Asymmetric synthesis of the stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylate

Article abstract of DOI:10.1039/b313386a

The stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylate may be prepared stereoselectively from diester derivatives of (E,E)-octa-2,6-diendioc acid, with the key step utilising the conjugate addition of homochiral lithium N-benzyl-N-α-methy

Full text of DOI:10.1039/b313386a

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Asymmetric synthesis of the stereoisomers of
2-amino-5-carboxymethyl-cyclopentane-1-carboxylate
Julio G. Urones,a Narciso M. Garrido,*a David Díez,a Mohamed M. El Hammoumi,a
Sara H. Dominguez,a J. Antonio Casaseca,a Stephen G. Daviesb and Andrew D. Smithb
a Departamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1-5,
37008, Salamanca, Spain. E-mail: nmg@usal.es
b The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY. E-mail: steve.davies@chem.ox.ac.uk
Received 24th October 2003, Accepted 26th November 2003
First published as an Advance Article on the web 5th January 2004
The stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylate may be prepared stereoselectively
from diester derivatives of (E,E)-octa-2,6-diendioc acid, with the key step utilising the conjugate addition of
homochiral lithium N-benzyl-N-α-methylbenzylamide. The trans-C(1)–C(2)-stereoisomers are readily prepared
via a diastereoselective tandem conjugate addition cyclisation protocol with lithium (R)-N-benzyl-N-α-methyl-
benzylamide, with subsequent hydrogenolysis and ester hydrolysis giving the (1R,2R,5R)- and (1R,2R,5S)-β-amino
diacids in good yields. The preparation of the cis-C(1)–C(2)-stereoisomers utilises a protocol involving N-oxidation
and Cope elimination of the major diastereoisomeric product arising from conjugate addition and cyclisation,
giving homochiral (R)-5-carboxymethyl-cyclopentene-1-carboxylate. Conjugate addition of either lithium (R)- or
(S)-N-benzyl-N-α-methylbenzylamide to (R)-5-carboxymethyl-cyclopentene-1-carboxylate, and diastereoselective
protonation with 2,6-di-tert-butyl phenol gives, after hydrogenolysis and ester hydrolysis, the (1S,2R,5R)- and
(1R,2S,5R)-β-amino diacids in good yield. The use of (S)-N-benzyl-N-α-methylbenzylamide in the initial
conjugate addition and cyclisation reaction, and subsequent repetition of the elimination and conjugate
addition strategy allows stereoselective access to all stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-
1-carboxylate.
Introduction
The asymmetric synthesis of polyfunctionalised cyclopentane
derivatives has been widely pursued in organic synthesis, pre-
dominantly due to their incorporation in a variety of natural
products including monoterpenes,1 nepetalactones2 and pros-
taglandins.3 A range of methodologies for the asymmetric syn-
thesis of cyclopentane derived β-amino acids has been devised,
with much recent interest focusing around strategies for the
asymmetric synthesis of the cis- and trans-diastereoisomers
of 2-aminocylopentanecarboxylic acid (cispentacin 1 and
transpentacin 2 respectively). The cis-diastereoisomer shows
potent antifungal activity4 while Fulop et al. have recently
demonstrated that oligomers of cispentacin adopt a sheet type
structure in DMSO.5 Furthermore, Gellman et al. have demon-
strated that short chain β-peptides derived from transpentacin
adopt 12-membered helical stuctures in both the solid state and
in solution,6 while 3-substituted transpentacin derivatives fold
in water, which should facilitate the design of β-peptides for
biological applications (Fig. 1).7
We have previously employed the highly diastereoselective
Fig. 1 Monomeric and oligomeric cispentacin and transpentacin.
conjugate addition of homochiral lithium amides to
α,β-unsaturated esters for the asymmetric synthesis of an
extensive range of β-amino acid derivatives,8 as illustrated in
Scheme 1 for the synthesis of (1R,2S)-cispentacin 1 and
(1S,2S)-transpentacin 2.9 Conjugate addition of homochiral
lithium (S)-N-benzyl-N-α-methylbenzylamide 6 to tert-butyl
cyclopentene-1-carboxylate 3 and subsequent N-deprotection
and ester hydrolysis gives (1R,2S)-cispentacin 1, while selective
epimerisation of β-amino ester (1R,2S,αS)-4 to the thermo-
dynamic epimer (1S,2S,αS)-5 and further deprotection gives
(1S,2S)-transpentacin 2.
stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-
carboxylate was investigated. Yamamoto et al. have previously
demonstrated that the addition of achiral lithium N-benzyl-N-
trimethylsilylamide to dimethyl (E,E)-octa-2,6-diendioate
facilitates tandem conjugate addition and intramolecular cyclis-
ation, generating the (1RS,2RS,5RS)-2-amino-5-carboxy-
methyl-cyclopentane-1-carboxylate skeleton.10 It was predicted
that the use of homochiral (R)- or (S)-lithium N-benzyl-N-α-
methylbenzylamide in this protocol, coupled with further
synthetic elaboration would give rise to the diastereo- and
enantiocontrolled construction of the steroisomers of 2-amino-
5-carboxymethyl-cyclopentane-1-carboxylate. The realisation
of this synthetic strategy is contained herein, part of which has
been communicated previously.11
To extend the generality of this methodology, and expand the
diversity of both cis- and transpentacin derivatives available for
secondary structural studies, the asymmetric synthesis of the
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 6 4 – 3 7 2
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with the absolute configuration at C(2) within (1R,2R,5R,αR)-8
and (1R,2R,5S,αR)-9 relative to the N-α-methylbenzyl stereo-
centre assigned by analogy with previous authenticated models
developed to explain the stereoselectivity observed during addi-
tion of lithium amide 6 to α,β-unsaturated acceptors.13 For
instance, the major diastereoisomer (1R,2R,5R,αR)-8 arising
from cyclisation of dimethyl (E,E)-7 showed a 4% NOE
enhancement between C(1)H and one of the C(5)CH2CO2Me
protons, a 9% NOE enhancement between C(1)H and one of
the NCH2Ph protons and a 5% enhancement between C(2)H
and C(5)H, indicating the anti-configuration between both
C(1)H and C(2)H, and C(1)H and C(5)H. For the minor
diastereoisomer (1R,2R,5S,αR)-9, 1H NMR ROESY experi-
ments indicated a syn-relationship between C(1)H and C(5)H,
and the anti-relationship between C(1)H and C(2)H (Fig. 2).
Scheme 1 Reagents and conditions: (i). Lithium (S)-N-benzyl-N-α-
methylbenzylamide 6, THF, Ϫ95 ЊC then 2,6-di-tert-butyl phenol;
(ii). KOtBu, tBuOH, rt; (iii). Pd/C, MeOH, H2 (5 atm), rt; (iv). TFA then
Dowex 50X8-200.
Results and discussion
Asymmetric tandem conjugate addition cyclisation; synthesis of
the trans-C(1)–C(2) stereoisomers
Initial studies concentrated upon studying the product distri-
bution arising from the conjugate addition of lithium (R)-N-
benzyl-N-α-methylbenzylamide 6 to a range of diester deriv-
atives of (E,E)-octa-2,6-diendioic acid. Conjugate addition of
lithium amide (R)-6 to dimethyl (E,E)-octa-2,6-diendioate 7 in
THF at Ϫ78 ЊC gave a 91 : 9 mixture of the two C(5)-epimeric
diastereoisomers (1R,2R,5R,αR)-8 and (1R,2R,5S,αR)-9.
Chromatographic purification enabled separation and charac-
terisation of the two β-amino ester diastereoisomers 8 and 9, in
86% overall yield, with none of the diamino ester product aris-
ing from double conjugate addition of lithium amide to (E,E)-7
visible by spectroscopic analysis of the crude reaction mixture.12
The generality of this protocol was explored further, via the
conjugate addition of lithium amide (R)-6 to either the di-3-
pentyl or di-tert-butyl ester derivatives 10 and 13, which fur-
nished a 92 : 8 and a 93 : 7 mixture of the separable C(5)
epimeric diastereoisomers 11 : 12 and 14 : 15 respectively in
good yields (83% and 90% yield overall) after chromatographic
purification (Scheme 2).
Fig.
2
1H NMR stereochemical analysis of major and minor
diastereoisomers 8 and 9.
This indicates that both diastereoisomers have identical
configurations at C(1) and C(2), but differ at C(5), consistent
with the expected high levels of stereocontrol in the initial
lithium amide conjugate addition reaction, with the mixture
of diastereoisomers arising upon cyclisation of the resultant
(Z)-β-amino enolate.14 The relative configuration within the
major diastereoisomer (1R,2R,5R,αR)-8 was further confirmed
unambiguously by X-ray crystallographic analysis, with the
absolute configuration arising from the known (R)-stereocentre
of the α-methylbenzylamine derived fragment (Fig. 3).
Fig. 3 Chem 3D representation of the X-ray crystal structure of
(1R,2R,5R,αR)-8 (some H omitted for clarity).
Scheme 2 Reagents and conditions: (i). Lithium (R)-N-benzyl-N-α-
methylbenzylamide 6, THF, Ϫ78 ЊC.
With a range of C(1)–C(2)-trans β-amino ester diastereo-
isomers in hand from this addition cyclisation protocol, the
di-tert-butyl ester derivatives (1R,2R,5R,αR)-14 and (1R,2R,
5S,αR)-15 were deprotected to their parent β-amino diacids.
In each case, the relative configuration within both the major
and minor diastereoisomers was assigned on the basis of either
1
1H NMR NOE difference or H NMR ROESY experiments,
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Hydrogenolysis of β-amino esters 14 and 15 to the corre-
sponding primary β-amino esters, a process we have previously
demonstrated occurs without loss of stereochemical integrity,15
furnished (1R,2R,5R)-16 and (1R,2R,5S)-17 in 83% and 74%
yield respectively, and in >98% de in each case. Subsequent
ester hydrolysis and purification by ion exchange chromato-
graphy gave the β-amino diacids (1R,2R,5R)-18 {[α]2D6 ϩ2.4
(c 1.0, H2O)} and (1R,2R,5S)-19 {[α]2D6 Ϫ35.0 (c 0.6, H2O)}
in quantitative yield and in >98% de in each case. With
(1R,2R,5R)-18 and (1R,2R,5S)-19 in hand, the preparation of
the enantiomeric β-amino diacids was investigated. Addition of
lithium (S)-N-benzyl-N-α-methylbenzylamide to the diester
13 and subsequent manipulation furnished β-amino diacids
(1S,2S,5S)-18 {[α]2D6 Ϫ 2.7 (c 0.6, H2O)} and (1S,2S,5R)-19
{[α]2D6 ϩ44.7 (c 1.0, H2O)]} in good yield, enantiomeric, respect-
ively, with (1R,2R,5R)-18 and (1R,2R,5S)-19 (Scheme 3).
right, having previously been synthesised in both racemic and
enantiomerically enriched form and used as building blocks for
the synthesis of a range of monoterpenes such as dolichodial
and mitsugashiwalactone.17 It was envisaged that the desired
acceptor would be readily available by N-oxidation and Cope
elimination18 of the trans-C(1)–C(2) diastereoisomeric prod-
ucts arising from tandem conjugate addition and cyclisation
protocol (Fig. 4).19
Fig. 4 Proposed route to cis-C(1)–C(2) stereoisomeric products.
In this fashion, treatment of dimethyl β-amino ester (1R,2R,
5R,αR)-8 with m-CPBA in DCM gave, after chromatographic
purification, the nitrone 21 in 59% yield {[α]2D6 Ϫ45.5 (c 1.19,
CHCl3), lit.,20 [α]2D0 Ϫ48.2 (c 1.0, CHCl3)} and (1E,5R)-5-carb-
oxymethyl-cyclopentene carboxylate 2021 in 85% yield and in
>95% de. The ee of (1E,5R)-20 was determined as >95% by
reduction to the diol (1E,5R)-24 {[α]2D6 ϩ11.3 (c 0.6, MeOH);
lit.17 [α]3D0 ϩ9.2 (c 0.68, MeOH)} and subsequent derivatisation
as the bis-Mosher’s ester and comparison of the resulting
spectra with an authentic racemic sample. In a similar fashion,
treatment of β-amino esters (1R,2R,5R,αR)-11 and (1R,2R,
5R,αR)-14 with m-CPBA gave the α,β-unsaturated acceptors 22
and 23 in 71% and 65% yield respectively, and in >95% de in
each case (Scheme 4).
Scheme 3 Reagents and conditions: (i). Pd/C, MeOH, H2 (6 atm),
rt; (ii). TFA, rt then Dowex 50 × 8–200.
Asymmetric synthesis of the C(1)–C(2)-cis diastereoisomers
With the asymmetric synthesis of the four C(1)–C(2)-trans
2-amino-5-carboxymethyl-cyclopentane-1-carboxylate stereo-
isomers complete, attention turned to the preparation of the set
of stereoisomers with the cis-C(1)–C(2) configuration. Previous
work from our laboratory has shown that conjugate addition of
lithium amides to cyclic α-alkyl-α,β-unsaturated acceptors and
subsequent diastereoselective protonation with the hindered
proton source 2,6-di-tert-butyl phenol gives rise to the cis-C(1)–
C(2) configuration with high levels of selectivity.16 It was
predicted that this methodology could be used to generate the
cis-C(1)–C(2) configuration of the desired 2-amino-5-carb-
oxymethyl-cyclopentane-1-carboxylate stereoisomers, through
the conjugate addition of a chiral lithium amide to a homo-
chiral 5-carboxyalkyl cyclopentene-1-carboxylate. Such chiral
α,β-unsaturated acceptors are highly desirable in their own
Scheme
4
Reagents and conditions: (i). m-CPBA, CHCl3, 0 ЊC;
(ii). LiAlH4, THF, rt.
Having demonstrated the generality of this N-oxidation and
elimination strategy, addition of lithium amides (S)- and (R)-6
to 23 was investigated. Conjugate addition of lithium amide
(S)-6 to 23 proceeded to generate a single diastereoisomeric
product (1R,2S,5R,αS)-25, isolated in 68% yield after chrom-
atographic purification. Conjugate addition of lithium amide
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(R)-6 under identical conditions furnished a 75 : 25 mixture of
the separable C(1) epimeric diastereoisomers (1S,2R,5R,αR)-26
and (1R,2R,5R,αR)-14, isolated in 62% overall yield (Scheme 5).
The minor diastereoisomer from the addition of lithium amide
(R)-6 in this protocol exhibited identical spectroscopic proper-
ties to the major diastereoisomer arising from the conjugate
addition cyclisation protocol, while the relative configuration
within β-amino esters (1R,2S,5R,αS)-25 and (1S,2R,5R,αR)-26
was proven by 1H NMR experiments. In all cases, the absolute
configuration at C(2) relative to the N-α-methylbenzyl stereo-
centre was assigned by analogy with the previous models
developed to explain the observed stereoselectivity of lithium
amide 6, consistent with the reactions proceeding under the
predominant stereocontrol of the chiral lithium amide, not the
chiral acceptor 23.
Scheme 6 Reagents and conditions: (i). Pd/C, MeOH, H2 (6 atm),
Scheme 5 Reagents and conditions: (i). Lithium (S)-N-benzyl-N-α-
methylbenzylamide 6, THF, Ϫ78 ЊC then 2,6-di-tert-butyl phenol,
Ϫ78 ЊC to rt; (ii). Lithium (R)-N-benzyl-N-α-methylbenzylamide 6,
THF, Ϫ78 ЊC then 2,6-di-tert-butyl phenol, Ϫ78 ЊC to rt.
rt; (ii). TFA, rt then Dowex 50 × 8–200.
pentane and cyclohexane derived β-amino acids is currently
under investigation in our laboratory.
With C(1)–C(2)-cis β-amino esters (1R,2S,5R,αS)-25 and
(1S,2R,5R,αR)-26 in hand, deprotection to the corresponding
β-amino diacids was followed. Hydrogenolysis with Pd/C gave
the primary β-amino esters 27 and 28 in 77% and 71% yield and
in >95% de in each case, with ester hydrolysis and ion exchange
chromatography giving (1S,2R,5R)-29 {[α]2D6 ϩ15.2 (c 0.3, 5.5 M
NH3(aq.)} and (1R,2S,5R)-30 {[α]2D6 ϩ24.6 (c 1.93, H2O)} in
>95% de. Repetition of this series of reactions in the enantio-
meric series gave (1R,2S,5S)-29 {[α]2D6 Ϫ31.9 (c 1.09, 5.5 M
NH3(aq.)} and (1S,2R,5S)-30 {[α]2D6 Ϫ 25.1 (c 0.57, H2O)}
(Scheme 6).
Experimental
General
1H NMR spectra were recorded in CDCl3 at 200 and 400 MHz
on Varian 200 VX and BRUKER DRX 400 instruments,
respectively. 13C NMR spectra were recorded in CDCl3 at 50
and 100 MHz on Varian 200 VX and BRUKER DRX 400
instruments, respectively in the deuterated solvent stated, and
multiplicities were determined by DEPT experiments. IR
spectra were registered using a BOMEM 100 FT IR spectro-
photometer. Optical rotations were determined using a Perkin-
Elmer 241 polarimeter in a 1 dm cell and are given in units of
10Ϫ1 deg cm2 gϪ1. Concentrations are quoted in g per 100 ml.
The electron impact (EI) mass spectra were run on a VG-TS 250
spectrometer at 70 eV ionising voltage. HRMS were recorded
using a VG Platform (Fisons) spectrometer using Chemical
Ionisation (ammonia as gas) or Fast Atom Bombardment
(FAB) techniques. Thin layer chromatography (TLC) was per-
formed on aluminium sheets coated with 60 F254 silica. Sheets
were visualised using iodine, UV light or 1% aqueous KMnO4
solution. Column chromatography was performed with Merck
silica gel 60 (70–230 mesh). Solvents and reagents were gener-
ally distilled prior to use: THF from sodium benzophenone
ketyl and dichloromethane from KOH.
Conclusions
In conclusion, the asymmetric synthesis of the eight
stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-
carboxylate has been achieved. The set of trans-C(1)–C(2)-
stereoisomeric β-amino diacids are readily prepared via a
diastereoselective tandem conjugate addition cyclisation
protocol with either lithium (R)- or (S)-N-benzyl-N-α-methyl-
benzylamide, hydrogenolysis and ester hydrolysis. The array of
cis-C(1)–C(2)-stereoisomeric β-amino diacids utilises a proto-
col involving N-oxidation and Cope elimination of the major
diastereoisomeric product arising from conjugate addition and
cyclisation, giving homochiral (R)- or (S)-5-carboxymethyl-
cyclopentene-1-carboxylate derivatives. Conjugate addition of
either lithium (R)- or (S)-N-benzyl-N-α-methylbenzylamide
and diastereoselective protonation with 2,6-di-tert-butyl
phenol, hydrogenolysis and ester hydrolysis, gives the cis-C(1)–
C(2)-stereoisomeric β-amino diacids. The extension of this
strategy for the preparation of a range of substituted cyclo-
General procedure 1
n-BuLi was added to a stirred solution of amine in THF at
Ϫ78 ЊC and was stirred for 30 minutes prior to the addition of
a solution of acceptor in THF at Ϫ78 ЊC. After two hours,
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saturated aqueous NH4Cl solution was added and the resultant
solution warmed to rt, partitioned between DCM (3 × 50 ml)
and brine, dried and concentrated in vacuo. Purification by
chromatography on silica gel gave the desired product.
procedures at room temperature. The structure was solved by
direct methods, all non-hydrogen atoms were refined with
anisotropic thermal parameters. The structure was refined
using SHELTL.22 Crystal data for 8 [C25H31NO4], colourless
block, M = 409.51, orthorhombic, space group P 21 21 21,
a = 18.0640(10) Å, b = 13.9610(10) Å, c = 9.1430(10) Å,
U = 2305.8(3) Å3, Z = 4, µ = 0.6343 mmϪ1, crystal dimensions
1.0 × 0.7 × 0.8 mm. A total of 2087 unique reflections were
measured for 4.00 < θ < 65.35 and 1934 reflections were used
in the refinement. The final parameters were wR2 = 0.1210
and R1 = 0.0457 [I > 2σ(I )]. Crystallographic data (excluding
structure factors) has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 220744. See http://www.rsc.org/suppdata/ob/
b3/b313386a/ for crystallographic data in.cif or other electronic
format.
General procedure 2
m-CPBA was added to a stirred solution of the β-amino diester
in DCM at 0 ЊC and was stirred for 24 hours before the addition
of 5 ml saturated Na2S2O3 solution. The resultant solution was
partitioned between DCM (3 × 25 ml) and water, dried and
concentrated in vacuo. Purification by chromatography on silica
gel gave the desired product.
General procedure 3
Pd/C (10% by mass) was added to a solution of β-amino ester in
AcOH (12 ml) and under hydrogen (5 atm) and was stirred at rt
overnight. After filtration through Celite (eluent DCM), the
resultant solution was concentrated in vacuo, dissolved in DCM
(3 × 50 ml) and washed with 10% NaHCO3 (aq.) solution, dried
and concentrated in vacuo. Purification by chromatography on
silica gel gave the desired product.
Preparation of di-3-pentyl (1R,2R,5R,ꢀR)- and (1R,2R,5S,
ꢀR)-2-N-benzyl-N-ꢀ-methylbenzylamino-5-carboxymethyl-cyclo-
pentane-1-carboxylate 11 and 12 respectively. Following general
procedure 1, 10 (631 mg, 2.03 mmol) in THF (3 ml), (R)-N-
benzyl-N-α-methylbenzylamine (973 mg, 4.61 mmol) in THF
(11 ml) and n-BuLi (1.6 M, 2.87 ml, 4.59 mmol) gave, after
chromatographic purification on silica (hexane–Et2O 49 : 1),
(1R,2R,5R,αR)-11 (816 mg, 77%); [α]2D6 Ϫ30.1 (c 1.55, CHCl3);
νmax 2969, 1728, 1454, 1170, 974, 698; δH (400 MHz, CDCl3)
0.78 (3H, t, J = 7.5, CH(CH2CH3)2), 0.83 (6H, t, J = 7.5,
CH(CH2CH3)2), 0.94 (3H, t, J = 7.5, CH(CH2CH3)2), 1.28 (3H,
d, J = 6.8, C(α)Me), 1.40–1.72, 1.75–1.85, 1.91–2.01 (9H, m;
2H, m and 1H, m, 2 × CH(CH2CH3)2, C(3)H2 and C(4)H2),
2.17 (1H, dd, J = 14.8, 9.6, CHAHCO2Me), 2.39 (1H, m, H-5),
2.50 (1H, dd, J = 9.6, 3.6, CHBHCO2Me), 2.53 (1H, app t,
J = 10.0, H-1), 3.71 (1H, m, H-2), 3.75 (2H, ABm, NCH2Ph),
3.86 (1H, q, J = 6.8, C(α)H ), 4.58 (1H, quintet, J = 6.0,
CH(CH2CH3)2), 4.71 (1H, quintet, J = 6.0, CH(CH2CH3)2),
7.11–7.51 (10H, m, Ar–H ); δC (50 MHz, CDCl3) 9.4, 9.5, 15.5,
25.8, 26.4, 26.7, 31.0, 39.0, 39.1, 50.0, 55.3, 58.0, 63.7, 76.6,
126.5, 126.6, 127.6, 128.1, 128.5, 141.6, 144.3, 171.7, 174.3; m/z
(CIϩ) 525 (8), 524 (52) 522 ((M ϩ H)ϩ, 100), 510 (4), 508 (16),
419 82), 418 (10); HRMS (CIϩ) C33H48O4N requires 522.3583;
found 522.3582. Further elution gave (1R,2R,5S,αR)-12
(64 mg, 6%); [α]2D6 Ϫ16.4 (c 0.87, CHCl3); νmax 2969, 1728, 1454,
1170, 957, 700; δH (400 MHz, CDCl3) 0.83 (3H, t, J = 5.8,
CH(CH2CH3)2), 0.86 (6H, t, J = 6.0, CH(CH2CH3)2), 0.97 (3H,
t, J = 5.8, CH(CH2CH3)2), 1.33 (3H, d, J = 6.8, C(α)Me), 1.35–
1.70, 1.70–1.92 (10H, m and 2H, m, 2 × CH(CH2CH3)2, C(3)H2
and C(4)H2), 2.17 (1H, dd, J = 15.2, 6.7, CHAHCO2Me), 2.37
(1H, dd, J = 15.2, 7.3, CHBHCO2Me), 2.48–2.56 (1H, m, H-5),
2.95 (1H, dd, J = 9.1, 6.1, H-1), 3.66–3.72 (1H, m, H-2), 3.73
(1H, AB, JAB = 14.8, NCHA), 3.83 (1H, AB, JAB = 14.8, NCHB),
3.88 (1H, q, J = 6.8, C(α)H ), 4.66 (1H, quintet, J = 6.0,
CH(CH2CH3)2), 4.95 (1H, quintet, J = 6.0, CH(CH2CH3)2),
7.15–7.55 (10H, m, Ar–H ); δC (50 MHz, CDCl3) 9.3, 9.5, 17.4,
25.7, 25.8, 26.3, 28.8, 31.1, 36.2, 38.9, 50.4, 51.3, 59.1, 64.0,
76.6, 126.5, 127.6, 128.0, 128.1, 142.0, 144.6, 172.4, 174.1; m/z
(CIϩ) 525 (3), 524 (25), 522 ((M ϩ H)ϩ, 100), 432 (6); HRMS
(CIϩ) C33H48O4N requires 522.3571; found 522.3583.
General procedure 4
The β-amino diester was dissolved in TFA and stirred for
2 hours at rt before concentration in vacuo. HCl (1 M, 0.5 ml)
was added and the resultant solution concentrated in vacuo.
The residue was purified by ion exchange chromatography on
Dowex 50X8-200.
Preparation of dimethyl (1R,2R,5R,ꢀR)- and (1R,2R,5S,ꢀR)-
2-N-benzyl-N-ꢀ-methylbenzylamino-5-carboxymethyl-cyclo-
pentane-1-carboxylate 8 and 9 respectively. Following general
procedure 1, 7 (110 mg, 0.56 mmol) in THF (1 ml), (R)-N-
benzyl-N-α-methylbenzylamine (135 mg, 0.64 mmol) in THF
(11 ml) and n-BuLi (1.6 M, 0.37 ml, 0.58 mmol) gave, after
chromatographic purification on silica (hexane–Et2O 9 : 1),
(1R,2R,5R,αR)-8 (184 mg, 80%); [α]2D6 Ϫ 51.3 (c 0.97, CHCl3);
mp 82–84 ЊC (Et2O–hexane); νmax 2950, 1740, 1450; δH (400
MHz, C6D6) 1.02 (1H, m, H-4A), 1.08 (3H, d, J = 6.9, C(α)Me),
1.35–1.5 (2H, m, C(3)H2), 1.71 (1H, m, H-4B), 2.02 (1H, dd,
J = 12.6, 9.2, CHAHCO2Me), 2.25 (1H, dd, J = 12.6, 3.6, CHB-
HCO2Me), 2.40 (1H, m, H-5), 2. 45 (1H, app t, J = 10.1, H-1),
3.28 (3H, s, CO2Me), 3.29 (3H, s, CO2Me), 3.45 (1H, AB, JAB
=
12.6, NCHAHPh), 3.55 (1H, dt, J = 10.1, 5.0, H-2), 3.65 (1H, AB,
JAB = 12.6, NCHAHBPh), 3.81 (1H, q, J = 6.9, C(α)H ), 7.01–7.33
(8H, m, Ar–H ), 7.51–7.58 (2H, m, Ar–H ); δC (100 MHz, CDCl3)
14.1, 26.4, 30.9, 38.1, 38.8, 50.0, 51.4, 55.3, 56.7, 63.3, 126.5,
126.6, 127.0, 127.8, 127.9, 128.2, 128.5, 128.8, 141.1, 144.2, 172.4,
174.7; m/z (CIϩ) 409 (Mϩ, 3), 394 (10), 250 (35), 146 (55), 105
(84), 91 (100), 77 (23), 51 (10); HRMS (CIϩ) C25H32NO4 requires
410.2331; found 410.2335. Further elution gave (1R,2R,5S,αR)-9
(14 mg, 6%); [α]2D6 Ϫ 20.1 (c 2.05, CHCl3); νmax 2951, 1738, 1435,
710; δH (400 MHz, C6D6) 1.1 (3H, d, J = 7.0, C(α)Me), 1.25–
1.32 (1H, m, H-4A), 1.38–1.42 (1H, m, H-3A), 1.51–1.59 (1H, m,
H-3B), 1.63–1.69 (1H, m, H-4B), 2.11 (1H, dd, J = 15.2, 6.7,
CHAHCO2Me), 2.35 (1H, dd, J = 15.2, 7.3, CHBHCO2Me), 2.38–
2.45 (1H, m, H-5), 2.91 (1H, dd, J = 9.1, 5.9, H-1), 3.26 (3H, s,
CO2Me), 3.32 (3H, s, CO2Me), 3.51 (2H, ABq, NCH2Ph), 3.78
(1H, q, J = 7.0, C(α)H ), 3.82 (1H, ddd, J = 9.1, 7.9, 3.8, H-2),
7.02–7.45 (10, m, Ar–H ); δC (100 MHz, CDCl3) 16.7, 29.4, 31.0,
33.7, 38.5, 49.9, 50.5, 51.0, 51.3, 58.2, 63.4, 126.5, 126.7, 127.5,
127.8, 128.1, 128.8, 141.6, 144.2, 172.7, 174.5; m/z (CIϩ) 410
((M ϩ H)ϩ, 100), 307 (4), 306 (20); HRMS (CIϩ) C25H32NO4
requires 410.2331; found 410.2341.
Preparation of di-tert-butyl (1R,2R,5R,ꢀR)- and (1R,2R,
5S,ꢀR)-2-N-benzyl-N-ꢀ-methylbenzylamino-5-carboxymethyl-
cyclopentane-1-carboxylate 14 and 15 respectively. Following
general procedure 1, 13 (650 mg, 2.44 mmol) in THF (10 ml),
(R)-N-benzyl-N-α-methylbenzylamine (878 mg, 4.14 mmol) in
THF (5 ml) and n-BuLi (1.6 M, 2.44 ml, 3.90 mmol) gave, after
chromatographic purification on silica (hexane–Et2O 9 : 1),
(1R,2R,5R,αR)-14 (1.0 g, 83%); [α]2D6 Ϫ 33.2 (c 0.57, CHCl3);
νmax 2974, 1728, 1454, 1386, 1148, 874, 748, 698; δH (400 MHz,
CDCl3) 1.31 (3H, d, J = 6.8, C(α)Me), 1.38 (18H, s,
CO2C(CH3)3), 1.43–1.47 (1H, m, H-4A), 1.71–1.77 (2H, m,
C(3)H2), 1.90–1.95 (1H, m, H-4B), 2.03 (1H, dd, J = 14.7, 9.7,
X-Ray crystal structure data for 8
Data were collected using a Seifert 3003 SC diffractometer with
graphite monochromated Cu–Kα radiation using standard
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 6 4 – 3 7 2
368

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t
CHAHCO2 Bu), 2.19–2.25 (1H, m, H-5), 2.34 (1H, dd, J = 14.7,
(2H, m, C(4)H2), 1.91–1.96 (1H, m, H-3A), 2.06–2.14 (1H, m,
t
t
4.3, CHBHCO2 Bu), 2.35 (1H, dd, J = 9.9, 8.9, H-1), 3.59 (1H,
H-3B), 2.14 (1H, dd, J = 15.4, 9.7, CHAHCO2 Bu), 2.40 (1H, dd,
t
app q, J = 8.9, H-2), 3.67 (1H, AB, JAB = 14.6, NCHA), 3.79
(1H, AB, JAB = 14.6, NCHB), 3.86 (1H, q, J = 6.8, C(α)H ), 7.1–
7.5 (10H, Ar–H ); δC (50 MHz, CDCl3) 15.0, 26.3, 28.0, 28.2,
30.5, 39.0, 39.9, 49.9, 55.7, 57.5, 63.0, 80.0, 80.2, 126.4, 126.6,
127.8, 127.9, 128.0, 128.5, 141.6, 144.1, 171.6, 179.3; m/z (EIϩ)
493 (3), 388 (10), 332 (4), 250 (18), 217 (20), 153 (40), 105 (55),
77 (100); HRMS (EIϩ) C31H43O4N requires 493.3192; found
493.3151. Further elution gave (1R,2R,5S,αR)-15 (82mg, 7%);
[α]2D6 Ϫ21.5 (c 0.93, CHCl3); νmax 2974, 2932, 1728, 1454, 1368,
1148, 698; δH (400 MHz, CDCl3) 1.26 (3H, d, J = 6.8, C(α)Me),
1.37 (9H, s, CO2C(CH3)3), 1.40 (9H, s, CO2C(CH3)3), 1.59–1.67
(2H, m, H-3A, H-4A), 1.70–1.76 (1H, m, H-4B), 1.84–1.90 (1H,
J = 15.4, 3.6, CHAHCO2 Bu), 2.50 (1H, dd, J = 8.5, 5.6, H-1),
2.70–2.76 (1H, m, H-5), 3.52–3.57 (1H, m, H-2); δH (100 MHz,
CDCl3) 28.1, 28.2, 29.8, 35.0, 37.5, 37.7, 55.4, 57.9, 80.1, 80.5,
171.8, 172.9; m/z (EIϩ) 300 (Mϩ, 1), 242 (12), 186 (80), 170
(100), 126 (46), 96 (8), 82 (40); HRMS (EIϩ) C16H29O4N
requires 299.2097; found 299.2113.
Preparation of di-tert-butyl (1S,2S,5R)-2-amino-5-carb-
oxymethyl-cyclopentane-1-carboxylate 17. Following general
procedure 3, (1S,2S,5R,αS)-15 (130 mg, 0.26 mmol) in AcOH
(8 ml), Pd/C (10% by mass, 52 mg) and hydrogen (5 atm) at rt
gave after purification by column chromatography (CHCl3–
MeOH 95 : 5), (1S,2S,5R)-17 (59 mg, 76%); [α]2D6 ϩ28.9 (c 1.09,
CHCl3).
t
m, H-3B), 2.13 (1H, dd, J = 15.7, 8.4, CHAHCO2 Bu), 2.34 (1H,
dd, J = 15.7, 6.6, CHBHCO2 Bu), 2.38–2.44 (1H, m, H-5), 2.80–
t
2.84 (1H, dd, J = 8.9, 5.4, H-1), 3.70–3.74 (1H, td, J = 8.9,
3.8, H-2), 3.77 (1H, AB, JAB = 14.6, NCHAHPh), 3.80 (1H, d,
Preparation of (1R,2R,5R)-2-amino-5-carboxymethyl-cyclo-
pentane-1-carboxylate 18. Following general procedure 4,
(1R,2R,5R)-16 (58 mg, 0.19 mmol) and TFA (1 ml) gave, after
ion exchange chromatography (Dowex 50X8-200), (1R,2R,5R)-
18 (36 mg, quant.); [α]2D6 ϩ2.4 (c 1, H2O); C8H13NO4 requires C,
51.33; H, 7.00; N, 7.48; found: C, 51.08; H, 6.99; N, 8.21;
νmax 3600–2500 (br), 2974, 1719, 1406, 1235, 665; δH (200 MHz,
D2O) 1.36–1.44 (1H, m, H-4A), 1.52–1.58 (1H, m, H-4B), 1.80–
2.10 (2H, m, C(3)H2), 2.25–2.60 (4H, m, H-1, H-5 and
CH2CO2H), 3.75 (1H, q, J = 7.8, H-2); δH (50 MHz, D2O) 31.6,
31.8, 41.1, 41.8, 56.4, 57.1, 178.5, 179.2; m/z (EIϩ) 188 (Mϩ, 48),
115 (28), 93 (100), 75(28); HRMS (EIϩ) C8H14O4N 188.0923;
found 188.0935.
JAB = 14.6, NCH HPh), 3.86 (1H, q, J = 6.8, C(α)H ), 7.10–7.60
B
(10H, Ar–H ); δC (100 MHz, CDCl3) 17.8, 28.1, 29.2, 30.9, 37.2,
39.2, 50.4, 51.2, 59.1, 64.0, 80.1, 126.5, 127.6, 128.0, 142.1,
144.8, 171.9, 173.9; m/z (EIϩ) 493 (Mϩ,2), 388 (10), 338 (9), 250
(18), 153 (25), 105 (100), 77 (94); HRMS (EIϩ) C31H43O4N
requires 493.3192, found 493.3226.
Preparation of di-tert-butyl (1S,2S,5S,ꢀS )- and (1S,2S,
5R,ꢀS )-2-N-benzyl-N-ꢀ-methylbenzylamino-5-carboxymethyl-
cyclopentane-1-carboxylate 14 and 15 respectively. Following
general procedure 1, 13 (590 mg, 2.1 mmol) in THF (3 ml),
(S)-N-benzyl-N-α-methylbenzylamine (973 mg, 4.6 mmol) in
THF (11 ml) and n-BuLi (1.6 M, 2.9 ml, 4.6 mmol) gave, after
chromatographic purification on silica (hexane–Et2O 9 : 1)
(1S,2S,5S,αS)-14 (878 g, 85%); [α]2D6 ϩ33.1 (c 0.54, CHCl3); fur-
ther elution gave (1S,2S,5R,αS)-15 (41 mg, 4%); [α]2D6 ϩ24.5
(c 0.73, CHCl3).
Preparation of (1S,2S,5S )-2-amino-5-carboxymethyl-cyclo-
pentane-1-carboxylate 18. Following general procedure 4,
(1S,2S,5S)-16 (55 mg, 0.18 mmol) and TFA (1.0 ml) gave, after
ion exchange chromatography (Dowex 50X8-200), (1S,2S,5S)-
18 (35 mg, quant.); [α]2D6 Ϫ2.7 (c 0.62, H2O); C8H13NO4 requires
C, 51.33; H, 7.00; N, 7.48; found: C, 51.12; H, 6.95; N, 7.77%;
HRMS (EIϩ) C8H14O4N 188.0923; found 188.0922.
Preparation of di-tert-butyl (1R,2R,5R)-2-amino-5-carboxy-
methyl-cyclopentane-1-carboxylate 16. Following general
procedure 3, (1R,2R,5R,αR)-14 (147mg, 0.3 mmol) in AcOH
(12 ml), Pd/C (10% by mass, 59 mg) and hydrogen (5 atm) at rt
gave, after purification by column chromatography (CHCl3–
MeOH 95 : 5), (1R,2R,5R)-16 (74mg, 83%); [α]2D6 ϩ5.7 (c 1.86,
CHCl3); νmax 3380, 2976, 2934, 1723, 1458, 1393, 1258, 1154,
972, 845; δH (400 MHz, CDCl3) 1.43 (9H, s, C(CH3)3), 1.46 (9H,
s, C(CH3)3), 1.66 (2H, br s, NH2), 1.85–1.89 (1H, m, H-4A),
1.90–1.95 (2H, m, C(3)H2), 1.96–1.99 (1H, m, H-4B), 2.01 (1H,
Preparation of (1R,2R,5S )-2-amino-5-carboxymethyl-cyclo-
pentane-1-carboxylate 19. Following general procedure 4,
(1R,2R,5S)-17 (11 mg, 0.04 mmol) and TFA (0.5 ml) gave, after
ion exchange chromatography (Dowex 50X8-200), (1R,2R,5S)-
19 (7 mg, quant.); [α]2D6 Ϫ35.0 (c 0.6, H2O); νmax 3600–2400 (br),
1717, 1233, 1018, 667; δH (200 MHz, D2O): 1.37–1.43 (1H, m,
H-4A), 1.52–1.58 (1H, m, H-4B), 1.88–1.93 (1H, m, H-3A), 2.15–
2.20 (1H, m, H-3B), 2.32 (2H, AB, J = 7.6, CH2CO2H), 2.72–
2.77 (1H, m, H-5), 2.98 (1H, dd, J = 8.5, 6.2, H-1), 3.90 (1H,
app q, J = 7.0, H-2); δC (50 MHz, D2O) 31.9, 32.4, 38.3, 40.0,
53.9, 56.0, 177.7, 179.1; m/z (EIϩ) 188 (Mϩ, 100), 172 (22), 142
(15), 125 (16), 105 (30), 93 (75), 75 (28), 57 (38); HRMS (EIϩ)
C8H14O4N requires 188.0923; found 188.0940.
t
dd, J = 9.1, 14.1, CHAHCO2 Bu), 2.13–2.20 (1H, dd, J = 10.0,
11.0, H-1), 2.47–2.53 (1H, m, H-5), 2.52 (1H, dd, J = 14.1, 3.6,
t
CHBHCO2 Bu), 3.41 (1H, app q, J = 7.4, H-2); δC (100 MHz,
CDCl3) 28.2, 28.3, 29.0, 34.0, 38.7, 41.2, 56.6, 60.1, 80.4, 81.7,
172.0, 173.8; m/z (EIϩ) 299 (Mϩ, 2), 242 (2), 186 (31), 170 (38),
126 (35), 107 (15), 77 (32); HRMS (EIϩ) C16H30O4N 300.2175,
found 300.2220.
Preparation of (1S,2S,5R)-2-amino-5-carboxymethyl-cyclo-
pentane-1-carboxylate 19. Following general procedure 4,
(1S,2S,5R)-17 (45 mg, 0.15 mmol) and TFA (1.0 ml) gave, after
ion exchange chromatography (Dowex 50X8-200), (1S,2S,5R)-
19 (28 mg, quant.); [α]2D6 ϩ44.7 (c 1.03, H2O), C8H14O4N
requires 188.0923; found 188.0919.
Preparation of di-tert-butyl (1S,2S,5S )-2-amino-5-carboxy-
methyl-cyclopentane-1-carboxylate 16. Following general
procedure 3, (1S,2S,5S,αS)-14 (130 mg, 0.27 mmol) in AcOH
(8 ml), Pd/C (10% by mass, 53 mg) and hydrogen (5 atm) at rt
gave, after purification by column chromatography (CHCl3–
MeOH 95 : 5), (1S,2S,5S)-16 (64mg, 81%); [α]2D6 Ϫ 6.3 (c 1.73,
CHCl3).
Preparation of dimethyl (1E,5R)-5-carboxymethyl-cyclo-
pentene-1-carboxylate 20 and (R)-N-benzylidene-N-ꢀ-methyl-
benzylamine-N-oxide 21. Following general procedure 2,
(1R,2R,5R,αR)-8 (173 mg, 0.42 mmol) in DCM (10 ml) and
m-CPBA (146 mg, 0.84 mmol) gave, after chromatographic
purification on silica gel (hexane–EtOAc 4 : 1), (1E,5R)-20
(70 mg, 85%); [α]2D6 ϩ30.7 (c 0.6, CHCl3); νmax 2953, 1738, 1628,
1098, 756; δH (400 MHz, CDCl3) 1.60–1.80 (2H, m, C(4)H2),
2.31 (1H, dd, J = 15.6, 10.3, CHAHCO2Me), 2.41–2.63 (2H, m,
C(3)H ), 2.87 (1H, dd, J = 15.6, 3.8, CHBHCO2Me), 3.34–3.40
Preparation of di-tert-butyl (1R,2R,5S )-2-amino-5-carb-
oxymethyl-cyclopentane-1-carboxylate 17. Following general
procedure 3, (1R,2R,5S,αR)-15 (58 mg, 0.12 mmol) in AcOH (8
ml), Pd/C (10% by mass, 23 mg) and hydrogen (5 atm) at rt gave,
after purification by column chromatography (CHCl3–MeOH
95 : 5), (1R,2R,5S)-17 (26 mg, 74%); [α]2D6 Ϫ25.2 (c 1.25,
CHCl3); νmax 2978, 1728, 1368, 1258, 1154, 845; δH (400 MHz,
CDCl3) 1.43 (9H, s, C(CH3)3), 1.46 (9H, s, C(CH3)3), 1.68–1.76
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 6 4 – 3 7 2
369

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(1H, m, H-5), 3.68 (3H, s, CO2Me), 3.74 (3H, s, CO2Me), 6.83
(1H, br s, H-2); δC (50 MHz, CDCl3) 29.9, 31.4, 38.3, 40.9, 51.3,
51.4, 138.1, 145.1, 165.1, 173.0. Further elution gave 21 (56 mg,
59%); [α]2D6 Ϫ 45.5 (c 1.19, CHCl3), [lit.,20 [α]2D0 Ϫ48.2 (c 1.0,
CHCl3)]; δH (400 MHz, CDCl3) 1.90 (3H, d, J = 6.8, C(α)Me),
5.21 (1H, q, J = 6.8, C(α)H ), 7.31–7.52 (10H, m, Ar–H ), 8.20–
8.26 (1H, m, NCHPh).
70%); [α]2D6 ϩ11.3 (c 0.6, MeOH); lit.17 [α]3D0 ϩ9.2 (c 0.68,
MeOH); νmax 3366, 2934, 2864, 1456, 1030, 1050, 806; δH (400
MHz, CDCl3) 2.65 (2H, m, H-3), 2.8 (1H, m, H-5), 3.75 (2H, m,
CH2OH, C-8), 4.23 (2H, br s, CH2OH, H-6), 5.68 (1H, br s,
H-2); δC (50 MHz, CDCl3) 30.7, 30.8, 36.6, 41.9, 60.7, 61.5,
126.8, 147.0.
Preparation of (S )-2-(2-hydroxymethyl-cyclopent-2-enyl)-
ethanol 24. LiAlH4 (30 mg) was added to a solution of (1E,5S)-
20 (20 mg, 0.10 mmol) in Et2O (4 ml) at 0 ЊC and stirred at rt
overnight before the addition of EtOAc and H2O (3 ml). The
resultant solution was partitioned between EtOAc and H2O,
dried and concentrated in vacuo. Chromatographic purification
on silica gel (EtOAc) gave (1E,5S)-24 (12 mg, 71%); [α]2D6 Ϫ14.0
(c 0.3, MeOH).
Preparation of dimethyl (1E,5S )-5-carboxymethyl-cyclo-
pentene-1-carboxylate 20. Following general procedure 2,
(1S,2S,5S,αS)-8 (49 mg, 0.12 mmol) in DCM (10 ml) and
m-CPBA (30 mg, 0.17 mmol) gave, after chromatographic puri-
fication on silica gel (hexane–Et2O 9 : 1), (1E,5S)-20 (20 mg,
84%); [α]2D6 Ϫ26.5 (c 1.0, CHCl3).
Preparation of di-3-pentyl (1E,5R)-5-carboxymethyl-cyclo-
pentene-1-carboxylate 22. Following general procedure 2,
(1R,2R,5R,αR)-11 (430 mg, 0.82 mmol) in DCM (36 ml) and
m-CPBA (373 mg, 2.16 mmol) gave, after chromatographic
purification on silica gel (hexane–Et2O 9 : 1), (1E,5R)-22 (182
mg, 71%) [α]2D6 ϩ31.2 (c 1.12, CHCl3); νmax 2971, 1711, 1630,
1260, 1096, 932, 750; δH (200 MHz, CDCl3) 0.80–1.00 (12H, m,
2 × CH(CH2CH3)2), 1.45–1.65 (8H, m, 2 × CH(CH2CH3)2),
1.65–1.80 (2H, m), 2.24 (1H, dd, J = 15.6, 10.5, CHAHCO2),
2.38–2.58 (2H, m, C(3)H2), 2.89 (1H, dd, J = 15.6, 3.2, CHB-
HCO2), 3.30–3.45 (1H, m, H-5), 4.76 (1H, quintet, J = 6.0,
CH(CH2CH3)2), 4.82 (1H, quintet, J = 6.0, CH(CH2CH3)2),
6.78 (1H, br s, H-2); δC (50 MHz, CDCl3) 9.5, 26.4, 29.6, 31.3,
38.7, 41.1, 76.3, 76.5, 138.8, 144.0, 164.6, 172.4; m/z (EIϩ) 310
(Mϩ, 5), 223 (7), 151 (100), 123 (70); HRMS (EIϩ) C18H30O4
requires 310.2144, found 310.2132; further elution gave nitrone
21 (90 mg, 50%).
Preparation of di-tert-butyl (1R,2S,5R,ꢀS )-2-N-benzyl-N-ꢀ-
methylbenzylamino-5-carboxymethyl-cyclopentane-1-carboxyl-
ate 25. Following general procedure 1, (1E,5R)-23 (98 mg,
0.35 mmol) in THF (2 ml), (S)-N-benzyl-N-α-methylbenzyl-
amine (161 mg, 0.75 mmol) in THF (5 ml) and n-BuLi (1.6 M,
0.47 ml, 0.75 mmol) gave, after chromatographic purification
on silica (hexane–Et2O 49 : 1), (1R,2S,5R,αS)-25 (116 mg,
68%); [α]2D6 Ϫ46.8 (c 1.72, CHCl3); νmax 2976, 1728, 1456, 1393,
1256, 1150, 735, 700; δH (400 MHz, CDCl3) 1.05 (1H, m, H-4A),
1.36 (3H, d, J = 6.8, C(α)Me), 1.43, 1.52 (2 × 9H, s, C(CH3)3),
1.57 (1H, m, H-3A), 1.84 (1H, m, H-3B), 1.97 (1H, m, H-4B),
t
2.02–2.10 (1H, dd, J = 14.7, 7.6, CHAHCO2 Bu), 2.18 (1H, dd,
t
J = 14.7, 6.9, CHBHCO2 Bu), 2.55–2.65 (1H, m, H-5), 2.60–2.65
(1H, dd, J = 9.9, 6.9, H-1), 3.25 (1H, ddd, J = 11.0, 8.4, 6.8,
H-2), 3.54 (1H, AB, JAB = 15.3, NCHA), 4.03 (1H, AB, JAB
=
15.3, NCHB), 4.25 (1H, q, J = 6.8, C(α)H ), 7.25–7.40 (10H, m,
Ar–H ); δC (100 MHz, CDCl3) 17.0, 28.1, 28.3, 29.7, 38.6, 42.3,
51.7, 54.4, 57.8, 63.9, 80.1, 126.2, 126.7, 127.9, 128.0, 142.5,
142.6, 171.5, 173.9; m/z (EIϩ) 493 (Mϩ,8), 472 (11), 387 (24),
332 (11), 250 (52), 216( 2), 146 (50), 105 (100), 77 (15); HRMS
(EIϩ) C31H43O4N requires 493.3192. found 493.3139.
Preparation of di-3-pentyl (1E,5S )-5-carboxymethyl-cyclo-
pentene-1-carboxylate 22. Following general procedure 2,
(1S,2S,5S,αS)-11 (187 mg, 0.36 mmol) in DCM (16 ml) and
m-CPBA (175 mg, 1.01 mmol) gave, after chromatographic
purification on silica gel (hexane–Et2O 95 : 5), (1E,5S)-22
(91 mg, 81%); [α]2D6 Ϫ29.6 (c 1.33, CHCl3).
Preparation of di-tert-butyl (1S,2R,5S,ꢀR)-2-N-benzyl-N-ꢀ-
methylbenzylamino-5-carboxymethyl-cyclopentane-1-carboxyl-
ate 25. Following general procedure 1, (1E,5S)-23 (127 mg,
0.45 mmol) in THF (2 ml), (R)-N-benzyl-N-α-methylbenzyl-
amine (304 mg, 1.44 mmol) in THF (3 ml) and n-BuLi (1.6 M,
0.87 ml, 1.39 mmol) gave, after chromatographic purification
on silica (hexane–Et2O 49 : 1), (1R,2S,5R,αS)-25 (143 mg,
65%); [α]2D6 ϩ50.3 (c 0.99, CHCl3).
Preparation of di-tert-butyl (1E,5R)-5-carboxymethyl-cyclo-
pentene-1-carboxylate 23. Following general procedure 2,
(1R,2R,5R,αR)-14 (547 mg, 1.1 mmol) in DCM (40 ml) and
m-CPBA (572 mg, 3.3 mmol) gave, after chromatographic puri-
fication on silica gel (hexane–EtOAc 4 : 1), (1E,5R)-23 (209 mg,
65%); [α]2D6 ϩ36.4 (c 2.2, CHCl3); νmax 2978, 2934, 1732, 1705,
1628, 1458, 1393, 1368, 1298, 1165, 851, 755; δH (400 MHz,
CDCl3) 1.43, 1.48 (2 × 9H, s, C(CH3)3), 1.65–1.85 (2H, m,
Preparation of di-tert-butyl (1S,2R,5R,ꢀR)- and (1R,2R,
5R,ꢀR)-2-N-benzyl-N-ꢀ-methylbenzylamino-5-carboxymethyl-
cyclopentane-1-carboxylate 26 and 14 respectively. Following
general procedure 1, (1E,5R)-23 (83 mg, 0.29 mmol) in THF
(2 ml), (R)-N-benzyl-N-α-methylbenzylamine (136 mg, 0.65
mmol) in THF (5 ml) and n-BuLi (1.6 M, 0.4 ml, 0.65 mmol)
gave, after chromatographic purification on silica (hexane–Et2O
49 : 1), (1S,2R,5R,αR)-26 (63 mg, 44%); [α]2D6 ϩ42.1 (c 1.26,
CHCl3); νmax 2976, 1728, 1493, 1454, 1368, 1258, 1154, 1028,
847, 746, 700; δH (400 MHz, CDCl3) 1.37 (3H, d, J = 6.8,
C(α)Me), 1.43, 1.51 (2 × 9H, s, C(CH3)3), 1.56–1.62 (2H, m,
C(4)H2), 1.70–1.80 (1H, m, H-3A), 1.92–2.02 (1H, m, H-3B),
t
C(4)H2), 2.12 (1H, dd, J = 15.6, 10.5, CHAHCO2 Bu), 2.30–2.40
t
(2H, m, C(3)H2), 2.89 (1H, dd, J = 15.6, 3.2, CHBHCO2 Bu),
3.30 (1H, m, H-5), 6.78 (1H, br s, H-2); δC (100 MHz, CDCl3)
28.0, 29.4, 31.1, 39.6, 41.1, 79.8, 80.0, 139.9, 143.1, 164.0, 171.8;
m/z (EIϩ) 282 (Mϩ, 5), 245 (10), 225 (12), 185 (25), 169 (28), 151
(35), 123 (16), 105 (9), 71 (12), 77 (12), 57 (100); HRMS (EIϩ)
C16H27O4 requires 283.1909; found 283.1903.
Preparation of di-tert-butyl (1E,5S )-5-carboxymethyl-cyclo-
pentene-1-carboxylate 23. Following general procedure 2,
(1S,2S,5S,αS)-14 (474 mg, 0.96 mmol) in DCM (24 ml) and
m-CPBA (504 mg, 2.9 mmol) gave, after chromatographic
purification on silica gel (hexane–EtOAc 95 : 5), (1E,5S)-23
(232 mg, 86%); [α]2D6 Ϫ35.3 (c 1.5, CHCl3).
t
2.18–2.38 (3H, m, H-5 and CHAHBHCO2 Bu), 3.03 (1H, dd,
J = 5.6, 5.1, H-1), 3.25 (1H, ddd, J = 11.2, 8.0, 6.5, H-2), 3.45
(1H, AB, JAB = 15.3, NCH HPh), 3.97 (1H, AB, JAB = 15.3,
A
NCH HPh), 4.27 (1H, q, J = 6.8, C(α)H ), 7.16–7.38 (10m,
B
Preparation of (1E,5R)-2-(2-hydroxymethyl-cyclopent-2-
enyl)-ethanol 24. LiAlH4 (30 mg) was added to a solution of
(1E,5R)-20 (66 mg, 0.34 mmol) in Et2O (4 ml) at 0 ЊC and
stirred at rt overnight before the addition of EtOAc and H2O
(3 ml). The resultant solution was partitioned between EtOAc
and H2O, dried and concentrated in vacuo. Chromatographic
purification on silica gel (EtOAc) gave (1E,5R)-24 (39 mg,
Ar–H ); δC (100 MHz, CDCl3) 17.7, 27.8, 28.1, 28.2, 28.8, 37.0,
37.8, 51.4, 52.3, 58.2, 65.8, 80.1, 80.4, 126.1, 126.8, 127.8, 128.0,
142.3, 143.1, 171.8, 172.5; m/z (EIϩ) 493 (Mϩ,8), 478 (10), 388
(35), 332 (14), 250 (62), 218 (16), 146 (50), 105 (100), 77 (15);
HRMS (EIϩ) C31H43O4N requires 493.3192; found 493.3215.
Further elution gave (1R,2R,5R,αR)-14 (26 mg, 18%) with
identical spectroscopic properties to that previously obtained.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 6 4 – 3 7 2
370

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Preparation of di-tert-butyl (1R,2S,5S,ꢀS )- and (1S,2S,
5S,ꢀS )-2-N-benzyl-N-ꢀ-methylbenzylamino-5-carboxymethyl-
cyclopentane-1-carboxylate 26 and 14 respectively. Following
general procedure 1, (1E,5S)-23 (97 mg, 0.34 mmol) in THF
(2 ml), (S)-N-benzyl-N-α-methylbenzylamine (232 mg, 1.1
mmol) in THF (6 ml) and n-BuLi (1.6 M, 0.69 ml, 1.1 mmol)
gave, after chromatographic purification on silica (hexane–Et2O
49 : 1), (1R,2S,5S,αS)-26 (82 mg, 48%); [α]2D6 Ϫ43.0 (c 1.6,
CHCl3); further elution gave (1S,2S,5S,αS)-14 (35 mg, 21%);
[α]2D6 ϩ33.2 (c 0.54, CHCl3).
48.5, 52.0, 174.4, 176.7; m/z (EIϩ) 188 (Mϩ, 1), 185 (50), 93
(100), 75 (30); HRMS (EIϩ) C8H13O4N requires 188.0923;
found 188.0922.
Preparation of (1R,2S,5S )-2-amino-5-carboxymethyl-cyclo-
pentane-1-carboxylate 29. Following general procedure 4,
(1R,2S,5S)-27 (9 mg, 0.03 mmol) and TFA (0.5 ml) gave, after
ion exchange chromatography (Dowex 50X8-200), (1R,2S,5S)-
29 (6 mg, quant.); [α]2D6 Ϫ31.9 (c 1.09, 5.5M NH3 aq.); HRMS
(EIϩ) C8H13O4N requires 188.0923; found 188.09238.
Preparation of di-tert-butyl (1S,2R,5R)-2-amino-5-carboxy-
methyl-cyclopentane-1-carboxylate 27. Following general
procedure 3, (1S,2R,5R,αR)-25 (41 mg, 0.08 mmol) in AcOH
(6 ml), Pd/C (10% by mass, 17 mg) and hydrogen (5 atm) at rt
gave after purification by column chromatography (CHCl3–
MeOH 95 : 5), (1S,2R,5R)-27 (19 mg, 77%); [α]2D6 ϩ25.8 (c 1.47,
CHCl3); νmax 3350, 2976, 1728, 1458, 1368, 1258, 1154; δH (200
MHz, CDCl3) 1.43 (9H, s, C(CH3)3), 1.47 (9H, s, C(CH3)3),
1.60–1.82 (3H, m, C(4)H2, H-3A), 1.96–2.04 (1H, m, H-3B),
2.21–2.50 (3H, m, CHAHBCOOtBu, H-5), 2.81–2.85 (1H, app t,
J = 6.0, 6.4, H-1), 3.40–3.58 (1H, m, H-2); δC (50 MHz, CDCl3)
28.2, 28.3, 28.6, 29.6, 38.0, 38.2, 51.7, 52.8, 80.3, 81.1, 171.7,
171.9; m/z (EIϩ) 299 (Mϩ, 1), 242 (7), 186 (42), 170 (60), 142
(15), 126 (30), 107 (20), 82 (30), 57 (100); HRMS (EIϩ)
C16H29O4N requires 299.2097; found: 299.2109.
Preparation of (1R,2S,5R)-2-amino-5-carboxymethyl-cyclo-
pentane-1-carboxylate 30. Following general procedure 4,
(1R,2S,5R)-28 (36 mg, 0.12 mmol) and TFA (0.6 ml) gave, after
ion exchange chromatography (Dowex 50X8-200), (1R,2S,5R)-
30 (23 mg, quant.); [α]2D6 ϩ24.6 (c 1.93, H2O); C8H13NO4: C,
51.33; H, 7.00; N, 7.48. found: C, 51.25; H, 7.11; N,
7.65%; νmax 3600–2400 (br), 1715, 1418, 1198, 799, 665;
δH (200 MHz, D2O) 1.32–1.38 (1H, m, H-4A), 1.71–1.79 (1H, m,
H-4B), 2.11–2.18 (2H, m, C(3)H2), 2.40–2.70 (3H, m,
CH2CO2H, H-5), 2.79 (1H, dd, J = 8.5, 7.8, H-1), 3.85 (1H,
app q, J = 5.8, H-2); δC (50 MHz, D2O) 26.6, 27.6, 35.9, 36.4,
48.4, 50.7, 173.3,174.7; m/z (EIϩ) 188 (Mϩ, 18), 137 (5), 115
(100), 93 (52), 75(8); HRMS (EIϩ) C8H13O4N 188.0923; found
188.0904.
Preparation of (1S,2R,5S )-2-amino-5-carboxymethyl-cyclo-
pentane-1-carboxylate 30. Following general procedure 4,
(1S,2R,5S)-28 (32 mg, 0.10 mmol) and TFA (1 ml) gave, after
ion exchange chromatography (Dowex 50X8-200), (1S,2R,5S)-
30 (19 mg, quant.); [α]2D6 Ϫ25.1 (c 0.57, H2O); HRMS (EIϩ)
C8H13O4N requires 188.0923; found 188.0941.
Preparation of di-tert-butyl (1R,2S,5S )-2-amino-5-carboxy-
methyl-cyclopentane-1-carboxylate 27. Following general
procedure 3, (1R,2S,5S,αS)-25 (71 mg, 0.14 mmol) in AcOH
(8 ml), Pd/C (10% by mass, 29 mg) and hydrogen (5 atm) at rt
gave after purification by column chromatography (CHCl3–
MeOH 95 : 5), (1R,2S,5S)-27 (36 mg, 84%); [α]2D6 Ϫ30.1 (c 1.07,
CHCl3).
Acknowledgements
Preparation of di-tert-butyl (1R,2S,5R)-2-amino-5-carboxy-
methyl-cyclopentane-1-carboxylate 28. Following general pro-
cedure 3, (1R,2S,5R,αS)-26 (100 mg, 0.21 mmol) in AcOH
(8 ml), Pd/C (10% by mass, 42 mg) and hydrogen (5 atm) at rt
gave, after purification by column chromatography (CHCl3–
MeOH 95 : 5), 28 (43 mg, 71%); [α]2D6 ϩ28.4 (c 1.45, CHCl3);
νmax 3390, 2976, 1728, 1393, 1368, 1258, 1154, 845; δH (400
MHz, CDCl3) 1.43 (9H, s, C(CH3)3), 1.46 (9H, s, C(CH3)3),
1.75–2.10 (4H, m, C(3)H2 and C(4)H2), 2.14 (1H, dd, J = 14.8,
The authors wish to thank the CICYT, Junta de Castilla y Leon
and F. S. E. for financial support (SA 036/01), the Spanish
Ministerio de Educacion y Cultura for a doctoral fellowship
(S. H. D), New College, Oxford for a Junior Research Fellow-
ship (A. D. S), and Dr A. Jiménez and Dr F. Sanz for X-ray
structure determination.
References and notes
t
8.7, CHAHCO2 Bu), 2.40–2.46 (1H, m, H-1), 2.46 (1H, dd,
1 T. Sakan, F. Murai, S. Asoe, S. B. Hyeon and Y. Hayashi, J. Chem.
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6, 3376 and references cited therein.
t
J = 14.8, 5.4, CHBHCO2 Bu), 2.64–2.72 (1H, m, H-2), 3.62 (2H,
br s, NH2); δC (100 MHz, CDCl3) 28.0, 28.2, 29.4, 34.4, 37.0,
40.8, 54.8, 56.0 m, 80.1, 80.5, 171.7, 172.5; m/z (EIϩ) 299 (Mϩ,
1), 242 (7), 186 (54), 170 (76), 152 (12), 126 (32), 82 (22), 57
(100); HRMS (EIϩ) C16H29O4N requires 299.2097, found
299.2113.
3 E. J. Corey and X-M Cheng, The Logic of Chemical Synthesis, John
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Preparation of di-tert-butyl (1S,2R,5S )-2-amino-5-carboxy-
methyl-cyclopentane-1-carboxylate 28. Following general
procedure 3, (1S,2R,5S,αR)-26 (141 mg, 0.28 mmol) in AcOH
(12 ml), Pd/C (10% by mass, 56 mg) and hydrogen (5 atm) at rt
gave, after purification by column chromatography (CHCl3–
MeOH 95 : 5), (1S,2R,5S)-28 (72 mg, 84%); [α]2D6 Ϫ30.9 (c 1.95,
CHCl3).
Preparation of (1S,2R,5R)-2-amino-5-carboxymethyl-cyclo-
pentane-1-carboxylate 29. Following general procedure 4,
(1S,2R,5R)-27 (36 mg, 0.12 mmol) and TFA (0.5 ml) gave, after
ion exchange chromatography (Dowex 50X8-200), (1S,2R,5R)-
29 (23 mg, quant.); [α]2D6.ϩ15.2 (c 0.3, 5.5M NH3 aq.);
νmax 3600–2400 (br), 1714, 1418, 1198, 799, 665; δC (200 MHz,
D2O) 1.49–1.53 (1H, m, H-4A), 1.77–1.83 (1H, m, H-3A), 1.90–
1.98 (1H, m, H-4B), 2.07–2.14 (1H, m, H-3B), 2.40–2.70 (3H, m,
CH2CO2H and H-5), 3.20 (1H, app t, J = 6.8, H-1), 3.75 (1H,
app q, J = 8.1, H-2); δC (50 MHz, D2O) 27.5, 27.7, 35.8, 37.5,
7 M. G. Woll, J. D. Fisk, P. R. LePlae and S. H. Gellman, J. Am.
Chem. Soc., 2002, 124, 12447.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 6 4 – 3 7 2
371

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8 M. E. Bunnage, A. N. Chernega, S. G. Davies and C. J. Goodwin,
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10 T. Uyehara, N. Shida and Y. Yamamoto, J. Am. Chem. Soc., 1992,
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14 For the preparation of the silyl ketene acetals arising from conjugate
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17 T. Yamame, M. Takahashi and K. Ogasawara, Synthesis, 1995, 444.
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19 We have previously used this N-oxidation–Cope elimination strategy
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11 J. G. Urones, N. M. Garrido, D. Díez, S. H. Dominguez and
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12 We have previously shown the utility of this double conjugate
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 6 4 – 3 7 2
372