Synthesis of 2-(4-carboxybutenyl)- and 2-(4-carboxybutynyl)-cyclopentene-1-carboxamides

Article abstract of DOI:10.1016/j.tet.2009.07.085

Syntheses of 2-(4-carboxybut-1-enyl/4-carboxypent-1-ynyl)cyclopentene-1-carboxamides, compounds designed to mimic the phosphoSer-Pro dipeptide motif (the recognition sequence for the prolyl cis-trans isomerase Pin1), have been developed. Stille, Sonogashira and Suzuki couplings were envisaged to join the pentynoic and pentenoic acid side chains to the 2-position of cyclopentene-1-carboxylate esters. The ring- and side-chain carboxylic acids required orthogonal protection for later attachment of a Ph-NH(4-nitrophenyl) unit to the cyclopentene-1-carbonyl. The cyclopentenecarboxylates were unmasked and standard PyBOP peptide coupling afforded the target compounds. Comparisons of two routes using Bu^t and Me esters are reported.

Full text of DOI:10.1016/j.tet.2009.07.085

Tetrahedron 65 (2009) 8176–8184
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2-(4-carboxybutenyl)- and 2-(4-carboxybutynyl)-cyclopentene-
1-carboxamides
*
Anne Beauchard, Victoria A. Phillips, Matthew D. Lloyd, Michael D. Threadgill
Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Syntheses of 2-(4-carboxybut-1-enyl/4-carboxypent-1-ynyl)cyclopentene-1-carboxamides, compounds
designed to mimic the phosphoSer–Pro dipeptide motif (the recognition sequence for the prolyl cis–trans
isomerase Pin1), have been developed. Stille, Sonogashira and Suzuki couplings were envisaged to join
the pentynoic and pentenoic acid side chains to the 2-position of cyclopentene-1-carboxylate esters. The
ring- and side-chain carboxylic acids required orthogonal protection for later attachment of a Ph-NH(4-
nitrophenyl) unit to the cyclopentene-1-carbonyl. The cyclopentenecarboxylates were unmasked and
standard PyBOP peptide coupling afforded the target compounds. Comparisons of two routes using But
and Me esters are reported.
Received 25 November 2008
Received in revised form 10 July 2009
Accepted 28 July 2009
Available online 6 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
the nitrogen or the carbon must be converted temporarily to an
sp3-like state to disturb the
p-bond-like nature of the amide. Pin1
Most peptide bonds in proteins are secondary amides and exist
almost exclusively in the trans-amide conformation. However,
peptide bonds to proline are tertiary amides and can exist in both
cis-amide and trans-amide conformations, with similar energy,1
which interconvert only slowly at 37 ꢀC. Since interchange of con-
formation is important in the folding of all proteins and in acti-
vating some, there exist peptidyl-prolyl cis–trans isomerases
(PPIases), which catalyse this interconversion.2 There are several
families of PPIases, which recognise different amino-acid se-
quences surrounding the Pro in the substrate proteins. The en-
dogenous substrate proteins for the prolyl cis–trans isomerase Pin1
all contain phosphoserine–proline or phosphothreonine–proline
units. Phosphorylation of proteins on SerPro or ThrPro sequences is
an important signalling mechanism controlling many cellular
processes, including cell cycle regulation, transcription and pro-
liferation. Deregulation of this process can result in cell trans-
formation and oncogenesis.3 Ser/Thr–Pro motifs are the major
phosphorylation sites for a large superfamily of kinases, including
cyclin-dependent kinases (CDKs), mitogen-activated protein ki-
employs a mechanism in which the carbonyl of 1 undergoes re-
versible nucleophilic attack by the Cys113 thiol/thiolate, located in
the active site (Scheme 1).5 This produces an intermediate 2 in
which the carbon is tetrahedral and the C–N bond is free to rotate to
give 3. After bond rotation, the thiol leaves, restoring the tertiary
amide but in the new conformation 4.
Nucleophilic
attack of
Cys113
-
O
O
N
N
-
S
S
NH
peptide’
NH
peptide’
O
O
O
O
O
O
O
OH
O
OH
P
P
-
-
1
2
Rotation about
single bond
’
’
NHpeptide
Elimination
NHpeptide
N
nases (MAPKs) and glycogen synthase kinase 3b (GSK-3b
),3 many of
of Cys113
O
O
O
which (and the corresponding phosphatases) are Pro-conforma-
tion-specific. For example, the MAPKs ERK2 and p42 phosphorylate
only the trans conformer of their substrate proteins.4
-
O
N
-
S
S
The PPIases differ in their catalytic molecular mechanisms. To
lower the energy barrier to rotation of the amide C–N bond, either
O
O
O
O
O
OH
O
P
P
-
-
OH
4
3
* Corresponding author. Tel.: þ44 1225 386840; fax: þ44 1225 386114.
E-mail address: m.d.threadgill@bath.ac.uk (M.D. Threadgill).
Scheme 1. Mechanism of cis4trans interconversion of phosphoSer–Pro peptides
catalysed by Pin1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.085

A. Beauchard et al. / Tetrahedron 65 (2009) 8176–8184
8177
As part of our studies on Pin1, we required molecules that could
mimic the phosphoserine–proline unit, such as 5 and 6 (Fig. 1). In
these compounds, the cyclopentene represents the pyrrolidine ring
of the Pro of 4, with the endocyclic C]C ensuring that the atom
corresponding to the N is sp2 and planar; the pendant carboxylate
mimics the anionic phosphate and the PheNP module represents
the continuing C-terminal peptide. The nitroanilide was required to
provide a suitable chromophore in the enzymic studies.
of t-butyl acetate 10 was alkylated with propargyl bromide to give
11 in high yield. Secondly, attempts to remove the alkyne proton
from 11 and quench with chlorotributylstannane failed but simple
heating of the alkyne with methoxytributylstannane provided the
required potential Stille coupling partner 12. Radical addition of
tributyltin hydride across the terminal alkynes of phenylethyne 7
and t-butyl prop-4-ynoate 11 furnished the vinylstannanes 9 and
13, respectively, as almost exclusively the required E stereoisomers.
These vinylstannanes were found to be unstable to extensive pu-
rification and were used immediately for the Stille coupling
reactions.
NHpeptide’
N
O
peptideHN
SnBu3
O
SnBu3
O
P O
OH
-
O
4
i
ii
H
N
H
N
Ph
NH
Ph
NH
8
7
9
O
O
O
Me
O
t
O
OBu
10
-
O
O
iii
-
NO2
NO2
SnBu3
O
O
SnBu3
5
6
Figure 1. Structures of target 2-(4-carboxybutynyl)cyclopentene-1-carboxamide 5 and
2-(4-carboxybutenyl)cyclopentene-1-carboxamide 6 in their carboxylate anionic forms
and comparison with sequence 4 recognised by Pin1.
iv
ii
t
t
t
O
OBu
O
OBu
O
OBu
13
11
12
2. Results and discussion
Scheme 2. Synthesis of Sonogashira and organo-tin Stille coupling partners. Reagents
and conditions: i, LiN(SiMe3)2, Bu3SnCl, THF ꢁ78 ꢀC, 99%; ii, Bu3SnH, AIBN, PhMe, 85 ꢀC,
50% (9), 60% (13), 40% (18); iii, LiNPri2, BrCH2C^CH, THF, HMPA, ꢁ78 ꢀC, 88%; iv,
Bu3SnOMe, 110 ꢀC, 88%.
Retrosynthetic analysis of the structure of 5 and 6 and related
structures indicated that the important disconnection would be
between the five-carbon pentynoic acid and pentenoic acid moie-
ties and the cyclopentene-1-carboxamide. This important bond
could then be formed by a Pd-catalysed coupling of a cyclopentenyl
triflate with an appropriate five-carbon coupling partner. Simple
methyl and ethyl esters of 2-triflyloxycyclopentene-1-carboxylic
acid have been reported to couple in this way with varying degrees
of success. These couplings include conventional Heck couplings of
alkenes,6 Negishi-type couplings with organo-zinc,7–9 organo-bis-
muth10 and organo-aluminium reagents,11 Suzuki reactions with
arylboronic acids,12,13 alkylboronic acids,14 pinacol-borates15,16 and
trifluoroborate anions,17 Sonogashira couplings with terminal al-
kynes18,19 and Buchwald couplings.20
The synthetic strategy thus involved preparation of cyclo-
pentene-1-carboxylic acid carrying a pentynoic acid or pentenoic
acid moiety at the 2-position. For later attachment of the PheNP
unit at the correct cyclopentenyl-1-carbonyl, the two carboxylic
acids required orthogonal ester protection, either as the 2-methyl
ester 50-t-butyl esters 17 and 19 (Schemes 3 and 6) or the 2-t-butyl
ester 50-methyl esters 42 and 45 (Scheme 8). Initially, the 2-methyl
ester strategy was investigated, as the starting methyl 2-oxocy-
clopentane-1-carboxylate is commercially available.
Scheme 3 shows the development of Stille and Sonogashira
coupling reactions with the cyclopentene triflate methyl ester 15.
Firstly, commercially available methyl 2-oxocyclopentanecarboxy-
late 14 was converted to 15 with triflic anhydride, by the method of
Norman et al.9 Stille coupling of the phenylethynylstannane 8 with
15, catalysed by palladium(II) acetate, proceeded in almost quan-
titative yield to give the 2-phenylethynyl product 16, indicating the
facile transfer of sp-hybridised carbon in the transmetallation step.
Interestingly, the corresponding Sonogashira reaction of 7 with 15
failed to give any identifiable coupling products, despite a report of
efficient Sonogashira coupling of 7 with the corresponding ethyl
ester.23 The situation was reversed for the couplings of the
i
CO2Me
ii
CO2Me
vii
O
14
OTf
15
iii
iv or v vi
A study was therefore initiated to develop suitable Pd-catalysed
couplings in this series, conducting model reactions as appropriate.
Sonogashira and Stille couplings were envisaged, so appropriate
coupling partners were prepared, as shown in Scheme 2. Firstly, to
supply compounds for model experiments, phenylethyne 7 was
deprotonated with lithium hexamethyldisilazide and the acetylenic
carbanion was quenched with chlorotributylstannane to afford the
phenylethynylstannane 8 in excellent yield. However, this approach
could not be used for synthesis of the t-butyl 5-tributylstannylpent-
4-ynoate 12. Firstly, the commercially available pent-4-ynoic acid
34 could not be readily converted to its t-butyl ester 11. The pro-
cedure of Trost21 was adapted; the anion formed by deprotonation
CO
2Me
CO
2Me
CO
CO
2Me
2Me
Ph
Ph
t
CO2Bu
t
CO2Bu
16
17
18
19
Scheme 3. Stille and Sonogashira with Me 2-TfO-cyclopentene-1-carboxylate 15. Re-
agents and conditions: i, Pri2NEt, Tf2O, CH2Cl2, 95%; ii, PhC^CH, various Pd catalysts; iii,
8, Pd(OAc)2, Ph3P, THF, 55 ꢀC, 99%; iv, 11, PdCl2, Ph3P, CuI, Et3N, THF, 98%; v, 12,
Pd(OAc)2, Ph3P, 22%; vi, 9, Pd(OAc)2, Ph3P, THF, 55 ꢀC, 95%; vii, 13, Pd(OAc)2, PPh3, THF,
57%.

8178
A. Beauchard et al. / Tetrahedron 65 (2009) 8176–8184
Ph
Ph
O
Cl
Ph
O
i
ii
H
N
H
N
BocHN
CO2H
BocHN
H3N
20
21
NO2
22
NO2
O
O
Ph
O2N
NO2
CO2Me
CO2Me
CO2Me
iii
iii
HN
O
NH
Ph
N
H
N
Ph
Ph
23
O
H
18
14
24
Scheme 4. Synthesis of Phe N-(4-nitrophenyl)amide 22 and preliminary studies on its reactions with 19 and 23. Reagents and conditions: i, POCl3, 4-nitroaniline, pyridine, ꢁ10 ꢀC,
84%; ii, HCl, CH2Cl2, 73%; iii, 22 (free base), DMAP, PhMe, reflux, 14%.
pentynoate esters, i.e., for
u
-alkylalkynes. Stille coupling of the
of the conjugate electrophilic system. Carboxylic acid 25 was then
used as a model for the peptide coupling reaction, in that reaction
with 22 and PyBOP gave amide 27 in good yield.
alkynylstannane 12 with 15 gave the required diester 17 in poor
yield but the analogous Sonogashira reaction of 11 with 15 was
highly efficient. Moving to the couplings of the vinylstannanes, the
reaction of the model phenylethenylstannane 9 with 15 gave an
excellent yield of the coupled product 18, as expected, with com-
plete retention of the E configuration, as demonstrated by the large
3J¼16 Hz for the vinyl protons in the 1H NMR spectrum. Corre-
spondingly, the coupling of the ester-bearing vinylstannane 13 with
15 provided the required orthogonally protected diester 19 in
a lower yield of 57%.
Assembly of the target phosphoSer–Pro peptide mimics 5 and 6
also required the preparation of
(Scheme 4). Conventional peptide couplings of Boc-
with the very weak nucleophile 4-nitroaniline failed but activation
of the carboxylic acid of 20 by treatment with phosphorus oxy-
chloride at low temperature, followed by reaction with the aniline,
gave 21 in good yield. Acid-catalysed deprotection gave the salt 22.
However, selective base hydrolysis of the methyl ester of the
orthogonal diester 17 could only be achieved in a maximum 5%
yield, using lithium hydroxide (Scheme 6). Reaction of the in-
coming nucleophile with the conjugated yne-ene-carbonyl unit is
likely to have resulted in the myriad of unidentifiable by-products.
The monoester 28 thus formed was coupled efficiently with 22 by
the PyBOP method to give 29, from which the side-chain But ester
was removed by acidolysis to provide the target carboxylic acid 5.
In the pentenoic acid series, the selective cleavage of the methyl
ester of 19 was also problematic, affording the monoester 30 in
a modest 24% yield, after optimisation. Again, the conjugated
electrophilic system led to the formation of unidentifiable by-
products. Coupling with 22 by the PyBOP method gave the amide
31, which was readily deprotected to afford 6 (Scheme 6).
L
-phenylalanine 4-nitroanilide 22
-PheOH 20
L
In the model series, direct treatment of the
ester 18 with 22 under forcing conditions failed to produce the
amide 23. Rationalising that the conjugated unsaturated system
a,b,g,d-unsaturated
i
CO2Me
CO2H
R
R
may hinder the reaction, it was repeated with the b-keto ester 14;
17,19
28,30
again, the ester failed to react but the enamine 24 was formed by
reaction at the electrophilic ketone. Thus it would be necessary to
hydrolyse the methyl cyclopentenecarboxylate ester to the corre-
sponding carboxylic acid to allow generation of a suitably reactive
electrophile for formation of the amide bond.
ii
Ph
NO2
H
N
iii
5,6
In model reactions (Scheme 5), the 2-(2-phenylethynyl)-
cyclopentenecarboxylate 16 was hydrolysed to the acid 25. The
corresponding phenylethenylcyclopentenecarboxylate 18 was cleaved
to the corresponding acid 26 with aqueous sodium hydroxide. In both
cases, the yield was modest, again indicating possible involvement
N
H
O
O
R
29,31
R
Yield (%)
t
28
30
29
31
5
C≡C(CH2)2CO2Bu
C=C(CH2)2CO2Bu
C≡C(CH2)2CO2Bu
C=C(CH2)2CO2Bu
C≡C(CH2)2CO2H
C=C(CH2)2CO2H
5
i
t
t
t
24
88
42
51
60
CO2Me
CO2H
R
R
16,18
25,26
6
ii
Ph
Scheme 6. Approaches to target phosphoSer–Pro mimics. Reagents and conditions:
i, LiOH, THF, MeOH, H2O; ii, 22, PyBOP, Et3N, CH2Cl2; iii, CF3CO2H, CH2Cl2.
NO2
H
N
N
H
O
O
R
The overall yields of the target compounds 5 and 6 by this
route, using couplings to the methyl ester 15, were 2.1% and 3.3%,
respectively, from 14. Thus the alternative orthogonal ester
protecting group strategy shown in Schemes 7 and 8 was
investigated.
For use in this 2-t-butyl ester 50-(m)ethyl ester sequence, ad-
dition of pinacol-borane across the alkene double bond of ethyl
pent-4-enoate 3222 proceeded regiospecifically to give the terminal
borate ester 33 in good yield; this is a potential Suzuki coupling
partner. Esterification of pent-4-ynoic acid 34 readily gave the
27
R
Yield (%)
25
26
27
C≡CPh
C=CPh
C≡CPh
57
33
76
Scheme 5. Model reactions for hydrolysis of Me esters and peptide coupling to PheNP.
Reagents and conditions: i, aq NaOH, EtOH; ii, 22, PyBOP, Et3N, CH2Cl2.

A. Beauchard et al. / Tetrahedron 65 (2009) 8176–8184
8179
O
i
B
O
t
t
i
CO2Bu
(CH2)4CO2Et
41
CO2Bu
OTf
CO2Et
CO2Et
40
32
33
ii or iii
SnBu3
iv
ii
iii
t
CO2Bu
CO2H
R
R
CO2H
CO2Me
CO2Me
36
42,45
43,46
34
35
v
COCl
CO2But
v
Ph
NO2
iv
H
N
t
vi
CO2Bu
5,6
CO2But
38
O
N
H
O
COCl
37
O
R
39
44,47
vi
R
Yield (%)
CO2But
42
45
43
46
44
47
5
C≡C(CH2)2CO2Me
C=C(CH2)2CO2Me
C≡C(CH2)2CO2Me
C=C(CH2)2CO2Me
C≡C(CH2)2CO2Me
C=C(CH2)2CO2Me
C≡C(CH2)2CO2H
C=C(CH2)2CO2H
23
84
33
72
23
42
22
68
OTf
40
Scheme 7. Preparation of coupling partners for alternative synthetic sequence. Re-
agents and conditions: i, Rh(PPh3)3Cl, pinacol-borane, CH2Cl2, 79%; ii, MeOH, TsOH$H2O,
CH2Cl2, 66%; iii, Bu3SnH, AIBN, PhMe, 85 ꢀC, 40%; iv, ButOH, PhNMe2, Et2O, 89%; v, NaH,
ButOH, PhMe, 60 ꢀC, 55%; vi, Et3N, Tf2O, ꢁ78 ꢀC, 63%.
6
methyl ester 35, which was converted to the vinylstannane 36 by
radical addition of tributyltin hydride, as for 9 and 13.
Scheme 8. Synthesis of 5 and 6 through couplings with But 2-TfO-cyclopentene-1-
carboxylate 40. Reagents and conditions: i, 33, various Pd catalysts, various conditions;
ii, 35, PdCl2, Ph3P, CuI, Et3N, THF, reflux; iii, 36, Ph3P, Pd(OAc)2, THF; iv, CF3CO2H,
CH2Cl2; v, 22, PyBOP, Et3N, CH2Cl2; vi, LiOH, THF, MeOH, H2O.
In this sequence, the vinyl triflate 40 has not been reported
previously and the corresponding
cially available. A Dieckmann condensation would form the
b
-keto ester 39 is not commer-
-keto
b
ester, although it may be subject to steric hindrance as the elec-
trophilic carbonyl is a t-butyl ester. The bis-acyl chloride 37 was
transformed to the bis-t-butyl 38 ester by reaction with t-butanol in
the presence of the weak base N,N-dimethylaniline (Scheme 7). The
Dieckmann cyclisation then proceeded smoothly, catalysed by so-
dium hydride in hot toluene, to form the 2-oxocyclopentane-
carboxylate ester 39 in good yield. The enol of this compound was
triflylated readily to afford the coupling partner 40.
3. Conclusion
Effective synthetic routes to 5 and 6 have been developed. Two
routes were compared, both relying on Pd-catalysed couplings to
2-triflyloxycyclopentene-1-carboxylate esters to assemble the core
carbon framework. Stille, Sonogashira and Suzuki couplings met
with widely varying degrees of success, depending on the condi-
tions used, the nature of the catalyst and the sp2- or sp3-character
of the coupling partner. Individual steps or routes were optimised
or studied using informative model reactions. The synthetic route
to 6 through Stille coupling of the vinylstannane 36 with t-butyl 2-
TfO-cyclopentene-1-carboxylate 40, deprotection, peptide coupling
with 22 and final cleavage of the side-chain methyl ester was
particularly effective. This work provides useful approaches to po-
tential conformationally controlled mimics of the phosphoser-
ylproline dipeptide motif. The results of the biochemical studies
will be published later elsewhere.
As shown in Scheme 8, the t-butyl ester vinyl triflate 40 reacted
with methyl pent-4-ynoate 35 in a Sonogashira coupling to give 42,
which is a regioisomer of 17. Now, cleavage of the ester to expose the
cyclopentene carboxylic acid could be effected under acidic condi-
tions, which would not affect the conjugated electrophilic system
adversely; treatment with trifluoroacetic acid gave the monoester 43
in excellent yield. Coupling with 22 using PyBOP gave 44, from which
the terminal methyl ester could be hydrolysed readily with mild base
to provide the target 5. That theyield in this hydrolysis is much higher
than the 5% achieved in the hydrolysis of the methyl esterof 17 attests
to the lower electrophilicity of the yne-ene-amide in 44, compared to
that of the yne-ene-ester in 17, leading to fewer side reactions. Un-
fortunately, all attempts to couple 40 with alkylboronic acids failed. In
particular, no coupling of the pinacol-borate 33, carrying the penta-
noate moiety, could be achieved, preventing access to the analogous
targets where the remote carboxylate is linked to the cyclopentene
ring through a fully flexible (CH2)4 chain. The improved yields of this
route were reflected in the corresponding reactions to make the
pentenoic acid 6. Stille coupling of 40 with the vinylstannane 36
proceeded in excellent yield to give 45, which is the regioisomer of
23. Selective acidolysis of the t-butyl ester furnished 46, which was
coupled by the PyBOP method to provide amide 47. Simple base-
catalysed hydrolysis then led to the target 6 in overall yields of 5.3%
4. Experimental
4.1. General
NMR spectra were recorded on JEOL/Varian GX270 and EX400
spectrometers of samples in CDCl3, unless otherwise stated. Mass
spectra were obtained using a Bru¨ker ESI-TOF spectrometer. IR
spectra were measured as thin films or as KBr discs on a Perkin–
Elmer RXI FT-IR spectrometer. The stationary phase for chroma-
tography was silica gel. Solvents were evaporated under reduced
pressure. Solutions in organic solvents were dried with MgSO4.
Melting points were determined by using a Reichert-Jung Thermo
Galen instrument and are uncorrected.
from acyl chloride 37 and 11% from
b-keto ester 39 (a more rigorous
comparison with the earlier synthetic sequence).

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A. Beauchard et al. / Tetrahedron 65 (2009) 8176–8184
4.2. N-(2-(5-Hydroxy-1-oxopent-1-ynyl)cyclopentene-1-
4.5. N-(2-(E-5-Hydroxy-1-oxopent-1-enyl)cyclopentene-1-
carbonyl)-L-phenylalanine N-(4-nitrophenyl)amide (5).
carbonyl)-L-phenylalanine N-(4-nitrophenyl)amide (6).
Method A
Method B
Ester 35 (40 mg, 75
m
mol) was stirred with CF3CO2H (2.0 mL)
Compound 47 (200 mg, 0.4 mmol) was stirred with LiOH$H2O
(43 mg, 1.0 mmol) in THF (1.0 mL), MeOH (0.5 mL) and water
(0.5 mL) for 16 h. Water (5 mL) and EtOAc (3 mL) were added to
the mixture, which was acidified by addition of aq H2SO4 (5%,
5.0 mL). The mixture was extracted rapidly with EtOAc (twice).
The combined extracts were washed (brine) and dried and the
solvent was evaporated to give 6 (130 mg, 68%), with properties
as above.
and CH2Cl2 (2.0 mL) for 2 h. The evaporation residue was dissolved
in MeOH (5 mL) and CH2Cl2 (5 mL) and the solvents were evapo-
rated. The residue, in CH2Cl2, was washed twice with water. Drying
and evaporation gave 5 (18 mg, 51%) as a white powder: mp 90–
92 ꢀC; IR nmax 3475, 3361, 1627, 1482 cmꢁ1; 1H NMR
d 1.79–1.80 (2H,
m, pentynyl 3-H2 or 4-H2), 1.84–1.85 (2H, m, cyclopentene 4-H2),
2.60–2.69 (4H, m, cyclopentene 3,5-H2), 3.12–3.14 (2H, m, pentynyl
4-H2 or 3-H2), 3.22 (1H, dd, J¼14.0, 7.0 Hz, Phe
J¼14.0, 7.0 Hz, Phe -H), 4.94–4.95 (1H, m, Phe
m, Ph-H5), 7.61 (2H, d, J¼8.6 Hz, Ar 2,6-H2), 8.11 (2H, d, J¼8.6 Hz, Ar
3,5-H2), 9.37 (1H, br, NH); 13C NMR (HMQC/HMBC)
21.47 (pen-
tynyl 3-C or 4-C), 26.43 (cyclopentene 4-C), 33.52 (cyclopentene 3-
C or 5-C), 36.93 (Phe -C), 39.79 (cyclopentene 5-C or 3-C), 46.33
(pentynyl 4-C or 3-C), 56.25 (Phe -C), 68.98 (pentynyl 1-C or 2-C),
101.53 (pentynyl 2-C or 1-C), 119.65 (Ar 2,6-C2), 124.85 (Ar 3,5-C2),
127.09 (Ph 4-C), 128.72 (Ph 3,5-C2), 129.18 (cyclopentene 1-C),
129.22 (Ph 2,6-C2), 136.39 (Ph 1-C), 140.36 (cyclopentene 2-C),
143.29 (Ar 1-C or 4-C), 143.69 (Ar 4-C or 1-C), 165.15 (C]O), 170.89
(C]O), 173.74 (C]O); MS (ES ꢁve ion) m/z 474.1674 (MꢁH)
(C26H24N3O6 requires 474.1665).
b
-H), 3.31 (1H, dd,
b
a-H), 7.20–7.28 (5H,
4.6. Phenylethynyltributylstannane (8)
d
LiN(SiMe3)2 (1.0 M in THF, 3.3 mL, 3.3 mmol) was added slowly
to ethynylbenzene 7 (280 mg, 2.7 mmol) in dry THF (5.0 mL) at
ꢁ78 ꢀC. The solution was stirred at ꢁ78 ꢀC for 1 h, then Bu3SnCl
(1.0 g, 3.3 mmol) was added dropwise and the mixture was allowed
to warm to 20 ꢀC. After 100 min, saturated aq NH4Cl (3.0 mL) was
added and the aq phase was extracted with Et2O (thrice). This
extract was washed with brine (twice) and dried and the solvent
was evaporated to give 8 (1.33 g, 99%) as a pale yellow liquid (lit.24
b
a
oil): IR nmax 2138, 1486 cmꢁ1
;
1H NMR
d
0.87 (9H, t, J¼7.4 Hz,
3ꢂMe), 1.05–1.06 (6H, m, 3ꢂSnCH2), 1.32 (6H, sextet, J¼7.4 Hz,
3ꢂCH2Me), 1.55–1.57 (6H, m, 3ꢂSnCH2CH2), 7.20–7.23 (3H, m, Ph
3,4,5-H3), 7.38–7.39 (2H, m, Ph 2,6-H2); 13C NMR (HMQC, HMBC)
4.3. N-(2-(5-Hydroxy-1-oxopent-1-ynyl)cyclopentene-1-
carbonyl)-
Method B
L
-phenylalanine N-(4-nitrophenyl)amide (5).
d
11.15 (3ꢂbutyl 1-C), 13.68 (3ꢂMe), 26.97 (3ꢂbutyl 3-C), 28.89
(3ꢂbutyl 2-C), 93.20 (C^C), 110.02 (C^C), 124.02 (Ph 1-C), 127.79
(Ph 4-C), 128.09 (Ph 3,5-C2), 131.91 (Ph 2,6-C2). This material was
used for subsequent couplings without further purification or
characterisation.
Compound 46 (10.0 mg, 20
(2.0 mg, 50 mol) in THF (1.0 mL), MeOH (0.5 mL) and water
mmol) was stirred with LiOH$H2O
m
(0.5 mL) for 16 h. Water (5 mL) and EtOAc (3 mL) were added to the
mixture, which was acidified by addition of aq HCl (0.5 M, 5.0 mL).
The mixture was extracted rapidly with EtOAc (twice). The com-
bined extracts were dried and the solvent was evaporated to give 5
(2.1 mg, 22%), with properties as above.
4.7. E-Phenylethenyltributylstannane (9)
Ethynylbenzene 7 (300 mg, 2.7 mmol) was heated with Bu3SnH
(950 mg, 3.3 mmol) and AIBN (45 mg, 0.27 mmol) in toluene
(10 mL) at 85 ꢀC for 1 h. Evaporation and chromatography (hexane)
gave 925 (520 mg, 50%) as a yellow oil: IR nmax 2955, 2923 cmꢁ1; 1H
4.4. N-(2-(E-5-Hydroxy-1-oxopent-1-enyl)cyclopentene-1-
carbonyl)-
Method A
L
-phenylalanine N-(4-nitrophenyl)amide (6).
NMR
d
0.79–1.00 (15H, m, 3ꢂCH2CH3), 1.33–1.34 (6H, m, 3ꢂBu 2-
H2), 1.52–1.54 (6H, m, 3ꢂBu 1-H2), 6.86 (2H, 2ꢂs, CH]CH), 7.21
(1H, t, J¼7.6 Hz, Ph 4-H), 7.32 (2H, t, J¼7.6 Hz, Ph 3,5-H2), 7.41 (2H,
The t-butyl ester 31 (70 mg, 140
mmol) was stirred with CF3CO2H
dd, J¼7.6, 1.2 Hz, Ph 2,6-H2); 13C NMR
d 9.6, 13.71, 27.30, 29.11,
(2.0 mL) and CH2Cl2 (2.0 mL) for 2 h. The evaporation residue was
dissolved in MeOH (5 mL) and CH2Cl2 (5 mL) and the solvents were
evaporated. The residue, in CH2Cl2, was washed twice with water.
Drying and evaporation gave 6 (40 mg, 60%) as a white powder: mp
125.97, 127.48, 128.45, 129.58, 138.82, 146.00. This material was
used for subsequent couplings without further purification or
characterisation.
98–100 ꢀC; IR nmax 3413, 1695, 1612, 1503 cmꢁ1; 1H NMR
d 1.85 (2H,
qn, J¼7.4 Hz, cyclopentene 4-H2), 2.35–2.49 (4H, m, pentenyl 3,4-
4.8. 1,1-Dimethylethyl pent-4-ynoate (11)
H4), 2.51–2.78 (4H, m, cyclopentene 3,5-H4), 3.11 (1H, dd, J¼14.0,
7.0 Hz, Phe
J¼7.4 Hz, Phe
b
-H), 3.21 (1H, dd, J¼14.0, 7.0 Hz, Phe
b
-H), 4.99 (1H, q,
BuLi (1.6 M in hexane, 13.5 mL, 21.6 mmol) was added to Pri2NH
(2.18 g, 21.6 mmol) in THF (200 mL) under N2 at ꢁ78 ꢀC. After
10 min, t-butyl acetate 10 (1.91 g, 18 mmol) was added and the
mixture was stirred for 1 h at ꢁ78 ꢀC. HMPA (9.4 mL, 54 mmol) was
added and the mixture was stirred for 5 min before 3-bromopro-
pyne (2.14 g, 18 mmol) was introduced. The mixture was stirred at
20 ꢀC for 21 h. The reaction was quenched with satd aq NH4Cl
(2.0 mL) before the mixture was diluted with hexane (100 mL) and
washed with aq HCl (1.0 M, twice) and with water (twice). Drying
and evaporation gave 1121 (2.44 g, 88%) as a yellow oil: IR nmax 2121,
a
-H), 5.90 (1H, td, J¼16.0, 5.8 Hz, pentenyl 2-H), 7.15
(1H, d, J¼16.0 Hz, pentenyl 1-H), 7.19–7.30 (5H, m, Ph-H5), 7.57 (2H,
d, J¼9.0 Hz, Ar 2,6-H2), 8.06 (2H, d, J¼9.0 Hz, Ar 3,5-H2), 9.66 (1H, br,
NH), 9.82 (1H, br, OH); 13C NMR (HMQC/HMBC)
d 21.94 (cyclo-
pentene 4-C), 27.87 (pentenyl 3-C or 4-C), 32.92 (pentenyl 4-C or 3-
C), 34.02 (cyclopentene 3-C or 5-C), 34.19 (cyclopentene 5-C or 3-C),
37.73 (Phe b-C), 55.39 (Phe a-C), 119.42 (Ar 2,6-C2), 124.76 (Ar 3,5-
C2), 125.99 (pentenyl 2-C), 127.20 (Ph 4-C), 128.74 (cyclopentene 1-
C),129.14 (Phe),129.21 (Phe),135.94 (pentenyl 1-C),136.06 (Ph 1-C),
143.57 (Ar 1-C or 4-C), 143.60 (Ar 4-C or 1-C), 150.44 (cyclopentene
2-C), 171.20 (cyclopentene 1-C]O), 176.45 (ArCONH), 176.99 (ester
C]O); MS (ES ꢁve ion) m/z 476.1826 (MꢁH) (C26H26N3O6 requires
476.1826).
1730 cmꢁ1
;
1H NMR
d
1.44 (9H, s, But), 1.95 (1H, t, J¼1.2 Hz, 5-H),
2.42–2.45 (4H, m, 3,4-H4); 13C NMR (HMBC)
d 14.46 (CH2), 28.06
(3ꢂMe), 34.44 (CH2), 68.75 (C^CH), 80.83 (Me3C), 82.75 (5-C),
171.08 (C]O).

A. Beauchard et al. / Tetrahedron 65 (2009) 8176–8184
8181
4.9. 1,1-Dimethylethyl 5-(tributylstannyl)pent-4-ynoate (12)
4.13. Methyl 2-(5-(1,1-dimethylethoxy)-5-oxopent-1-
ynyl)cyclopent-1-enecarboxylate (17). Method B
Compound 11 (500 mg, 3.2 mmol) was heated with Bu3S-
nOMe (1.03 g, 3.2 mmol) at 110 ꢀC for 4 h. Evaporation and
chromatography (hexane) gave 12 (1.26 g, 88%) as a pale yellow
The triflate 15 (77 mg, 0.28 mmol) was stirred at 55 ꢀC with 12
(150 mg, 0.34 mmol), Ph3P (10 mg, 39 mol) and Pd(OAc)2 (4.4 mg,
20 mol) for 1 h. Evaporation and chromatography (hexane/EtOAc
m
oil: IR nmax 2221, 1728 cmꢁ1
;
1H NMR
d
0.89 (9H, t, J¼7.4 Hz,
m
3ꢂBu 4-H3), 0.93 (6H, t, J¼7.4 Hz, 3ꢂBu 1-H2), 1.30 (6H, sextet,
J¼7.4 Hz, 3ꢂBu 2-H2), 1.42 (9H, s, But), 1.48–1.50 (6H, m, 3ꢂBu
3-H2), 2.44 (2H, t, J¼7.4 Hz, 3-H2), 2.48 (2H, t, J¼7.4 Hz, 2-H2);
3:2) gave 17 (17 mg, 22%), with properties as above.
13C NMR (HMQC/HMBC)
d
10.92 (3ꢂBu 1-C), 13.64 (3ꢂBu 4-C),
4.14. Methyl E-2-(2-phenylethenyl)cyclopentene-
1-carboxylate (18)
16.22 (3-C), 26.96 (3ꢂBu 2-C), 28.08 (C(CH3)3), 28.82 (3ꢂBu 3-
C), 35.35 (2-C), 80.48 (C(CH3)3), 82.37 (4-C), 109.58 (5-C), 171.36
(C]O). This compound was too unstable to provide a mass
spectrum.
The triflate 15 (300 mg, 1.1 mmol) was stirred with 9 (500 mg,
1.3 mmol), Ph3P (40 mg, 0.15 mmol) and Pd(OAc)2 (17 mg, 77 mmol)
in dry THF (2.0 mL) at 55 ꢀC under N2 for 1 h. Evaporation and
chromatography (hexane/EtOAc 19:1) gave 18 (240 mg, 95%) as
4.10. Methyl 2-trifluoromethanesulfonyloxycyclopentene-
1-carboxylate (15)
white crystals: mp 36–37 ꢀC; IR nmax 1698, 1588, 1433 cmꢁ1 1H
;
NMR
d
1.92 (2H, qn, J¼7.4 Hz, 4-H2), 2.74 (2H, t, J¼7.6 Hz, 3-H2), 2.80
Pri2NEt (30 mL) was added to methyl 2-oxocyclopentane-
carboxylate 14 (5.0 g, 35 mmol) in dry CH2Cl2 (70 mL) at ꢁ78 ꢀC.
After 10 min, trifluoromethanesulfonic anhydride (11.8 g, 42 mmol)
was added dropwise, followed by slow warming to 20 ꢀC during
16 h. The mixture was washed with water (50 mL) and aq citric acid
(10%, twice). Drying, evaporation and chromatography (hexane/
EtOAc 19:1) gave 159 (9.13 g, 95%) as a pale yellow oil: IR nmax 1725,
(2H, t, J¼7.6 Hz, 5-H2), 3.78 (3H, s, Me), 6.75 (1H, d, J¼16 Hz, ethenyl
1-H), 7.25 (1H, t, J¼7.2 Hz, Ph 4-H), 7.33 (2H, t, J¼7.2 Hz, Ph 3,5-H2),
7.51 (2H, d, J¼7.2 Hz, Ph 2,6-H2), 8.05 (1H, d, J¼16 Hz, ethenyl 2-H);
13C NMR
d 21.42, 34.06, 34.27, 51.19, 123.74, 127.15, 128.33, 128.65,
129.49, 135.31, 136.99, 152.38, 166.41; MS m/z 229.1208 (MþH)
(C15H17O2 requires 229.1223).
1668, 1426, 1354, 1208, 1141 cmꢁ1; 1H NMR
4-H2), 2.66–2.78 (4H, m, 3,5-H4), 3.78 (3H, s, Me); 13C NMR
29.14, 32.74, 51.84, 118.31 (q, J¼250 Hz CF3), 122.97, 153.97, 162.68;
19F NMR (CDCl3)
d
2.01 (2H, qn, J¼7.4 Hz,
4.15. Methyl E-2-(5-(1,1-dimethylethoxy)-1-oxopent-1-
enyl)cyclopentene-1-carboxylate (19)
d
18.78,
d
ꢁ74.50 (s); MS m/z 297.0032 (MþNa)
Alkyne 11 (500 mg, 3.3 mmol) was heated with Bu3SnH (1.12 g,
3.9 mmol) and AIBN (52 mg, 0.32 mmol) in toluene (10 mL) at 85 ꢀC
for 1 h. Evaporation and chromatography (hexane) gave crude 13
(0.88 g, 60%) as a yellow oil: IR nmax 1732 cmꢁ1. The triflate 15
(150 mg, 0.56 mmol) was stirred with 13 (300 mg, 0.67 mmol),
(C8H9F3NaO5S requires 297.0020).
4.11. Methyl 2-phenylethynylcyclopentene-1-carboxylate (16)
The triflate 15 (300 mg, 1.1 mmol) was stirred with 8 (510 mg,
1.3 mmol), Ph3P (40 mg, 0.15 mmol) and Pd(OAc)2 (17 mg, 77 mmol)
in dry THF (3.0 mL) at 55 ꢀC under N2 for 1 h. Evaporation and
Ph3P (20 mg, 78 mmol) and Pd(OAc)2 (8.8 mg, 39 mmol) in dry THF
(2.0 mL) at 55 ꢀC under N2 for 1 h. Evaporation and chromatogra-
phy (hexane/CH2Cl2 3:2) gave 19 (90 mg, 57%) as a pale yellow oil:
IR nmax 1728 cmꢁ1; 1H NMR 1.42 (9H, s, But), 1.84 (2H, qn, J¼7.4 Hz,
4-H2), 2.35 (2H, t, J¼7.2 Hz, pentenyl 4-H2), 2.44 (2H, t, J¼7.2 Hz,
pentenyl 3-H2), 2.61 (2H, t, J¼7.6 Hz, 3-H2 or 5-H2), 2.65 (2H, t,
J¼7.6 Hz, 5-H2 or 3-H2), 3.72 (3H, s, Me), 5.92 (1H, dt, J¼6.6, 15.7 Hz,
pentenyl 2-H), 7.27 (1H, d, J¼15.7 Hz, pentenyl 1-H); 13C NMR
chromatography (hexane/EtOAc 19:1) gave 16 (260 mg, 99%) as
yellow crystals: mp 109–109ꢀC; IR nmax 2215, 1728 cmꢁ1 1H NMR
;
d
1.96 (2H, qn, J¼7.6 Hz, 4-H2), 2.72–2.75 (4H, m, 3,5-H4), 3.80 (3H,
s, Me), 7.30–7.34 (3H, m, Ph 3,4,5-H3), 7.50 (2H, dd, J¼6.8, 2.8 Hz, Ph
2,6-H2); 13C NMR (HMQC, HMBC)
22.27 (4-C), 33.32 (3-C or 5-C),
d
39.17 (5-C or 3-C), 51.44 (Me), 85.67 (C^C), 99.73 (C^C), 122.96 (Ph
1-C), 128.31 (Ph 3,5-C2), 128.79 (Ph 4-C), 131.88 (Ph 2,6-C2), 134.73
and 137.89 (1,2-C2), 164.98 (C]O); MS m/z 227.1067 (MþH)
(C15H15O2 requires 227.1022).
(HMQC, HMBC) d 21.26 (4-C), 28.03 (C(CH3)3), 28.64 (pentenyl 3-C),
34.02 (3-C or 5-C), 34.16 (5-C or 3-C), 34.87 (pentenyl 4-C), 51.02
(Me), 80.30 (C(CH3)3), 126.21 (pentenyl 1-C), 127.60 (1-C), 136.51
(pentenyl 2-C), 152.13 (2-C), 166.31 (CO2Me), 172.13 (CO2But); MS
m/z 303.1571 (MþNa) (C16H24NaO4 requires 303.1572), 247.0943
(MþNa–Me2C]CH2) (C12H16NaO4 requires 247.0947).
4.12. Methyl 2-(5-(1,1-dimethylethoxy)-5-oxopent-1-
ynyl)cyclopent-1-enecarboxylate (17). Method A
Compound 11 (54 mg, 0.4 mmol) was boiled under reflux under
4.16. N-(1,1-Dimethylethoxycarbonyl)-L-phenylalanine
N2 with 15 (110 mg, 0.4 mmol), PdCl2 (3.0 mg, 20
mmol), Ph3P
N-(4-nitrophenyl)amide (21)
(10 mg, 40 mol), CuI (4.0 mg, 20 mol) and Et3N (60 mg,
m
m
0.6 mmol) in THF (3.0 mL) for 90 min. Evaporation and chroma-
POCl3 (1.68 g, 11 mmol) was added dropwise to a vigorously
stirred mixture of Boc- -PheOH 20 (2.65 g, 10 mmol) and 4-nitro-
tography (hexane/EtOAc 9:1) gave 17 (110 mg, 98%) as a pale yellow
L
oil: IR nmax 2222, 1731, 1698 cmꢁ1
;
1H NMR
d
1.44 (9H, s, But), 1.88
aniline (1.38 g, 10 mmol) in dry pyridine (30 mL) at ꢁ10 ꢀC. After
15 min, the reaction was quenched by addition of ice-water
(100 mL) and the mixture was extracted with EtOAc (thrice). The
combined extracts were washed with satd aq NaHCO3 (twice) and
brine (twice). Drying and evaporation gave 21 (3.25 g, 84%) as a pale
yellow powder: mp 158–160 ꢀC (lit.27 mp 150–151 ꢀC); IR nmax
(2H, qn, J¼7.4 Hz, 4-H2), 2.50 (2H, t, J¼7.4 Hz, pentynyl 4-H2), 2.58
(2H, tt, J¼7.4, 2.3 Hz, 3-H2 or 5-H2), 2.66 (2H, H, tt, J¼7.4, 2.3 Hz, 5-
H2 or 3-H2), 2.69 (2H, t, J¼7.0 Hz, pentenyl 3-H2), 3.73 (3H, s, Me);
13C NMR (HMQC/HMBC)
d 16.02 (pentynyl 3-C), 22.10 (4-C), 28.05
(C(CH3)3), 33.06 (5-C or 3-C), 34.57 (pentynyl 4-C), 39.46 (3-C or 5-
C), 51.32 (OMe), 76.69 (pentynyl 1-C), 80.76 (C(CH3)3), 99.94
(pentynyl 2-C), 135.45 (3-C or 5-C), 136.76 (5-C or 3-C), 165.04
(cyclopentene 1-C]O), 171.05 (pentynyl 5-C); MS m/z 579.2867
(2 MþNa) (C32H44NaO8 requires 579.2928), 301.1384 (MþNa)
(C16H22NaO4 requires 301.1410); 279.1568 (MþH) (C16H23O4 re-
quires 279.1590).
3286,1717,1549,1507 cmꢁ1; 1H NMR
J¼14.0, 7.7 Hz, -H), 3.16 (1H, dd, J¼14.0, 8.3 Hz,
J¼7.3 Hz,
d
1.41 (9H, s, But), 3.11 (1H, dd,
b
b
-H), 4.48 (1H, br q,
a
-H), 5.10 (1H, br d, J¼7.3 Hz, BocNH), 7.20–7.30 (5H, m,
Ph-H5), 7.54 (2H, d, J¼9.0 Hz, Ar 2,6-H2), 8.13 (2H, d, J¼9.0 Hz, Ar
3,5-H2), 8.60 (1H, br, ArNH); MS m/z 408.1518 (MþNa)
(C20H23NaN3O5 requires 408.1535).

8182
A. Beauchard et al. / Tetrahedron 65 (2009) 8176–8184
4.17.
L
-Phenylalanine N-(4-nitrophenyl)amide
200 mmol) and Et3N (33 mg, 330 mmol) in CH2Cl2 (5.0 mL) for 24 h.
hydrochloride (22)
Evaporation and chromatography (hexane/EtOAc 1:1) gave 27
(60 mg, 76%) as a yellow powder: mp 110–112 ꢀC; IR nmax 3403,
HCl was passed through 21 (3.25 g, 8.43 mmol) in CH2Cl2
(100 mL) for 1 h. The precipitate was collected and dried to give 22
(1.98 g, 73%) as a pale yellow powder: mp 140–141 ꢀC; IR nmax
3268, 2121, 1627, 1508 cmꢁ1
;
1H NMR
d
1.94 (2H, qn, J¼7.4 Hz, 4-
H2), 2.79–2.80 (2H, m, 3-H2), 2.81–2.83 (2H, m, 5-H2), 3.08 (1H, dd,
J¼13.7, 7.4 Hz, -H), 3.22 (1H, dd, J¼13.7, 6.6 Hz, -H), 5.05 (1H, q,
J¼7.4 Hz, -H), 7.08–7.15–7.20 (5H, m, Phe Ph-H5) 7.34–7.39 (3H, m,
b
b
3043, 2927, 1695, 1569, 1512 cmꢁ1; 1H NMR ((CD3)2SO)
d
3.14 (1H,
a
dd, J¼13.8, 7.4 Hz,
b
-H), 3.24 (1H, dd, J¼13.8, 6.1 Hz,
b
-H), 4.31–
Ph 3,4,5-H3), 7.47 (2H, d, J¼8.0 Hz, Ph 2,6-H2), 7.59 (2H, d, J¼9.1 Hz,
4.32 (1H, m,
a
-H), 7.22–7.34 (5H, m, Ph-H5), 7.89 (2H, d, J¼9.0 Hz,
Ar 2,6-H2), 7.96 (1H, d, J¼7.4 Hz), 8.27 (2H, d, J¼9.1 Hz, Ar 3,5-H2),
Ar 2,6-H2), 8.25 (2H, d, J¼9.0 Hz, Ar 3,5-H2), 8.49 (3H, br, NþH3),
9.55 (1H, s, NH); 13C NMR (HMQC, HMBC)
d
21.86 (4-C), 33.84 (3-C
11.75 (1H, br, NH); 13C NMR
d
37.26, 54.74, 119.86, 125.61, 127.90,
or 5-C), 38.18 (Phe b-C), 39.75 (5-C or 3-C), 55.93 (Phe a-C), 84.71
129.17, 130.07, 135.00, 143.46, 144.40, 168.20; MS m/z 308.1012
(MþNa) (C15H15N3NaO3 requires 308.1011), 286.1188 (MþH)
(C15H16N3O3 requires 286.1188).
(C^C), 101.89 (C^C), 119.38 (Ar 2,6-C2), 121.55 (Cq), 124.87 (Ar 3,5-
C2), 127.20 (Phe Ph 4-C), 128.73 (Phe Ph 3,5-C2þPh 3,5-C2), 129.19
(Cq), 129.31 (Phe Ph 2,6-C2), 129.74 (Ph 4-C), 131.88 (Ph 2,6-C2),
136.09 (Cq), 140.87 (Cq), 143.44 (Cq), 143.84 (Cq), 165.00 (C]O),
170.05 (C]O); MS m/z 480.1919 (MþH) (C29H26N3O4 requires
480.1853).
4.18. N-(2-Methoxycarbonylcyclopenten-1-yl)-
alanine N-(4-nitrophenyl)amide (24)
L-phenyl-
Compound 14 (355 mg, 2.5 mmol) was heated with DMAP
(91 mg, 0.75 mmol) and 22 (free base, 1.6 g, 5.0 mmol) in PhMe
(15 mL) at reflux for 19 h. Evaporation and chromatography (hex-
ane/EtOAc 7:3) gave 24 (140 mg, 14%) as a pale yellow oil: IR nmax
4.22. 2-(5-(1,1-Dimethylethoxy)-1-oxopent-1-ynyl)-
cyclopentene-1-carboxylic acid (28)
The diester 17 (830 mg, 2.8 mmol) was stirred with LiOH$H2O
(320 mg, 7.6 mmol) in THF (4.0 mL), MeOH (2.0 mL) and water
(2.0 mL) for 16 h. Water (5 mL) was added to the evaporation res-
idue. The solution was washed with Et2O (2ꢂ5 mL) and acidified
with aq H2SO4 (5%) before being extracted rapidly with Et2O
(3ꢂ10 mL). The combined extracts were washed with brine and
dried. Evaporation gave 28 (40 mg, 5%) as a pale yellow oil: IR nmax
1684, 1591, 1508 cmꢁ1
;
1H NMR
d
1.75, (2H, qn, J¼7.4 Hz, cyclo-
pentene 4-H2), 2.31–2.38 (2H, m, cyclopentene 3-H2), 2.46 (2H, t,
J¼7.4 Hz, cyclopentene 5-H2), 3.11 (1H, dd, J¼14.0, 8.2 Hz, Phe -H),
3.33 (1H, dd, J¼14.0, 4.0 Hz, Phe -H), 3.70 (3H, s, OMe), 4.22–4.23
(1H, m, Phe
-H), 7.23–7.33 (5H, m, Ph-H5), 7.60 (1H, d, J¼7.8 Hz,
Phe NH), 7.69 (2H, d, J¼9.0 Hz, Ar 2,6-H2), 8.20 (2H, d, J¼9.0 Hz, Ar
2,6-H2), 8.40 (1H, s, ArNH); 13C NMR (HMQC/HMBC)
20.60
(cyclopentene 4-C), 29.09 (cyclopentene 5-C), 32.27 (cyclopentene
3-C), 39.35 (Phe -C), 50.54 (OMe), 61.27 (Phe -C), 98.13 (cyclo-
b
b
a
d
2222, 1733 cmꢁ1; 1H NMR
d
1.43 (9H, s, But), 1.88 (2H, qn, J¼7.4 Hz,
4-H2), 2.50 (2H, t, J¼7.4 Hz, pentynyl 4-H2), 2.62 (2H, dt, J¼7.7,
b
a
1.9 Hz, pentynyl 3-H2), 2.66–2.75 (4H, m, 3,5-H4); 13C NMR
d 14.27,
pentene 2-C), 119.44 (Ar 2,6-C2), 124.96 (Ar 3,5-C2), 127.38 (Ph 4-C),
128.78 (Ph 3,5-C2), 129.37 (Ph 2,6-C2), 135.82 (Ph 1-C), 142.80 (Ar 1-
C), 143.86 (Ar 4-C), 162.17 (cyclopentene 1-C), 168.64 (amide C]O),
170.79 (ester C]O); MS m/z 432.1513 (MþNa) (C22H23N3NaO5 re-
quires 432.1535), 410.1708 (MþH) (C22H24N3O5 requires 410.1715).
16.13, 20.09, 28.13 (C(CH3)3), 33.00, 34.38, 39.88, 81.04 (pentynyl 2-
C), 102.12 (pentynyl 1-C), 136.80 (Cq), 137.35 (Cq), 168.35 (C]O),
171.11 (C]O); MS (ES ꢁve ion) m/z 263.1224 (MꢁH) (C15H19O4
requires 263.1283).
4.23. N-(2-(5-(1,1-Dimethylethoxy)-1-oxopent-1-ynyl)-
4.19. 2-Phenylethynylcyclopentene-1-carboxylic acid (25)
cyclopentene-1-carbonyl)-L-phenylalanine
N-(4-nitrophenyl)amide (29)
Ester 16 (150 mg, 0.66 mmol) was treated with aq NaOH in EtOH,
as for the synthesis of 26, to give 2523 (40 mg, 57%) as a pale yellow
The carboxylic acid 28 (40 mg, 150 mmol) was treated with 22,
PyBOP and Et3N, as for the synthesis of 27 except that the chro-
matographic eluant was hexane/EtOAc (7:3), to give 29 (70 mg,
oil: IR nmax 2351, 1636, 1510 cmꢁ1; 1H NMR
d
1.98 (2H, qn, J¼7.4 Hz,
4-H2), 2.75–2.78 (4H, m, 3,5-H4), 7.28–7.33 (3H, m, Ph 3,4,5-H4), 7.49
(2H, d, J¼6.6 Hz, Ph 2,6-H2); MS 235.0737 (MþNa) (C14H12NaO2
requires 235.0729), 213.0910 (MþH) (C14H13O2 requires 213.0910).
88%) as a pale yellow oil: IR nmax 3423, 2121, 1726, 1632, 1508 cmꢁ1
;
1H NMR
d
1.42 (9H, s, But), 1.85 (2H, qn, J¼7.4 Hz, 4-H2), 2.44 (2H,
dd, J¼1.4, 5.5 Hz, pentynyl 3-H2), 2.55–2.70 (6H, m, pentenyl 4-H2
4.20. E-2-(2-Phenylethenyl)cyclopentene-1-carboxylic
acid (26)
and 3,5-H4), 3.12 (1H, dd, J¼14.0, 10.1 Hz, Phe
b
-H), 3.22 (1H, dd,
-H), 7.17–
J¼14.0, 6.6 Hz, Phe -H), 5.01 (1H, dd, J¼10.1, 6.6 Hz, Phe
b
a
7.25 (5H, m, Ph-H5), 7.64 (2H, d, J¼7.2 Hz, Ar 2,6-H2), 8.10 (2H, d,
Ester 18 (130 mg, 0.57 mmol) was stirred with aq NaOH (5 M,
0.13 mL, 0.63 mmol) in EtOH (30 mL) for 16 h. The evaporation
residue, in water (10 mL), was acidified to pH 2 with aq HCl (0.5 M)
and extracted with EtOAc (thrice). The extract was dried and the
solvent was evaporated to give 26 (40 mg, 33%) as a colourless gum:
J¼7.2 Hz, Ar 3,5-H2), 9.59 (1H, br, NH); 13C NMR
d 15.83, 21.65, 28.17,
33.53, 33.96, 38.20, 39.70, 41.00, 55.71, 81.09, 102.24, 119.35, 124.92,
127.11, 128.67, 129.20, 129.46, 136.34, 140.40, 143.39, 144.06, 164.79,
169.97, 170.97; MS m/z 1085.4608 (2 MþNa) (C60H66N6O12Na re-
quires 1085.4544); 554.2238 (MþNa) (C30H33N3O6Na requires
554.2267).
IR nmax 1731 cmꢁ1
;
1H NMR
d
1.90–1.96 (2H, qn, J¼7.4 Hz, 4-H2),
2.72–2.82 (4H, m, 3,5-H4), 6.73 (1H, d, J¼16.2 Hz, ethenyl 1-H),
7.30–7.33 (3H, m, Ph 3,4,5-H3), 7.49 (2H, d, J¼7.2 Hz), 8.06 (1H, d,
4.24. E-2-(5-(1,1-Dimethylethoxy)-1-oxopent-1-enyl)-
cyclopentene-1-carboxylic acid (30)
J¼16.2 Hz); 13C NMR
d
14.50, 21.49, 34.20, 34.42, 60.03, 123.96,
127.19, 128.37, 128.74, 135.16, 137.16, 151.99; MS (ES ꢁve ion)
213.0941 (MꢁH) (C14H13O2 requires 213.0921).
Diester 19 (90 mg, 0.32 mmol) was stirred with LiOH$H2O
(13.4 mg, 0.32 mmol) in THF (2.0 mL), MeOH (1.0 mL) and water
(1.0 mL) for 6 h. The solvents were evaporated and water (5 mL)
was added. The solution was washed with Et2O (twice) and acidi-
fied with aq HCl (0.5 M) to pH 5. The mixture was immediately
extracted with Et2O (thrice). The combined extracts were washed
with brine and dried. Evaporation gave 30 (20 mg, 24%) as
4.21. N-(2-Phenylethynylcyclopentene-1-carbonyl)-
L-phenylalanine N-(4-nitrophenyl)amide (27)
2-Phenylethynylcyclopentene-1-carboxylic acid 25 (35 mg,
170 mmol) was stirred with 22 (53 mg, 170 mmol), PyBOP (100 mg,

A. Beauchard et al. / Tetrahedron 65 (2009) 8176–8184
8183
a colourless oil: IR nmax 3424,1710,1633 cmꢁ1; 1H NMR
d
1.42 (9H, s,
HCl (2 M, twice), satd aq NaHCO3 (twice) and satd brine. Drying and
But),1.84–1.85 (2H, m, 4-H2), 2.25–2.37 (2H, m, CH2), 2.43–2.56 (2H,
m, CH2), 2.64–2.73 (4H, m, 3,5-H4), 5.93–6.05 (1H, m, pentenyl 2-
H), 7.29 (1H, d, J¼15.4 Hz, pentenyl 1-H); MS m/z 289.1439 (MþNa)
(C15H22NaO4 requires 289.1410).
evaporation gave 38 (14.2 g, 89%) as white crystals: mp 25–28 ꢀC
(lit.28 mp 29–31 ꢀC); 1H NMR
d
1.40 (18H, s, 2ꢂBut), 1.54–1.58 (4H,
m, 3,4-H4), 2.18–2.19 (4H, m, 2,5-H4).
4.29. 1,1-Dimethylethyl 2-oxocyclopentanecarboxylate (39)
4.25. N-(2-(E-5-(1,1-Dimethylethoxy)-1-oxopent-1-
enyl)cyclopentene-1-carbonyl)-
N-(4-nitrophenyl)amide (31)
L
-phenylalanine
NaH (3.52 g, 60% in oil, 88 mmol) was washed thrice with
pentane and suspended in PhMe (40 mL). This suspension was
heated to 60 ꢀC. The diester 38 (300 mg, 1.7 mmol) in ButOH
(300 m
L) was added and the mixture was stirred at 60 ꢀC for 30 min.
The carboxylic acid 30 (90 mg, 340
mmol) was treated with 22,
PyBOP and Et3N, as for the synthesis of 27, to give 31 (70 mg, 42%) as
a white powder: mp 78–80 ꢀC; IR nmax 3288, 1720, 1622, 1565,
Further 38 (7.30 g, 27.6 mmol) in PhMe (10 mL) was added and the
mixture was stirred at 100ꢀC for 4 h. The mixture was cooled to 5 ꢀC
and MeOH (2.0 mL), water (2.0 mL) and satd aq NH4Cl (10 mL) were
added sequentially and carefully. The aq phase was extracted with
PhMe (thrice). The combined organic phases were dried. Evapora-
tion and chromatography (hexane/EtOAc 20:1/10:1) gave 39
1508 cmꢁ1; 1H NMR 1.42 (9H, s, But), 1.83–1.93 (2H, m, 4-H2), 2.29
d
(2H, t, J¼7.0 Hz, pentenyl 4-H2), 2.39 (2H, q, J¼7.0 Hz, pentenyl 3-
H2), 2.60–2.69 (4H, m, 3,5-H4), 3.17–3.26 (2H, m, Phe
b
a
-H2), 4.02
-H), 5.95–
(1H, d, J¼5.1 Hz, Phe -NH), 4.90 (1H, ca. q, J¼7 Hz, Phe
a
5.97 (1H, m, pentenyl 1-H), 7.23–7.32 (6H, m, pentenyl 2-HþPh-H5),
(2.97 g, 55%) as a colourless oil (lit.29 oil): 1H NMR 1.41 (9H, s, But),
d
7.57–7.61 (2H, m, Ar 3,5-H2), 8.13 (2H, d, J¼9.0 Hz, Ar 3,5-H2), 9.36–
1.84–1.85 (1H, m, 4-H), 2.03–2.29 (5H, m, 3,4,5-H5), 3.02 (1H, t,
J¼8.5 Hz, 1-H).
9.38 (1H, m, ArNH); 13C NMR (HMQC/HMBC)
d
21.36 (cyclopentene
4-C), 28.08 (C(CH3)3), 28.66 (pentenyl 3-C), 33.90 (cyclopentene
3,5-C2), 34.84 (pentenyl 2-C), 36.74 (Phe -C), 55.37 (Phe -H),
b
a
4.30. 1,1-Dimethylethyl 2-trifluoromethanesulfonyloxy-
cyclopentene-1-carboxylate (40)
70.54, 71.24, 119.29 (Ar 2,6-C2), 124.89 (Ar 3,5-C2), 126.36, 127.33
(Ph 4-C), 128.86, 128.88, 128.96 (Ph 3,5-C2), 129.21 (Ph 2,6-C2),
134.33, 136.07, 136.14, 137.01, 150.96, 167.44 (cyclopentene 1-C]O),
169.86 (Phe C]O), 172.04 (ester C]O); MS m/z 1089.4926
(2 MþNa) (C60H70N6NaO12 requires 1089.4949), 556.2403 (MþNa)
(C30H35N3NaO6 requires 556.2424), 534.2587 (MþH) (C30H36N3O6
requires 534.2598), 478.1972 (MþHꢁMe2C]CH2) (C26H28N3O6
requires 478.1978).
Et3N (660 mg, 6.5 mmol) was added to 39 (1.00 g, 5.4 mmol) in
CH2Cl2 (10 mL) at ꢁ78 ꢀC, followed by (F3CSO2)2O (1.59 g,
5.9 mmol). The mixture was stirred for 5 h. Washing (water, aq HCl,
aq NaHCO3), drying, evaporation and chromatography (hexane/
EtOAc 10:1) gave 40 (1.07 g, 63%) as a colourless oil: IR nmax 2907,
1689, 1663, 1419 cmꢁ1 1H NMR 1.49 (9H, s, But), 1.95 (2H, qn,
; d
J¼7.7 Hz, 4-H2), 2.59–2.73 (4H, m, 3,5-H4); 13C NMR
d 19.0, 28.2,
4.26. Ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-
pentanoate (33)
29.8, 33.3, 82.5, 121.0 (q, J¼251 Hz CF3), 124.9, 156.2, 166.8; 19F NMR
(CDCl3)
d
ꢁ74.34 (s); MS m/z 317.0670 (MþH) (C11H16F3O5S requires
317.0670), 339.0481 (MþNa) (C11H15F3NaO5S requires 339.0489).
Rh(PPh3)3Cl (72 mg, 78 mmol) was stirred in CH2Cl2 (10 mL) for
5 min. 4,4,5,5-Tetramethyl-1,3,2-dioxaborane (499 mg, 3.9 mmol)
was added and the mixture was stirred for 5 min. Ethyl pent-4-
enoate 3222 (500 mg, 3.9 mmol) was added and the mixture was
stirred for 16 h. Washing (water), drying, evaporation and chro-
matography (CH2Cl2/CH2Cl2/EtOH 200:1) gave 33 (788 mg, 79%)
4.31. 1,1-Dimethylethoxycarbonyl 2-(5-methoxy-1-oxopent-
1-ynyl)cyclopentene-1-carboxylate (42)
Alkyne 35 (200 mg, 1.9 mmol) was heated at reflux under N2
with 40 (590 mg, 1.9 mmol), PdCl2 (16 mg, 90
mmol), Ph3P (49 mg,
as a colourless oil: 1H NMR
d
0.77 (2H, t, J¼7.8 Hz, 5-H2), 1.22 (12H,
190 mol), CuI (18 mg, 90 mol) and Et3N (283 mg, 2.8 mmol) in
m
m
s, dioxaborole-Me4), 1.23 (3H, t, J¼7.4 Hz, CH2CH3), 1.41–1.42 (2H,
m, 4-H2), 1.60–1.62 (2H, m, 3-H2), 2.27 (2H, t, J¼6.8 Hz, 2-H2), 4.09
THF (10 mL) for 2 h. Evaporation and chromatography (hexane/
EtOAc 7:3) gave 42 (110 mg, 23%) as a pale yellow oil: IR nmax 3423,
(2H, q, J¼7.4 Hz, OCH2); 13C NMR (HMQC, HMBC)
d
14.22 (CH2CH3),
2121, 1731 cmꢁ1; 1H NMR
d
1.48 (9H, s, But), 1.84 (2H, qn, J¼7.4 Hz,
23.61 (CH2), 24.66 (4ꢂMe), 24.78 (4-C), 27.56 (3-C), 34.21 (2-C),
60.11 (OCH2), 82.94 (2ꢂCMe2), 173.87 (C]O). This material was
used without further purification or characterisation.
4-H2), 2.55 (2H, d, J¼6.8 Hz, pentenyl 3-H2 or 4-H2), 2.61 (4H, dd,
J¼6.9, 1.4 Hz, 3,5-H4), 2.74 (2H, t, J¼6.9 Hz, pentenyl 4-H2 or 3-H2),
3.69 (3H, s, OMe); 13C NMR
d 15.95, 22.07, 28.29, 33.28, 33.38, 39.72,
51.92, 80.48, 127.69, 130.00, 133.47, 135.20, 172.34; MS m/z 301.1406
(MþNa) (C16H22O4Na requires 301.1415), 279.1568 (MþH)
(C16H23O4 requires 279.1596).
4.27. Methyl pent-4-ynoate (35)
Pent-4-ynoic acid 34 (500 mg, 5.0 mmol) was boiled under
reflux with TsOH$H2O (95 mg, 500
mmol) in MeOH (2.0 mL) and
4.32. N-(2-(5-Methoxy-1-oxopent-1-ynyl)cyclopentene-1-
CH2Cl2 (4.0 mL) for 24 h. Satd aq NH4Cl (2 mL) was added and the
mixture was extracted with Et2O (4ꢂ15 mL). Drying and careful
evaporation gave 35 (370 mg, 66%) as a pale yellow liquid (lit.26 bp
carbonyl)-L-phenylalanine N-(4-nitrophenyl)amide (44)
The diester 42 (110 mg, 0.4 mmol) was treated with CF3CO2H
and CH2Cl2, as for the synthesis of 6 (Method A), to give 43 (30 mg,
143–144 ꢀC): IR nmax 2121, 1735 cmꢁ1 1H NMR
; d 1.96 (1H, t,
J¼2.2 Hz, 5-H), 2.47–2.54 (4H, m, 2,3-H4), 3.68 (3H, s, Me); 13C NMR
33%) as a pale yellow oil: 1H NMR
2.60–2.62 (2H, m, pentynyl 3-H2 or 4-H2), 2.65–2.79 (6H, m, 3,5-H4
d
1.90 (2H, t, J¼7.7 Hz, 4-H2),
d
14.40, 33.20, 51.90, 69.08, 82.51, 172.31; MS m/z 111.0456 (MþH)
(C6H7O2 requires 111.0446).
and pentynyl 4-H2 or 3-H2), 3.60 (3H, s, OMe). Compound 43
(30 mg, 140
synthesis of 29, to give 44 (15.8 mg, 23%) as a colourless oil: IR nmax
3423, 2121, 1726, 1632, 1560 cmꢁ1; 1H NMR
mmol) was treated with 22, PyBOP and Et3N, as for the
4.28. Bis(1,1-dimethylethyl) hexanedicarboxylate (38)
d
1.87 (2H, qn, J¼7.4 Hz,
Hexanedioyl dichloride 37 (11.39 g, 62 mmol) in Et2O (50 mL)
was added dropwise to ButOH (14.2 g, 192 mmol) and PhNMe2
(22.5 g, 186 mmol) and the mixture was stirred for 16 h before
being diluted with water. The organic phase was washed with aq
cyclopentene 4-H2), 2.56 (2H, t, J¼6.8 Hz, pentynyl 3-H2 or 4-H2),
2.62–2.70 (6H, m, cyclopentene 3,5-H4 and pentynyl 4-H2 or 3-H2),
3.18–3.32 (2H, m, Phe
b
-H2), 3.69 (3H, s, OMe), 4.96 (1H, q, J¼6.8 Hz,
Phe
a
-H), 7.22–7.27 (5H, m, Ph-H5), 7.61 (2H, d, J¼9.1 Hz, Ar 2,6-H2),

8184
A. Beauchard et al. / Tetrahedron 65 (2009) 8176–8184
8.14 (2H, d, J¼9.1 Hz, Ar 3,5-H2), 9.13 (1H, s, NH); 13C NMR
d
15.71,
7.23–7.31 (5H, m, Ph-H5), 7.60 (2H, d, J¼9.0 Hz, Ar 2,6-H2), 8.12 (2H,
21.66, 32.57, 33.57, 37.50, 39.76, 52.12, 56.04, 100.00 (pentynyl 1-C
or 2-C), 101.76 (pentynyl 2-C or 1-C), 119.36, 119.97, 124.47, 125.01,
127.19, 128.82, 129.17, 129.39, 140.60, 143.75, 161.34 (C]O), 169.84
(C]O), 171.82 (C]O); MS m/z 512.1749 (MþNa) (C27H27N3NaO6
requires 512.1797).
d, J¼9.0 Hz, Ar 3,5-H2); 13C NMR (HMQC/HMBC)
d 21.34 (pentenyl
4-C), 28.30 (cyclopentene 3-C or 4-C or 5-C), 33.26 (cyclopentene 3-
C or 4-C or 5-C), 33.90 (cyclopentene 3-C or 4-C or 5-C), 34.15
(pentenyl 3-C), 37.00 (Phe b-C), 51.67 (Me), 55.32 (Phe a-C), 119.28
(Ar 2,6-C2), 124.88 (Ar 3,5-C2), 126.05 (pentenyl 1-jC), 127.25 (Ph 4-
C), 128.26 (Cq), 128.90 (Ph-C), 129.18 (Ph), 136.06 (cyclopentene 2-
C), 136.45 (pentenyl 2-C), 143.70 (Cq), 143.42 (Ar 3,5-C2 or 2,6-C2),
143.62 (Ar 2,6-C2 or 3,5-C2), 167.34 (C]O), 169.97 (C]O), 173.14
(C]O); MS m/z 492.2085 (MþH) (C27H30N3O6 requires 492.2134).
4.33. 1,1-Dimethylethyl E-2-(5-methoxy-1-oxopent-
1-enyl)cyclopentene-1-carboxylate (45)
Methyl pent-4-ynoate 35 (280 mg, 2.5 mmol) was heated at
85 ꢀC with Bu3SnH (870 mg, 3.0 mmol) and AIBN (41 mg, 250
mmol)
in PhMe (10 mL) for 1 h. Evaporation and chromatography (hexane/
EtOAc 3:2) gave 36 (380 mg, 40%) as a pale yellow oil: IR nmax
1743 cmꢁ1. The triflate 40 (540 mg, 1.7 mmol) and 36 (820 mg,
Acknowledgements
We thank Dr. Timothy J. Woodman (University of Bath) for some
of the NMR spectra and Dr. Anneke Lubben (University of Bath) for
the mass spectra. We are grateful to Cancer Research UK for a pro-
ject grant in support of this work.
2.0 mmol) were stirred with Ph3P (62 mg, 240
(27 mg, 120
mol) in dry THF (10 mL) at 55 ꢀC under N2 for 1 h.
Evaporation and chromatography (hexane/EtOAc 9:1) gave 45
mmol) and Pd(OAc)2
m
(400 mg, 84%) as a colourless oil: IR nmax 1737 cmꢁ1; 1H NMR
d 1.49
(9H, s, But), 1.80 (2H, qn, J¼7.4 Hz, 4-H2), 2.45 (2H, t, J¼5.8 Hz,
pentenyl 4-H2), 2.47 (2H, q, J¼5.8 Hz, pentenyl 3-H2), 2.60–2.62
(4H, m, 3,5-H2), 3.66 (3H, s, Me), 5.88 (1H, td, J¼6.0, 15.6 Hz, pen-
tenyl 2-H), 7.26 (1H, d, J¼16.4 Hz, pentenyl 1-H); 13C NMR (HMQC/
References and notes
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d 21.14 (4-C), 28.28 (C(CH3)3), 28.39 (pentenyl 3-C), 33.46
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80.08 (C(CH3)3),126.58 (pentenyl 1-C),130.02 (Cq),135.26 (pentenyl
2-C), 150.21 (Cq), 165.47 (C]O), 173.30 (C]O). This compound was
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4.34. E-2-(5-Methoxy-1-oxopent-1-enyl)cyclopentene-
1-carboxylic acid (46)
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The diester 45 (400 mg, 1.4 mmol) was treated with CF3CO2H
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72%) as a pale yellow oil: IR nmax 2946, 1728 cmꢁ1 1H NMR
; d 1.85
(2H, qn, J¼7.4 Hz, 4-H), 2.46 (2H, t, J¼5.8 Hz, pentenyl 3-H2), 2.51
(2H, q, J¼5.8 Hz, pentenyl 4-H2), 2.67–2.69 (4H, m, 3,5-H2), 3.66
(3H, s, Me), 5.99 (1H, td, J¼6.3, 16.0 Hz, pentenyl 2-H), 7.30 (1H, d,
13. Selle`s, P.; Mueller, U. Org. Lett. 2004, 6, 277–279.
J¼16.0 Hz, pentenyl 1-H); 13C NMR
d 13.69, 18.87, 21.31, 27.11, 28.47,
33.47, 34.66, 51.79, 126.59, 137.23, 171.08, 173.38. This compound
was used immediately without further characterisation.
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4.35. N-(2-(5-E-Methoxy-1-oxopent-1-enyl)cyclopentene-1-
carbonyl)-L-phenylalanine N-(4-nitrophenyl)amide (47)
18. Li, H.; Yang, H.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2004, 69, 4500–4508.
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Compound 46 (230 mg, 1.0 mmol) was treated with 22, PyBOP
and Et3N, as for the synthesis of 29, to give 47 (210 mg, 42%) as
a pale yellow powder: mp 74–75 ꢀC; IR nmax 3434, 1737, 1619, 1563,
1511, 1342 cmꢁ1
;
1H NMR
d
1.83–1.90 (2H, m, cyclopentene 3-H2),
2.36–2.46 (6H, m, pentene 3-H2 and cyclopentene 3,5-H4), 2.61 (2H,
t, J¼7.0 Hz, pentenyl 4-H2), 3.16 (1H, dd, J¼14.0, 7.8 Hz, Phe -H),
3.25 (1H, dd, J¼14.0, 6.6 Hz, Phe -H), 3.65 (3H, s, Me), 4.93 (1H, q,
J¼7.0 Hz, Phe -H), 5.89 (1H, td, J¼6.6, 16.0 Hz, pentenyl 2-H), 6.09
(1H, d, J¼7.4 Hz, Phe -NH), 7.20 (1H, d, J¼16.0 Hz, pentenyl 1-H),
24. Lorberth, J. J. Organomet. Chem. 1969, 16, 327–331.
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29. Henderson, D.; Richardson, K. A.; Taylor, R. J. K.; Saunders, J. Synthesis 1983,
996–997.
b
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