar-C), 132.9 (Quat. Ar-C), 133.2 (Quat Ar-C), 135.5 (Ar-C), 135.6 (Ar-C), 135.8
(CH=CH2), 139.3 (C4), 153.0 (C2), 169.9 (C6); max (thin film), 3336 (N-H), 1638
(C=O); m/z calculated for C28H35N3O5Si [M+H]+, 522.2419, found 522.2436.
36
1.4.13 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)
-3’,4’-dihydroxyoxolan-2’-yl)-2-(iso-butylamino)pyrimidin-6(1H)one 30e
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100mg,
0.21 mmol, 1.0 eq) and iso-butylamine (154mg, 0.21 mL, 2.1 mmol, 10.0 eq) 3((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl) -3’,4’-dihydroxyoxolan-2’-yl)-2(iso-butylamino)pyrimidin-6(1H)-one was obtained as a colourless solid (72mg, 0.13
mmol, 64%), mp = 197-198˚C. A drop of D2O was added to the analytical sample before
the 1H NMR analysis.
H (400 MHz, DMSO-d6), 0.91 (6H, d, J = 6.5 Hz, CH(CH3)2), 1.06 (9H, s, C(CH3)3), 1.891.99 (1H, m, CH(CH3)2), 3.01-3.16 (2H, m, N-CH2), 3.82-3.85 (1H, m, C4’-H), 3.88 (1H,
dd, J = 4.5, 11.5 Hz, C5’-H1), 3.97 (1H, dd, J = 3.0, 11.5 Hz, C5’-H2), 4.12 (1H, app t, J
= 6.5 Hz, C3’-H), 4.30 (1H, app t, J = 6.0 Hz, C2’-H), 5.29 (1H, d, J = 7.5 Hz, C5-H),
5.94 (1H, d, J = 6.0 Hz, C1’-H), 7.46-7.56 (6H, m, Ar-H), 7.62 (1H, d, J = 7.5 Hz, C4-
H), 7.66-7.72 (4H, m, Ar-H); C (100 MHz, DMSO-d6), 19.3 (Si-C(CH3)3), 20.6 (CHCH3),
20.7 (CHCH3), 27.1 (Si-C(CH3)3), 27.4 (CH(CH3)2), 48.8 (N-CH2), 62.9 (C5’), 74.7 (C3’),
76.0 (C2’), 83.0 (C4’), 85.9 (C1’), 105.0 (C5), 128.3 (Ar-C), 128.4 (Ar-C), 130.4 (Ar-C),
130.5 (Ar-C), 132.9 (Quat. Ar-C), 133.2 (Quat Ar-C), 135.5 (Ar-C), 135.6 (Ar-C), 139.3
(C4), 153.3 (C2), 169.9 (C6); max (thin film), IR 3336 (N-H), 1638 (C=O); m/z
calculated for C29H39N3O5Si [M+H]+, 538.2732, found 538.2750.
37
1.4.14 3-((2’R,3’S,4’S,5’R)-5’-((tert-utyldiphenylsilyl)oxymethyl)
-3’,4’-dihydroxyoxolan-2’-yl)-2-(benzylamino)pyrimidin-6(1H)one 30i
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100mg,
0.21 mmol, 1.0 eq) and benzylamine (208 mg, 0.24 mL, 2.1 mmol, 10.0 eq) 3((2’R,3’S,4’S,5’R)-5’-((tert-utyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)-2(benzylamino)pyrimidin-6(1H)-one was obtained as a colourless solid (67mg, 0.12
mmol, 56%), mp = 174-175˚C. A drop of D2O was added to the analytical sample before
the 1H NMR analysis.
H (400 MHz, DMSO-d6), 1.02 (9H, s, C(CH3)3), 3.78-3.82 (1H, m, C4’-H), 3.85 (1H, dd,
J = 4.0, 11.5 Hz, C5’-H1), 3.93 (1H, dd, J = 3.0, 11.5 Hz, C5’-H2), 4.10 (1H, app t, J =
6.5 Hz, C3’-H), 4.29 (1H, app t, J = 6.0 Hz, C2’-H), 4.44-4.53 (2H, m, N-CH2), 5.25 (1H,
d, J = 7.5 Hz, C5-H), 5.96 (1H, d, J = 6.0 Hz, C1’-H), 7.23-7.24 (1H, m, Ar-H), 7.30-
7.32 (3H, m, Ar-H), 7.42-7.50 (6H, m, Ar-H), 7.62-7.67 (5H, m, Ar-H, C4-H); C (100
MHz, DMSO-d6), 19.3 (Si-C(CH3)3), 27.1 (Si-C(CH3)3), 44.2 (N-CH2), 62.9 (C5’), 74.5
(C3’), 76.5 (C2’), 83.0 (C4’), 86.0 (C1’), 105.3 (C5), 127.0 (Ar-C), 127.5 (Ar-C), 128.4
(Ar-C), 128.5 (Ar-C), 128.6 (Ar-C), 130.4 (Ar-C), 130.5 (Ar-C), 132.9 (Quat. Ar-C),
133.2 (Quat Ar-C), 135.5 (Ar-C), 135.6 (Ar-C), 135.8 (Ar-C), 139.3 (C4), 140.0 (Quat.
Ar-C), 153.2 (C2), 169.8 (C6); max (thin film), 3217 (N-H), 1640 (C=O); m/z calculated
for C32H37N3O5Si [M+H]+, 572.2575, found 572.2600.
38
1.4.15 3-((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)
-3’,4’-dihydroxyoxolan-2’-yl)-2-(cyclohexylamino)pyrimidin6(1H)-one 30j
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100mg,
0.21
mmol,
1.0
eq)
and
cyclohexylamine
(183
mg,
2.1
mmol,
10.0
eq)
3-
((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl) -3’,4’-dihydroxyoxolan-2’-yl)-2(cyclohexylamino)pyrimidin-6(1H)-one was obtained as a colourless solid (60mg, 0.11
mmol, 51%), mp = 178-179˚C. A drop of D2O was added to the analytical sample before
the 1H NMR analysis.
H (400 MHz, DMSO-d6), 0.98 (9H, s, C(CH3)3), 1.14-1.28 (1H, m, aryl-H), 1.13-1.29
(4H, m, aryl-H), 1.50-1.57 (1H, m, aryl-H), 1.61-1.68 (2H, m, aryl-H), 1.73-1.81 (2H,
m, aryl-H), 3.72-3.78 (2H, m, C4’-H, NH-CH), 3.81 (1H, dd, J = 4.5, 11.5 Hz, C5’-H1),
3.91 (1H, dd, J = 3.0, 11.5 Hz, C5’-H2), 4.08 (1H, app t, J = 6.5, C3’-H), 4.28 (1H, app
t, J = 6.0, C2’-H), 5.26 (1H, d, J=7.5 Hz, C5-H), 5.85 (1H, d, J = 6.0, C1’-H), 7.36-7.48
(6H, m, Ar-H), 7.57-7.61 (4H, m, Ar-H), 7.65 (1H, d, J = 7.5 Hz, C4-H); C (100 MHz,
DMSO-d6), 15.6 (CH2), 19.3 (Si-C(CH3)3), 25.5 (CH2), 25.8 (CH2), 27.1 (Si-C(CH3)3),
32.5 (CH2), 32.7 (CH2), 50.2 (N-CH), 63.0 (C5’), 74.7 (C3’), 76.0 (C2’), 82.9 (C4’), 85.7
(C1’), 105.0 (C5), 128.4 (Ar-C), 128.4 (Ar-C), 130.4 (Ar-C), 130.5 (Ar-C), 132.9 (Quat.
Ar-C), 133.2 (Quat Ar-C), 135.4 (Ar-C), 135.6 (Ar-C), 139.7 (C4), 152.5 (C2), 169.9
(C6); max (thin film), 3249 (N-H), 1636 (C=O); m/z calculated for C31H41N3O5Si [M+H]+,
564.2888, found 564.2912.
39
1.4.16 3-((2’R,3’S,4’S,5’R)-5’-((tertButyldiphenylsilyl)oxymethyl) -3’,4’-dihydroxyoxolan-2’-yl)-2(pentylamino)pyrimidin-6(1H)-one 30g
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100mg,
0.21 mmol, 1.0 eq) and amylamine (183 mg, 0.24 mL, 2.1 mmol, 10.0 eq) 3((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl) -3’,4’-dihydroxyoxolan-2’-yl)-2(pentylamino)pyrimidin-6(1H)-one was obtained as a colourless solid (71mg, 0.13 mmol,
61%), mp = 185-186˚C. A drop of D2O was added to the analytical sample before the 1H
NMR analysis.
H (400 MHz, DMSO-d6), 0.86 (3H, t, J = 7.0 Hz, CH3), 1.01 (9H, s, C(CH3)3), 1.22-1.33
(4H, m, alkyl-H), 1.46-1.54 (2H, m, NCH2CH2), 3.12-3.29 (2H, m, N-CH2), 3.76-3.79
(1H, m, C4’-H), 3.82 (1H, dd, J = 4.5, 11.5 Hz, C5’-H1), 3.92(1H, dd, J = 3.0, 11.5 Hz,
C5’-H2), 4.06 (1H, app t, J = 6.5, C3’-H), 4.26 (1H, app t, J = 6.0, C2’-H), 5.24 (1H, d,
J = 7.5 Hz, C5-H), 5.87 (1H, d, J = 6.0, C1’-H), 7.40-7.50 (6H, m, Ar-H), 7.56 (1H, d, J
= 7.5 Hz, C4-H), 7.61-7.67 (4H, m, Ar-H); C (100 MHz, DMSO-d6), 14.4 (CH2CH3), 19.3
(Si-C(CH)3), 22.5 (CH3CH2), 27.1 (Si-C(CH3)3), 28.7 (CH2), 29.1 (CH2), 41.4 (N-CH2),
62.9 (C5’), 74.7 (C3’), 76.0 (C2’), 82.9 (C4’), 85.8 (C1’), 104.9 (C5), 128.4 (Ar-C),
128.4 (Ar-C), 130.4 (Ar-C), 130.5 (Ar-C), 132.9 (Quat. Ar-C), 133.2 (Quat Ar-C), 135.4
(Ar-C), 135.6 (Ar-C), 139.4 (C4), 153.1 (C2), 170.0 (C6); max (thin film), 3363 (N-H),
1634 (C=O); m/z calculated for C30H41N3O5Si [M+H]+, 552.2888, found 552.2911.
40
1.4.17 3-((2’R,3’S,4’S,5’R)-5’-((tertButyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)-2(hexylamino)pyrimidin-6(1H)-one 30h
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100mg,
0.21 mmol, 1.0 eq) and hexylamine (212mg, 0.28 mL, 2.1 mmol, 10.0 eq) 3((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)-2(hexylamino)pyrimidin-6(1H)-one was obtained as a colourless solid (62mg, 0.11 mmol,
52%), mp = 181-182˚C. A drop of D2O was added to the analytical sample before the 1H
NMR analysis.
H (400 MHz, DMSO-d6), 0.81 (3H, t, J = 7.0 Hz, CH3), 0.98 (9H, s, C(CH3)3), 1.19-1.26
(6H, m, alkyl-H), 1.42-1.50 (2H, m, NCH2CH2), 3.12-3.29 (2H, m, N-CH2), 3.75-3.79
(1H, m, C4’-H), 3.82 (1H, dd, J = 4.5, 11.5 Hz, C5’-H1), 3.91-3.93 (1H, m, C5’-H2), 4.07
(1H, app t, J = 6.5, C3’-H), 4.26 (1H, app t, J = 6.0, C2’-H), 5.26 (1H, d, J=7.5 Hz, C5H), 5.84 (1H, d, J = 6.0, C1’-H), 7.38-7.48 (6H, m, Ar-H), 7.58-7.64 (4H, m, Ar-H, C4H); C (100 MHz, DMSO-d6), 14.4 (CH2CH3), 19.3 (Si-C(CH3)3), 22.6 (CH3CH2), 26.6
(CH2), 27.1 (Si-C(CH3)3), 29.0 (CH2), 31.6 (CH2), 41.4 (N-CH2), 62.9 (C5’), 74.7 (C3’),
76.0 (C2’), 82.9 (C4’), 85.3 (C1’), 104.9 (C5), 128.4 (Ar-C), 128.4 (Ar-C), 130.4 (Ar-C),
130.5 (Ar-C), 132.9 (Quat. Ar-C), 133.2 (Quat Ar-C), 135.4 (Ar-C), 135.5 (Ar-C), 139.4
(C4), 153.1 (C2), 170.0 (C6); max (thin film), 3364 (N-H), 1635 (C=O); m/z calculated
for C31H43N3O5Si [M+H]+, 566.3045, found 566.3052.
41
1.4.18 3-((2’R,3’S,4’S,5’R)-5’-((tertButyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)-2(iso-pentylamino)pyrimidin-6(1H)-one 30k
Following general amination procedure from 5’-O-TBDPS-2,2’-anhydrouridine (100mg,
0.21 mmol, 1.0 eq) and iso-pentylamine (183 mg, 0.24 mL, 2.1 mmol, 10.0 eq) 3((2’R,3’S,4’S,5’R)-5’-((tert-Butyldiphenylsilyl)oxymethyl)-3’,4’-dihydroxyoxolan-2’-yl)-2(iso-pentylamino)pyrimidin-6(1H)-one was as a colourless solid (67mg, 0.12 mmol,
58%), mp = 182-183˚C. A drop of D2O was added to the analytical sample before the 1H
NMR analysis.
H (400 MHz, DMSO-d6), 0.89 (6H, d, J = 6.5 Hz, CH2(CH3)2), 1.02 (9H, s, C(CH3)3),
1.38-1.43 (2H, m, CH2CH(CH3)2), 1.54-1.64 (1H, m, CH(CH3)2), 3.15-3.32 (2H, m, NCH2), 3.76-3.79 (1H, m, C4’-H), 3.82 (1H, dd, J = 4.5, 11.5 Hz, C5’-H1), 3.91 (1H, dd, J
= 3.0, 11.5 Hz, C5’-H2), 4.06 (1H, app t, J = 6.5, C3’-H), 4.23 (1H, app t, J = 6.0, C2’H), 5.24 (1H, d, J = 7.5 Hz, C5-H), 5.86 (1H, d, J = 6.0, C1’-H), 7.42-7.48 (7H, m, Ar-
H), 7.61-7.66 (5H, m, Ar-H, C4-H); C (100 MHz, DMSO-d6), 19.3 (Si-C(CH3)3), 23.0
(CHCH3), 25.8 (CH(CH3)2), 27.1 (Si-C(CH)3), 38.0 (NHCH2CH2), 39.7 (N-CH2), 62.9
(C5’), 74.7 (C3’), 76.0 (C2’), 82.9 (C4’), 85.8 (C1’), 105.0 (C5), 128.4 (Ar-C), 128.4
(Ar-C), 130.4 (Ar-C), 130.5 (Ar-C), 132.9 (Quat. Ar-C), 133.2 (Quat Ar-C), 135.5 (Ar-
C), 135.6 (Ar-C), 139.4 (C4), 153.1 (C2), 169.9 (C6); max (thin film), 3330 (N-H), 1637
(C=O); m/z calculated for C30H41N3O5Si [M+H]+, 552.2888, found 552.2906
42
2. Functionalised Amino Acids via the BellušClaisen Rearrangement
2.1 Introduction
2.1.1 Amino Acids and Peptides
Amino acids are organic molecules that have both an amine (-NH2) and a carboxyl
(-COOH) functional group.64 Amino acids usually refers to the amino-alkanoic acids,
N3H+-(CR1R2)n-CO2- where n = 1 for amino acids, n = 2 for amino acids and so on.
Figure 7 depicts the structure of an amino acid where R is a side chain. The differing
side groups, R, determine the properties of the amino acids.
Figure 7: Amino Acid Structure65
Hundreds of amino acids have been discovered which occur in living organisms and the
majority are -amino acids.66 They can be present as a single amino acid or as
components of peptides, proteins and other amides.64 A peptide consists of a chain of
fifty amino acids or less which are joined by peptide bonds. A polypeptide consists of
chains of more than fifty amino acids and proteins are formed of several polypeptides.65
Nineteen amino acids and one imino acid, proline,67 are used by cells for protein
synthesis. These are called proteogenic, or primary, amino acids and are found within
proteins that are coded for the standard genetic code.65 With the exception of glycine, all
proteogenic amino acids have an
asymmetric centre and thus can have two
enantiomers.68 Enantiomers are non-superimposable mirror images (Figure 8).69 Proteins
and the majority of naturally occurring peptides contain the L-amino acids.
43
Figure 8: Enantiomers of Proline
Amino acids have shown a wide range of biological activities and are used for a range of
treatments.
For
example,
tyrosine
is
a
precursor
of
the
neurotransmitters
norepinephrine, epinephrine and dopamine which are used for mood regulation and
therefore tyrosine supplements have been used for stress reduction.70,71
Cysteine is
needed for the skin facilitating the production of collagen and it also helps in detoxifying
harmful toxins. Cysteine supplements have also been tried in the treatment of
arthritis.72,73 L-Glutamine is used to maintain the lining of the gut as well as other
essential functions such as the immune system. L-Glutamine supplements have been
used to treat Irritable Bowel Syndrome.74 Further, in addition to nutritional supplements,
amino acids are used in the synthesis of other products such as cosmetics and
surfactants.75,76
Most proteogenic acids are readily available, and can be bought in gram quantities for a
modest cost especially compared to other enantiomerically pure compounds. However, in
addition to the primary amino acids, there are hundreds of non-proteogenic amino acids
that are not used in protein synthesis.64 These have become important as tools for
modern drug discovery research, particularly when incorporated into peptides.77,78 It is
possible to acquire non-proteogenic amino acids from nature, but this involves
harvesting from natural sources that can be time-consuming and expensive. Therefore it
is preferable to synthesize these products in the laboratory where possible.
This study investigates the application of Belluš-Claisen rearrangement as a method of
producing non-protegenic amino acids and dipeptides in a one-pot reaction.
2.1.2 The Claisen Rearrangement
The Claisen rearrangement has seen wide use in synthetic organic chemistry because of
the stereoselective nature of the bond formation, and the potential to obtain useful
polyfunctionalised products.79,80 The reaction’s usefulness is reflected in the extensive
44
library of research that has been published and modern variants have secured the
continued reputation of this highly useful synthetic tool.79
The process discovered in 1912 by Ludwig Claisen, was the first recorded example of a
[3,3]-sigmatropic rearrangement.81,80
A sigmatropic rearrangement occurs in an
intramolecular process whereby a -bond is created between atoms that were not linked
and a previous bond is broken i.e. the -bond migrates (Figure 9 and Figure 10).
Figure 9: A [3,3] sigmatropic rearrangement82
Two numbers set in the brackets [i,j] are used to specify the order of a sigmatropic
rearrangement. These numbers can be ascertained by counting the atoms from the
original position that the bond has moved from. Each of the original termini is given
the number 1. Thus in Figure 9, each terminus of the -bond has migrated from C-1 to
C-3, so the order is [3,3].
Figure 10: A [1,5] sigmatropic rearrangement82
In Figure 10, the carbon terminus has moved from C-1 to C-5, but the hydrogen
terminus has not moved at all, so the order is [1,5].82
The [3,3]-sigmatropic rearrangement is a reliable and proven method for the
stereoselective construction of carbon–carbon or carbon–heteroatom bonds.83 The
Claisen rearrangement is a [3,3]-sigmatropic rearrangement of an allyl vinyl ether 38 to
give the corresponding ,-unsaturated carbonyl compound 39 (Scheme 11).80 Formerly,
the Claisen reaction specifically refers to an allylic ether, with the aza-Claisen and thioClaisen referring to rearrangements of allylic amines and allylic sulphides respectively.
45
Scheme 11: The Claisen Rearrangement80
Claisen substrates proceed through highly ordered six-membered transition states
allowing
control
over
the
stereochemistry
depending
on
the
precursors.
(Scheme 12).84
Scheme 12: Highly ordered six-membered transition state84
Subsequent research by other groups found that the conditions reported by Claisen on
aromatic substrates could be successfully applied to aliphatic skeletons. For example,
ethyl -cinnamyloxycrotonate 43 undergoes a [3,3] rearrangement to give keto ester
44 under heating in the presence of ammonium chloride (Scheme 13).80,85
Scheme 13: Rearrangement of ethyl -cinnamyloxycrotonate
Claisen rearrangements of allyl vinyl ethers need high temperatures, about 200 oC.86
Such harsh conditions can lead to decomposition of the final product. Further, synthesis
of the vinyl ether moiety starting material is a challenging process. Many variants have
been reported where attempts have been made to enable a synthetically useful process
using
milder
intermediate
experimental
in
separately.80,85
situ
to
conditions,
bypass
the
faster
need
reaction
to
times
synthesize
or
the
generating
starting
the
material
The methods used included the use of different substituents, different
methods to access a suitable intermediate to undergo [3,3] sigmatropic rearrangement
and variations in the carbon skeleton of the substrate as well as the catalyst, if any.80,87
Some examples are discussed below.
46
2.1.3 Claisen Variants
2.1.3.1 The Eschenmoser-Claisen Rearrangement.
The Eschenmoser-Claisen rearrangement is considered to be one of the more useful
pericyclic reactions.88 Building on the investigation of amide acetals by Meerwein et al.,89
Eschenmoser reported that heating allylic alcohols 45 with dimethylacetamide dimethyl
acetal 46 gave -unsaturated amide 48 (Scheme 14).84,90 Following alcohol exchange
and elimination of methanol intermediate ketene N,O-acetal 47 is formed in situ. This
undergoes [3,3] sigmatropic rearrangement to give resulting product. The electron
donating amino substituent in the intermediate drastically increases the reaction rate of
the pericyclic step.84
Scheme 14: The Eschenmoser–Claisen Rearrangement
Compared to the Johnson and Ireland variants mentioned below, the Eschenmoser
version often provides better yields with superior stereo-selectivity. The reaction also
has the advantage of employing neutral conditions in the formation of the N,O-ketene
intermediate which allows sensitive substrates to be used in the reaction, provided that
they
can
withstand
the
high
temperatures
that
are
frequently
required.
The
Eschenmoser–Claisen rearrangement has proven to have extensive scope and has been
used in the synthesis of complex molecules,91 steroids,92 drugs and natural products.93,94,
Hart and Chen (1993) employed the Eschenmoser-Claisen rearrangement as one of the
key steps in the first total synthesis of stenine 5195. The primary alcohol had to be TBS
protected to prevent competitive activation and cyclization. After protection, silyl ether
49 was refluxed with dimethylacetamide dimethyl acetal 46 in xylenes for 4 hours to
give the desired amide 50 in excellent 93% yield (Scheme 15).
47
Scheme 15: The Eschenmoser–Claisen Rearrangement used in total synthesis of stenine 5195
2.1.3.2 The Johnson Rearrangement.
The
Johnson-Claisen
rearrangement
is
closely
related
to
the
Eschenmoser
rearrangement, proceeding through a ketene acetal. Here, an allylic alcohol 53 is heated
with ethyl orthoacetate 52 and acid to give mixed ortho ester 54. The ortho ester 54
then loses ethanol to generate the ketene acetal 55 which proceeds to undergo
rearrangement to give to ,-unsaturated ester 56 (Scheme 16).96 The traditional Claisen
rearrangement, namely the allyl vinly ether rearrangement, is typically a two-step
process but in the Johnson-Claisen rearrangement the ketene acetal formation and the
rearrangement are completed in one step.90
Scheme 16: The Johnson–Claisen Rearrangement
The Johnson-Claisen rearrangement has been used in the synthesis of steroids,97
prostaglandins,98 antitumour compounds,99 and alkaloids.100,101 Danishefsky et al. (2002)
used the Johnson-Claisen rearrangement to synthesize a key intermediate in their total
synthesis of gelsemine (Figure 11).
48
Figure 11: Gelsemine
A Horner-Wadsworth-Emmons condensation, followed by reduction of the ketone of the
allylic alcohol, gave a mixture of stereiosmers 58. The Johnson-Claisen rearrangement
was cleverly employed whereby treatment with triethylorthoacetate and a catalytic
amount of propionic acid gave the identical ,-unsaturated ester 60 with both the vinyl and -caroxymethyl functionalities at the correct positions for the following
synthetic steps (Scheme 17)102.
Scheme 17: Synthesis of ,-unsaturated ester 60
102
2.1.3.3 The Ireland-Claisen Rearrangement
The Ireland-Claisen rearrangement represented a significant development of the Claisen
rearrangement because, compared to other rearrangements, this reaction proceeded
under milder conditions with temperatures under 100˚C.103,104The inspiration for this
work was a study by Rathke and Lindert in 1971, who demonstrated that it was possible
to generate ester enolates under mild conditions.105,106 Ireland and Mueller reported the
rearrangement of allyl trimethylsilyl ketene acetal 63, prepared by formation of allylic
ester enolate 62 from ester 61 followed by reaction with trimethylsilyl chloride. The
subsequent rearrangement followed by hydrolysis gave the ,-unsaturated carboxylic
acid 64 (Scheme 18).
49
Scheme 18: Ireland-Claisen Rearrangement103
The Ireland-Claisen reaction has a number of advantages including the ease of synthesis
of the ester enolate, the ability to control E/Z selectivity in the product, a frequently high
degree of transference of chirality from the starting material to the newly formed
stereocenters in product 64 and a high degree of alkene stereocontrol. It has thus been
widely developed in organic syntheses and has been used in various applications
including
the
synthesis
of
polyether
antibiotics107,
natural
products108
and
the
80,109
preparation of polyfunctionalised structures.
Corey et al. (1999) used the Ireland-Claisen rearrangement as part of the first total
synthesis of aspidophytine 67 more than a quarter of a century after the elucidation of
its structure.110 A key intermediate, isopropyl ester 66, was derived by treating allylic
acetate 65 with LDA and TBSCl to give a chiral carboxylic acid. Esterification with EDCl
as the coupling reagent provided the desired ester in 57% overall yield (Scheme 19).
Scheme 19: Ireland-Claisen Rearrangement used in total synthesis of aspidophytine 67
50
110
2.1.3.4 The Reformatsky-Claisen Rearrangement.
The [3,3] sigmatropic rearrangement of zinc enolates, termed the Reformatsky-Claisen
rearrangement, was reported in 1973.111 Baldwin’s study showed that zinc enolates,
generated by the Reformatsky reaction of αhaloesters 68 with zinc dust, at 80 to 140
˚C, led to the corresponding
,δ-unsaturated zinc carboxylates 70 via enolate 69
(Scheme 20). This work was significant in that it proceeded under neutral conditions.
Yields varied widely depending upon substitution and the solvent used. For example,
when R1=R2=Me and R3=R4=H, using the solvent was benzene and a temperature of
80˚C, a stoichiometric yield was reported. The yield drastically changed to less than
15% when R1=R2=R3=R4=H, xylene was the solvent and the temperature was 140 ˚C.111
Scheme 20: Reformatsky-Claisen Rearrangement111
The Reformatsky-Claisen rearrangement will also proceed when a silylating agent is
used, where the most probable intermediate is a silyl ketene acetal. The rearrangement
most often reported in the literature involve heating a substrate with zinc dust and a
silylating reagent in a polar aprotic solvent.84,112,113
An example of its synthetic application was the rearrangement of fluorinated substrates.
Fluorinated ketones have been found to be effective enzyme inhibitors.114 With this
discovery the ability to synthesize molecules with fluorine substituents adjacent to a
carbonyl group became a major research target. This was one of the earliest applications
of the Reformatsky-Claisen rearrangement, for example the conversion of allyl
chlorodifluoroacetate 71 to difluoroacid 72 (Scheme 21).115
Scheme 21: Synthesis of difluoroacid 72115
51
2.1.4 The Belluš-Claisen Rearrangement
In 1978, Belluš and Malherbe discovered a new ketene-Claisen reaction during an
attempt to prepare the 2-chlorocyclobutanone derivative 77 (Scheme 22).116,117
Scheme 22: First observation of the Belluš-Claisen Rearrangement116
Chloro(trichloroethyl)ketene 74 was prepared from acyl chloride 73 via zinc copper
couple catalysed dehalogenation. When ketene 74 was then reacted with allylic ether 75
at ambient room temperature a mixture of products was obtained, comprised of the
desired [2+2] cycloaddition product 77 and the -unsaturated ester 79. On analysis it
was found that this byproduct was the result of an alternate reaction pathway, where the
nucleophilic oxygen atom of the allylic ether 75 can compete successfully with the
double bond in 75 for the electrophilic ketene. This meant that, as well as expected
intermediate 76, zwitterionic enolate intermediate 78 was also formed. This is perfectly
set up to undergo [3,3]-sigmatropic rearrangements to give ,- unsaturated ester 79.
52
The original Claisen reaction required high temperatures and since the 1970s, cationaccelerated
and anion-accelerated rearrangements have been utilised to reduce the
temperature of the reaction, speed up the rate and to enable the synthesis of a wider
range of molecules that might otherwise decompose at higher temperatures.118,119 For
example, the Ireland Claisen rearrangement is an anion accelerated process.103,120 The
Belluš-Claisen rearrangement was the first reported rearrangement that had a
zwitterionic intermediate.116 The effect on the reaction is extraordinary and is due to
charge neutralisation providing a significant driving force. Whereas a typical Claisen
rearrangement needs temperatures in excess of 150˚C to proceed, the Belluš-Claisen
rearrangement will occur readily at room temperature.
Figure 12: Dipole Accelerated Claisen Rearrangements
It was reported that the new reaction could tolerate a broad range of cyclic and acyclic
ethers and sulfides 83 to give the corresponding of ,-unsaturated ester and thioester
85 (Scheme 23).116
Scheme 23: General scheme for first reported Belluš-Claisen Rearrangement116
This research inspired work undertaken by the MacMillan group, who conducted a
thorough investigation into a novel acyl-Claisen reaction based on the Belluš-Claisen
variant. The range of ketenes that could be used were highly limited and it was reported
that
only
highly
electrophilic
ketenes
such
as
dichloroketene
117
chloro(trichloroethyl)ketene were found to work satisfactorily.
and
Detailed inspection of
these reports by the MacMillan group discovered an alternate explanation. They reported
53
that the only productive reactions were those where the ketenes were generated by in
situ zinc dehalogenation.121 The MacMillan group determined that the zinc chloride
(ZnCl2) produced during the reaction was not just an unwanted by-product, but in fact,
was an essential part of the reaction122. Using Lewis acids to activate ketenes is not an
unknown process123 and it seemed likely that a Lewis acid was activating the ketene
towards nucleophilic attack.
This theory was supported by attempts to use chlorocyanoketene 87, a highly electron
deficient ketene, in the Belluš-Claisen reaction. The chlorocyanoketene was generated by
thermolysis (Scheme 24) and the reaction was therefore performed without any Lewis
acidic metal salt to act as a catalyst. Less than 5% of the product arising from a Claisen
rearrangement could be isolated, even when elevated temperatures were used.124
Scheme 24: Generation of chlorocyanoketene124
The MacMillan group determined that Lewis acid activated ketene 90 would be
susceptible to the addition of a tertiary allylic amine 91 (Scheme 25).124
Scheme 25: New Lewis Acid-Catalysed Claisen Rearrangement122
54
2.1.4.1 Enantioselective Claisen Rearrangements.
Several studies have reported the fact that, in the presence of Lewis acids, Claisen
rearrangements are accelerated.125,126 This led to the study of the effects of chiral Lewis
acids relating to the enantioselectivity of the reaction in an attempt to determine ligands
which accelerate the reaction and achieve optimum chirality transfer.80
In 2002, Hiersemann and Abraham reported the first successful enantioselective catalytic
Claisen Rearrangement (Scheme 26).
Chiral bis(oxazoline)copper(II) 96 was used to
catalyse the rearrangement of 2-alkoxycarbonyl-substituted allyl vinyl ethers 95 in a
bidentate manner. Very high yields were reported (94% to 100%).127
Scheme 26: The catalytic enantioselective Claisen Rearrangement of 2-alkoxycarbonylsubstituted allyl vinyl ethers127
The scope of this reaction is limited because of the necessity for an ester group at the 2position to act as a chelating group and the difficulties in the synthesis of allyl vinyl ether
moieties.127 The MacMillan group sought to develop an enantioselective catalytic Claisen
rearrangement which had general synthetic ability.
2.1.4.2 Enantioselective Acyl-Claisen Rearrangement.
The MacMillan group also looked into developing an enantioselective catalytic Claisen
rearrangement as part of their work on the acyl-Claisen rearrangement. This led to the
development of several chiral Lewis acids of which 98 was found to be the most effective
(Figure 13).
55
Figure 13: Chiral Lewis acid complex 98128
Using this Lewis acid catalyst the first example of an enantioselective acyl-Claisen
reaction was reported128 However, when published in 2001 this reaction was not
catalytic. It required a large excess of the Lewis acid to give good enantiomeric
selectivity (Scheme 27 and Table 5). The MacMillan group theorized that this was due to
a competing non-metal mediated rearrangement pathway.124
Scheme 27: Catalysed Acyl-Claisen Rearrangement128
Table 5: Effect of chiral Lewis acid loading
Entry
Mol % 98
Yield (%)
ee (%)
1
50
81
42
2
100
63
81
3
200
80
91
When the Belluš-Claisen reaction is performed using allylic amines (Scheme 28)116 the
reaction proceeds via zwitterion 104, formed from the allylic amine 102 upon reaction
with a ketene 103. The ketene used can be an isolated starting material or generated in
56
situ, such as from dehydrohalogenation of an acyl chloride. When using an acyl chloride
it is possible that the allylic amine may react with the acyl chloride 105 to form an acyl
ammonium salt 106. This is physically incapable of undergoing the desired [3,3]
rearrangement. Only after dehydrohalogenation of the salt can the rearrangement to
give the desired amide 107 take place.
Scheme 28: Mechanism of Belluš-Claisen Rearrangement116
The MacMillan group found that various Lewis acids were able to catalyze the reaction of
substituted ketenes with a range of allylic tertiary amine substrates. However their initial
method of ketene generation was not ideal. Bromoacetyl bromide was treated with zinc
in THF and the resulting ketene was co-distilled with the THF solution at reduced
pressure into a liquid nitrogen cooled Schlenk flask. This procedure had two major
drawbacks:
1) It was necessary to co-distil the ketenes with ethereal solvents and so the
molecular weight of the ketenes had to be low.
2) There was a degree of inaccuracy because it was extremely difficult to work out
the concentration of the ketene solution produced and thus it was normally used
in considerable excess.
After some research, an alternate method for ketene generation was chosen for the
remainder of their investigation. Base-promoted dehydrohalogenation of acid chlorides
had been used for over a century and was first demonstrated in 1911 by Staudinger.129
The method is robust and is capable of generating a broad range of mono and di
substituted ketenes. Furthermore, there was evidence of trapping the generated ketenes
57
in situ with differing reaction mixtures, for example with enol silanes, alkenes, carbonyl
compounds and imines.130 Most importantly from the view of the MacMillan group, this
reaction generated ketenes without generating Lewis acid metal byproducts.124
We proposed to extrapolate the Belluš-Claisen rearrangement to prepare functionalised
amino acids by C-allylation. As proof of concept the reaction was to be first attempted by
reacting N-phthaloylglycyl chloride 108 with a N,N-dimethyl amine 109. (Scheme 29).
This was very similar to the MacMillan work so we expected this to be successful.
Scheme 29: Proposed scheme for synthesis of 2-Phthaloyl-N,N-dimethylpent-4-enamide
If the reaction could be made to work satisfactorily it would then be repeated with
suitable allylated amino acid derivatives 111 to synthesize non-proteinogenic dipeptides
112 (Scheme 30).
Scheme 30: Proposed scheme for synthesis of non-proteogenic dipeptides
If this general reaction scheme proved viable, it was hoped that the rearrangement could
then be applied to more peptides such as 113 (Scheme 31). This would give a process
that allows addition of an amino acid to a peptide chain as well as creation of a new
stereocentre to give -allylated peptides like 114 using a single rearrangement reaction.
58
Scheme 31: Proposed scheme for [3,3] Belluš Claisen Rearrangement performed on generic
peptide
2.2 Results and Discussion
A Belluš-Claisen rearrangement was carried out using N,N-dimethyl allyl amine 109
(Scheme 33). This reagent was chosen because structurally it was the least complex
tertiary amine that could be used in the [3,3] sigmatropic rearrangement. N-phthaloyl
protected glycyl chloride 108 was chosen for the ketene precursor, which was
synthesized from commercially available N-phthaloyl glycine 115 following a procedure
by Balenovic et al.(Scheme 32)131
Scheme 32: Synthesis of N-phthaloylglycyl chloride 3131
The MacMillan group had already reported a successful rearrangement using Nphthaloylglycyl chloride as the ketene precursor. However, the amine used in their
example was an allyl morpholine derivative that had a number of advantages over the
dimethylallyl amine that we wished to use. Firstly, the electron-withdrawing ability of the
morpholine oxygen can increase the speed of the sigmatropic rearrangement by
destabilizing the cationic charge on the nitrogen of the zwitterionic intermediate.
Secondly, the separation of the product from the metal centre can be improved. This is
due to the relatively weaker electron donating capability of the morpholine nitrogen
which will make the amide carbonyl produced in the reaction less Lewis basic. In theory,
this improves the rate of the catalyst turnover and also increases the speed of the
reaction.124,128
59
Reaction of N-phthaloylglycyl chloride 108 with diisopropylethylamine gives ketene 116
(Scheme 33). This is followed by nucleophilic attack on the ketene by dimethylallylamine
109
to
give
zwitterionic
intermediate
117.
This
underwent
[3,3]
sigmatropic
rearrangement to give amide 110. Titanium tetrachloride was used as the Lewis acid in
this reaction.
Scheme 33: Synthesis of 2-phthaloyl-N,N-dimethylpent-4-enamide
1
H NMR analysis showed the appearance of the expected product in the reaction
mixture. The creation of a new asymmetric centre was supported by the appearance in
the 1H NMR of a splitting pattern at 2.78-3.20 characteristic of diastereotopic protons 
to an asymmetric center (Figure 14).
60
Figure 14: 1H NMR of 2-phthaloyl-N,N-dimethylpent-4-enamide 108 showing AB splitting pattern
at 2.76-3.21 ppm
A similar splitting pattern is reported for N-phthaloylallylglycine 118 at 2.90-3.14 (Figure
15).132 Following purification by column chromatography an overall yield of 6% was
obtained.
Figure 15: N-phthaloylallylglycine132
Titanium tetrachloride is a strong Lewis acid that has been used to considerably improve
the electrophilicity of substrates. It has been successfully utilised in Diels-Alder
reactions but it can create side reactions resulting in product decomposition.133,134,135
Likewise, while it has successfully been used in Belluš-Claisen reactions with a selection
61
of simple allylic tertiary amines, when used with more complex allylic amines often
results in product decomposition or recovery of starting material.79 Due to this alternate
Lewis acids were considered.
TMS triflate 119 (Figure 16) is a milder Lewis acid which has been used successfully in
Belluš-Claisen rearrangements.79 Repeating the reaction, this time with a stoichiometric
quantity of silyl triflate, did give a significant improvement with a final yield of 29%.
During these attempts to improve yield it was also noted that the purity of Nphthaloylglycyl chloride 108 had a significant effect on the final yield. Either freshly
prepared or freshly recrystallized material was necessary to get full conversion of the
reaction to the desired starting material.
Figure 16: TMS triflate
The next attempt to increase the yield was the use of ytterbium triflate as the Lewis acid
catalyst. Ytterbium triflate catalyzed Claisen rearrangements in good yields have been
reported.122,136,137 The reaction was repeated using ytterbium triflate (Scheme 34).
Scheme 34: Alternate Lewis acid catalyst
Ytterbium triflate was bought as the hydrate and had to be dried before use. Unless
sufficiently dried before use, ytterbium triflate can give poor yields when being used as a
Lewis acid.138 Initially the reaction was attempted using ytterbium triflate hydrate that
had been pre-dried under 0.7 mm pressure using a high vacuum oil pump for three
hours. However, this failed to give any of the desired product.
After this significantly harsher conditions were used to dry the catalyst. The reaction was
repeated using ytterbium triflate that had been left to dry for 16 hours under 0.7 mm
vacuum at 140 ˚C. This gave a quantitative crude yield, with 1H NMR analysis showing
the majority to be product. On being left to stand, the crude product solidified. Re-
62
crystallisation from an IPA/iPr2O mixture gave pure 2-phthaloyl-N,N-dimethylpent-4enamide, in 57% yield.
An alternate protecting group for the ketene precursor was also investigated. N-Tosyl
glycine 121 was synthesized and converted to acid chloride 122 using literature
methods.139 However, attempts to perform the Belluš-Claisen using acid chloride 122
proved unsuccessful. All attempts to perform the rearrangement using acid chloride 122
returned only starting materials and N-tosyl glycine 121.
Scheme 35: N-Tosyl glycyl chloride synthesis
2.2.1 Application to Amino Acids
The next step was to apply this chemistry to allylated amino acids anaolgues and to
investigate whether a chiral molecule would affect the selectivity of the generating of the
new asymmetric centre in the rearranged product. The first experiment was performed
on the simplest available chiral amino acid, alanine. The methyl ester hydrochloride salt
was refluxed in acetonitrile with allyl bromide and sodium hydrogen carbonate to give
the desired allylated analogue. Purification by flash column chromatography gave N,Ndiallyl alanine methyl ester 123 in 72% yield. The rearrangement reaction was
attempted using the previously tried conditions: diisopropylethylamine, N-phthalylglycyl
chloride and ytterbium triflate as the Lewis acid catalyst (Scheme 36).
Scheme 36: Belluš-Claisen Rearrangement of N,N-diallyl alanine methyl ester
On the first attempted rearrangement, a mixture of starting material and rearranged
products 124 and 125 was identified in the crude. An acid wash was used to separate
63
the starting material and the amide product to give a crude yield of 39% of the two
isomeric products. Again, use of freshly re-crystallized N-phthalylglycyl chloride resulted
in a reaction that gave total conversion by
1
H NMR analysis. Purification by column
chromatography gave a 60:40 mixture of dipeptides 124 and 125 in a yield of 48%.
(Calculation of stereochemistry is discussed below)
Given this encouraging starting point it was hoped to expand the reaction using a diverse
range of more complex amino acids. All diallylated amino acid derivatives 111 were
synthesized directly from the appropriate amino acid hydrochloride 126 by refluxing in
acetronitrile with allyl bromide 127. (Scheme 37 and Table 6)
Scheme 37: Synthesis of diallylated amino acid derivatives
Table 6: Synthesis of di-allylated amino acid derivatives
Rearrangements
Entry
Compound
R
Yield (%)
1
111a
(CH3)2CH-
70
2
111b
(CH3)2CH2CH-
61
3
111c
CH3CH2(CH3)CH-
69
were
then
attempted,
again
using
diisopropylethylamine,
N-
phthalylglycyl chloride and ytterbium triflate as the Lewis acid catalyst. However, all
attempts only returned the unreacted diallylated amino acid derivative and phthaloyl
glycine. All the reactions were repeated using freshly prepared acyl chlorides and dried
ytterbium triflate but again only starting materials were returned.
The lack of the corresponding rearranged product was unexpected. The amino acids
derivatives used were not radically different to diallylalanine methyl ester. Alanine
derivative 123 had successfully undergone the desired [3,3] rearrangement. Valine,
leucine and isoleucine have only a slight increase in the complexity of the carbon chain
on the amino acid, with an extra three or four carbons on the chain terminus.
64
The reaction was then repeated with di-allyl isoleucine methyl ester, refluxing in DCM
when the addition of the acyl chloride was complete. This again returned the di-allyl
isoleucine methyl ester starting material and N-phthaloylglycine. The reaction was then
repeated using dichloroethane as the solvent. After refluxing overnight this again
returned only di-allyl isoleucine methyl ester starting material and N-phthaloylglycine.
For avoidance of doubt, the reaction was performed in DCE with di-allyl alanine methyl
ester
123
that
gave
the
expected
dipeptide
product
in
45%
yield
and
a
diastereoisomeric ratio of 60:40.
The last amino acid variant tried was N-allyl proline methyl ester 129. The monoallayted variant of L-proline proved challenging to synthesize at first. Using the previous
allyl bromide/sodium hydrogen carbonate conditions with one equivalent of allyl bromide
produced a mixture of diallylated quaternary ammonium 130 and the desired N-allyl
proline methyl ester 129 (Scheme 38). This mixture of products resulted in a very
inefficient conversion to the desired product.
Scheme 38: First attempt of synthesis of N-allyl proline methyl ester
Repeating the reaction at room temperature in DMF proved significantly more selective,
giving only the desired mono-allyl product 129. Purification by flash chromatography
gave the product in 46% yield.
Scheme 39: Belluš-Claisen Rearrangement of allyl proline methyl ester
65
Using the same base, ketene precursor and Lewis acid for the reaction, the
rearrangement successfully proceeded to give the expected dipeptides 131 and 132
(Scheme 39). The diastereoselectivity of the reaction was significantly better than when
using alanine, giving a 75:25 ratio.
Removal of impurities proved straightforward, with flash column chromatography giving
a pure mixture of diastereomeric products. However, separation of the major and minor
diastereomers proved challenging due to the almost identical rate of elution of the two
isomers. HPLC was investigated as a possible method of purification but did not give
sufficient separation of the diastereomers. A drastic increase in silica used (100g silica
per gram product) finally produced diastereomerically enriched samples. Following
controlled crystallization with a combination of IPA and tert-butyl ether gave dipeptide
131 in sufficient purity to allow X-ray crystallography (Figure 17). The rearrangement
was therefore favouring the generation of an (R) stereocentre.
Figure 17: X-ray data of (S)-methyl 1-((R)-2-(1,3-dioxoisoindolin-2-yl)pent-4-enoyl)pyrrolidine2-carboxylate 131
66
[3,3]-Sigmatropic rearrangements proceed through highly ordered six membered
transition states which allows for chirality transfer from a stereogenic centre. When the
asymmetric centre is incorporated into the cyclic framework of the transition state chiral
information can be transferred in a concise and predictable manner.80 Belluš et al.
reported the first diastereoisomeric reaction between allyl sulfide 133 and dichloro acyl
chloride 134 (Scheme 40). The resulting zwitterionic intermediate 135 then underwent
[3,3]-sigmatropic rearrangement to give silyl ester 136. The rearrangement is directed
by substituent X. The resulting 1,3-diaxial repulsive interactions in the intermediate
results in the stereochemistry of 136 being preferred.140
Scheme 40: Diasteroselective Ketene-Claisen Rearrangement140
When the asymmetric centre is outside the transition state framework it can be more
difficult to achieve high enantioselectivity. For the ketene-Claisen reaction using N-allyl
proline methyl ester 129 the resulting stereochemistry of the product is determined by
two sequential steps. Firstly, the addition of nucleophiles to monosubstituted ketenes
usually results in the formation of the (Z)-enolate 140 (Scheme 41).141 The LUMO
(lowest unoccupied molecular orbital) of the ketene is the C=O * orbital and as a result,
nucleophiles that react with the ketene would have to overcome substantial steric
interactions with the substituents to form the (E)-enolate 138.142 Therefore, nucleophiles
will prefer to attack opposite the substituent, resulting in (Z)-enolate formation.
Scheme 41: Preference for (Z)-enolate formation in addition to mono-substituted ketene
67
The second step, the resulting carbon-carbon bond formation during the [3.3]
rearrangement, will be influenced by the stereochemistry of the proline moiety of
zwitterionic intermediate 141. The fused five membered ring will restrict the relative
position asymmetric centre, increasing the difficulty of attacking one face of the
molecule. This would favour pathway A (Scheme 42), giving the (R) stereocentre.
Scheme 42: Preference for R stereochemistry
Following the success with N-allyl proline we planned to synthesize a range of allylated
proline variants 145 to see if the reaction could tolerate substitutions on the allyl chain.
Making the allyl proline anolgues was straight forward. Replacing allyl bromide with a
suitably substituted alkyl bromide 144 gave the desired products 145 in yields of 4062% (Scheme 43 and Table 7).
Scheme 43: Synthesis of N-Allyl Proline Methyl Ester derivatives
68
Table 7: Synthesis of N-Allyl Proline Methyl Ester derivatives
Entry
Compound
R1
R2
R3
Yield (%)
1
145a
Me
H
H
49
2
145b
Me
Me
H
62
3
145c
H
H
Me
53
4
145d
Et
H
H
55
5
145e
Ph
H
H
40
6
145f
CO2Me
H
H
59
Once products 145 had been successfully synthesized, Belluš-Claisen rearrangements
were
attempted
with
them.
The
same
reaction
conditions
were
used
with
a
stoichiometric amount of ytterbium triflate as the Lewis acid. The reaction proved robust
to a variety of allyl anologues, giving the rearranged dipeptides predominately of 146
and 147 in moderate to good yields (40-70 %) (Scheme 44 and Table 8).
Scheme 44: Belluš-Claisen Rearrangement with N-Allyl Proline Methyl Ester derivatives
Table 8: Belluš-Claisen rearrangement with N-Allyl Proline Methyl Ester derivatives
Major
Entry
product
Ratio of
R
R
1
R
2
Yield (%)
dipeptides 146
and 147
1
146a
Me
H
H
42
66:33
2
146b
Me
Me
H
40
54:46
3
146c
H
H
Me
49
75:25
4
146d
Et
H
H
70
78:22
5
146e
Ph
H
H
51
54:46
6
146f
CO2Me
H
H
47
54:46
69
Purification of these diasteriomeric mixtures again proved challenging. Given the time
constraints of the project it was not possible to isolate samples of sufficient purity for Xray crystallography for all variants of the reaction. However, a sample of 147d was
isolated that allowed crystal data to be collected (Figure 18).
Figure 18: 147d
Claisen type rearrangements will preferentially go through a chair-like transition state
that will give the corresponding syn product (Scheme 45).97 This is favoured because it
is typically lower in energy than that of the corresponding boat transition state. When a
second asymmetric centre was created during the rearrangement (Table 8, Entries 1, 46) the products were overwhelmingly two diastereomers, even though there are four
possible products.
70
Scheme 45: Syn/anti control in Claisen type reactions
2.2.2 Reaction Optimization
2.2.2.1 Solvent Screen
A solvent screen was carried out on the Belluš-Claisen reaction otherwise using the same
conditions with N-allyl proline methyl ester. Polar protic solvents readily react with acyl
chlorides to return carboxylic acids, thus a selection of non-polar and polar aprotic
solvents was chosen (Scheme 46 and Table 9). Of those solvents tried, the reaction only
went to completion in chlorinated solvents- chloroform and dichloroethane. Yield and
selectivity were similar to DCM (Table 9, Entries 1-3). Diethyl ether is a common solvent
for Belluš-Claisen type reactions, however some of the reagents used in the reaction
were not soluble which almost certainly led to trace yields (Table 9, Entry 4). No
conversion was observed when using highly polar solvents such as acetonitrile and DMF
(Table 9, Entries 6 and 8).
Scheme 46: Solvent Screen
71
Table 9: Solvent Screens
Entry
Solvent
Yield (%)
Diastereoisomeric
ratio
1
DCM
44
75:25
2
CHCl3
41
75:25
3
DCE
42
75:25
4
Et2O
0
-
5
THF
0
-
6
DMF
0
-
7
DMSO
0
-
8
MeCN
0
-
9
EtOAc
0
-
2.2.2.2 Base Screen
For completeness, a base screen was performed to investigate the effect of the base
used on the reaction (Scheme 47 and Table 10). Surprisingly of the tertiary amine bases
only diisopropylethyl
amine gave moderate conversion to the desired product.
Triethylamine did result in poor conversion to the desired product but showed no
improvement in diastereomeric selectivity. Pyridine, DMAP and DBU either gave trace
amounts of product or failed to show any conversion. All inorganic bases used failed to
show conversion.
The results of the screen were showed no correlation to pKa values, although how
hindered the base was did seem to correlate with how effective the conversion was.
Scheme 47: Base Screen
72
Table 10: Base Screens
Base
Entry
pKa143,144
Yield (%)
Diastereomeric ratio
1
i
Pr2EtN
10.75
51
75:25
2
Et3N
10.75
18
75:25
3
DBU
12
0
-
4
DMAP
9.2
0
-
5
Pyridine
5.2
0
-
6
NaOH
15.7
0
-
7
KOH
0
-
8
NaHCO3
0
-
The MacMillan group reported similar problems when they tried alternate bases and
speculated that nucleophlic tertiary amines were catalyzing an alternate pathway to give
a non-desired side product. Nucleophlic tertiary bases act as a catalyst in the formation
of -lactones by dimerization of ketenes in a known process. 124 This competing pathway
could explain the generally poor yield with only hindered tertiary bases given any
notable yield.
Scheme 48: Tertiary amine catalyzed formation of -lactone
73
2.2.2.3 Lewis Acid Screen
Preferably, a catalytic amount of Lewis acid could be used in the reaction. All reactions
done until this point had used stoichiometric quantities of ytterbium triflate to drive the
reaction to completion. Due to ytterbium triflate having a relatively high molecular mass
(620 g/mmol), this made the problem significantly more pronounced because by mass it
accounts for nearly 50% of the reaction mixture. A Lewis acid that could get the same
yields with a far smaller loading would represent a major improvement. A screen of
Lewis acids was attempted (Scheme 49 and Table 11).
Scheme 49: Lewis Acid Screen
Table 11: Lewis Acid Screens
Entry
Lewis acid
Yield
Ratio
1
Yb(OTf)3
47
75:25
2
TiCl4
17
80:20
3
Cu(OTf)2
0
-
4
TiCl4(THF)2
29
80:20
5
FeCl3
0
-
6
Fe(acac)3
0
-
7
Mg(OTf)2
0
-
8
Sm(OTf)3
0
-
9
i
0
-
Ti(O Pr)4
Most Lewis acids screened failed to give the desired rearranged products 131 and 132.
Of the Lewis acids tried only titanium tetrachloride and titanium tetrachloride THF
complex gave any of the desired dipeptides. Following on from this both ytterbium
74
triflate and titanium tetrachloride were screened again, this time using increasingly
smaller sub-stoichiometric amounts (Scheme 50 and Table 12).
Scheme 50: Lewis Acid Loading Screen
Table 12: Catalyst loading screen
Entry
Lewis acid
Stochiometry
Yield (%)
Ratio
1
Yb(OTf)3
100
49
75:25
2
Yb(OTf)3
50
26
75:25
3
Yb(OTf)3
25
0
-
4
Yb(OTf)3
10
0
-
5
TiCl4
50
27
80:20
6
TiCl4
25
25
80:20
7
TiCl4
10
19
80:20
8
TiCl4(THF)2
50
34
75:25
9
TiCl4(THF)2
25
29
75:25
10
TiCl4(THF)2
10
17
75:25
The failure of the reaction when a sub-stoichiometric amount of ytterbium triflate was
used was cause for concern. The Lewis acid should be able to act as a catalyst in the
reaction, being recycled after addition to the ketene and the subsequent rearrangement.
The fact that a stoichiometric amount was needed strongly suggests that the Lewis acid
was failing to dissociate from the amide after the rearrangement or that it was being
poisoned in the reaction. In either case, the catalyst was failing to turnover. Conversely,
both TiCl4 and TiCl4(THF)2 were found to still be effective at sub-stoichiometric amounts.
Indeed, there was a small improvement in yield against using titanium tetrachloride in
stoichiometric amounts. However, the overall yield of the reactions remained low.
75
2.2.3 Temperature Control
Further attempts to improve the reaction were employed by investigating the effects of
temperature. It was hoped that:1. an increase in selectivity could be achieved by using sub zero temperatures
or
2. heating would allow either less Lewis acid to be used or would be able to force rearrangements to occur that had failed at room temperatures.
2.2.3.1 Conventional Method
Typically the reaction was run at room temperature and went to completion within 4
hours. Some experiments were attempted with various temperature gradients. The
reaction was attempted at -78 ˚C in the hope that a significantly lower temperature
would increase the stereo control of the reaction.
A modest increase of the ratio of diastereomers was seen, going from 75:25 to 80:20.
This was accompanied by a drastic reduction in conversion. Analysis of the crude mixture
revealed that the reaction had not gone to completion and after purification an overall
yield of only 17% was obtained. The reaction was repeated with cooling only during the
addition of N-phthaloylglycyl chloride. After this, it was allowed to warm to room
temperature and stirred for an additional 24 hours. 1H NMR analysis of the crude mixture
showed an improvement in conversion but nonetheless 47% of the starting material
remained. The drastic reduction in yield was not worth the slight increase in stereocontrol and further attempts were abandoned.
2.2.3.2 Microwave
Following the successful use of the microwave to perform aminations of anhydrouridine,
it was hoped to apply the same chemistry to the Belluš Claisen rearrangement.
The reaction has been successfully performed with alanine and various allylated proline
variants. Unfortunately, attempts to expand the chemistry beyond these reactions have
had limited success. Any allylated amino acids with more complicated side chains than
alanine failed to rearrange at all, returning only starting material. Further, attempts to
use stoichiometric quantities of ytterbium catalyst were also unsuccessful.
76
It was hoped that higher temperatures and greater pressures achievable by the
microwave would provide sufficient activation energy to enable the reaction to work
successfully.
As a starting point, the successful N-allyl proline methyl ester rearrangement would be
performed in the microwave. It takes the reaction at least 4 hours under conventional
conditions, including a slow 2 hour addition step. It was hoped that simply performing
this reaction in the microwave would, at a minimum, speed up the reaction. If it could be
successfully performed then other amino acids would be attempted.
Table 13 summarizes the result of this line of investigation. Because the reactions were
performed in DCM, the microwave allowed dramatically higher temperatures than would
be possible using conventional conditions. Ultimately, very high temperatures were
necessary to drive the reaction to completion in a short time frame. Interestingly, higher
temperatures seemed to have no effect on the stereo-control of the reaction, with a
75:25 ratio of diastereoisomers still being obtained in all cases.
Scheme 51: Microwave Irradiation Screen of Reactions
Table 13: Microwave N-allyl proline methyl ester rearrangement
Reaction Time
Temperature
Yield (%)
Ratio
(min)
(˚C)
10
80
0
-
10
90
0
-
20
90
0
-
30
90
0
-
30
100
<5
60
120
21
75:25
30
140
37
75:25
77
Despite the acyl chloride being added to the reaction mixture in one portion, it is worth
noting that no [2+2] cyclisation products were observable in the reaction mixture. The
Belluš Claisen reaction typically requires a controlled addition of the acyl chloride to the
reaction mixture as the formation of [2+2] side products from the ketene are a serious
detriment to the reaction124. It is probable that the phthaloyl protecting group is simply
so bulky that it is preventing the [2+2] side reaction from occurring. This is also
supported by the fact that the major side products observable by
1
H NMR in failed
reactions were the unreacted allylated amino acid derivative and N-phthaloyl glycine. No
cycloadduct was seen in any reaction mixture.
2.2.3.3 Ring Closing Metathesis
Separation
of
the
diastereoisomer
mixtures
produced
during
the
Belluš-Claisen
rearrangement, while not impossible, proved to be very difficult. Besides very time
consuming purification methods, one idea investigated was the chemical transformation
of un-separated mixtures to aid in purification. Dipeptides 114 and 115, produced from
N,N-diallyl alanine methyl ester, are perfectly set up for a ring closing metathesis
(Scheme 52).
Scheme 52: Ring closing metathesis of dipeptides 114 and 115
The reaction proved straightforward, with 2nd Generation Grubbs145 catalyst giving the
expected product 159 on the first attempt in good yield (87%). It had been hoped that
the increased rigidity of the seven membered ring would help to differentiate the
products, making column chromatography easier. Unfortunately this was not the case
because the mixtures were not any easier to separate than the original dipeptide.
78
2.3 Conclusions and Future Work
A Belluš-Claisen rearrangement carried out with dimethylallylamine 109 with Nphthaloylglycyl chloride 108 as the ketene precursor has been initially investigated and a
method developed to synthesise 2-phthaloyl-N,N-dimethylpent-4-enamide 110. Out of a
variety of Lewis acid catalysts so far tried, it has been found that anhydrous ytterbium
triflate catalyst gives the best yield.
The rearrangement has been attempted with a variety of allyated amino acids. N,Ndiallyl alanine methyl ester 123 and N-allyl proline methyl ester 129 both gave
successful rearrangements. Use of N-allyl proline in particular was found to result in a
moderately diastereospecific methodology. However, attempts to repeat the reaction
with structurally more complex amino acids did not result in successful rearrangements.
Further optimisation of the reaction is required to improve the diastereoselectivity of the
reaction.
2.4 Experimental
Reagents were purchased from Sigma-Aldrich, Acros, Alfa Aesar, Fisher Scientific, TCI
UK or Lancaster Research Chemicals and were not purified except where stated.
Solvents were purchased anhydrous and stored over molecular sieves, or distilled under
nitrogen from an appropriate drying agent.
THF and diethylether were distilled from
sodium benzophenone ketyl radical while DCM and acetonitrile were distilled from
calcium hydride. Thin layer chromatography was performed on aluminum sheets coated
with Merck silica gel 60 F254 with visualisation using potassium permanganate solution
and/or scrutinised under 254 nm UV light. Column chromatography was performed using
Silica 60 (35-70 microns) supplied by Fisher.
Nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker Advance
400 NMR spectrometer (1H NMR at 400 MHz,
13
C NMR at 100 MHz) with the appropriate
deuterated solvent. Chemical shifts in 1H NMR spectra are expressed as ppm downfield
from TMS and in
13
C NMR, are relative to internal standard, and reported as singlet (s),
doublet (d), triplet (t), quartet (q) and combinations thereof, or multiplet (m). Coupling
constants (J) are quoted in Hz and are rounded to the nearest 0.5 Hz.
Mass
spectrometry was performed using a Bruker MicroTOF-Q instrument with electrospray
ionisation in the positive mode.
FT-IR data was acquired using Thermo Electron
Corporation Nicolet 380 FTIR with Smart Orbit diamond window instrument with
79
wavenumbers being reported in cm-1. All melting points were obtained using a Stuart
SMP10 melting point instrument. Microwave reactions were performed using a Milestone
MicroSYNTH reactor and SK10 vessel containing one magnetic stirring bead. Twist
control, rotor control, start parameters and continuous power were all selected. T1
control was used with 60 % stirring.
2.4.1 N-Phthaloylglycyl Chloride 108
131
N-Phthaloylglycine (7.0 g, 34.1 mmol) was refluxed in thionyl chloride (19.6 g, 12 ml,
164.5 mmol) for 1 hour. The solution was then concentrated in vacuo and the remaining
residue was distilled at 110˚C /0.7mm (corrected boiling point of 320 ˚C at 760 mm)
which, on cooling, gave a colourless solid. (6.0 g, 27.1 mmol, 79%) mp = 83-85 ˚C. (lit
84-85 ˚C). Lit. boiling point 190-192 ˚C /15 mm (corrected boiling point of 320 ˚C at
760 mm).
H (400 MHz, CDCl3), 4.15 (2H, s, NCH2), 7.77 (2H, m, Ar-H), 7.86 (2H, m, Ar-H). C(100
MHz, CDCl3), 38.4 (NCH2), 123.5 (Ar-C), 132.0 (Ar-C), 134.2 (Quat. Ar-C), 167.6 (NCO),
169.2 (COCl).max (thin film, cm-1), 2978 (C-H), 2938 (C-H), 1802 (COCl), 1768 and
1710 (CONCO); m/z (ES+) calculated for C10H7O4N (hydrolysed product) [M+H]+;
206.0448. found 206.0453.
2.4.2 N-Tosylglycine 121146
Glycine (2.60g, 30.0 mmol, 1.0 eq) was dissolved in 50 mL of 1.5M NaOH at room
temperature and p-toluenesulfonyl chloride (6.80 g, 36.0 mmol, 1.2 eq) in Et 2O (30 mL)
was added. After leaving to stir overnight 6M HCl was be added until pH = 2. The Et2O
layer was separated and the aqueous layer was extracted with Et 2O (3 x 40 mL). The
80
combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to
give the product. Recrystallization from Et2O gave the product as a white powder (2.91
g, 11.8 mmol, 39%). Mp = 146-149 ˚C. lit 147.6 ˚C.
H (400 MHz, (CD3)2CO), 2.27 (3H, s, CH3), 3.64 (2H, d, J = 6.0 Hz, CH2), 6.52 (1H, t, J
= 6.0 Hz, NH), 7.25 (2H, d, J = 8.0 Hz, Ar-H), 7.63 (2H, d, J = 8.0 Hz, Ar-H). C (100
MHz, CDCl3), 20.5 (CH3), 43.7 (CH2), 127.0 (Ar-C), 129.5 (Ar-C), 137.9 (Quat. Ar-C),
143.1 (Quat. Ar-C), 169.5 (COOH).max (thin film, cm-1), 3353 (C-H), 1709 (CO); m/z
(ES+) calculated for C9H11SO4N [M+H]+; 230.0482. found 230.0485.
2.4.3 N-Tosylglycyl Chloride 122139
N-Tosylglycine (2.48g, 10.0 mmol, 1.0 eq) was dissolved in Et 2O (25 mL) and
PCl5
(3.09g, 15.0 mmol, 1.5 eq) was added. The reaction was left to stir for 30 minutes until
all organic material has dissolved. The reaction was then allowed to stir for a further 30
minutes. Excess PCl5 was removed by filtration and hexane (100 mL) was added. The
solution was set aside at 0˚C for four hours.
The crystalline acid chloride will then be filtered off, washed with hexane and dried under
vacuum to give the product as a colourless solid (1.59 g, 6.42 mmol, 64%) mp = 81-85
˚C. Lit 82-83˚C.
H (400 MHz, CDCl3), 2.44 (3H, s, CH3), 4.27 (2H, s, CH2), 5.25 (1H, br s, NH), 7.34 (2H,
d, J = 8.0 Hz, Ar-H), 7.75 (2H, d, J = 8.0 Hz, Ar-H). C (100 MHz, CDCl3), 21.6 (CH3),
53.6 (CH2), 127.1 (Ar-C), 130.0 (Ar-C), 136.1 (Quat. Ar-C), 144.5 (Quat. Ar-C), 171.0
(COOH).max (thin film, cm-1), 2980 (C-H), 1802 (COCl).
2.4.4 General Belluš-Claisen Procedure
Modifying a procedure by MacMillan et al122, to a solution of dried Yb(OTf)3 (1.0 eq) in
dry DCM (20 mL) was added N,N-dimethylallylamine (1.0 eq) followed by N,Ndiisopropylethylamine (2.0 eq). The solution was stirred for 5 min before a solution of Nphthaloylglycyl chloride (1.5 eq) in dry DCM (10 mL) was added drop-wise over 2 hours.
81
The resulting dark orange mixture was then stirred for an additional 2 hours. The
reaction was then diluted with diethyl ether (20 mL), treated with aqueous NaOH (1M;
10 mL) and stirred for a further 10 minutes. The aqueous layer was extracted with
diethyl ether (3 x 40 mL) and the organic layers combined, washed with brine (3 x 20
mL), and dried over Na2SO4, filtered and concentrated in vacuo. Purification by column
chromatography and/or re-crystalization gave the desired product
2.4.5 2-Phthaloyl-N,N-dimethylpent-4-enamide 110
Following general Belluš Claisen procedure from dried Yb(OTf)3 (1.24 g, 2.00 mmol, 1.0
eq),
N,N-dimethylallylamine
(170
mg,
0.24
mL,
2.00
mmol,
1.0
eq),
N,N-
diisopropylethylamine (517 mg, 0.70 mL, 4.00 mmol, 2.0 eq) and N-phthaloylglycyl
chloride (670 mg, 3.00 mmol, 1.5 eq) 2-phthaloyl-N,N-dimethylpent-4-enamide was
obtained as a yellow oil that solidified on standing. This was recrystallised from IPA/tertbutyl methyl ether to give the product as a pale yellow solid. (311 mg, 1.14 mmol, 57%)
mp = 106-107 ˚C.
H (400 MHz, CDCl3), 2.76-2.83 (1H, app m, CH2), 2.98 (6H, s, CH3), 3.12-3.20 (1H, app
m, J = 10.5 Hz, CH2), 5.00 (1H, app d, J = 10.0 Hz, NCH), 5.07-5.12 (2H, app m, trans
CH=CH2, CH), 5.78 (1H, dddd, J = 4.0 Hz, J = 5.5 Hz, J = 10.0 Hz, J = 17.0 Hz,
CH=CH2), 7.71-7.76 (2H, m, C=CH), 7.83-7.87 (2H, m, C=CH-CH). C (100 MHz, CDCl3),
33.4 (NCHCH2), 36.3 (NCH3), 37.0 (NCH3), 51.1 (NCHCO), 118.7 (CH=CH2), 123.5 (ArC), 131.5 (Quat. Ar-C), 133.7 (CH2=CH), 134.2 (Ar-C), 167.8 (NCO), 168.1 (CON(CH3)2.
max (thin film, cm-1), 2965 (C-H), 1716 (Ester CO2), 1387 (C-H); m/z (ES+) calculated
for C15H16O3N2 [M+H]+; 273.1234. found 273.1246.
2.4.6 General Diallylation Procedure
147
Amino methyl ester hydrochloride (1.0 eq) was added to a mixture of allyl bromide
(2.2eq) and sodium hydrogen carbonate (4.0 eq) in acetronitrile (40 mL). The reaction
was heated to 70 oC and left to stir overnight under nitrogen. After 18 hours the reaction
82
was cooled to room temperature and the resulting precipitated salt removed by filtration.
The mixture was then concentrated in vacuo to give the crude product which was
purified by column chromatography (ethyl acetate) to give the product.
2.4.7 N,N-Diallyl alanine methyl ester 123147
Following N-allylation procedure from L-alanine methyl ester hydrochloride (2.00g, 14.3
mmol, 1.0 eq), allyl bromide (3.81g, 2.73 mL, 31.5 mmol, 2.2 eq) and sodium hydrogen
carbonate (4.81g, 57.3 mmol, 4.0 eq) N,N-diallyl alanine methyl ester was obtained as a
pale yellow oil (1.89 g, 10.3 mmol, 72%).
H (400 MHz, CDCl3), 1.26 (3H, d, J = 7.0, CHCH3), 3.13 (2H, ddt, J = 1.0, J = 7.0, J =
14.5 Hz, NCHAHB), 3.26 (2H, ddt, J = 1.5, J = 5.5, J =14.5 Hz, NCHAHB), 3.60 (1H, q, J
= 7.0 Hz, CHCH3), 3.69 (3H, s, OCH3), 5.10 (2H, ddd, J = 1.0, J = 3.0, J = 10.0 Hz, cis
CH=CH2), 5.19 (2H, ddd, J = 1.5, J = 3.0, J = 17.0 Hz, trans CH=CH2), 5.80 (2H, dddd,
J = 5.0, J = 7.0, J = 10.0, J = 17.0, CH2=CH). C (100 MHz, CDCl3), 14.6 (CHCH3), 51.1
(OCH3), 53.4 (NCH2), 57.1 (CH), 117.0 (CH=CH2), 136.4 (CH=CH2), 174.2 (CO). m/z
(ES+) calculated for C10H17NO2 [M+H]+; 184.1332. found 184.1339.
2.4.8 N,N-Diallyl isoleucine methyl ester 111c
Following N-allylation procedure from L-isoleucine methyl ester hydrochloride (2.0g, 11.0
mmol, 1.0 eq), allyl bromide (2.93g, 2.10 mL, 24.2 mmol, 2.2eq) and sodium hydrogen
carbonate (3.70g, 44.0 mmol, 4.0 eq) N,N-diallyl isoleucine methyl ester was obtained
as a pale yellow oil. (1.89 g, 8.25 mmol, 75%)
83
H (400 MHz, CDCl3), 0.81 (3H, d, J = 6.5 Hz, CHCH3), 0.85 (3H, t, J = 7.5 Hz, CH2CH3),
1.10-1.17 (1H, m, CH3CHAHB), 1.66-1.80 (1H, m, CH3CHAHB), 1.81-1.93 (1H, m,
NCHCH), 2.82 (2H, app dd, J = 8.0, J = 14.5 Hz, NCHAHB), 3.09 (1H, d, J = 11.0 Hz,
NCH), 3.41 (2H, app dt, J = 2.0, J =14.5 Hz, NCHAHB), 3.69 (3H, s, OCH3), 5.09 (2H,
app d, J = 10.0 Hz, cis CH=CH2), 5.18 (2H, app d, J = 17.0 Hz, trans CH=CH2), 5.75
(2H, dddd, J = 4.5, J = 9.0, J = 10.0, J = 17.0 Hz, CH 2=CH). C (100 MHz, CDCl3), 10.1
(CH2CH3), 15.9 (CHCH3), 24.8 (CH3CH2), 33.2 (NCHCH), 50.5 (OCH3), 53.3 (NCH2), 67.0
(NCH), 116.9 (CH=CH2), 136. 6 (CH=CH2), 173.0 (CO). m/z (ES+) calculated for
C13H23NO2 [M+H]+; 226.1802. found 226.1812.
2.4.9 N,N-Diallyl valine methyl ester 111a
Following N-allylation procedure from L-valine methyl ester hydrochloride (2.0g, 11.9
mmol, 1.0 eq), allyl bromide (3.18g, 2.27 mL, 26.2 mmol, 2.2eq) and sodium hydrogen
carbonate (4.01g, 143.3 mmol, 4.0 eq) N,N-diallyl valine methyl ester was obtained as a
yellow oil. (1.53 g, 7.26 mmol, 61%)
H (400 MHz, CDCl3), 0.85 (3H, d, J = 6.5 Hz, CHCH3), 0.96 (3H, d, J = 6.5 Hz, CHCH3),
1.98-2.07 (1H, m, (CH3)2CH), 2.83 (2H, app dd, J = 8.0, J = 15.0 Hz, NCHAHB x 2), 2.96
(1H, d, J = 11.0 Hz, CHCO), 3.41 (2H, ddt, J = 2.0, J = 4.0, J = 15.0 Hz, NCHAHB x 2),
3.69 (3H, s, OCH3), 5.10 (2H, dd, J = 2.0, 10.0 Hz, cis CH=CH2), 5.19 (2H, ddd, J = 1.0,
2.0, 17.0 Hz, trans CH=CH2), 5.75 (2H, dddd, J = 4.0, J = 8.0, J = 10.0, J = 17.0 Hz,
CH2=CH). C (100 MHz, CDCl3), 19.5 (CHCH3), 19.9 (CHCH3), 27.6 (CH(CH3)2), 50.6
(OCH3), 53.3 (NCH2), 68.8 (NCH), 116.8 (CH=CH2), 136.6 (CH=CH2), 173.0 (CO). m/z
(ES+) calculated for C12H21NO2 [M+H]+; 212.1645. found 212.1655.
2.4.10 N,N-Diallyl leucine methyl ester 111b
84
147
Following N-allylation procedure from L-leucine methyl ester hydrochloride (2.0g, 11.0
mmol, 1.0 eq), allyl bromide (2.93g, 2.10 mL, 24.2 mmol, 2.2eq) and sodium hydrogen
carbonate (3.70g, 44.0 mmol, 4.0 eq) N,N-diallyl leucine methyl ester was obtained as a
yellow oil. (1.69 g, 7.48 mmol, 68%)
H (400 MHz, CDCl3), 0.87 (3H, d, J = 6.5 Hz, CHCH3), 0.90 (3H, d, J = 6.5 Hz, CHCH3),
1.46-1.60 (2H, m, CHCH2), 1.65-1.73 (1H, m, CH(CH3)2), 3.03 (2H, app dd, J = 7.5, J =
14.5 Hz, NCHAHB), 3.35 (2H, ddt, J = 1.5, J = 4.5, J = 14.5 Hz, NCHAHB), 3.52 (1H, dd, J
= 7.0, J = 8.0 Hz, CHCO), 3.68 (3H, s, OCH3), 5.10 (2H, app d, J = 10.0 Hz, cis
CH=CH2), 5.18 (2H, app d, J = 17.0 Hz, trans CH=CH2), 5.72 (2H, dddd, J = 5.0, J =
7.0, J = 10.0, J = 17.0 Hz, CH2=CH). C (100 MHz, CDCl3), 22.0 (CHCH3), 23.0 (CHCH3),
24.6 (CH(CH3)2), 38.6 (NCHCH2), 50.9 (OCH3), 53.4 (NCH2), 59.9 (NCH), 117.0
(CH=CH2), 136.7 (CH=CH2), 174.2 (CO). m/z (ES+) calculated for C16H23NO2 [M+H]+;
226.1802. found 226.1811.
2.4.11 General Mono Allylation Procedure
L-proline methyl ester hydrochloride (1.0 eq) was taken up in DMF (50 mL) and cooled
to 0 ˚C. Allyl bromide (1.1 eq) was then added, followed by triethylamine (2.0 eq). The
reaction was allowed to warm to room temperature and left to stir overnight under
nitrogen. After 18 hours the reaction was quenched with H 2O (50 mL) and extracted with
EtOAc (40 mL x 3). The organic layers were combined, washed with H 2O (30 mL x 3)
and dried over Na2SO4, filtered and concentrated in vacuo to give the crude. The product
was purified by column chromatography (90:10 hexanes: ethyl acetate) to give the
product.
2.4.12 N-Allyl proline methyl ester 129148
Following mono N-allylation procedure from L-proline methyl ester hydrochloride (5.00g,
30.2 mmol, 1.0 eq), allyl bromide (4.02g, 2.87 mL, 33.2 mmol, 1.1 eq) and
triethylamine (6.11 g, 8.4 mL, 60.4 mmol, 2.0 eq) N-Allyl proline methyl ester was
obtained as a pale yellow oil (2.61 g, 5.32 mmol, 44%).
85
H (400 MHz, CDCl3), 1.75-1.87 (1H, m, NCHCHH), 1.88-1.99 (2H, m, NCHCHH + NCH2CHH),
2.07-2.20 (1H, m, NCH2CHH), 2.38 (1H, q, J = 9.0 Hz, NCH), 3.09-3.19 (2H, m,
CHCO + NCHH-CH=CH2), 3.31 (1H, app dd, J = 6.5, J = 13.0 Hz, NCHH-CH=CH2), 3.72
(3H, s, OCH3), 5.09 (1H, dd, J = 1.0, J = 10.0 Hz, cis CH=CH2), 5.18 (1H, dd, J = 1.0, J
= 17.0 Hz, trans CH=CH2), 5.92 (1H, ddt, J = 7.0, J = 10.0, J = 17.0 Hz, CH2=CH).C
(100 MHz, CDCl3), 23.0 (NCHCH2), 29.5 (NCH2CH2), 51.8 (OCH3), 53.5 (NCH2CH2), 57.8
(NCH2CH), 65.2 (CHCO), 117.4 (CH=CH2), 135.2 (CH=CH2), 174.6 (CO). max (thin film,
cm-1), 2951 (C-H), 1732 (Ester CO2), 1435 (Alkene C-H), 1195 and 1167 (C-N); m/z
(ES+), calculated for C9H15NO2 [M+H]+; 170.1176. found 170.1193.
2.4.13 (S)-Methyl 2-((R)-N-allyl-2-(1,3-dioxoisoindolin-2-yl)pent4-enamido)propanoate 124
Following general Belluš Claisen procedure from dried Yb(OTf)3 (620 mg, 1.00 mmol, 1.0
eq),
N,N-diallylalanine
methyl
ester
(183
mg,
1.00
mmol,
diisopropylethylamine (258 mg, 0.25 mL, 2.00 mmol, 2.0 eq and
1.0
eq),
N,N-
N-phthaloylglycyl
chloride (335 mg, 1.50 mmol, 1.5 eq) (S)-Methyl 2-((R)-N-allyl-2-(1,3-dioxoisoindolin-2yl)pent-4-enamido)propanoate was obtained as a yellow oil. Purification by column
chromatography (diethyl ether) yielded the two diastereoisomers in a 60:40 ratio as a
yellow oil. On standing overnight the oil solidified to give a pale yellow solid. (178 mg,
0.48 mmol, 48%). mp = 82-86 ˚C.
H (400 MHz, CDCl3), 1.43 (3H, d, J = 7.0 Hz, Minor CHCH3), 1.49 (3H, d, J = 7.0 Hz,
Major CHCH3), 2.78-2.81 (1H, m, CHCHAHB), 3.06-3.22 (1H, m, CHCHAHB), 3.69 (3H, s,
Major OCH3), 3.72 (3H, s, Minor OCH3), 3.97 (2H, d, J = 5.0 Hz, NCH2), 4.14 (1H, q, J =
7.0 Hz, Major CHCH3), 4.46 (1H, q, J = 7.0 Hz, Minor CHCH3), 4.88-5.30 (5H, m,
CH=CH2 x 2, (CO)2NCH), 5.60-5.86 (2H, m, CH2=CH x 2), 7.71-7.75 (2H, m, Ar-H),
7.81-7.85 (2H, m, Ar-H). C (100 MHz, CDCl3), (Major diastereoisomer), 14.6 (CHCH3),
33.5 (CHCH2), 50.6 (NCH2), 51.0 (CHCH2), 52.2 (OCH3), 55.7 (CHCH3), 117.6 (CH=CH2),
118.8 (CH=CH2), 123.5 (Ar-C), 131.7 (Quat. Ar-C), 133.0 (CH2=CH), 133.5 (CH2=CH),
134.2
(Ar-C),
167.5
(N(CO)2),
168.9
(CH(CO)NCH),
171.8
(COCH3),
(Minor
diastereoisomer), 14.3 (CHCH3), 33.3 (CHCH2), 48.7 (NCH2), 54.9 (CHCH3), 117.0
86
(CH=CH2), 123.4 (Ar-C), 131.7 (Quat. Ar-C), 133.2 (CH2=CH), 133.5 (CH2=CH), 134.1
(Ar-C), 168.9 (CH(CO)NCH), 171.8 (COCH3). max (thin film, cm-1), 2949 (C-H), 1709
(Ester CO2), 1646 (Amide); m/z (ES+) calculated for C20H22O5N2 [M+H]+; 371.1601.
found 371.1604.
2.4.14 (S)-Methyl 1-((R)-2-(1,3-dioxoisoindolin-2-yl)pent-4enoyl)pyrrolidine-2-carboxylate 131
Following general Belluš Claisen procedure from dried Yb(OTf)3 (1.24 g, 2.00 mmol, 1.0
eq),
N-Allyl
proline
methyl
ester
(338
mg,
2.00
mmol,
1.0
eq),
N,N-
diisopropylethylamine (517 mg, 0.70 mL, 4.00 mmol, 2.0 eq) and N-phthaloylglycyl
chloride (670 mg, 3.00 mmol, 1.5 eq) (S)-Methyl 1-((R)-2-(1,3-dioxoisoindolin-2yl)pent-4-enoyl)pyrrolidine-2-carboxylate was obtained as a yellow oil. Purification by
column chromatography yielded the two diastereoisomers in a 75:25 ratio as a yellow
oil. (421 mg, 0.44 mmol, 59%). On standing overnight the product solidified as a yellow
solid. Recrystalisation from diisopropylether/IPA isolated the major diasteriosmer as pale
colourless crystals. mp = 139-143 ˚C.
H (400 MHz, CDCl3), 1.83-2.03 (3H, m, NCHCHAHBCH2, NCH2CHAHB), 2.18-2.25 (1H, m,
NCHCHAHBCH2), 2.85 (1H, dtt, J = 1.5, J = 5.5, J = 14.5 Hz, (CO) 2NCHCHAHB), 3.09 (1H,
app dt, J = 9.5, J = 14.5 Hz, (CO)2NCHCHAHB), 3.36-3.42 (1H, m, NCHAHBCH2), 3.563.62, (1H, m, NCHAHBCH2), 3.70 (3H, s, OCH3), 4.54 (1H, dd, J = 6.0, J = 8.5 Hz,
CHCONCH), 4.96-5.02 (2H, m, (CO)2NCH + CH=CH2 cis), 5.08 (1H, dd, J = 1.0, 17.0 Hz,
CH=CH2 trans), 5.76 (1H, dddd, J = 5.5, J = 9.0, J = 10.0, J = 17.0 Hz, CH=CH2), 7.74
(2H, dd, J = 3.0, J = 5.5 Hz, Ar-H), 7.88 (2H, dd, J = 3.0, J = 5.5 Hz, Ar-H). C (100
MHz, CDCl3), 25.3 (NCHCH2CH2), 28.8 (NCH2CH2), 33.0 (CH2CH=CH2), 47.0 (NCH2CH2),
51.9 ((CO)2NCH), 52.2 (OCH3), 59.6 (CONCHCO), 118.8 (CH=CH2), 123.6 (Ar-C), 131.5
(Quat. Ar-C), 133.5 (CH2=CH), 134.2 (Ar-C), 166.9 (CH(CO)NCH), 167.3 (N(CO)2),
172.1 (COCH3). max (thin film, cm-1), 2980 (C-H), 1381 (C-H); m/z (ES+) calculated for
C15H17O3N2 [M+H]+; 273.12. found 273.12.
87
2.4.15 (S)-Methyl 1-((S)-2-(1,3-dioxoisoindolin-2-yl)pent-4enoyl)pyrrolidine-2-carboxylate 132
H (400 MHz, CDCl3), 1.88-2.13 (4H, m, NCHCHAHBCH2, NCH2CHAHB), 2.89 (1H, dtt, J =
1.5, J = 5.5, J = 14.5 Hz, (CO)2NCHCHAHB), 3.13 (1H, app dt, J = 9.5, J = 14.5 Hz,
(CO)2NCHCHAHB), 3.30-3.37 (1H, m, NCHAHBCH2), 3.66-3.71, (1H, m, NCHAHBCH2), 3.74
(3H, s, OCH3), 4.50 (1H, dd, J = 6.0, J = 8.5 Hz, CHCONCH), 5.00-5.06 (2H, m,
(CO)2NCH + CH=CH2 cis), 5.09 (1H, app dq, J = 1.0, 17.0 Hz, CH=CH2 trans), 5.78 (1H,
dddd, J = 5.5, J = 9.0, J = 10.0, J = 17.0 Hz, CH=CH2), 7.74 (2H, dd, J = 3.0, J = 5.5
Hz, Ar-H), 7.85 (2H, dd, J = 3.0, J = 5.5 Hz, Ar-H). C (100 MHz, CDCl3), 24.9
(NCHCH2CH2), 28.7 (NCH2CH2), 33.0 (CH2CH=CH2), 46.9 (NCH2CH2), 52.3 ((CO)2NCH),
52.3 (OCH3), 59.4 (CONCHCO), 118.7 (CH=CH2), 123.6 (Ar-C), 131.5 (Quat. Ar-C),
133.6 (CH2=CH), 134.2 (Ar-C), 167.1 (CH(CO)NCH), 167.7 (N(CO)2), 172.5 (COCH3).
2.4.16 N-Crotyl L-proline methyl ester 145a
Following mono N-allylation procedure from L-Proline methyl ester hydrochloride (2.00g,
12.1 mmol, 1.0 eq), crotyl bromide (1.80g, 1.37 mL, 13.3 mmol, 1.1 eq) and
triethylamine (2.47 g, 3.40 mL, 24.2 mmol, 2.0 eq) N-Crotyl L-proline methyl ester was
obtained as a mix of cis and trans products as a pale yellow oil (1.09 g, 5.93 mmol,
49%).
H (400 MHz, CDCl3), 0.97 (3H, d, J = 7.5 Hz, CHCH3), 1.66-1.78 (1H, m, NCHCHAHB),
1.79-1.82 (2H, m, NCHCHAHB + NCH2CHAHB), 1.88-1.97 2.09-2.16 (1H, m, NCH2CHAHB),
88
2.35 (1H, app q, J = 9.0 Hz, NCHAHBCH2), 3.06–3.17 (4H, m, NCHAHBCH2, NCH2CH,
CHCO), 3.71 (3H, s, OCH3), 5.50-5.63 (2H, m, CH=CHCH3, CH=CHCH3).C (100 MHz,
CDCl3), 17.7 (CHCH3), 23.0 (NCHCH2), 29.5 (NCH2CH2), 51.8 (OCH3), 53.5 (NCH2CH2),
56.9 (NCH2CH), 65.3 (CHCO), 127.8 (CH3CH=CH), 128.8 (CH3CH=CH), 174.8 (CO). max
(thin film, cm-1), 2951 (C-H), 1732 (Ester CO2), 1435 (Alkene C-H), 1195 and 1168 (CN); m/z (ES+), calculated for C10H17NO2 [M+H]+; 184.1332. found 184.1339.
2.4.17 N-(2-Methylprop-2-en-1-yl)-L-proline methyl ester 145c
Following mono N-allylation procedure from L-Proline methyl ester hydrochloride (2.00g,
12.1 mmol, 1.0 eq), 1-bromo-2-methylpropene (1.80 g, 1.37 mL, 13.3 mmol, 1.1 eq)
and triethylamine (2.47 g, 3.40 mL, 24.2 mmol, 2.0 eq) N-(2-Methylprop-2-en-1-yl)-Lproline methyl ester was obtained as a pale yellow oil. (1.16 g, 6.41 mmol, 53%)
H (400 MHz, CDCl3), 1.78 (3H, s, CCH3), 1.75-1.86 (1H, m, NCHCHAHB), 1.87-2.00 (2H,
m, NCHCHAHB + NCH2CHAHB), 2.09-2.18 (1H, m, NCH2CHAHB), 2.35 (1H, app q, J = 8.0
Hz, 1H, m, NCHAHBCH2), 2.96 (1H, d, J = 12.5 Hz, NCHAHB-CH=CH2), 3.05-3.10 (1H, m,
NCHAHBCH2), 3.19 (1H, dd, J = 5.5, J = 9.0 Hz, CHCO), 3.22 (1H, d, J = 12.5 Hz,
NCHAHB-CH=CH2), 3.70 (3H, s, OCH3), 4.79 (1H, s, cis C=CH2), 4.86 (1H, s, trans
C=CH2).C (100 MHz, CDCl3), 20.8 (CCH3), 23.1 (NCHCH2), 29.4 (NCH2CH2), 51.6
(OCH3), 53.5 (NCH2CH2), 61.7 (CH2-C=CH), 65.6 (CHCO), 112.7 (C=CH2), 143.6
(C=CH2), 174.8 (CO). max (thin film, cm-1), 2951 (C-H), 1732 (Ester CO2), 1435 (Alkene
C-H), 1195 and 1167 (C-N); m/z (ES+) calculated for C10H17NO2 [M+H]+; 184.1332.
found 184.1346.
89
2.4.18 N-(3-Methylbut-2-enyl)-L-proline methyl ester 145b
Following mono N-allylation procedure from L-Proline methyl ester hydrochloride (2.00g,
12.1 mmol, 1.0 eq), 3,3-dimethylallyl bromide (1.98g, 1.53 mL, 13.3 mmol, 1.1 eq) and
triethylamine (2.47 g, 3.40 mL, 24.2 mmol, 2.0 eq) N-(3-Methylbut-2-enyl)-L-proline
methyl ester product as a pale yellow clear oil. (1.48 g, 7.50 mmol, 62%)
H (400 MHz, CDCl3), 1.65 (3H, s, cis CH3), 1.71 (3H, d, J = 1.0 Hz trans CH3), 1.71-1.83
(1H, m, NCHCHAHB), 1.88-1.97 (2H, m, NCHCHAHB, NCH2CHAHB), 2.05-2.17 (1H, m,
NCH2CHAHB), 2.36 (1H, app q, J = 8.0 Hz, 1H, m, NCHAHBCH2), 3.09 (1H, dd, J = 7.0, J
= 13.0 Hz, NCHAHBCH=C), 3.11-3.20 (2H, m, CHCO, NCHAHBCH2), 3.27 (1H, dd, J = 7.5,
J = 13.0 Hz, NCHAHBCH=C), 3.71 (3H, s, OCH3), 5.29 (1H, app tquin, J = 1.0 , J = 7.0
Hz, C=CH).C (100 MHz, CDCl3), 17,8 (cis CH3), 23.0 (NCHCH2), 25.8 (trans CH3), 29.4
(NCH2CH2), 51.8 (OCH3), 51.8 (NCH2CH=C), 53.5 (NCH2CH2), 65.4 (CHCO), 121.0
(CH2CH=C), 135.1 (CH2CH=C), 174.8 (CO). max (thin film, cm-1), 2951 (C-H), 1732
(Ester CO2), 1435 (Alkene C-H), 1193 and 1167 (C-N); m/z (ES+) calculated for
C15H19NO2 [M+H]+; 198.1489. found 198.1510.
2.4.19 N-Cinnamyl-L-proline methyl ester 145e
Following mono N-allylation procedure from L-Proline methyl ester hydrochloride (5.00g,
30.3 mmol, 1.0 eq) cinnamyl bromide (6.55g, 33.3 mmol, 1.1 eq) and triethylamine
90
(6.18 g, 8.51 mL, 60.5 mmol, 2.0 eq) N-Cinnamyl-L-proline methyl ester was obtained
as an orange oil. (4.31 g, 17.6 mmol, 40%)
H (400 MHz, CDCl3), 1.74-1.86 (1H, m, NCHCHAHB), 1,88-2.01 (2H, m, NCHCHAHB,
NCH2CHAHB), 2.07-2.20 (1H, m, NCH2CHAHB), 2.41 (1H, app q, J = 8.5 Hz, 1H,
NCHAHBCH2), 3.16-3.23 (2H, m, NCHAHBCH2, CHCO), 3.30 (1H, dd, J = 7.0, J = 13.0,
NCHAHB-CH), 3.41 (1H, dd, J = 7.0, J = 13.5 Hz, NCHAHB-CH), 3.63 (3H, s, OCH3), 6.33
(1H, app dt, J = 7.0 , J = 16.0 Hz, Ph-CH=CH), 6.50 (1H, d, J = 16.0 Hz, Ph-CH).C
(100 MHz, CDCl3), 23.1 (NCHCH2), 29.6 (NCH2CH2), 51.8 (OCH3), 53.8 (NCH2CH2), 57.12
(NCH2CH), 65.4 (CHCO), 126.3 (Ar-C), 126.8 (PhCH=CH), 127.4 (Ar-C), 128.5 (Ar-C),
132.5 (PhCH=CH), 136.9 (Quat. Ar-C), 174.7 (NCHCO). max (thin film, cm-1), 2950 (C-
H), 1731 (Ester CO2), 1435 (Alkene C-H), 1195 and 1167 (C-N); m/z (ES+) calculated
for C15H19NO2 [M+H]+; 246.1489. found 246.1511.
2.4.20 N-(4-Methoxy-4-oxobut-2-en-1-yl)-L-Proline methyl ester
145f
Following mono N-allylation procedure from L-Proline methyl ester hydrochloride (1.00g,
6.04 mmol, 1.0 eq), methyl trans-4-bromo-2-butenoate (1.19 g, 2.87 mL, 6.67 mmol,
1.1 eq) and triethylamine (1.23 g, 1.69 mL, 12.1 mmol, 2.0 eq) N-(4-Methoxy-4oxobut-2-en-1-yl)-L-Proline methyl ester was obtained as a pale yellow oil. (810 mg,
3.56 mmol, 59%)
H (400 MHz, CDCl3), 1.79-2.19 (3H, m, NCHCHAHB, NCHCHAHB, NCH2CHAHB), 2.09-2.19
(1H, m, NCH2CHAHB), 2.45 (1H, app q, J = 8.0 Hz, 1H, m, NCHAHBCH2), 3.12-3.17 (1H,
m, NCHAHBCH2), 3.23-3.26 (1H, m, CHCO), 3.27 (1H, ddd, J = 1.5, J = 6.5, J = 15.0 Hz,
NCHAHB-CH=CH2), 3.51 (1H, ddd, J = 1.5, J = 6.0, J = 15.0 Hz, NCHAHB-CH=CH2), 3.71
(3H, s, NCHC(O)OCH3), 3.73 (3H, s, CH=CHC(O)OCH3), 5.99 (1H, dt, J = 1.5 , J = 15.5
Hz, cis C=CH2), 7.0 (1H, dt, J = 6.5, J = 15.5 Hz, trans C=CH2).C (100 MHz, CDCl3),
91
23.1 (NCHCH2), 29.3 (NCH2CH2), 51.4 (CH=CHC(O)OCH3), 51.8 (NCHC(O)OCH3), 53.4
(NCH2CH2), 54.9 (NCH2-CH=CH), 65.1 (CHCO), 122.6 (CH2CH=CH), 145.2 (CH2CH=CH),
166.5 (CH=CHCO), 174.1 (NCHCO). max (thin film, cm-1), 2951 (C-H), 1732 (Ester CO2),
1435 (Alkene C-H), 1195 and 1167 (C-N); m/z (ES+) calculated for C11H17NO4 [M+H]+;
228.1230. found 228.1237.
2.4.21 N-(Pent-2-enyl)-L-proline methyl ester 145d
Pent-2-en-1-ol (1.15 g, 1.38 mL, 13.3 mmol, 1.1 eq) was taken up in Et2O (15 mL) and
cooled to 0 ˚C. Phosphorus tribromide (1.80 g, 0.63 mL, 6.66 mmol, 0.55 eq) was then
added dropwise and allowed to stir at room temperature for 18h. On completion the
reaction was quenched with H2O and extracted with Et2O (3 x 20 mL). The organic layers
were combined, dried over Na2SO4, filtered and concentrated in vacuo. Following mono
N-allylation procedure from the resulting oil, L-proline methyl ester hydrochloride
(2.00g, 12.1 mmol, 1.0 eq) and triethylamine (2.47 g, 3.40 mL, 24.2 mmol, 2.0 eq) N(Pent-2-enyl)-L-proline methyl ester was obtained as a pale yellow oil. (1.31 g, 6.66
mmol, 55%)
H (400 MHz, CDCl3), 0.97 (3H, t, J = 7.5 Hz, CH2CH3), 1.77-1.82 (1H, m, NCHCHAHB),
1.88-1.95 (2H, m, NCHCHAHB + NCH2CHAHB), 1.99-2.06 (2H, m, CH2CH3), 2.09-2.16
(1H, m, NCH2CHAHB), 2.34 (1H, app q, J = 9.0 Hz, NCHAHBCH2), 3.07 – 3.22 (4H, m,
NCHAHBCH2, NCH2, CHCO), 3.71 (3H, s, OCH3), 5.52 (1H, ddt, J = 1.0, J = 6.5, J = 15.5
Hz, NCH2CH=CH), 5.65 (1H, dt, J = 6.0, J = 15.5 Hz, NCH2CH=CH).C (100 MHz, CDCl3),
13.4 (CH2CH3), 23.1 (NCHCH2), 25.3 (CH2CH3), 29.6 (NCH2CH2), 51.8 (OCH3), 53.6
(NCH2CH2), 57.1 (NCH2CH), 65.3 (CHCO), 125.5 (NCH2CH=CH), 135.8 (NCH2CH=CH2),
174.9 (CO). max (thin film, cm-1), 2951 (C-H), 1732 (Ester CO2), 1435 (Alkene C-H),
1195 and 1167 (C-N); m/z (ES+) calculated for C11H19NO2 [M+H]+; 198.1489. found
198.1493.
92
2.4.22 (S)-Methyl 1-((2R,3S)-2-(1,3-dioxoisoindolin-2-yl)-3methylpent-4-enoyl)pyrrolidine-2-carboxylate 146a
Following general Belluš Claisen procedure from dried Yb(OTf)3 (620 mg, 1.00 mmol, 1.0
eq),
N-Crotyl-L-proline
methyl
ester
(183
mg,
1.00
mmol,
1.0
eq),
N,N-
diisopropylethylamine (258 mg, 0.35 mL, 2.00 mmol, 2.0 eq) and N-phthaloylglycyl
chloride (335 mg, 1.50 mmol, 1.5 eq) (S)-Methyl 1-((2R,3S)-2-(1,3-dioxoisoindolin-2yl)-3-methylpent-4-enoyl)pyrrolidine-2-carboxylate was obtained following purification
by column chromatography (Et2O) that yielded the two major diastereoisomers in a
1.9:1.0 ratio as a yellow oil. (157 mg, 0.42 mmol, 42%).
H (400 MHz, CDCl3), 0.99 (3H, s, J = 7.0 Hz, CHCH3), 1.83-2.21 (4H, m, NCHCHAHBCH2,
NCH2CHAHB), 3.50-3.80 (3H, m, NCH2CH2, CHCH3), 3.63 (2H, s, major diastereoisomer
OCH3), 3.72 (1H, s, minor diastereoisomer OCH3), 4.43-4.54 (1H, m, NCHCH2), 4.684.80 (1H, m, (CO)2NCH), 5.08-5.27 (2H, m, CH=CH2), 5.89 (1H, ddd, J = 7.5, J = 10.5,
J = 17.5 Hz, CH=CH2), 7.75-7.77 (2H, m, Ar-H), 7.88-7.90 (2H, m, Ar-H). C (100 MHz,
CDCl3), 16.3 (CHCH3), 25.1 (NCHCH2), 28.8 (NCH2CH2), 35.9 (CHCH=CH2), 47.1
(NCH2CH2), 52.1 (OCH3), 56.5 ((CO)2NCH), 59.1 (NCHCH2), 116.4 (CH=CH2), 123.6 (ArC), 131.4 (Quat. Ar-C), 134.3 (Ar-C), 139.6 (CH2=CH), 166.3 (CH(CO)NCH), 167.5
(N(CO)2), 172.1 (COCH3). m/z (ES+) calculated for C20H22O5N2 [M+H]+; 371.1601. found
371.1602.
2.4.23 (S)-Methyl 1-((R)-2-(1,3-dioxoisoindolin-2-yl)-4methylpent-4-enoyl)pyrrolidine-2-carboxylate 146c
93
Following general Belluš Claisen procedure from dried Yb(OTf)3 (620 mg, 1.00 mmol, 1.0
eq), N-(2-methylprop-2-en-1-yl)-L-proline methyl ester (183 mg, 1.00 mmol, 1.0 eq),
N,N-diisopropylethylamine (258 mg, 0.35 mL, 2.00 mmol, 2.0 eq) and N-phthaloylglycyl
chloride (335 mg, 1.50 mmol, 1.5 eq) (S)-Methyl 1-((R)-2-(1,3-dioxoisoindolin-2-yl)-4methylpent-4-enoyl)pyrrolidine-2-carboxylate was obtained following purification by
column chromatography yielding the two diastereoisomers in a 3.0:1 ratio as a yellow
oil. (182 mg, 0.49 mmol, 49%). On standing the product solidified to give a yellow solid
mp = 146-148 ˚C.
H (400 MHz, CDCl3), 1.77 (3H, s, CCH3), 1.77-2.25 (4H, m, NCHCHAHB, NCH2CHAHB),
2.64-2.72 (1H, m, CCHAHB), 3.19-3.45 (2H, m, NCHAHBCH2, CCHAHB), 3.58-3.62 (1H, m,
NCHAHBCH2), 3.69 (2.2H, s, major diastereoisomer OCH3), 3.74 (0.8H, s, minor
diastereoisomer OCH3), 4.50-5.56 (1H, m, CHCONCH), 4.65 (1H, s, CH=CH2 cis), 4.69
(1H, s, CH=CH2 trans), 5.16 (1H, dt, J = 3.5, J = 14.5 Hz, (CO)2NCH), 7.73-7.74 (2H,
m, Ar-H), 7.83-7.87 (2H, m, Ar-H). C (100 MHz, CDCl3), (major diastereoisomer), 21.9
(CCH3), 25.3 (NCHCH2CH2), 28.8 (NCH2CH2), 36.5 (CH2C=CH2), 47.0 (NCH2CH2), 50.5
((CO)2NCH), 52.2 (OCH3), 59.7 (CONCHCO), 114.4 (C=CH2), 123.6 (Ar-C), 131.6 (Quat.
Ar-C), 134.1 (Ar-C), 141.1 (CH2=C), 167.3 (CH(CO)NCH), 167.6 (N(CO)2), 172.1
(COCH3), (minor diastereoisomer), 22.0 (CCH3), 25.0 (NCHCH2CH2), 28.7 (NCH2CH2),
36.3 (CH2C=CH2), 47.9 (NCH2CH2), 50.8 ((CO)2NCH), 52.3 (OCH3), 59.4 (CONCHCO),
114.2 (C=CH2), 123.5 (Ar-C), 131.5 (Quat. Ar-C), 134.2 (Ar-C), 141.2 (CH2=C), 167.2
(CH(CO)NCH), 167.4 (N(CO)2), 172.6 (COCH3). max (thin film, cm-1), 2973 (C-H), 1711
(Ester CO2), 1655 (Amide); m/z (ES+) calculated for C20H22O5N2 [M+H]+; 371.1601.
found 371.1602.
2.4.24 (S)-Methyl 1-((R-2-(1,3-dioxoisoindolin-2-yl)-3,3dimethylpent-4-enoyl)pyrrolidine-2-carboxylate 146b
Following general Belluš Claisen procedure from dried Yb(OTf)3 (620 mg, 1.00 mmol, 1.0
eq), N-(3-methylbut-2-enyl)-L-proline methyl ester (197 mg, 1.00 mmol, 1.0 eq), N,N94
diisopropylethylamine (258 mg, 0.35 mL, 2.00 mmol, 2.0 eq) and N-phthaloylglycyl
chloride (335 mg, 1.50 mmol, 1.5 eq) (S)-Methyl 1-((R-2-(1,3-dioxoisoindolin-2-yl)-3,3dimethylpent-4-enoyl)pyrrolidine-2-carboxylate was obtained following purification by
column chromatography (diethyl ether) yielding the two diastereoisomers in a 1.1:1
ratio as a yellow oil that solidified on standing. (155 mg, 0.40 mmol, 40%) mp = 142145 ˚C.
H (400 MHz, CDCl3), 1.27 (3H, s, CCH3), 1.28 (3H, s, CCH3), 1.76-2.22 (4H, m,
NCHCHAHB,
A
NCH2CHAHB),
2.83-3.06
(1H,
m,
NCHAHBCH2),
3.46-3.61
((1H,
m,
B
NCH H CH2), 3.70 (1.6H, s, major diastereoisomer OCH3), 3.73 (1.4H, s, minor
diastereoisomer OCH3), 4.44-4.59 (1H, m, NCHCH2), 4.78 (1H, s, (CO)2NCH), 4.94-5.00
(2H, m, CH=CH2), 6.27-6.36 (1H, m, CH=CH2), 7.74 -7.78 (2H, m, Ar-H), 7.84-7.91
(2H, m, Ar-H). C (100 MHz, CDCl3), (major diastereoisomer), 24.5 (CCH3), 25.2 (CCH3),
25.2 (NCHCH2), 28.6 (NCH2CH2), 42.3 (C(CH3)2), 46.9 (NCH2CH2), 52.2 (OCH3), 58.1
(NCHCH2), 59.4 ((CO)2NCH), 112.3 (CH=CH2), 123.7 (Ar-C), 131.1 (Quat. Ar-C), 134.4
(Ar-C), 145.5 (CH2=CH), 165.2 (CH(CO)NCH), 167.6 (N(CO)2), 172.2 (COCH3), (minor
diastereoisomer), 24.1 (CCH3), 24.9 (CCH3), 24.9 (NCHCH2), 28.6 (NCH2CH2), 42.4
(C(CH3)2), 46.9 (NCH2CH2), 58.4 (NCHCH2), 59.4 ((CO)2NCH), 112.2 (CH=CH2), 123.7
(Ar-C), 131.3 (Quat. Ar-C), 134.4 (Ar-C), 145.4 (CH2=CH), 165.9 (N(CO)2), 172.7
(COCH3). max (thin film, cm-1), 2980 (C-H), 1388 (C-H); m/z (ES+) calculated for
C21H24O5N2 [M+H]+; 385.1758 found 385.1760.
2.4.25 (S)-Methyl 1-((2S,3S)-2-(1,3-dioxoisoindolin-2-yl)-3phenylpent-4-enoyl)pyrrolidine-2-carboxylate 147e
Following general Belluš Claisen procedure from dried Yb(OTf)3 (620 mg, 1.00 mmol, 1.0
eq),
N-Cinnamyl-L-proline
methyl
ester
(245
mg,
1.00
mmol,
1.0
eq),
N,N-
diisopropylethylamine (258 mg, 0.35 mL, 2.00 mmol, 2.0 eq) and N-phthaloylglycyl
chloride (335 mg, 1.50 mmol, 1.5 eq) (S)-Methyl 1-((2S,3S)-2-(1,3-dioxoisoindolin-2yl)-3-phenylpent-4-enoyl)pyrrolidine-2-carboxylate was obtained following purification
by column chromatography (diethyl ether) yielding the two diastereoisomers in a 1.1:1
95
ratio as a colourless oil.
(222 mg, 0.51 mmol, 51%). A second column managed to
isolate a sample of the minor diastereoisomer in a 3:1 ratio.
H (400 MHz, CDCl3), 1.83-2.21 (4H, m, NCHCHAHBCH2, NCH2CHAHB), 3.49-3.56 (1H, m,
NCHAHBCH2), 3.68-3.74 (1H, m, NCHAHBCH2), 3.64 (3H, s, major diastereoisomer OCH3),
3.74 (3H, s, minor diastereoisomer OCH3), 4.57 (1H, dd, J = 5.5, J = 8.5 Hz, NCHCH2),
4.96 (1H, dd, J = 7.5, J = 11.0 Hz, CHCH=CH2), 5.15-5.30 (3H, m, (CO)2NCH, CH=CH2),
6.06 (1H, ddd, J = 7.5, J = 10.5, J = 17.5 Hz, CH=CH2), 7.60 (2H, dd, J = 3.0, J = 5.5
Hz, Ar-H), 7.68 (2H, dd, J = 3.0, J = 5.5 Hz, Ar-H). C (100 MHz, CDCl3), 25.2 (NCHCH2),
28.9 (NCH2CH2), 47.2 (NCH2CH2), 48.0 (CHCH=CH2), 52.2 (OCH3), 54.6 ((CO)2NCH),
59.3 (NCHCH2), 117.7 (CH=CH2), 123.3 (Ar-C), 126.9 (Ar-C), 128.5 (Ar-C), 128.6 (ArC), 131.1 (Quat. Ar-C), 133.9 (Ar-C), 137.9 (CH2=CH), 139.0 (Quat, Ar-C), 165.9
(CH(CO)NCH), 167.1 (N(CO)2), 172.1 (COCH3). max (thin film, cm-1), 2979 (C-H), 1716
(Ester CO2); m/z (ES+) calculated for C25H24O5N2 [M+H]+; 433.1758. found 433.1760.
2.4.26 (S)-Methyl 1-((2R,3S)-2-(1,3-dioxoisoindolin-2-yl)-3(methoxycarbonyl)pent-4-enoyl)pyrrolidine-2-carboxylate 146f
Following general Belluš Claisen procedure from dried Yb(OTf)3 (620 mg, 1.00 mmol, 1.0
eq), N-(4-methoxy-4-oxobut-2-en-1-yl)-L-proline methyl ester (227 mg, 1.00 mmol, 1.0
eq), N,N-diisopropylethylamine (258 mg, 0.35 mL, 2.00 mmol, 2.0 eq) and Nphthaloylglycyl chloride (335 mg, 1.50 mmol, 1.5 eq) (S)-Methyl 1-((2R,3S)-2-(1,3dioxoisoindolin-2-yl)-3-(methoxycarbonyl)pent-4-enoyl)pyrrolidine-2-carboxylate
was
obtained as a viscous oil. Purification by column chromatography (diethyl ether) yielded
the two diastereoisomers in a 1.1:1 ratio as a yellow oil. (194 mg, 0.47 mmol, 47%).
H (400 MHz, CDCl3), 1.84-2.12 (4H, m, NCHCHAHBCH2, NCH2CHAHB), 3.58 (3H, s, OCH3),
3.65 (3H, s, OCH3), 4.45-4.61 (2H, m, (CO)2NCH, CONCHCO), 5.24-5.38 (2H, m,
CH2=CHCH + CH=CH2), 5.99 (1H, ddd, J = 9.0, J = 10.0, J = 17.0 Hz, CH=CH2), 7.74
(2H, dd, J = 3.0, J = 5.5 Hz, Ar-H), 7.87 (2H, dd, J = 3.0, J = 5.5 Hz, Ar-H). C (100
MHz, CDCl3), 25.1 (NCHCH2), 28.9 (NCH2CH2), 47.2 (NCH2CH2), 48.9 (NCH), 52.2
(OCH3), 52.3 (OCH3), 53.0 (CH2=CHCH), 59.3 (NCH), 121.1 (CH=CH2), 123.7 (Ar-C),
131.4 (Quat. Ar-C), 131.9 (CH2=CH), 134.3 (Ar-C), 165.1 (CH(CO)NCH), 167.0
96
(N(CO)2), 171.6 (COCH3), 171.9 (COCH3); max (thin film, cm-1), 2980 (C-H), 1717 (Ester
CO2), 1657 (Amide); m/z (ES+) calculated for C21H22O7N2 [M+H]+; 415.1500. found
415.1500.
2.4.27 (S)-Methyl 1-((2S,3R)-2-(1,3-dioxoisoindolin-2-yl)-3ethylpent-4-enoyl)pyrrolidine-2-carboxylate 147d
Following general Belluš Claisen procedure from dried
Yb(OTf)3 (620 mg, 1.00 mmol,
1.0 eq), N-(pent-2-enyl)-L-proline methyl ester (197 mg, 1.00 mmol, 1.0 eq), N,Ndiisopropylethylamine (258 mg, 0.35 mL, 2.00 mmol, 2.0 eq) and N-phthaloylglycyl
chloride (335 mg, 1.50 mmol, 1.5 eq) (S)-Methyl 1-((2S,3R)-2-(1,3-dioxoisoindolin-2yl)-3-ethylpent-4-enoyl)pyrrolidine-2-carboxylate
Purification
by
column
chromatography
was
(diethyl
obtained
ether)
diastereoisomers in a 3.5:1.0 ratio as a yellow oil.
as
yielded
a
the
viscous
two
oil.
major
(271 mg, 0.70 mmol, 70%).
Recrystallization from diisopropylether/IPA gave an isolated sample as a pale colourless
solid of the minor diastereomer. mp = 135-140 ˚C.
H (400 MHz, CDCl3), 0.87 (3H, t, J = 7.5 Hz, CH2CH3), 1.21-1.32 (1H, m, CHAHBCH3),
1.51-1.57 (1H, m, CHAHBCH3), 1.87-1.98 (2H, m, NCHCHAHBCH2, NCH2CHAHB), 2.01-2.14
(2H, m, NCHCHAHBCH2, NCH2CHAHB), 3.46-3.54 (1H, m, CHCH=CH2), 3.61-3.75 (2H, m,
NCHAHBCH2), 3.69 (2.3H, s, major diastereoisomer OCH3), 3.70 (0.7H, s, minor
diastereoisomer OCH3), 4.42 (1H, dd, J = 4.0, J = 8.0 Hz, NCHCH2), 4.86 (1H, d, J =
10.0 Hz, (CO)2NCH), 5.22-5.27 (2H, m, CH=CH2), 5.69-5.78 (1H, m, CH=CH2), 7.73
(2H, dd, J = 3.0, J = 5.5 Hz, Ar-H), 7.85 (2H, dd, J = 3.0, J = 5.5 Hz, Ar-H). C (100
MHz, CDCl3), 11.1 (CH2CH3), 23.4 (CH2CH3), 24.9 (NCHCH2), 29.0 (NCH2CH2), 43.9
(CHCH=CH2), 47.2 (NCH2CH2), 52.0 (OCH3), 55.9 ((CO)2NCH), 59.3 (NCHCH2), 119.0
(CH=CH2), 123.5 (Ar-C), 131.6 (Quat. Ar-C), 134.2 (Ar-C), 136.5 (CH2=CH), 167.1
(CH(CO)NCH), 168.0 (N(CO)2), 172.3 (COCH3). m/z (ES+) calculated for C21H24O5N2
[M+H]+; 385.1758. found 385.1758.
97
2.4.28 Methyl (2S)-2-(3-(1,3-dioxoisoindolin-2-yl)-2-oxo-2,3,4,7tetrahydro-1H-azepin-1-yl)propanoate 159
Grubbs second generation catalyst (229 mg, 0.027 mmol, 0.1 eq) in DCM (2.5 mL) was
added
to
a
solution
of
(S)-Methyl
2-(N-allyl-2-(1,3-dioxoisoindolin-2-yl)pent-4-
enamido)propanoate (100 mg, 0.27 mmol, 1.0 eq) in DCM (2.5 mL). The reaction was
allowed to stir at room temperature until consumption of starting material as monitored
by TLC. The reaction mixture was then concentrated in vacuo and purified by column
chromatography (diethyl ether) to give the product as a mixture of diastereoisomers (75
mg, 0.24 mmol, 87%).
H (400 MHz, CDCl3), 1.17 (0.9H, app t, J = 7.0 Hz, Minor CHCH3), 1.33 (2.1H, app t, J
= 7.5 Hz, Major CHCH3), 2.44-2.48 (1H, m, CHCHAHB), 3.43-3.57 (1H, m, NCHAHB), 3.61
(3H, s, OCH3), 3.62-3.73 (1H, m, CHCHAHB), 3.30-3.34 (0.3H, m, Minor NCHAHB), 4.384.42 (0.7H, m, Major NCHAHB), 5.20 (0.3H, q, J = 7.0 Hz, Minor CHCH3), 5.52 (0.7H, q, J
= 7.5 Hz, Major CHCH3), 5.47 (0.3H, dd, J = 3.0, J = 13.5 Hz, Minor NCH), 5.57 (0.7H,
dd, J = 3.0, J = 13.5 Hz, Major NCH) 5.73-5.85 (2H, m, CH=CH), 7.63-7.65 (2H, m, Ar-
H), 7.77-7.79 (2H, m, Ar-H). C (100 MHz, CDCl3), (Major diastereoisomer), 14.4
(CHCH3), 28.7 (CHCH2), 40.8 (NCH2), 50.1 (CHCH2), 51.3 (OCH3), 51.6 (CHCH3), 123.4
(CH=CH), 122.4 (Ar-C), 128.1 (Quat. Ar-C), 129.0 (CH=CH), 133.0 (Ar-C), 167.2
(N(CO)2), 169.2 (CH(CO)NCH), 171.0 (COCH3), (Minor diastereoisomer), 13.9 (CHCH3),
28.3 (CHCH2), 41.4 (NCH2), 50.3 (CHCH2), 51.2 (OCH3), 52.2 (CHCH3), 123.0 (CH=CH),
122.4 (Ar-C), 128.1 (Quat. Ar-C), 130.9 (CH=CH), 133.0 (Ar-C), 167.2 (N(CO)2), 169.0
(CH(CO)NCH), 171.0 (COCH3). max (thin film, cm-1), 2952 (C-H), 1713 (Ester CO2), 1660
(Amide); m/z (ES+) calculated for C18H18O5N2 [M+H]+; 343.1288. found 343.1296.
98
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