Kinetic resolution of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates for the synthesis of homochiral 3-alkyl-cispentacin and 3-alkyl-transpentacin derivatives

Article abstract of DOI:10.1039/b407559e

High levels of stereocontrol are observed in the conjugate addition of lithium dibenzylamide to tert-butyl (RS)-3-alkylcyclopentene-l-carboxylates (alkyl = Et, Bn), with addition occurring exclusively anti- to the 3-alkyl substituent. Treatment of a range of tert-butyl (RS)-3-alkylcyclopentene-l-carboxylates (alkyl = Et, Bn, 'Pr, 'Bu) with lithium (RS)-N-benzyl-N-α-methylbenzylamide indicates that good enantiorecognition is observed (E > 80) in their mutual kinetic resolution. In these reactions, conjugate addition of the lithium amide occurs exclusively anti- to the 3-alkyl substituent, with subsequent C(1)-protonation occurring preferably anti- to the 2-amino group in the 3-Et, 3-Bn and 3-'Pr cases, giving predominantly the corresponding 1,2-syn-2,3-anti-diastereoisomers. Conjugate addition to (RS)-3-tert-butyl cyclopentene-l-carboxylate results in exclusive 2,3-anti-addition and a reversal in C(1)-protonation selectivity, giving predominantly the 1,2-anti-2,3-anti-diastereoisomer. Furthermore, the kinetic resolution of the tert-butyl (RS)-3-alkylcyclopentene-l-carboxylates (alkyl = Et, Bn, 'Pr, 'Bu) with lithium (S)-N-benzyl-N-αmethylbenzylamide proceeds efficiently, giving, at between 47 and 51% conversion, the resolved 3-alkylcyclopentene-l-carboxylates in >85 to >98% ee and the β-amino ester products of conjugate addition in high de, consistent with E > 80 in each case. Subsequent deprotection of the 1,2-syn-2,3-anti-3-alkyl-β-amino esters (alkyl = Et, Bn, 'Pr) by hydrogenolysis and ester hydrolysis gives the corresponding 1,2-syn-2,3-anti-3-alkylcispentacins in >98% de and 98 ±1% ee. Selective epimerisation of the 1,2-syn-2,3-anti-3-alkyl-β-amino esters (alkyl = Et, Bn, 'Pr, 'Bu) by treatment with KO'Bu in 'BuOH gives the corresponding 1,2-anti-2,3-anti-3-alkyl-β-amino esters in quantitative yield and in >98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving the corresponding 1,2-anti-2,3-anti-3-alkylcispentacin hydrochlorides in >98% de.

Full text of DOI:10.1039/b407559e

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A R T I C L E
Kinetic resolution of tert-butyl (RS)-3-alkylcyclopentene-1-
carboxylates for the synthesis of homochiral 3-alkyl-cispentacin and
3-alkyl-transpentacin derivatives
Mark E. Bunnage,a Stephen G. Davies,*b Richard M. Parkin,b Paul M. Roberts,b
Andrew D. Smithb and Jonathan M. Witheyb
a
Discovery Chemistry, IPC 818, Pfizer Global Research and Development, Sandwich, Kent,
UK CT13 9NJ
b
The Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, UK OX1 3TA. E-mail: steve.davies@chem.ox.ac.uk
Received 20th May 2004, Accepted 17th August 2004
First published as an Advance Article on the web 20th October 2004
High levels of stereocontrol are observed in the conjugate addition of lithium dibenzylamide to tert-butyl (RS)-3-
alkylcyclopentene-1-carboxylates (alkyl = Et, Bn), with addition occurring exclusively anti- to the 3-alkyl substituent.
Treatment of a range of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, iPr, tBu) with lithium
(RS)-N-benzyl-N-a-methylbenzylamide indicates that good enantiorecognition is observed (E > 80) in their mutual
kinetic resolution. In these reactions, conjugate addition of the lithium amide occurs exclusively anti- to the 3-alkyl
substituent, with subsequent C(1)-protonation occurring preferably anti- to the 2-amino group in the 3-Et, 3-Bn and
3-iPr cases, giving predominantly the corresponding 1,2-syn-2,3-anti-diastereoisomers. Conjugate addition to (RS)-
3-tert-butyl cyclopentene-1-carboxylate results in exclusive 2,3-anti -addition and a reversal in C(1)-protonation
selectivity, giving predominantly the 1,2-anti-2,3-anti-diastereoisomer. Furthermore, the kinetic resolution of
the tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, iPr, tBu) with lithium (S)-N-benzyl-N-a-
methylbenzylamide proceeds efficiently, giving, at between 47 and 51% conversion, the resolved 3-alkylcyclopentene-
1-carboxylates in >85 to >98% ee and the b-amino ester products of conjugate addition in high de, consistent with
E > 80 in each case. Subsequent deprotection of the 1,2-syn-2,3-anti-3-alkyl-b-amino esters (alkyl = Et, Bn, iPr)
by hydrogenolysis and ester hydrolysis gives the corresponding 1,2-syn-2,3-anti-3-alkylcispentacins in >98% de
and 98 ± 1% ee. Selective epimerisation of the 1,2-syn-2,3-anti-3-alkyl-b-amino esters (alkyl = Et, Bn, iPr, tBu) by
treatment with KOtBu in tBuOH gives the corresponding 1,2-anti-2,3-anti-3-alkyl-b-amino esters in quantitative
yield and in >98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving the corresponding
1,2-anti-2,3-anti-3-alkylcispentacin hydrochlorides in >98% de.
Introduction
The generation of bespoke pseudopeptide sequences that ex-
hibit highly ordered secondary and tertiary structures in both
solution and solid phase has developed into a highly competi-
tive field of research in recent years, with the ability to predict
the conformation of a given peptide sequence from knowledge
of its primary structure an elusive goal. While much effort has
been directed towards understanding the factors that control
the secondary structure of a-peptides, the utility of peptides
incorporating the b-amino acid structural motif has recently
been investigated widely, most notably by Seebach1 and Gell-
man.2 For instance, Gellman et al. have shown that b-peptides
derived from trans-2-aminocyclopentanecarboxylic acid (trans-
pentacin) 1 adopt a helical stucture in both the solid state and in
solution,3 while Fülop et al. have shown that homo-oligomers of
Fig. 1 Secondary structure of poly homo-pentacins.
cis-2-aminocyclopentanecarboxylic acid (cispentacin) 2 form a
sheetlike secondary structure in solution (Fig. 1).4 The ability of
mixed a,b-peptides containing both a-amino and b-amino acid
derivatives to adopt a preferred conformation in solution has
also been reported recently.5
requires an initial evaluation of the level of stereocontrol
offered by the chiral a,b-unsaturated ester undergoing con-
jugate addition, which is achieved through the addition of an
achiral lithium amide to the ester. If the a,b-unsaturated ester
shows high facial selectivity upon conjugate addition, the level
of enantiorecognition between the chiral a,b-unsaturated ester
and a chiral lithium amide is evaluated through their mutual
kinetic resolution [addition of (RS)-ester to an excess of an
(RS)-lithium amide]. In this approach,8 the effects of mass
action are eliminated, allowing the maximum stereoselectivity
factor (E) for the reaction to be calculated independent of the
reaction conversion, as it is identical to the diastereoselectivity
observed in the reaction.9 If high enantiorecognition is seen
between the reacting partners in a mutual kinetic resolution,
then efficient kinetic resolution may be expected upon the
We have shown extensively that the conjugate addition of
lithiumamides derived from a-methylbenzylamine to a,b-
unsaturated acceptors may be used for the asymmetric synthesis
of b-amino acid derivatives.6 This methodology has recently been
utilised for the synthesis of (1R,2S,3R)-3-methylcispentacin 5
in >98% de and 98 ± 1% ee and (1S,2S,3R)-3-methyltrans-
pentacin 7 in >98% de and 97 ± 1% ee by the kinetic resolution
of tert-butyl (RS)-3-methylcyclopentene-1-carboxylate 3 with
lithium (S)-N-benzyl-N-a-methylbenzylamide (Scheme 1).7
The protocol that we use to understand fully the stereo-
selectivity observed in these kinetic resolution reactions
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4
3 3 3 7

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t
Scheme 2 Reagents and conditions: (i) PhNMe2 (3.15 eq), BuOH
(3.25 eq), Et2O, rt; (ii) NaH (1.05 eq), tBuOH (cat), PhMe, D; (iii) NaH
(1.05 eq) then n-BuLi (1.0 eq), then RX (1.1 eq), −78 to 0 °C; (iv) NaBH4,
EtOH, 0 °C; (v) TsCl (1.1 eq), pyridine, 0 °C to rt; (vi) DBU, DCM, 0 °C;
(vii) PPh3 (1.5 eq), DIAD (1.3 eq), THF, 0 °C to rt.
ethyl (RS)-3-iso-propyl cyclopentene-1-carboxylate 16, with
transesterification giving the tert-butyl (RS)-3-iso-propyl cyclo-
pentene-1-carboxylate 17 (Scheme 3).17
Scheme 1 Reagents and conditions: (i) lithium (S)-N-benzyl-N-
a-methylbenzylamide 8, THF, −78 °C then 2,6-di-tert-butylphenol,
t
THF, −78 °C to rt; (ii) KOtBu, BuOH, D, 3 h; (iii) Pd(OH)2 on C,
MeOH, H2 (5 atm); (iv) TFA then Dowex 50WX8-200; (v) TFA then
HCl(aq) and recrystallisation.
addition of homochiral lithium amide to the (RS)-ester. To
understand fully the reactivity and stereoselectivity observed
in these kinetic resolution reactions, the forced reaction of the
‘mismatched’ pairing allows the preparation of the minor dia-
stereoisomers of the kinetic resolution reaction, while an evalu-
ation of the evolution of the ee of the substrate with conversion
allows the theoretical and experimentally observed values for
the kinetic resolution reaction to be compared. As part of our
ongoing studies concerning the application of kinetic resolution
strategies in asymmetric synthesis,10,11 and to provide a general
route to the synthesis of stereodefined 3-alkyl-cispentacin and
3-alkyl-transpentacin analogues to facilitate an understanding
of the secondary structure of peptides derived thereof, we report
herein the generality of this strategy through the investigation of
the kinetic resolution of a range of tert-butyl (RS)-3-alkylcyclo-
pentene-1-carboxylates with homochiral lithium amides.
Scheme 3 Reagents and conditions: (i) NaH (1.05 eq), then 2-iodo-
propane (1.1 eq), −78 to 0 °C; (ii) NaOEt, EtOH, D; (iii) NaBH4,
EtOH, 0 °C; (iv) TsCl (1.1 eq), pyridine, 0 °C to rt; (v) DBU, DCM,
0 °C; (vi) PPh3 (1.5 eq), DIAD (1.3 eq), THF, 0 °C to rt; (vii) KOH, D;
(viii). isobutylene, H2SO4 (cat).
The synthesis of the (RS)-3-tert-butyl derivative 19 neces-
sitated an alternative synthetic strategy, via alkylation of the
trimethylsilyl enol ether of cyclopentanone18 with TiCl4 and
tert-butyl chloride and subsequent acylation with NaH and
dimethyl carbonate generating b-keto ester 18 as a 65:35 mix-
ture of diastereoisomers. Further manipulation generated the
desired (RS)-3-tert-butyl acceptor 19 (Scheme 4).19
Results and discussion
Synthesis of a range of tert-butyl (RS)-3-alkyl–cyclopentene-1-
carboxylates (alkyl = Et, Bn, iPr, tBu)
To investigate the generality of this kinetic resolution protocol,
the effects of increasing size and branching in the 3-alkyl group
upon the level of stereocontrol and enantiorecognition in these
reactions was proposed, which necessitated the synthesis of
tert-butyl (RS)-3-ethyl, (RS)-3-benzyl, (RS)-3-iso-propyl and
(RS)-3-tert-butyl cyclopentene-1-carboxylates. The (RS)-3-
ethyl and (RS)-3-benzyl derivatives 11 and 12, respectively, were
readily prepared on a multigram scale from adipoyl chloride
via consecutive esterification,12 Dieckmann cyclisation13 and
regioselective c-alkylation with either ethyl iodide or benzyl
bromide, furnishing the c-alkyl b-keto esters 9 and 10 as a
70:30 mixture of diastereoisomers in each case. Chemoselective
NaBH4 reduction to the alcohol, followed by either tosylation
and subsequent elimination, or treatment with PPh3/diisopropyl
azodicarboxylate (DIAD)14 gave the desired (RS)-3-ethyl and
(RS)-3-benzyl derivatives 11 and 12, respectively, in reasonable
yield (Scheme 2).
Attempted application of this protocol to the synthesis of
the 3-iso-propyl cyclopentene-1-carboxylate proved unsuccess-
ful, with attempted alkylation of the dianion of b-keto ester 13
with 2-iodopropane returning only starting material. However,
alkylation of the mono enolate of ethyl b-keto ester 13 with
2-iodopropane proceeded smoothly, giving a,a-dialkyl b-keto
ester 14 in 91% yield,15 with subsequent rearrangement upon
treatment with NaOEt giving the 3-iso-propyl b-keto ester 15
as a 65:35 mixture of diastereoisomers in 72% yield.16 Subse-
quent reduction, followed by either tosylation and elimination
or treatment with PPh3/diisopropyl azodicarboxylate, furnished
Scheme 4 Reagents and conditions: (i) TMSCl, NEt3, D; then tBuCl,
i
TiCl4; (ii) NaH, dimethyl dicarbonate; (iii) NaBH4, PrOH, 0 °C to
rt; (iv) PPh3 (1.5 eq), DIAD (1.3 eq), THF, 0 °C to rt; (v) KOH, D;
(vi) isobutylene, H2SO4 (cat).
Evaluating substrate control: Conjugate addition of lithium
dibenzylamide to tert-butyl (RS)-3-ethyl- and (RS)-3-benzyl-
cyclopentene-1-carboxylates
With a range of (RS)-3-alkyl-cyclopentene-1-carboxylates in
hand, the level of stereoinduction commanded by (RS)-3-ethyl
11 and (RS)-3-benzyl 12 upon conjugate addition of lithium
dibenzylamide was evaluated. In each case, only the C(1)-
epimeric b-amino esters were observed in an 85:15 ratio, with
the major diastereoisomers 20 and 21 having the syn-1,2-anti-
2,3-arrangement, and the minor diastereoisomers 22 and 23 the
anti-1,2-anti-2,3-arrangement.20 Chromatographic purification
yielded an inseparable mixture of diastereoisomers without
enhancement of diastereoisomeric purity, giving 20:22 (85:15)
in 71% yield and 21:23 (85:15) in 77% yield. In both cases, treat-
t
ment of the diastereoisomeric mixture with KOtBu in BuOH
allowed quantitative conversion to the thermodynamic anti-
1,2-anti-2,3 diastereoisomers 22 and 23 in >98% de in each case
(Scheme 5). This study indicates that complete diastereofacial
3 3 3 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4

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control at the C(2)-centre during conjugate addition of lithium
dibenzylamide to the face of the acceptor anti- to that of the
stereocontrolling 3-alkyl substituent is observed in these reac-
tions, with the mixture of diastereoisomers arising only as a con-
sequence of low diastereoselectivity upon enolate protonation.
Although the conjugate addition of lithium dibenzylamide to
(RS)-3-iso-propyl 17 and (RS)-3-tert-butyl 19 was not evalu-
ated, these substrates were expected to show similar high levels
of anti-2,3 facial control.
reversal of selectivity, giving preferably the 1,2-anti-2,3-anti-dia-
stereoisomer 34. Chromatographic purification and/or recrystal-
lisation allowed the isolation and characterisation of the major
diastereoisomeric 3-ethyl-, 3-benzyl- and 3-iso-propyl-1,2-syn-
2,3-anti-b-amino esters 24–26 in >98% de, with subsequent
conversion to the corresponding thermodynamically favoured
1,2-anti-2,3-anti-diastereoisomers 27–29 (>98% de) achieved
t
in quantitative yield by treatment with KOtBu in BuOH. In
the 3-tert-butyl case, exposure of the 23.1:76.9 mixture of
1,2-syn-2,3-anti- and 1,2-anti-2,3-anti-diastereoisomers 33:34
to equilibrating conditions allowed complete and quantitative
conversion to the 1,2-anti-2,3-anti-diastereoisomer 34. These
experiments confirm that, in each case, the two major diastereo-
isomers from the mutual resolution protocol of the range of
(RS)-3-alkyl-cyclopentene-1-carboxylates 11, 12, 17 and 19 are
epimeric at C(1), with complete 2,3-anti- stereocontrol being
achieved upon conjugate addition.21
Scheme 5 Reagents and conditions: (i) Lithium dibenzylamide,
t
THF, −78 °C; (ii) NH4Cl(aq); (iii) KOtBu, BuOH, D, 3 h (R = Et);
(iv) KOtBu, tBuOH, rt, 7 d (R = Bn).
Mutual kinetic resolution of tert-butyl (RS)-3-alkyl–cyclo-
pentene-1-carboxylates with lithium (RS)-N-benzyl-N-a-methyl-
benzylamide
Having shown that high levels of substrate control operate in
the conjugate addition of lithium dibenzylamide to (RS)-11
and (RS)-12, the mutual kinetic resolution of the full range of
(RS)-a,b-unsaturated esters 11, 12, 17 and 19 with lithium (RS)-
N-benzyl-N-a-methylbenzylamide 8 was investigated to evaluate
the maximum value of the stereoselectivity factors (E) for their
respective reactions.8 Addition of (RS)-amide 8 to the (RS)-3-
ethyl, (RS)-3-benzyl and (RS)-3-iso-propyl esters indicated the
Scheme 6 Reagents and conditions: (i) lithium (RS)-N-benzyl-N-a-
methylbenzylamide (2 eq), THF, −78 °C; (ii) 2,6-di-tert-butylphenol,
t
i
t
THF, −78 °C to rt; (iii) KOtBu, BuOH, D, 3 h (R = Et, Pr, Bu);
(iv) KOtBu, tBuOH, rt, 7 days (R = Bn).
1
presence of three diastereoisomers by H NMR spectroscopic
analysis, with the two C(1) epimeric diastereoisomers 24–26
and 27–29 predominating in each case, with ca. 1% of the third
diastereoisomer 30–32 noted. In each case, the sum of the two
C(1) epimeric diastereoisomers to the third diastereoisomer
(A + B:C, Scheme 6) allowed E to be evaluated as >80, >160
and >140, respectively, with the major diastereoisomeric prod-
ucts 24–26 assigned the expected 1,2-syn-2,3-anti- configuration
on the assumption that conjugate addition proceeds pre-
dominantly anti- to the 3-alkyl group, with protonation of the
resultant enolate anti- to the 2-amino functionality (Scheme 6).7
Application of this protocol for addition of lithium (RS)-N-
benzyl-N-a-methylbenzylamide to the (RS)-3-tert-butyl accep-
tor 19 resulted in a 23.1:76.9 mixture of the 1,2-syn-2,3-anti-
and 1,2-anti-2,3-anti diastereoisomers 33 and 34. Although
exclusive anti- addition of the lithium amide relative to the
3-alkyl substituent is observed in all cases, the incorporation of
branched substituents in the 3-position of the cyclopentene-1-
carboxylate has a notable effect upon the selectivity of enolate
protonation at C(1). Protonation occurs predominantly anti- to
the 2-amino group in the 3-ethyl, 3-benzyl and 3-iso-propyl
cases, giving preferentially the 1,2-syn-2,3-anti-diastereoisomers
24–26, but the steric bulk of the 3-tert-butyl group results in a
Kinetic resolution of tert-butyl (RS)-3-alkyl-cyclopentene-1-
carboxylates with lithium (S)-N-benzyl-N-a-methylbenzylamide
With high levels of enantiorecognition noted between accep-
tors (RS)-11, 12, 17 and 19 and lithium (RS)-N-benzyl-N-a-
methylbenzylamide, the kinetic resolutions of (RS)-11, 12,
17 and 19 were attempted with homochiral lithium (S)-N-
benzyl-N-a-methylbenzylamide 8. Treatment of (RS)-3-ethyl,
(RS)-3-benzyl and (RS)-3-iso-propyl esters 11, 12 and 17 with
between 0.6 and 0.9 eq of lithium amide (S)-8 gave, at 47 to 51%
conversion, a mixture of three b-amino ester diastereoisomers,
the configurations within which (A:B:C) were identified as
shown in Scheme 7. As expected, conjugate addition anti- to
the 3-alkyl substituent was noted in each case, with high levels
of syn-1,2-selectivity upon protonation. However, addition of
(S)-8 (0.7 eq) to the (RS)-3-tert-butyl ester 19 gave, at 51%
conversion, a 31.9:66.9:1.2 mixture of diastereoisomers,22 with
only moderate anti-1,2-selectivity upon protonation. Chro-
matographic purification gave the major 3-ethyl, 3-benzyl and
3-iso-propyl-b-amino ester diastereoisomers 24–26 in >98% de
and an inseparable 32.2:67.8 mixture of 3-tert-butyl diastereo-
isomers 33:34 in 32–41% isolated yield. The resolved acceptors
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4
3 3 3 9

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(S)-11, (R)-12, (R)-17 and (S)-19 were also isolated in 36–43%
yield, and in >86 to >99 ± 1% ee,23 consistent with an E value
of >80 in each case. The relative configurations within the three
diastereoisomers were identical to those observed in the mutual
recognition protocol, and in the 3-iso-propyl series, analytical
samples of all three diastereoisomers 26, 29 and 32 were isolated
after exhaustive chromatographic purification and fractional
crystallisation. The relative configurations within diastereo-
isomers 26, 29 and 32 were proven independently by 1H NMR
NOE difference analysis, with the configuration within the third
diastereoisomer consistent with the ‘mismatched’ addition of
the lithium amide to the substrate (Fig. 2).
Fig. 2 Selected NOE difference enhancements for diastereoisomers
26, 29 and 32; other NOE enhancements omitted for clarity.
diastereoisomeric products arising from kinetic resolution
have the 2,3-anti- relative configuration in which the known
stereodirecting properties of the chiral lithium amide and (RS)-
acceptor combine in a “matched”fashion, with the ratio of these
diastereoisomers reflecting the selectivity upon protonation of a
common b-amino enolate. However, the 2,3-anti- configuration
contained within the minor third diastereoisomer 39 (consistent
i
with 32, R = Pr) indicates preferential conjugate addition of
lithium amide (S)-8 anti- to the 3-alkyl substituent, contrary to
the expected diastereofacial preference of lithium amide (S)-8,
consistentwiththe3-alkylsubstituentbeingthedominantstereo-
controlling feature in this reaction (Fig. 3).
Fig. 3 Possible diastereoisomeric b-amino ester products obtained
upon addition of lithium (S)-N-benzyl-N-a-methylbenzylamide 8 to
tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (ignoring proton-
ation selectivity).
To investigate this theory, the ability of the 3-iso-propyl
substituent to overcome the usual diastereofacial bias shown
by homochiral lithium N-benzyl-N-a-methylbenzylamide was
investigated through reaction of the mismatched combination
of (S)-3-iso-propyl acceptor 17 and lithium amide (R)-8. The
desired (S)-3-iso-propyl acceptor 17 was prepared from b-
amino ester (1S,2S,3S,aS)-29 (>98% de)24 in 35% overall yield,
by chemoselective N-debenzylation to afford b-amino ester 40,25
and subsequent N-methylation and N-oxidation/Cope elimina-
tion.26 The ee of (S)-17 was established to be >98% by 1H NMR
chiral shift experiments in the presence of Eu(hfc)3 and compari-
son with an authentic racemic sample (Scheme 8).
Conjugate addition of lithium amide (R)-8 to acceptor
(S)-17 gave an 88:11.1:0.9 mixture of diastereoisomers
(1R,2S,3S,aR)-32:(1S,2S,3S,aR)-41:(1S,2R,3R,aR)-42 in 64%
yield, with 1H NMR spectroscopic analysis of the major prod-
uct (1R,2S,3S,aR)-32 indicating that this was identical to the
minor third diastereoisomer arising from the kinetic resolution
protocol. Purification by chromatography and subsequent
recrystallisation gave (1R,2S,3S,aR)-32 as a single diastereo-
isomer in 29% yield, the relative configuration within which
Scheme 7 Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-
methylbenzylamide 8 (eq), THF, −78 °C; (ii) 2,6-di-tert-butylphenol,
THF, −78 °C to rt.
These results indicate good correlation between the levels of
enantiorecognition observed in the mutual and kinetic resolu-
tion reactions, and verify that mutual kinetic resolution allows
the identification of efficient kinetic resolution procedures.
Investigation of the enantiorecognition in the kinetic resolution
of tert-butyl (RS)-3-alkyl-cyclopentene-1-carboxylates with
lithium (S)-N-benzyl-N-a-methylbenzylamide
a. Minor diastereoisomer identification: evaluation of the
mismatched reaction product. Having demonstrated the viability
of this lithium amide mediated kinetic resolution methodo-
logy, studies were directed towards understanding further the
stereochemical course of these reactions. In the resolution
reactions, four possible diastereoisomeric products 36–39 may
arise [ignoring C(1) protonation selectivity]. The two major
3 3 4 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4

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Scheme 9 Reagents and conditions: (i) (R)-8, THF, −78 °C; (ii) 2,6-di-
Scheme 8 Reagents and conditions: (i) CAN (2.1 eq), MeCN:H2O
(5:1), rt; (ii) MeI; (iii) mCPBA, CHCl3, rt.
tert-butylphenol, THF, −78 °C to rt; (iii) KOtBu, tBuOH, D, 3 h.
was established by single crystal X-ray diffraction, with the
absolute configuration known relative to the (R)-a-methylbenzyl
stereogenic centre (Fig. 4). As expected, epimerisation of a
mixed fraction of (1R,2S,3S,aR)-32:(1S,2S,3S,aR)-41 gave
(1S,2S,3S,aR)-41 as a single diastereoisomer in quantitative
yield, establishing them as epimeric at C(1) (Scheme 9).
Scheme 10 Reagents and conditions: (i) Pd(OH)2 on C, MeOH, H2
(5 atm).
although markedly lower levels of selectivity for the ‘matched’
anti-2,3-diastereoisomers upon conjugate addition were noted in
the kinetic resolution experiments. As these resolution reactions
were run close to 50% conversion in each case, this difference in
selectivity arises as a consequence of mass action due to the ac-
cumulation of the slower reacting enantiomer of the 3-alkyl ac-
ceptor under the reaction conditions. To confirm this hypothesis
by drowning out the mass action effect, addition of a large excess
(10 eq) of (RS)-3-alkyl-acceptors 11, 12 and 17 to the homochi-
ral lithium amide (S)-8 was performed, which at 87–97% conver-
sion (with respect to the lithium amide) was found to reproduce
essentially the diastereoselectivities noted in the mutual kinetic
resolution experiments. Less than 1.5% of a third diasteroisomer
was noted in each of these reactions, corresponding to 2,3-anti-
selectivity in the range of >98.5:1.5. This is consistent with the
third, minor diastereoisomeric product in the kinetic resolution
protocol arising from the stereochemically mismatched pairing
reaction as a consequence of mass action (Scheme 11).
Fig. 4 Chem 3D representation of the X-ray crystal structure of
(1R,2S,3S,aR)-32 (some H omitted for clarity).
The assigned configurations within the 3-iso-propyl series
of diastereoisomers were verified further by hydrogenolysis
of (1R,2S,3S,aS)-26 (the major product from kinetic reso-
lution) and (1R,2S,3S,aR)-32 (the major product from the
mismatched addition), which both gave the primary b-amino
ester (1R,2S,3S)-43. This verifies the hypothesis that the 3-alkyl
substituent, not the lithium amide, is the dominating factor
affecting the stereoselectivity in these reactions (Scheme 10).
c. Evolution of ee in kinetic resolution. To further our under-
standing of the kinetic resolution reaction, the evolution of ee
in the substrate with increasing conversion during the resolution
of (RS)-3-benzyl-12 was monitored (Fig. 5). Evaluation of the
stereoselectivity factor by linear regression allows quantifica-
tion of E = 164, in agreement with the values of >160 and >120
from the mutual and kinetic resolution protocols, respectively,
and with excellent agreement between the experimentally deter-
mined and theoretical values. As expected, at a conversion of
approximately 51%, the acceptor (R)-12 is recovered in essen-
tially homochiral form.
b. Effects of mass action in the resolution reaction. With the
diastereoisomeric configurations formed in the kinetic resolu-
tion protocol unambiguously assigned, attention turned to a
full analysis of the product distributions arising from these
reactions. Close examination indicated a reasonable correlation
between the levels of syn-1,2-protonation selectivity noted in the
mutual kinetic resolution and kinetic resolution experiments,
Although not included in the graphical representation of
Fig. 5, the use of more than one equivalent of homochiral lithium
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4
3 3 4 1

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under the reaction conditions, presumably via a c-deprotonation
and subsequent in situ reprotonation mechanism. As this phe-
nomenon is seen only with >1 eq of lithium amide, these results
are consistent with a simple model in which initial binding and
activation of the a,b-unsaturated ester by lithium co-ordination
to a lithium amide leads to subsequent conjugate addition or, in
the presence of excess lithium amide, to competitive c-deprot-
onation by lithium amide. Further evidence for this mechanism
may be derived from analysis of the diastereoselectivity of the
isolated b-amino ester products from the kinetic resolution
reactions, with excellent correlation between experimentally
observed and theoretical values observed with less than 1 eq
of lithium amide, with anomalous results only obtained with
a molar excess of lithium amide (S)-8. For example, at 97%
1
conversion, H NMR analysis indicates an 8% de in favour of
the matched 2,3-anti-diastereoisomers. At this conversion, this
level of stereoselectivity cannot ordinarily be obtained, as the
theoretical diastereoisomer ratio (matched 2,3-anti-diastereo-
isomers:mismatched 2,3-anti-diastereoisomers) should be 50:47
(3% de) in which all of the faster reacting (S)-ester substrate
enantiomer is consumed, leaving the slower reacting mismatched
(R)-substrate. This discrepancy may be ascribed to a process in
which the ester substrate enantiomers are racemised under the
reaction conditions by a c-deprotonation mechanism.
Scheme 11 Reagents and conditions: (i) Lithium (S)-N-benzyl-N-a-
methylbenzylamide (0.1 eq), THF, −78 °C; (ii) 2,6-di-tert-butylphenol,
THF, −78 °C to rt.
Deprotection: Asymmetric synthesis of 3-alkylcispentacin and 3-
alkyltranspentacin analogues
With the homogenous 3-ethyl, 3-benzyl and 3-iso-propyl-syn-
1,2-anti-2,3-b-amino esters 24–26 (>98% de) in hand from the
kinetic resolution protocol, deprotection to their respective
3-alkylcispentacin derivatives was investigated. Pd mediated
N-debenzylation of 24–26 gave the corresponding primary b-
amino esters, with subsequent treatment with TFA giving the
desired 3-alkylcispentacins 44–46 in good yield (61–72%) and
in >98% de and 98 ± 1% ee27 after purification by ion exchange
chromatography. The 3-ethyl, 3-benzyl and 3-iso-propyl-syn-
1,2-anti-2,3-b-amino esters 24–26 and the 32.2:67.8 mixture
of syn-1,2-anti-2,3-:anti-1,2-anti-2,3- 3-tert-butyl b-amino ester
diastereoisomers 33:34 were subsequently converted quantita-
tively to their thermodynamic anti-1,2-anti-2,3-diastereoisomers
27–29 and 34 in >98% de, with subsequent hydrogenolysis and
ester hydrolysis giving the 3-alkyltranspentacin hydrochlorides
47–50 in good yield (61–72%) and in >98% de (Scheme 12).
In conclusion, we have demonstrated the generality of the
kinetic resolution of (RS)-3-alkyl-cyclopentene-1-carboxylates
with homochiral lithium (S)-N-benzyl-N-a-methylbenzylamide
and have used this protocol for the synthesis of 3-alkylcispentacin
and 3-alkyltranspentacin analogues in high de and high ee. The
further applications of this protocol to the parallel kinetic resolu-
tion of (RS)-3-alkylcyclopentene-1-carboxylates and the kinetic
and parallel kinetic resolution of a range of (RS)-5-alkylcyclo-
pentene-1-carboxylates are reported in the following papers,
while bioactivity studies and the secondary structural studies of
oligomers of these building blocks are in progress.
Experimental
General experimental
All reactions were carried out under nitrogen or argon using
standard vacuum line techniques and glassware that was flame
dried and cooled under nitrogen. THF was distilled from sodium/
benzophenone ketyl; n-butyllithium was used as a solution in
hexane and was titrated against diphenylacetic acid prior to use.
All other reagents were used as supplied without further purifica-
tion. Flash column chromatography was performed on silica gel
(Kieselgel 60). TLC was performed on Merck aluminium sheets
coated with 0.2 mm silica gel 60 F254. Plates were visualised either
by UV light (254 nm), iodine, ammonium molybdate (7% solution
in ethanol), potassium permanganate (1% in 2% aqueous acetic
acid, containing 7% potassium carbonate) or Draggendorf’s
Fig. 5 Evolution of ee of recovered acceptor in the kinetic resolution
of (RS)-3-benzyl–12.
amide gives anomalous results, with the ee of the recovered sub-
strate decreasing from the >98% ee measured at 81% conversion
with 0.9 eq of lithium amide to 36% ee at 98% conversion with
2.0 eq of lithium amide. This decrease in ee at high conversion is
consistent with epimerisation of the chiral a,b-unsaturated ester
3 3 4 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4

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followed by NH4Cl (aq, sat) solution to excess. The solution was
diluted with Et2O and the aqueous phase separated and extracted
with Et2O (2×). The combined organic extracts were dried over
MgSO4, filtered and concentrated in vacuo to give the crude b-hy-
droxy ester. The individual products were purified as described.
General procedure 3: PPh3/DIAD mediated elimination to fur-
nish a,b-unsaturated acceptors. A solution of the b-hydroxy ester
and PPh3 (1.5 eq) in anhydrous THF was cooled to 0 °C prior to
the dropwise addition of DIAD (1.3 eq). The reaction mixture
was warmed to rt, whereat it was stirred overnight. The solvent
was removed in vacuo and n-pentane (50 ml) added. After stirring
at rt for 0.5 h, the precipitate was removed by filtration and the
filtrate concentrated in vacuo. Additional n-pentane was added
and the process repeated a further two times. Concentration in
vacuo of the resultant filtrate furnished a yellow oil, which was
passed through a silica gel plug (eluting 2% Et2O/n-pentane) to
give the requisite a,b-unsaturated acceptor.
General procedure 4: Lithium amide conjugate additions.
A solution of the amine in anhydrous THF under an inert
atmosphere was cooled to −78 °C, prior to the slow addition
of n-butyllithium (titrated before use, 1 eq). The resultant
pink solution was stirred for 1 h at this temperature before the
requisite a,b-unsaturated acceptor as a solution in anhydrous
THF was added dropwise via syringe. The resulting mixture
was stirred for 3 h at −78 °C after which time the reaction was
quenched by addition of either (a) a precooled solution of 2,6-
di-tert-butylphenol in anhydrous THF; or (b) NH4Cl (aq, sat)
solution. The resultant mixture was kept at −78 °C for 0.5 h and
then allowed to warm to rt over 1 h. NH4Cl (aq, sat) solution was
added and the mixture diluted with Et2O. The organic layer was
separated and the aqueous layer extracted with Et2O (3×). The
combined organic extracts were dried over MgSO4, filtered and
concentrated in vacuo to give the crude products. The individual
products were purified as described.
Scheme 12 Reagents and conditions: (i) Pd(OH)2 on C, MeOH, H2
(5 atm); (ii) TFA:DCM (1:1) then HCl, Et2O; (iii) Dowex 50WX8-200;
(iv) KOtBu, tBuOH, D, 3 h (R = Et, iPr, tBu); (v) KOtBu, tBuOH, rt, 7 d
(R = Bn).
reagent.28 Infrared spectra were recorded as thin films or KBr
discs using a Perkin-Elmer PARAGON 1000 FT-IR spectrome-
ter, with selected peaks reported in cm−1. 1H and 13C NMR spectra
were recorded on Varian Gemini 200 (1H 200 MHz, 13C 50 MHz),
Bruker DPX-200 (1H 200 MHz, 13C 50 MHz), Bruker DPX-400
or AVANCE AV-400 (1H 400 MHz, 13C100 MHz), or Bruker AM-
500 (1H500 MHz, 13C125 MHz) spectrometers. Chemical shifts
(dH) are reported in parts per million (ppm) and are referenced to
the residual solvent peak, with coupling constants (J) measured in
hertz. Low resolution mass spectra (m/z) were recorded on either
a VG Masslab 20-250 instrument (CI, NH3) or Platform instru-
ment (APCI). Major peaks are listed with intensities quoted as
percentages of the base peak. Accurate mass measurements were
recorded on a VG Autospec and a Waters 2790-Micromass LCT
electrospray ionisation mass spectrometer operating at a resolu-
tion of 5000 full width half height. Positive ion spectra were cali-
brated relative to PEG with tetraoctylammonium bromide as the
internal lock mass. Negative ion spectra were calibrated relative to
poly-DL-alanine with leucine enkephalin as the internal lock mass.
Optical rotations were recorded on a Perkin-Elmer 241 polarim-
eter, using a path length of 10 cm, in spectroscopic grade solvents
(Aldrich), with concentrations (c) given in g per 100 cm3, solvent
and temperature as recorded. Melting points were recorded on a
Gallenkamp Hot Stage apparatus and are uncorrected.
General procedure 5: Lithium amide kinetic resolutions. A solu-
tion of the amine in anhydrous THF under an inert atmosphere
was cooled to −78 °C, prior to the slow addition of n-butyllithium
(titrated before use, 1 eq). The resultant pink solution was stirred
for 1 h at this temperature before being added, via cannula, to the
requisite tert-butyl (RS)-3-alkylcyclopentene-1-carboxylate as
a solution in anhydrous THF at −78 °C. The resulting mixture
was stirred for 3 h at −78 °C after which time the reaction was
quenched by addition of a precooled solution of 2,6-di-tert-
butylphenol in anhydrous THF. The resultant mixture was kept
at −78 °C for 0.5 h, then allowed to warm to rt over 1 h. Saturated
aqueous NH4Cl solution was added and the mixture diluted with
Et2O. The organic layer was separated and the aqueous layer ex-
tracted with Et2O (3×). The combined organic extracts were dried
over MgSO4, filtered and concentrated in vacuo to give the crude
products. The individual products were purified as described.
General procedure 6: Epimerisation of b-amino esters. To a
solution of the substrate in tert-butanol was added a catalytic
quantity of potassium tert-butoxide (ca. 20 mg). The resultant
mixture was heated at reflux for 3 h then allowed to cool (n.b.
in the case of adducts of tert-butyl (RS)-3-benzylcyclopentene-
1-carboxylate, the epimerisation was carried out at rt over 7 d
to prevent ester cleavage). The reaction was quenched by addi-
tion of NH4Cl (aq, sat) and the mixture diluted with Et2O. The
organic layer was separated and the aqueous layer extracted
with Et2O (3×). The combined organic extracts were dried over
MgSO4, filtered and concentrated in vacuo to give the crude
product. The individual products were purified as described.
General procedure 1: Double enolate formation. Sodium
hydride (60 wt% in mineral oil) was first prepared for use by
careful washing with n-pentane (3×) and discarding the super-
natant. The liberated sodium hydride (1.05 eq) was suspended
in anhydrous THF and cooled to 0 °C. A solution of the b-keto
ester in anhydrous THF was added dropwise and stirring contin-
ued for 20 min after the evolution of H2(g) had ceased. n-Butyl-
lithium (titrated before use, 1.05 eq) was added dropwise and the
reaction mixture stirred for an additional 0.5 h, prior to cooling
to −78 °C. The dianion was used immediately and the individual
products purified as described.
General procedure 2: NaBH4 reduction of b-keto esters. To a
stirred solution of the b-keto ester in EtOH at 0 °C was added
portionwise NaBH4 (1 eq). The reaction mixture was stirred for
an additional 1 h, after which distilled water was added dropwise,
General procedure 7: Hydrogenolysis of b-amino esters using
Pearlman’s catalyst. A solution of the substrate in MeOH was
placed in a Fischer-Porter bottle. The vessel was pump-filled five
times with nitrogen prior to charging with Pd(OH)2 (20 wt% on
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4
3 3 4 3

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carbon, 20% by mass of substrate used). The reaction mixture
was stirred rapidly at rt overnight, after which time the solu-
tion was filtered through a pad of Celite®, washed through with
MeOH and concentrated in vacuo to give the crude product. The
individual products were purified as described.
onated with sodium hydride (1.14 g, 28.6 mmol) then n-butyl-
lithium (1.6 M, 17.9 ml, 28.6 mmol) in accordance with general
procedure 1. Ethyl iodide (2.40 ml, 29.8 mmol) was added neat,
dropwise, and the mixture stirred for 0.5 h at −78 °C before being
allowed to slowly warm to 0 °C. The reaction was quenched by
sequential addition of MeOH (2 ml), H2O (5 ml) and NH4Cl (aq,
sat, 50 ml). The organic layer was separated and the aqueous
layer extracted with Et2O (3 × 50 ml). The combined organic
extracts were dried (MgSO4), filtered and concentrated in vacuo
to give the crude product as a yellow oil. The residue was puri-
fied by flash chromatography on silica gel (5% Et2O/n-pentane)
to give 9 (5.32 g, 92%) as a colourless oil; mmax (film) 1749s, 1721s,
1161m; major diastereoisomer: dH (400 MHz, CDCl3) 0.95 (3H,
t, J 7.5, CH2CH3), 1.22–1.42 (2H, m, C(4)HA and CHAHBCH3),
1.47 (9H, s, OC(CH3)3), 1.83 (1H, m, CHAHBCH3), 2.02–2.50
(4H, m, C(3)H, C(4)HB and C(5)H2), 3.03 (1H, dd, J 11.1, 8.3,
C(1)H); dC (100 MHz, CDCl3) 11.7 (CH2CH3), 22.6 (CH2CH3),
25.0 (C(5)), 26.7 (C(4)), 28.0 (OC(CH3)3), 50.7 (C(3)), 56.2
General procedure 8: TFA cleavage furnishing free amino acids.
TFA was added to a solution of the crude b-amino ester at rt and
stirred for 16 h. Concentration in vacuo gave an oil, which was
dissolved in MeOH (2 ml) and HCl in Et2O (sat, 2 ml). Concen-
tration in vacuo gave a pale brown solid, which was partitioned
between Et2O (4 ml) and H2O (4 ml). The aqueous phase was
separated and concentrated to a quarter of its volume and
chromatographed using Dowex 50WX8-200 resin to give the
free amino acid.
General procedure 9: TFA cleavage furnishing amino acid
hydrochloride salts. TFA was added to a solution of the crude
b-amino ester at rt and stirred for 16 h. Concentration in vacuo
gave an oil, which was dissolved in MeOH (2 ml) and HCl in
Et2O (sat, 2 ml). Concentration in vacuo gave a pale brown solid,
which was partitioned between Et2O (4 ml) and H2O (4 ml). The
aqueous phase was concentrated to afford the crude b-amino
acid as its hydrochloride salt. The individual products were puri-
fied as described.
t
(C(1)), 81.6 (OC(CH3)3), 168.9 (CO2 Bu), 214.3 (C(2)); minor
diastereoisomer: dH (400 MHz, CDCl3) 0.89 (3H, t, J 7.4,
CH2CH3), 1.22–1.42 (2H, m, C(4)HA and CHAHBCH3), 1.46
(9H, s, OC(CH3)3), 1.83 (1H, m, CHAHBCH3), 2.02–2.50 (4H, m,
C(3)H, C(4)HB and C(5)H2), 3.15 (1H, m, C(1)H); dC (100 MHz,
CDCl3) 10.7 (CH2CH3), 22.6 (CH2CH3), 25.2 (C(5)), 27.0 (C(4)),
28.0 (OC(CH3)3), 50.3 (C(3)), 55.4 (C(1)), 81.6 (OC(CH3)3),
t
+
168.9 (CO2 Bu), 215.3 (C(2)); m/z (CI+, NH3) 230 (MNH4 , 5),
+
Preparation of di-tert-butyl adipate
213 (MH+, 5), 175 (MNH4 –C4H8, 100), 157 (MH+–C4H8, 10%);
HRMS, found 213.1492; C12H21O3 (MH+) requires 213.1491.
To a rapidly stirred solution of tert-butanol (77.7 ml, 0.81 mol)
and N,N-dimethylaniline (99.7 ml, 0.79 mol) in diethyl ether
(200 ml) at 0 °C was added dropwise a solution of adipoyl
chloride (36.3 ml, 0.25 mol) in diethyl ether (100 ml). The mixture
was stirred for 20 h at rt, after which time the mixture was diluted
with H2O (100 ml) and the ethereal layer separated. The organic
layer was washed with HCl (aq, 2 M, 5 × 50 ml), NaHCO3 (aq,
sat, 2 × 50 ml) and brine (aq, sat, 100 ml), then dried (MgSO4),
filtered and concentrated in vacuo. The title compound (57.3 g,
89%) was obtained as a colourless oil, which slowly crystallised
on standing; mp 28–29 °C (lit.3 29–31 °C); dH (200 MHz, CDCl3)
1.45 (18H, s, OC(CH3)3), 1.56–1.73 (4H, m, C(3)H2 and C(4)H2),
2.15–2.32 (4H, m, C(2)H2 and C(5)H2), with all other spectro-
scopic data consistent with that previously reported.12
Preparation of tert-butyl 3-benzyl-2-oxocyclopentane-1-carboxy-
late 10
A
solution of tert-butyl 2-oxocyclopentane-1-carboxylate
(5.0 g, 27.3 mmol) in anhydrous THF (100 ml) at −78 °C was
deprotonated with sodium hydride (1.14 g, 28.6 mmol) then
n-butyllithium (1.6 M, 17.9 ml, 28.6 mmol) in accordance with
general procedure 1. Benzyl bromide (3.56 ml, 29.8 mmol) was
added neat, dropwise, and the mixture stirred for 0.5 h at −78 °C
before being allowed to slowly warm to 0 °C. The reaction was
quenched by sequential addition of MeOH (2 ml), H2O (5 ml)
and NH4Cl (aq, sat, 50 ml). The organic layer was separated
and the aqueous layer extracted with Et2O (3 × 50 ml). The
combined organic extracts were dried (MgSO4), filtered and
concentrated in vacuo to give the crude product as a yellow oil.
The residue was purified by flash chromatography on silica gel
(5% Et2O/n-pentane) to give 10 (6.66 g, 89%) as a colourless oil;
mmax (film) 1716s, 1146m; major diastereoisomer: dH (400 MHz,
CDCl3) 1.48 (9H, s, OC(CH3)3), 1.49 (1H, m, C(4)HA), 1.99–2.40
(3H, m, C(4)HB and C(5)H2), 2.54 (1H, m, C(3)H), 2.60 (1H,
m, CHAHBPh), 3.02 (1H, dd, J 10.6, 8.5, C(1)H), 2.17 (1H, m,
CHAHBPh), 7.16–7.31 (5H, m, Ph); dC (100 MHz, CDCl3) 24.8
(C(5)), 26.8 (C(4)), 27.9 (OC(CH3)3), 35.4 (CH2Ph), 51.1 (C(3)),
56.1 (C(1)), 81.7 (OC(CH3)3), 126.5 (p-Ar), 128.7 and 129.1
(o-, m-Ar), 139.9 (ipso-Ar), 169.0 (CO2tBu), 215.7 (C(2)); minor
diastereoisomer: dH (400 MHz, CDCl3) 1.48 (9H, s, OC(CH3)3),
1.49 (1H, m, C(4)HA), 1.86 (1H, m, C(5)HA), 1.99–2.40 (3H, m,
C(3)H, C(4)HB and C(5)HB), 2.60 (1H, m, CHAHBPh), 3.17 (1H,
m, CHAHBPh), 3.20 (1H, m, C(1)H), 7.16–7.31 (5H, m, Ph); dC
(100 MHz, CDCl3) 25.0 (C(5)), 27.2 (C(4)), 27.9 (OC(CH3)3),
35.8 (CH2Ph), 50.8 (C(3)), 55.2 (C(1)), 81.7 (OC(CH3)3), 126.5 (p-
Ar), 128.7 and 129.1 (o, m-Ar), 139.7 (ipso-Ar), 169.0 (CO2tBu),
Preparation of tert-butyl 2-oxocyclopentane-1-carboxylate
Sodium hydride (60% suspension in mineral oil, 8.0 g, 0.20 mol)
was first prepared for use by careful washing with n-pentane
(3 × 50 ml) and discarding the supernatant. The liberated sodium
hydride was then suspended in anhydrous toluene (400 ml) and the
mixture heated to 60 °C. A solution of di-tert-butyladipate (2.0 g)
in tert-butanol (2 mL) was added in one portion followed by, after
an additional 30 min, the dropwise addition of the remaining di-
tert-butyl adipate (50.0 g, 0.19 mol) in toluene (50 ml). Once ad-
dition was complete the reaction mixture was heated at 100 °C for
3 h, then allowed to cool in an ice bath. The reaction was quenched
by cautious, sequential addition of MeOH (10 ml), H2O (10 ml)
and NH4Cl (aq, sat, 100 ml). The organic layer was separated
and the aqueous layer extracted with toluene (3 × 50 ml). The
combined organic extracts were dried (MgSO4), filtered and
concentrated in vacuo to give the crude product as a yellow oil.
Subsequent purification by vacuum distillation (bp 110–112 °C,
10 mm Hg; lit.4 80–85 °C, 2 mm Hg) gave the title compound
(32.1 g, 84%) as a colourless oil; dH (200 MHz, CDCl3) 1.45 (9H, s,
OC(CH3)3), 1.74–1.97 (1H, m, C(4)HA), 2.05–2.33 (5H, m, C(3)H2,
C(4)HB and C(5)H2), 3.05 (1H, app t, J 8.7, C(1)H), with all other
spectroscopic data consistent with that previously reported.13
+
215.7 (C(2)); m/z (CI+, NH3) 292 (MNH4 , 85), 275 (MH+, 10),
+
236 (MNH4 –C4H8, 100), 219 (MH+−56, 24%); HRMS, found
275.1649; C17H23O3 (MH+) requires 275.1647.
Preparation of ethyl 2-oxo-1-(1-methylethyl)-cyclopentane-1-
carboxylate 14
Preparation of tert-butyl 3-ethyl-2-oxocyclopentane-1-carboxy-
late 9
A mixture of b-keto ester 13 (15.0 g, 96.0 mmol), anhydrous
K2CO3 (53.1 g, 0.384 mol) and isopropyl iodide (38.4 ml,
0.38 mol) in acetone (300 ml) was heated at reflux for 6 h.
A solution of tert-butyl 2-oxocyclopentane-1-carboxylate (5.0 g,
27.3 mmol) in anhydrous THF (100 ml) at −78 °C was deprot-
3 3 4 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4

View Article Online
Following cooling to rt the mixture was filtered, the residue
washed with acetone (3 × 20 ml) and the filtrate concentrated in
vacuo to afford the crude product as a yellow oil. Purification by
flash chromatography on silica gel (10% Et2O/n-pentane) gave 14
(17.3 g, 91%) as a colourless oil; dH (200 MHz, CDCl3) 0.84 (3H,
d, J 6.8, CH(CH3ACH3B)), 0.89 (3H, d, J 6.8, CH(CH3ACH3B)),
1.26 (3H, t, J 6.9, OCH2CH3), 1.80–2.70 (7H, m, C(3)H2, C(4)H2,
C(5)H2 and CH(CH3)2), 4.18 (2H, m, OCH2CH3), with all other
spectroscopic data consistent with that previously reported.15
C(5)H2), with all other spectroscopic data consistent with that
previously reported.29
(iii) Preparation of methyl 2-oxo-3-(1,1-dimethylethyl)-
1-cyclopentanecarboxylate. Sodium hydride (60% suspension
in mineral oil, 3.00 g, 74.8 mmol) was first prepared for use
by careful washing with n-pentane (3 × 20 ml) and discard-
ing the supernatant. To a vigorously stirred solution of the
liberated sodium hydride in DMF (50 ml) at 0 °C was added
neat, dropwise, (1,1-dimethylethyl)-1-cyclopentanone (5.00 g,
35.6 mmol). The reaction was allowed to warm to rt whereat
it was stirred for 3 h. Dimethyl carbonate (6.44 g, 71.5 mmol)
was added and stirring continued for 12 h. The reaction was
quenched by dropwise addition of H2O (10 ml) and neutralised
with NH4Cl (aq, sat, ca. 50 ml). The aqueous phase was sepa-
rated and extracted with Et2O (3 × 50 ml) and the combined
organic extracts were dried (MgSO4), filtered and concentrated
in vacuo. Purification by flash chromatography on silica gel (10%
Et2O/n-pentane) gave 18 (5.02 g, 71%) as a colourless oil; major
diastereoisomer: dH (200 MHz, CDCl3) 1.00 (9H, s, C(CH3)3),
1.55–2.65 (5H, m, C(3)H, C(4)H2 and C(5)H2), 3.08 (1H, dd, J
11.8, 8.2, C(1)H), 3.76 (3H, s, OCH3); minor diastereoisomer:
dH (200 MHz, CDCl3) 0.98 (9H, s, C(CH3)3), 1.55–2.65 (5H, m,
C(3)H, C(4)H2 and C(5)H2), 3.26 (1H, m, C(1)H), 3.76 (3H, s,
OCH3), with all other spectroscopic data consistent with that
previously reported.19
Preparation of ethyl 3-(1-methylethyl)-2-oxo-cyclopentane-1-
carboxylate 15
To a freshly prepared solution of sodium ethoxide in EtOH
(1.37 g, 60.4 mmol Na in 50 ml absolute EtOH) was added
neat, dropwise, ethyl-2-oxo-1-(1-methylethyl)-cyclopentane-1-
carboxylate 14 (10.0 g, 50.4 mmol). The solution was heated
at reflux for 3 h, after which time half the solvent was removed
by distillation. Toluene (100 ml) was added and the remaining
EtOH removed by azeotropic distillation. The reaction mixture
was heated at reflux for a further 3 h, cooled to 0 °C and then
quenched by addition of NH4Cl (aq, sat, 50 ml). The aqueous
layer was separated and extracted with toluene (2 × 50 ml) and
the combined organic extracts dried (MgSO4), filtered and con-
centrated in vacuo. Purification by flash chromatography on
silica gel (10% Et2O/n-pentane) gave 15 (7.20 g, 72%) as a colour-
less oil; major diastereoisomer: dH (400 MHz, CDCl3) 0.90 (3H,
d, J 6.8, CH(CH3ACH3B)), 1.07 (3H, d, J 6.8, CH(CH3ACH3B)),
1.29 (3H, m, OCH2CH3), 1.64 (1H, m, C(4)HA), 2.01–2.40 (5H,
m, C(3)H, C(4)HB, C(5)H2 and CH(CH3)2), 3.06 (1H, dd, J 11.4,
8.4, C(1)H), 4.20 (2H, m, OCH2CH3); minor diastereoisomer:
dH (400 MHz, CDCl3) 0.92 (3H, d, J 6.8, CH(CH3ACH3B)), 1.05
(3H, d, J 6.8, CH(CH3ACH3B)), 1.28 (3H, m, OCH2CH3), 1.64
(1H, m, C(4)HA), 2.01–2.40 (5H, m, C(3)H, C(4)HB, C(5)H2
and CH(CH3)2), 3.26 (1H, m, C(1)H), 4.20 (2H, m, OCH2CH3),
with all other spectroscopic data consistent with that previously
reported.16
Preparation of tert-butyl (RS)-3-ethylcyclopentene-1-carboxy-
late 11
(i) Preparation of tert-butyl 2-hydroxy-3-ethylcyclopentane-
1-carboxylate. The b-keto ester 9 (4.00 g, 18.8 mmol) in EtOH
(30 ml) was treated with NaBH4 (0.71 g, 18.8 mmol) in
accordance with general procedure 2, giving the title compound
(3.75 g, 93%) as a complex mixture of diastereoisomers. This
material was used without purification, although for the
purposes of analysis a small quantity was subjected to flash
chromatography on silica gel (20% Et2O/n-pentane) to give the
title compound as a colourless oil; mmax(film) 3473br s, 1705s,
1155m; major diastereoisomer: dH (400 MHz, CDCl3) 0.94 (3H,
t, J 7.4, CH2CH3), 1.15–1.22 (2H, m, C(4)HA and CHAHBCH3),
1.45 (1H, m, C(5)HA), 1.46 (9H, s, OC(CH3)3), 1.84 (1H, m,
CHAHBCH3), 1.90–2.04 (3H, m, C(3)H, C(4)HB and C(5)HB),
2.69 (1H, ddd, J 9.1, 8.5, 5.6, C(1)H), 3.17 (1H, br s, OH),
3.98 (1H, dd, J 5.6, 3.9, C(2)H); dC (50 MHz, CDCl3) 12.3
(CH2CH3), 26.2 (C(5)), 26.7 (CH2CH3), 28.0 (OC(CH3)3), 28.6
(C(4)), 48.8 (C(1) and C(3)), 78.3 (C(2)), 81.0 (OC(CH3)3),
Preparation of methyl 2-oxo-3-(1,1-dimethylethyl)-1-cyclo-
pentanecarboxylate 18
(i) Preparation of 1-trimethylsilyloxycylopentene. To a rap-
idly stirred solution of cyclopentanone (20.0 g, 0.24 mol) and
trimethylsilylchloride (30.2 ml, 0.24 mol) in DMF (100 ml) was
added dropwise triethylamine (33.2 ml, 0.24 mol). The resulting
mixture was heated at 100 °C for 12 h, cooled to rt and then
diluted with n-pentane (200 ml) and H2O (200 ml). The organic
layer was separated and the aqueous layer extracted with n-
pentane (2 × 100 ml). The combined organic extracts were
washed with 1:1 HCl (2 M aq, 100 ml)/brine (aq, sat, 100 ml),
NaHCO3 (aq, sat, 100 ml) and then dried (MgSO4), filtered and
concentrated in vacuo. Purification by vacuum distillation (bp
54–56 °C, 21 mm Hg; lit.8 45 °C, 11 mm Hg) gave the title com-
pound (27.5 g, 74%) as a colourless oil; dH (200 MHz, CDCl3)
0.22 (9H, s, Si(CH3)3), 1.79–2.04 (2H, m, C(4)H2), 2.12–2.31 (4H,
m, C(3)H2 and C(5)H2), 4.63 (1H, br s, C(2)H), with all other
spectroscopic data consistent with that previously reported.18
t
174.7 (CO2 Bu); minor diastereoisomer: dH (400 MHz, CDCl3)
0.95 (3H, t, J 7.4, CH2CH3), 1.44 (1H, m, CHAHBCH3), 1.47
(9H, s, OC(CH3)3), 1.50–1.71 (3H, m, C(3)H, C(4)HA and
CHAHBCH3), 1.79–2.08 (3H, m, C(4)HB and C(5)H2), 2.69
(1H, app td, J 10.0, 3.5, C(1)H), 3.08 (1H, br s, OH), 4.25 (1H,
app t, J 3.5, C(2)H); dC (50 MHz, CDCl3) 12.7 (CH2CH3), 22.0
(C(5)), 25.2 (CH2CH3), 28.0 (OC(CH3)3 and C(4)), 47.6 (C(3)),
t
50.1 (C(1)), 74.3 (C(2)), 81.0 (OC(CH3)3), 174.9 (CO2 Bu);
+
m/z (CI+, NH3) 215 (MH+, 10), 176 (MNH4 –C4H8, 100), 159
(MH+–C4H8, 20%); HRMS, found 215.1645; C12H23O3 (MH+)
requires 215.1647.
(ii) Preparation of (1,1-dimethylethyl)-1-cyclopentanone.
To a stirred solution of titanium tetrachloride (14.1 ml,
0.13 mol) and tert-butyl chloride (15.7 ml, 0.143 mol) in DCM
(100ml)at −45°C, wasaddeddropwiseasolutionof 1-trimethyl-
silyloxycylopentene (20.1 g, 0.13 mol) in DCM (50 ml). After
2 h the reaction mixture was warmed to 0 °C and neutralised by
addition of NaHCO3 (aq, sat, 100 ml). The aqueous phase was
separated and extracted with DCM (3 × 50 ml). The combined
organic extracts were dried (MgSO4), filtered and concentrated
in vacuo. Purification by vacuum distillation (bp 86–88 °C,
18 mm Hg; lit.9 95 °C, 45 mm Hg) gave the title compound
(7.1 g, 39%) as a colourless oil; dH (200 MHz, CDCl3) 0.96 (9H,
s, C(CH3)3), 1.50–2.50 (7H, m, C(2)H, C(3)H2, C(4)H2 and
(ii) Preparation of tert-butyl (RS )-3-ethylcyclopentene-
1-carboxylate 11. tert-Butyl 2-hydroxy-3-ethylcyclopentane-
1-carboxylate (3.00 g, 14.0 mmol) in THF (50 ml) was
treated with PPh3 (5.51 g, 21.0 mmol) and DIAD (3.60 ml,
18.3 mmol) in accordance with general procedure 3, giving
(RS )-11 (2.39 g, 87%) as a volatile, colourless liquid; mmax
(film) 1709s, 1631m, 1167m; dH (400 MHz, CDCl3) 0.94 (3H,
t, J 7.4, CH2CH3), 1.37 (1H, m, CHAHBCH3), 1.49 (9H, s,
OC(CH3)3), 1.46–1.54 (2H, m, CHAHBCH3 and C(4)HA), 2.12
(1H, dddd, J 13.0, 8.6, 8.6, 4.5, C(4)HB), 2.48 (1H, m, C(5)HA),
2.53 (1H, m, C(5)HB), 2.70 (1H, m, C(3)H ), 6.61 (1H, app q,
J 2.0, C(2)H ); dC (50 MHz, CDCl3) 12.0 (CH2CH3), 27.7
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4
3 3 4 5

View Article Online
(CH2CH3), 28.0 (OC(CH3)3), 29.5 (C(5)), 30.8 (C(4)), 47.9
(C(3)), 79.9 (OC(CH3)3), 137.7 (C(1)), 146.2 (C(2)), 165.4
1200m; major diastereoisomer: dH (400 MHz, CDCl3) 0.88 (3H,
d, J 6.6, CH(CH3ACH3B)), 0.97 (3H, d, J 6.6, CH(CH3ACH3B)),
1.24 (1H, m, C(4)HA), 1.28 (3H, t, J 7.1, CH2CH3), 1.52 (1H, m,
CH(CH3)2), 1.70 (1H, m, C(3)H), 1.87–1.98 (3H, m, C(4)HB and
C(5)H2), 2.52 (1H, br s, OH), 2.69 (1H, m, C(1)H), 4.03 (1H, m,
C(2)H), 4.21 (2H, q, J 7.1, CH2CH3); dC (50 MHz, CDCl3) 14.0
(OCH2CH3), 20.0 (C(5)), 21.0 (C(4)), 26.7 (CH(CH3ACH3B)),
27.1 (CH(CH3ACH3B)), 30.7 (CH(CH3)2), 49.4 (C(3)), 54.5
(C(1)), 60.5 (OCH2CH3), 76.3 (C(2)), 174.7 (CO2tBu); m/z (CI+,
NH3) 218 (MNH4+, 5), 201 (MH+, 100), 183 (MH+–H2O, 20%);
HRMS, found 201.1493; C11H21O3 (MH+) requires 201.1491.
t
+
(CO2 Bu); m/z (CI+, NH3) 214 (MNH4 , 20), 197 (MH+, 45),
+
158 (MNH4 –C4H8, 100), 141 (MH+–C4H8, 10), 123 (MH+-74,
35), 95 (MH+-101, 55%); HRMS, found 197.1548; C12H21O2
(MH+) requires 197.1542.
Preparation of tert-butyl (RS)-3-benzylcyclopentene-1-carboxy-
late 12
(i) Preparation of tert-butyl 2-hydroxy-3-benzylcyclo-
pentane-1-carboxylate. The b-keto ester 10 (4.00 g, 14.5 mmol)
in EtOH (30 ml) was treated with NaBH4 (0.55 g, 14.5 mmol)
in accordance with general procedure 2, giving the title com-
pound (3.63 g, 90%) as a complex mixture of diastereoisomers.
This material was used without purification, although for the
purposes of analysis a small quantity was subjected to flash
chromatography on silica gel (20% Et2O/n-pentane) to give the
title compound as a colourless oil; mmax (film) 3471br s, 1704s
1154m; major diastereoisomer: dH (400 MHz, CDCl3) 1.28 (1H,
m, C(4)HA), 1.48 (9H, s, OC(CH3)3), 1.89–1.99 (3H, m, C(3)H,
C(4)HB and C(5)HA), 2.31 (1H, m, C(5)HB), 2.46 (1H, dd, J
13.6, 9.0, CHAHBPh), 2.78–2.85 (2H, m, CHAHBPh and C(1)H),
2.98 (1H, br s, OH), 4.03 (1H, dd, J 5.7, 4.4, C(2)H), 7.15–7.31
(5H, m, Ph); dC (50 MHz, CDCl3) 26.2 (C(5)), 28.0 (OC(CH3)3),
28.3 (C(4)), 39.6 (CH2Ph), 48.1 (C(3)), 48.2 (C(1)), 77.9 (C(2)),
81.2 (OC(CH3)3), 126.1 (p-Ar), 128.5 and 129.1 (o, m-Ar), 140.8
(ipso-Ar), 174.7 (CO2tBu); minor diastereoisomer: dH (400 MHz,
CDCl3) 1.46 (9H, s, OC(CH3)3), 1.68–1.81 (2H, m, C(3)H and
C(4)HA), 1.89–2.10 (3H, m, C(4)HB and C(5)H2), 2.64 (2H, m,
C(1)H and CHAHBPh), 2.94 (1H, dd, J 13.5, 8.1, CHAHBPh),
3.26 (1H, br s, OH), 4.15 (1H, app t, J 3.4, C(2)H), 7.15–7.31
(5H, m, Ph); dC (50 MHz, CDCl3) 25.4 (C(5)), 28.0 (OC(CH3)3
and C(4)), 35.3 (CH2Ph), 47.8 (C(3)), 49.8 (C(1)), 74.0 (C(2)),
81.2 (OC(CH3)3), 125.9 (p-Ar), 128.4 and 129.0 (o, m-Ar), 142.0
(ii) Preparation of ethyl (RS)-3(1-methylethyl)-cyclo-
pentene-1-carboxylate. Ethyl 2-hydroxy-3-(1-methylethyl)-
cyclopentane-1-carboxylate (3.00 g, 15.0 mmol) in THF
(50 ml) was treated with PPh3 (5.90 g, 22.5 mmol) and DIAD
(3.86 ml, 19.6 mmol) in accordance with general procedure 3,
giving the title compound (2.24 g, 82%) as a colourless oil;
mmax(film) 1716s, 1634m; dH (400 MHz, CDCl3) 0.90 (3H, d, J 7.1,
CH(CH3ACH3B)), 0.94 (3H, d, J 7.1, CH(CH3ACH3B)), 1.30 (3H,
t, J 7.1, CH2CH3), 1.57–1.67 (2H, m, CH(CH3)2 and C(4)HA),
2.07 (1H, dddd, J 13.0, 8.6, 8.6, 4.3, C(4)HB), 2.49–2.65 (3H, m,
C(3)H and C(5)H2), 4.14–4.24 (2H, m, CH2CH3), 6.75 (1H, app
q, J 2.0, C(2)H); dC (50 MHz, CDCl3) 14.1 (OCH2CH3), 20.2
and 20.4 (CH(CH3)2), 27.3 (C(5)), 31.0 (C(4)), 32.1 (CH(CH3)2),
53.5 (C(3)), 60.1 (OCH2CH3), 136.7 (C(1)), 146.2 (C(2)), 165.9
+
(CO2Et); m/z (CI+, NH3) 200 (MNH4 , 70), 183 (MH+, 100%);
HRMS, found 183.1391; C11H19O2 (MH+) requires 183.1385.
(iii) Preparation of tert-butyl (RS)-3-(1-methylethyl)-
cyclopentene-1-carboxylate 16. To a solution of ethyl (RS)-3-(1-
methylethyl)-cyclopentene-1-carboxylate (2.00 g, 10.0 mmol) in
MeOH (20 ml) was added KOH (aq, 2 M, 20 ml) and the mixture
heated at 60 °C for 12 h. Following cooling to rt the mixture was
acidified to pH 1 by addition of HCl (aq, 2 M, 20 ml) then
diluted with Et2O (50 ml). The aqueous layer was separated
and extracted with Et2O (3 × 30 ml) and the combined organic
extracts were dried (MgSO4), filtered and concentrated in vacuo
to afford the crude acid30 (1.69 g, quantitative) as a pale yellow
oil; dH (200 MHz, CDCl3) 0.90 (3H, d, J 7.0, CH(CH3ACH3B)),
0.94 (3H, d, J 7.0, CH(CH3ACH3B)), 1.56–1.73 (2H, m,
CH(CH3)2 and C(4)HA), 2.08 (1H, dddd, J 13.0, 8.5, 8.5, 4.5,
C(4)HB), 2.43–2.71 (3H, m, C(3)H and C(5)H2), 6.90 (1H, app q,
J 2.0, C(2)H). A solution of the crude acid (1.60 g, 10.4 mmol)
in DCM (20 ml) was cooled to −78 °C and 20 ml of iso-
butylene (condensed by passing the gas into a conical flask held
at −78 °C) added, followed by H2SO4 (98%, 1 drop). The reaction
mixture was held at −78 °C for 4 h, and then allowed to warm to
rt overnight. The mixture was diluted with H2O (10 ml) and the
aqueous layer separated and extracted with DCM (3 × 20 ml).
The combined organic layers were dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash chromatography on
silica gel (2% Et2O/n-pentane) gave (RS)-16 (1.22 g, 56% from
ethyl (RS)-3-(1-methylethyl)-cyclopentene-1-carboxylate) as a
colourless oil; mmax (film) 1709s, 1633m, 1171s; dH (400 MHz,
CDCl3) 0.90 (3H, d, J 6.7, CH(CH3ACH3B)), 0.94 (3H, d, J 6.7,
CH(CH3ACH3B)), 1.50 (9H, s, OC(CH3)3), 1.54–1.64 (2H, m,
CH(CH3)2 and C(4)HA), 2.05 (1H, dddd, J 13.0, 8.7, 8.7, 4.3,
C(4)HB), 2.44–2.60 (3H, m, C(3)H and C(5)H2), 6.64 (1H, app
q, J 2.0, C(2)H); dC (50 MHz, CDCl3) 20.2 and 20.5 (CH(CH3)2),
27.4 (C(5)), 28.0 (OC(CH3)3), 31.1 (C(4)), 32.2 (CH(CH3)2),
53.5 (C(3)), 79.9 (OC(CH3)3), 138.3 (C(1)), 145.1 (C(2)), 165.4
+
(ipso-Ar), 174.9 (CO2tBu); m/z (CI+, NH3) 294 (MNH4 , 10), 277
+
(MH+, 25), 238 (MNH4 –C4H8, 100), 221 (MH+–C4H8, 30%);
HRMS, found 277.1827; C17H25O3 (MH+) requires 277.1804.
(ii) Preparation of tert-butyl (RS)-3-benzylcyclopentene-
1-carboxylate 12. tert-Butyl 2-hydroxy-3-benzylcyclopentane-
1-carboxylate (3.00 g, 10.9 mmol) in THF (50 ml) was treated
with PPh3 (4.28 g, 16.3 mmol) and DIAD (2.79 ml, 14.2 mmol)
in accordance with general procedure 3, giving (RS)-12 (2.56 g,
91%) as a white crystalline solid; mp 32–34 °C; elemental analy-
sis, found C, 78.9; H, 8.5%; C17H22O2 requires C, 79.0; H, 8.6%;
mmax (film) 1707s, 1629m, 1167m; dH (400 MHz, CDCl3) 1.49
(9H, s, OC(CH3)3), 1.61 (1H, m, C(4)HA), 2.09 (1H, dddd, J
13.0, 8.8, 8.8, 4.5, C(4)HB), 2.49 (1H, m, C(5)HA), 2.56 (1H,
m, C(5)HB), 2.65 and 2.77 (2H, ABX system, JAB 13.5, JAX
8.0, JBX 7.3, CH2Ph), 3.10 (1H, m, C(3)H), 6.58 (1H, app q, J
2.0, C(2)H), 7.19–7.33 (5H, m, Ph); dC (50 MHz, CDCl3) 28.1
(OC(CH3)3), 29.7 (C(5)), 30.7 (C(4)), 41.0 (CH2Ph), 47.9 (C(3)),
80.1 (OC(CH3)3), 126.2 (p-Ar), 128.6 and 129.0 (o, m-Ar), 138.3
t
(C(1)), 140.7 (ipso-Ar), 145.5 (C(2)), 165.3 (CO2 Bu); m/z (CI+,
+
+
NH3) 276 (MNH4 , 40), 259 (MH+, 10), 220 (MNH4 –C4H8,
100), 203 (MH+–C4H8, 10), 185 (MH+-74, 10), 158 (MH+-102,
20), 91 (C7H7 , 60%).
+
Preparation of tert-butyl (RS)-3-(1-methylethyl)-cyclopentene-
1-carboxylate 16
(i) Preparation of ethyl 2-hydroxy-3-(1-methylethyl)-cyclo-
pentane-1-carboxylate. The b-keto ester 15 (4.00 g, 20.2 mmol)
in EtOH (30 ml) was treated with NaBH4 (0.76 g, 20.2 mmol)
in accordance with general procedure 2, giving the title com-
pound (3.45 g, 85%) as a complex mixture of diastereoisomers.
This material was used without purification, although for the
purposes of analysis a small quantity was subjected to flash
chromatography on silica gel (20% Et2O/n-pentane) to give the
title compound as a colourless oil; mmax (film) 3485br s, 1716s and
t
+
(CO2 Bu); m/z (CI+, NH3) 228 (MNH4 , 15), 211 (MH+, 30),
+
172 (MNH4 –C4H8, 100%); HRMS, found 211.1695; C13H23O2
(MH+) requires 211.1698.
Preparation of 19
(i) Preparation of methyl 2-hydroxy-3-(1,1-dimethyl-
ethyl)-cyclopentane-1-carboxylate. The b-keto ester 18 (4.00 g,
20.2 mmol) in EtOH (30 ml) was treated with NaBH4 (0.76 g,
3 3 4 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4

View Article Online
20.2 mmol) in accordance with general procedure 2, giving the
title compound (3.72 g, 92%) as a complex mixture of diastereo-
isomers. This material was used without purification, although
for the purposes of analysis a small quantity was subjected to
flash chromatography on silica gel (20% Et2O/n-pentane) to
give the title compound as a colourless oil; mmax (film) 3507br s,
1716s; major diastereoisomer: dH (400 MHz, CDCl3) 1.03 (9H, s,
C(CH3)3), 1.43 (1H, br s, OH), 1.53 (1H, m, C(4)HA), 1.68–1.86
(3H, m, C(3)H, C(4)HB and C(5)HA), 2.13 (1H, m, C(5)HB), 2.52
(1H, m, C(1)H), 3.69 (3H, s, OCH3), 4.48 (1H, m, C(2)H); dC
(50 MHz, CDCl3) 24.1 (C(5)), 26.1 (C(4)), 29.2 (C(CH3)3), 31.4
(C(CH3)3), 51.7 (CO2Me), 53.9 (C(3)), 55.0 (C(1)), 77.5 (C(2)),
after quenching with NH4Cl (aq, sat, 5 ml) and purification
by flash chromatography on silica gel (2% Et2O:n-pentane),
the diastereoisomeric products (1RS,2SR,3RS)-20 and
(1SR,2SR,3RS)-22 as an 84:16 mixture (142 mg, 71%); NMR
datafor(1RS,2SR,3RS)-20(assignedfromthediastereoisomeric
mixture): dH (400 MHz, CDCl3) 0.88 (3H, t, J 7.5, CH2CH3),
1.03 (1H, m, CHAHBCH3), 1.13 (1H, m, C(4)HA), 1.58 (9H, s,
OC(CH3)3), 1.67–1.81 (2H, m, C(5)HA and CHAHBCH3), 1.91
(1H, m, C(5)HB), 2.07 (1H, m, C(4)HB), 2.34 (1H, app quintet of
doublets, J 8.8, 4.0, C(3)H), 2.93 (1H, m, C(1)H) overlays 2.98
(1H, m, C(2)H), 3.80 and 3.86 (2 × 2H, AB system, JAB 13.9,
N(CH2Ph)2), 7.21–7.42 (10H, m, Ph); dC (100 MHz, CDCl3) 12.3
(CH2CH3), 27.2 and 27.4 (CH2CH3 and C(5)), 28.1 (OC(CH3)3),
28.5 (C(4)), 40.4 (C(3)), 46.3 (C(1)), 54.4 (N(CH2Ph)2), 67.9
(C(2)), 80.2 (OC(CH3)3), 126.7 (p-Ph), 128.4 and 128.8 (o-, m-
Ph), 140.4 (ipso-Ph), 175.6 (CO2tBu).
+
176.7 (CO2Me); m/z (CI+, NH3) 218 (MNH4 , 50), 201 (MH+,
20), 183 (MH+–H2O, 100%); HRMS, found 201.1487; C11H21O3
(MH+) requires 201.1491.
The mixture of (1RS,2SR,3RS)-20 and (1SR,2SR,3RS)-
22 (120 mg, 0.31 mmol) was re-dissolved in tert-butanol and
epimerised under thermodynamic conditions in accordance
with general procedure 6. Purification by flash chromatogra-
phy on silica gel (2% Et2O:n-pentane) gave (1SR,2SR,3RS)-
22 (118 mg, quantitative) as a pale yellow crystalline solid;
mp 58–60 °C; elemental analysis, found C, 79.5; H, 8.7; N,
3.6%; C26H35NO2 requires C, 79.4; H, 9.0; N, 3.6%; mmax (KBr)
3059s, 3028s, 2974s, 2873s, 1717s, 1603m, 1495m, 1452m,
1363s, 1254m, 1145s, 1072m, 965m, 845m, 751s; dH (400 MHz,
CDCl3) 0.84 (1H, t, J 7.4, CH2CH3), 1.09 (1H, m, CHAHBCH3),
1.32 (1H, m, C(4)HA), 1.50 (9H, s, OC(CH3)3), 1.72–1.87 (5H,
m, CHAHBCH3, C(3)H, C(4)HB and C(5)H2), 2.90 (1H, app q,
J 7.1, C(1)H), 3.17 (1H, dd, J 7.9, 7.5, C(2)H), 3.54 and 3.79
(2 × 2H, AB system, JAB 13.8, N(CH2Ph)2), 7.21–7.39 (10H,
m, Ph); dC (100 MHz, CDCl3) 12.4 (CH2CH3), 26.6 (CH2CH3),
28.1 (OC(CH3)3), 29.2 and 29.3 (C(4) and C(5)), 44.4 (C(1)),
44.6 (C(3)), 54.9 (N(CH2Ph)2), 69.7 (C(2)), 79.8 (OC(CH3)3),
126.7 (p-Ph), 128.0 and 128.8 (o-, m-Ph), 140.2 (ipso-Ph),
(ii) Preparation of ethyl (RS)-3-(1,1-dimethylethyl)-cyclo-
pentene-1-carboxylate. Methyl 2-hydroxy-3-(1,1-dimethyl-
ethyl)-cyclopentane-1-carboxylate (3.00 g, 15.0 mmol) in THF
(50 ml) was treated with PPh3 (5.90 g, 22.5 mmol) and DIAD
(3.86 ml, 19.6 mmol) in accordance with general procedure 3,
giving the title compound (2.35 g, 86%) as a colourless oil; dH
(400 MHz, CDCl3) 0.90 (9H, s, C(CH3)3), 1.58–1.77 (1H, m,
C(4)HA), 1.97 (1H, dddd, J 13.1, 8.8, 8.8, 4.4, C(4)HB), 2.50–2.69
(3H, m, C(3)H and C(5)H2), 3.74 (3H, s, OCH3), 6.78 (1H, app q,
J 2.0, C(2)H), with all other spectroscopic data consistent with
that previously reported.19
(iii) Preparation of tert-butyl (RS)-3-(1,1-dimethylethyl)-
cyclopentene-1-carboxylate 19. To a solution of ethyl (RS)-
3-(1,1-dimethylethyl)-cyclopentene-1-carboxylate (2.00 g,
11.0 mmol) in MeOH (20 ml) was added KOH (aq, 2 M, 20 ml)
and the mixture heated at 60 °C for 12 h. Following cooling to
rt the mixture was acidified to pH 1 by addition of HCl (aq,
2 M, 20 ml) then diluted with Et2O (50 ml). The aqueous
layer was separated and extracted with Et2O (3 × 30 ml) and
the combined organic extracts were dried (MgSO4), filtered and
concentrated in vacuo to afford the crude acid10 (1.85 g, quan-
titative) as a pale yellow oil; dH (400 MHz, CDCl3) 0.91 (9H, s,
C(CH3)3), 1.73–1.80 (1H, m, C(4)HA), 2.01 (1H, dddd, J 13.2,
8.8, 8.8, 4.4, C(4)HB), 2.50–2.59 (2H, m, C(5)H2), 2.69 (1H, m,
C(3)H), 6.93 (1H, app q, J 2.0, C(2)H). A solution of the crude
acid (1.80 g, 10.7 mmol) in DCM (20 ml) was cooled to −78 °C
and 20 ml of isobutylene (condensed by passing the gas into
a conical flask held at −78 °C) added, followed by H2SO4 (98%,
1 drop). The reaction mixture was held at −78 °C for 4 h, and
then allowed to warm to rt overnight. The mixture was diluted
with H2O (10 ml) and the aqueous layer separated and extracted
with DCM (3 × 20 ml). The combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. Purification by
flash chromatography on silica gel (2% Et2O/n-pentane) gave
(RS)-19 (1.70 g, 71% from ethyl (RS)-3-(1,1-dimethylethyl)-
cyclopentene-1-carboxylate) as a colourless oil; mmax (film) 1710s,
1634m, 1168s; dH (400 MHz, CDCl3) 0.89 (9H, s, C(3)C(CH3)3),
1.50 (9H, s, OC(CH3)3), 1.70 (1H, m, C(4)HA), 2.01 (1H, dddd, J
13.2, 8.8, 8.8, 4.4, C(4)HB), 2.42–2.60 (2H, m, C(5)H2), 2.63 (1H,
m, C(3)H), 6.65 (1H, app q, J 2.0, C(2)H); dC (50 MHz, CDCl3)
25.2 (C(4)), 27.4 (C(3)C(CH3)3), 28.0 (OC(CH3)3), 31.2 (C(5)),
33.1 (C(3)C(CH3)3), 57.6 (C(3)), 79.9 (OC(CH3)3), 138.6 (C(1)),
t
176.5 (CO2 Bu); m/z (ESI+) 394 (MH+, 100), 338 (MH+–C4H8,
15%); HRMS, found 394.2750; C26H36NO2 (MH+) requires
394.2746.
Preparation of tert-butyl (1RS,2SR,3SR)-3-benzyl-2-(N,N-
dibenzylamino)-cyclopentane-1-carboxylate 21 and tert-butyl
(1SR,2SR,3SR)-3-benzyl-2-(N,N-dibenzylamino)-cyclopentane-
1-carboxylate 23
Followinggeneralprocedure4, n-BuLi(2.5M, 1.20ml, 3.0mmol),
dibenzylamine (0.58 ml, 3.0 mmol) in THF (10 ml) and (RS)-12
(200 mg, 1.0 mmol) in THF (2 ml) gave, after quenching with
NH4Cl (aq, sat, 5 ml) and purification by flash chromatography
on silica gel (2% Et2O:n-pentane), the diastereoisomeric prod-
ucts (1RS,2SR,3SR)-21 and (1SR,2SR,3SR)-23 as an 83:17
mixture (350 mg, 77%); NMR data for (1RS,2SR,3SR)-21
(assigned from the diastereoisomeric mixture): dH (400 MHz,
CDCl3) 1.19 (1H, m, C(4)HA), 1.59 (9H, s, OC(CH3)3), 1.70
(1H, m, C(5)HA), 1.87–1.92 (2H, m, C(4)HB and C(5)HB), 2.19
(1H, dd, J 13.6, 10.4, C(3)CHACHBPh), 2.72 (1H, app quintet
of doublets, J 8.8, 4.0, C(3)H), 2.99 (1H, td, J 8.0, 4.8, C(1)H),
3.09 (1H, dd, J 9.6, 8.0, C(2)H), 3.16 (1H, dd, J 13.6, 4.0,
C(3)CHAHBPh), 3.85 and 3.98 (2 × 2H, AB system, JAB 14.0,
N(CH2Ph)2), 7.10–7.45 (15H, m, Ph); dC (100 MHz, CDCl3)
27.1 (C(5)), 28.2 (OC(CH3)3), 28.6 (C(4)), 40.6 (C(3)CH2Ph),
40.9 (C(3)), 45.8 (C(1)), 54.6 (N(CH2Ph)2), 67.9 (C(2)), 80.3
(OC(CH3)3), 125.6 and 126.9 (p-Ph), 128.2, 128.9 and 129.0 (o-,
m-Ph), 140.3 and 141.5 (ipso-Ph), 175.5 (CO2tBu).
t
+
144.5 (C(2)), 165.3 (CO2 Bu); m/z (CI+, NH3) 242 (MNH4 ,
5), 225 (MH+, 20), 186 (MNH4 –C4H8, 100%); HRMS, found
+
225.1856; C14H25O2 (MH+) requires 225.1855.
The mixture of (1RS,2SR,3SR)-21 and (1SR,2SR,3SR)-
23 (300 mg, 0.66 mmol) was re-dissolved in tert-butanol
and epimerised under thermodynamic conditions (7 d, rt)
in accordance with general procedure 6. Purification by flash
chromatography on silica gel (2% Et2O:n-pentane) gave
(1SR,2SR,3SR)-23 (296 mg, quantitative) as a white crystalline
solid; mp 86–88 °C; mmax (KBr) 3058s, 3025s, 3004s, 2930s, 2866s,
2807s, 1715s, 1602m, 1494s, 1453s, 1362s, 1251m, 1151s, 967m,
Preparation of tert-butyl (1RS,2SR,3RS)-3-ethyl-2-(N,N-
dibenzylamino)-cyclopentane-1-carboxylate 20 and tert-butyl
(1SR,2SR,3RS)-3-ethyl-2-(N,N-dibenzylamino)-cyclopentane-
1-carboxylate 22
Following general procedure 4, n-BuLi (2.5 M, 0.61 ml,
1.53 mmol), dibenzylamine (0.29 ml, 1.53 mmol) in THF
(5 ml) and (RS)-11 (100 mg, 0.51 mmol) in THF (1 ml) gave,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4
3 3 4 7

View Article Online
Preparation of tert-butyl (1R,2S,3R,aS)-3-ethyl-2-(N-benzyl-N-
a-methylbenzylamino)-cyclopentane-1-carboxylate 24 via kinetic
resolution
877m, 747s, 697s; dH (400 MHz, CDCl3) 1.36 (1H, m, C(4)HA),
1.51 (1H, s, OC(CH3)3), 1.59 (1H, m, C(4)HB), 1.80–1.84 (2H,
m, C(5)H2), 2.15–2.22 (2H, m, C(3)CHAHBPh and C(3)H),
2.96 (1H, m, C(1)H), 3.13 (1H, dd, J 13.6, 4.2, C(3)CHAHBPh),
3.26 (1H, dd, J 8.4, 7.2, C(2)H), 3.59 and 3.85 (2 × 2H,
AB system, JAB 13.7, N(CH2Ph)2), 7.04–7.44 (15H, Ph); dC
(100 MHz, CDCl3) 28.6 (OC(CH3)3), 29.4 (C(5)), 29.9 (C(4)),
40.4 (C(3)CH2Ph), 44.3 (C(1)), 45.7 (C(3)), 55.5 (N(CH2Ph)2),
70.2 (C(2)), 80.5 (OC(CH3)3), 126.1 and 127.3 (p-Ph), 128.6,
129.4, 140.6 and 142.3 (o-, m-Ph), 140.6 and 142.3 (ipso-Ph),
Following general procedure 5, n-BuLi (1.6 M, 0.56 ml,
0.9 mmol), (S)-N-benzyl-N-a-methylbenzylamine (191 mg,
0.9 mmol) in THF (20 ml) and (RS)-11 (196 mg, 1.0 mmol)
in THF (2 ml) gave, after quenching with 2,6-di-tert-butyl-
phenol (409 mg, 1.98 mmol) in THF (5 ml), (1R,2S,3R,aS)-24,
(1S,2S,3R,aS)-27 and (1S,2R,3S,aS)-30 in a 93.3:2.5:4.2 ratio.
The amines were separated from the unused acceptor by dissolv-
ing the crude mixture in n-pentane (25 ml) and passing HCl (g)
through the mixture. The n-pentane was decanted from the solid,
neutralised (NaHCO3) and concentrated in vacuo to give the
crude acceptor, which was purified by flash chromatography on
silica gel (2% Et2O:n-pentane) furnishing (S)-11 (71 mg, 36%)
{[a]2D4 −68.3, (c 1.3, CHCl3)}, with spectroscopic data identical to
the racemate. The adducts (1R,2S,3R,aS)-24, (1S,2S,3R,aS)-27
and (1S,2R,3S,aS)-30 were neutralised (KOH) and purified by
flash chromatography in the same manner as the racemate, to
give the diastereoisomerically pure product (1R,2S,3R,aS)-24
(130 mg, 32%) as a colourless oil; [a]2D3 −125.3 (c 1.1, CHCl3),
with spectroscopic data identical to the racemate.
t
176.9 (CO2 Bu); m/z (ESI+) 456 (MH+, 100), 400 (MH+-C4H8,
15%); HRMS, found 456.2901; C31H38NO2 (MH+) requires
456.2903.
Preparation of (RS), (R)- and (S)-N-benzyl-N-a-methylbenzyl-
amine
Benzaldehyde (90.0 g, 0.85 mmol) was added to a stirred solu-
tion of (RS)-a-methylbenzylamine (100 g, 0.83 mol) in EtOH
(400 ml) and heated at reflux for 3 h. Following cooling to 0 °C
NaBH4 (31.4 g, 0.83 mol) was added portionwise. The reac-
tion mixture was warmed to rt whereat it was stirred for 3 d.
The solvent was removed in vacuo and the residue partitioned
between H2O (100 ml) and DCM (150 ml). The aqueous phase
was separated and extracted with DCM (3 × 100 ml) and the
combined organic layers dried (MgSO4), filtered and concen-
trated in vacuo to give the crude amine as a colourless oil. The
crude material was dissolved in Et2O (1000 ml) and the solu-
tion treated with HCl (g). The collected white precipitate was
recrystallised from DCM:n-pentane, furnishing the purified
hydrochloride salt (192 g, 93%) which could be stored indefi-
nitely. The free amine was regenerated by treatment with 1 M
NaOH solution and extracted with DCM (3 × 100 ml) to give
(RS)-N-benzyl-N-a-methylbenzylamine as a colourless oil as
required; dH (200 MHz, CDCl3) 1.44 (3H, d, J 6.6, C(a)Me),
1.86 (1H, br s, NH), 3.68 and 3.72 (2 × 1H, AB system, JAB 13.2,
NCH2Ph), 3.90 (1H, q, J 6.6, C(a)H), 7.29–7.47 (10H, m, Ph).
The (R)-enantiomer (184 g, 89%) {[a]2D4 +52.9 (c 1.0, CHCl3)},
and (S)-enantiomer (186 g, 90%) {[a]2D3 −53.1 (c 1.0, CHCl3),
lit.31 −53.6 (c 3.8, CHCl3)}, were prepared on an identical scale
and in an analogous fashion.
Preparation of tert-butyl (1S,2S,3R,aS)-3-ethyl-2-(N-benzyl-
N-a-methylbenzylamino)-cyclopentane-1-carboxylate 27 via
epimerisation
Following general procedure 6, a solution of (1R,2S,3R,aS)-24
(102 mg, 0.25 mmol) in tBuOH (10 ml) was treated with KOtBu
and heated at reflux for 3 h. Purification by flash chromato-
graphy on silica gel (2% Et2O:n-pentane) gave (1S,2S,3R,aS)-27
(100 mg, quantitative) in >98% de as a colourless oil; [a]2D5+21.2
(c 0.80, CHCl3); mmax (film) 2959s, 1720s, 1493m, 1454m, 1367m,
1154s, 700m; dH (400 MHz, CDCl3) 0.83 (3H, t, J 7.4, CH2CH3),
1.16 (1H, m, CHAHBCH3), 1.20 (1H, d, J 6.8, C(a)Me) overlays
1.21 (1H, m, C(4)HA), 1.43 (9H, s, OC(CH3)3), 1.67–1.70 (4H,
m, C(3)H, C(4)HB and C(5)H2), 1.73 (1H, m, CHAHBCH3), 2.67
(1H, m, C(1)H), 3.27 (1H, dd, J 8.0, 5.5, C(2)H), 3.71 and 3.84
(2 × 1H, AB system, JAB 15.8, NCH2Ph) overlays 3.87 (1H, q, J
6.8, C(a)H), 7.20–7.44 (10H, m, Ph); dC (100 MHz, CDCl3) 13.1
(CH2CH3), 22.6 (C(a)Me), 26.8 (C(5)), 28.6 (OC(CH3)3), 29.8
(CH2CH3), 31.0 (C(4)), 46.1 (C(3)), 47.0 (C(1)), 51.5 (NCH2Ph),
62.2 (C(2)), 69.7 (C(a)H), 80.2 (OC(CH3)3), 126.8 and 127.1 (p-
Ph), 127.9, 128.3, 128.5 and 128.6 (o-, m-Ph), 143.8 and 145.8
Preparation of tert-butyl (1RS,2SR,3RS,aSR)-3-ethyl-2-(N-
benzyl-N-a-methylbenzylamino)-cyclopentane-1-carboxylate 24
t
(ipso-Ph), 176.9 (CO2 Bu); m/z (APCI+) 408 (MH+, 100%);
Following general procedure 4, n-BuLi (1.6 M, 1.88 ml,
3.00 mmol), (RS)-N-benzyl-N-a-methylbenzylamine (636 mg,
3.00 mmol) in THF (20 ml) and (RS)-11 (196 mg, 1.00 mmol) in
THF (2 ml) gave, after quenching with 2,6-di-tert-butylphenol
(660 mg, 3.20 mmol) in THF (5 ml), (1RS,2SR,3RS,aSR)-24,
HRMS, found 408.2902; C27H38NO2 (MH+) requires 408.2903.
Preparation of tert-butyl (1RS,2SR,3SR,aSR)-3-benzyl-2-(N-
benzyl-N-a-methylbenzylamino)-cyclopentane-1-carboxylate 25
(1SR,2SR,3RS,aSR)-27 and (1SR,2RS,3SR,aSR)-30 in
a
Following general procedure 4, n-BuLi (1.6 M, 1.88 ml,
3.00 mmol), (RS)-N-benzyl-N-a-methylbenzylamine (636 mg,
3.00 mmol) in THF (20 ml) and (RS)-12 (258 mg, 1.00 mmol) in
THF (2 ml) gave, after quenching with 2,6-di-tert-butylphenol
(660 mg, 3.20 mmol) in THF (5 ml), (1RS,2SR,3SR,aSR)-25,
96.9:1.9:1.2 ratio. Purification by flash chromatography on
silica gel (2% Et2O:n-pentane) gave (1RS,2SR,3RS,aSR)-24
(279 mg, 71%) as a clear oil; elemental analysis, found C, 79.7;
H, 8.8; N, 3.0%; C27H37NO2 requires C, 79.6; H, 9.2; N, 3.4%;
mmax (film) 2965s, 1719s, 1493m, 1454m, 1366s, 1145s, 700s; dH
(400 MHz, CDCl3) 0.82 (3H, t, J 7.2, CH2CH3), 0.89–0.98 (1H,
m, CHAHBCH3), 1.00–1.09 (1H, m, C(4)HA), 1.18 (3H, d, J 6.8,
C(a)Me), 1.52 (9H, s, OC(CH3)3) overlays 1.50–1.54 (1H, m,
C(5)HA), 1.73 (1H, m, C(5)HB), 1.86 (1H, m, CHAHBCH3), 1.99
(1H, m, C(4)HB), 2.07 (1H, m, C(3)H), 2.54 (1H, app td, J 7.2,
4.0, C(1)H), 2.92 (1H, dd, J 10.0, 7.6, C(2)H), 3.94 and 4.18
(2 × 1H, AB system, JAB 15.6, NCH2Ph) overlays 4.17 (1H, q,
J 6.8, C(a)H), 7.20–7.49 (10H, m, Ph); dC (100 MHz, CDCl3)
12.5 (CH2CH3), 21.2 (C(a)Me), 27.2 (C(5)), 27.3 (CH2CH3),
27.8 (C(4)), 28.1 (OC(CH3)3), 41.8 (C(3)), 46.7 (C(1)), 51.0
(NCH2Ph), 60.4 (C(a)H), 68.8 (C(2)), 78.0 (OC(CH3)3), 126.2
and 126.8 (p-Ph), 127.4, 127.7, 128.1 and 128.2 (o-, m-Ph),
(1SR,2SR,3SR,aSR)-28 and (1SR,2RS,3RS,aSR)-31 in
a
97.6:1.8:0.6 ratio. Purification by flash chromatography on
silica gel (2% Et2O:n-pentane) gave (1RS,2SR,3SR,aSR)-25
(347 mg, 74%) as a clear oil; mmax (film) 3061w, 3026m, 2973s,
2870w, 1718s, 1602w, 1494m, 1453m, 1366s, 1146s, 700s; dH
(400 MHz, CDCl3) 1.10 (1H, m, C(4)HA), 1.27 (3H, d, J 6.8,
C(a)Me), 1.57 (9H, s, OC(CH3)3) overlays 1.58 (1H, m, C(5)HA),
1.71–1.84 (2H, m, C(4)HB and C(5)HB), 2.06 (1H, dd, J 13.2,
11.2, C(3)CHAHBPh), 2.47 (1H, m, C(3)H), 2.64 (1H, m,
C(1)H), 3.10 (1H, dd, J 10.3, 7.9, C(2)H), 3.33 (1H, dd, J 13.2,
3.0, C(3)CHAHBPh), 4.08 and 4.33 (2 × 1H, AB system, JAB
16.0, NCH2Ph) overlays 4.30 (1H, q, J 6.8, C(a)H), 6.98–7.63
(15H, m, Ph); dC (100 MHz, CDCl3) 22.0 (C(a)Me), 27.7 (C(4)
and C(5)), 28.6 (OC(CH3)3), 41.4 (C(3)CH2Ph), 43.0 (C(3)),
46.9 (C(1)), 51.5 (NCH2Ph), 61.2 (C(a)H), 69.7 (C(2)), 80.6
(OC(CH3)3), 126.1, 126.8 and 127.4 (p-Ph), 127.9, 128.2, 128.6,
t
143.6 and 145.4 (ipso-Ph), 176.1 (CO2 Bu); m/z (APCI+) 408
(MH+, 100), 352 (MH+–C4H8, 10%); HRMS, found 408.2890;
C27H38NO2 (MH+) requires 408.2903.
3 3 4 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4

View Article Online
128.8, 128.9 and 129.2 (o-, m-Ph), 142.4, 144.0 and 145.9 (ipso-
m, C(4)HA), 1.39–1.44 (1H, m, C(5)HA), 1.55 (9H, s, OC(CH3)3),
t
Ph), 176.3 (CO2 Bu); m/z (APCI+) 470 (MH+, 100%); HRMS,
1.68–1.80 (2H, m, C(4)HB and C(5)HB), 2.03 (1H, app septet of
doublets, J 7.2, 3.2, CH(CH3)2), 2.16 (1H, m, C(3)H), 2.63 (1H,
app td, J 7.2, 3.6, C(1)H), 3.09 (1H, dd, J 10.8, 7.2, C(2)H),
3.92 and 4.24 (2 × 1H, AB system, JAB 16.4, NCH2Ph) over-
lays 4.23 (1H, q, J 6.8, C(a)H), 7.21–7.49 (10H, m, Ph); dC
(100 MHz, CDCl3) 15.1 (CH(CH3ACH3B)), 21.3 (C(5)), 22.3
(CH(CH3ACH3B)), 22.7 (C(a)Me), 26.9 (CH(CH3)2), 28.0 (C(4)),
28.1 (OC(CH3)3), 45.8 (C(3)), 46.6 (C(1)), 50.8 (NCH2Ph),
61.6 (C(2)), 66.2 (C(a)H), 80.0 (OC(CH3)3), 126.0 and 126.2
(p-Ph), 127.3, 127.6, 128.0 and 128.2 (o, m-Ph), 144.2 and 145.7
found 470.3056; C32H40NO2 (MH+) requires 470.3059.
Preparation of tert-butyl (1R,2S,3S,aS)-3-benzyl-2-(N-benzyl-
N-a-methylbenzylamino)-cyclopentane-1-carboxylate 25 via
kinetic resolution
Following general procedure 5, n-BuLi (1.6 M, 0.38 ml,
0.60 mmol), (S)-N-benzyl-N-a-methylbenzylamine (127 mg,
0.60 mmol) in THF (20 ml) and (RS)-12 (258 mg, 1.00 mmol)
in THF (2 ml) gave, after quenching with 2,6-di-tert-butyl-
phenol (272 mg, 1.32 mmol) in THF (5 ml), (1R,2S,3S,aS)-25,
(1S,2S,3S,aS)-28 and (1S,2R,3R,aS)-31 in a 96.9:1.4:1.7 ratio.
The amines were separated from the unused acceptor by dissolv-
ing the crude mixture in n-pentane (25 ml) and passing HCl (g)
through the mixture. The n-pentane was decanted from the solid,
neutralised (NaHCO3) and concentrated in vacuo to give the
crude acceptor, which was purified by flash chromatography on
silica gel (2% Et2O:n-pentane) furnishing (R)-12 (101 mg, 39%)
{[a]2D4 −74.2 (c 0.90, CHCl3)}, with spectroscopic data identical
to the racemate. The adducts (1R,2S,3S,aS)-25, (1S,2S,3S,aS)-
28 and (1S,2R,3R,aS)-31 were neutralised (KOH) and purified
by flash chromatography in the same manner as the racemate,
to give the diastereoisomerically pure product (1R,2S,3S,aS)-
25 (192 mg, 41%) as a white crystalline solid; mp 86–88 °C;
[a]2D3 −45.1 (c 1.0, CHCl3); elemental analysis, found C, 81.6; H,
8.4; N, 3.0%; C32H39NO2 requires C, 81.8; H, 8.4; N, 3.0%, with
spectroscopic data identical to the racemate.
t
(ipso-Ph), 176.0 (CO2 Bu); m/z (APCI+) 422 (MH+, 100), 366
(MH+–C4H8, 60%); HRMS, found 422.3049; C28H40NO2 (MH+)
requires 422.3059.
Preparation of tert-butyl (1R,2S,3S,aS)-3-(1-methylethyl)-2-
(N-benzyl-N-a-methylbenzylamino)-cyclopentane-1-carboxylate
26 via kinetic resolution
Following general procedure 5, n-BuLi (1.6 M, 1.76 ml,
2.8 mmol), (S)-N-benzyl-N-a-methylbenzylamine (592 mg,
2.8 mmol) in THF (50 ml) and (RS)-17 (832 mg, 4.0 mmol)
in THF (6 ml) gave, after quenching with 2,6-di-tert-butyl-
phenol (1.27 g, 6.16 mmol) in THF (10 ml), (1R,2S,3S,aS)-
26, (1S,2S,3S,aS)-29 and (1S,2R,3R,aS)-32 in a 93.8:4.7:1.5
ratio. The amines were separated from the unused acceptor by
dissolving the crude mixture in n-pentane (50 ml) and passing
HCl (g) through the mixture. The n-pentane was decanted from
the solid, neutralised (NaHCO3) and concentrated in vacuo to
give the crude acceptor, which was purified by flash chroma-
tography on silica gel (2% Et2O:n-pentane) furnishing (R)-17
(356 mg, 43%) {[a]2D4 −48.3 (c 0.80, CHCl3)}, with spectroscopic
data identical to the racemate. The adducts (1R,2S,3S,aS)-
26, (1S,2S,3S,aS)-29 and (1S,2R,3R,aS)-32 were neutralised
(KOH) and purified by repeated flash chromatography and
fractional crystallisation to give the diastereoisomerically
pure products: (1R,2S,3S,aS)-26 (588 mg, 35%) as a white
crystalline solid; mp 71–73 °C; [a]2D3 −89.5 (c 0.49, CHCl3);
elemental analysis, found C, 80.1; H, 9.3; N, 2.9%; C28H39NO2
requires C, 79.8; H, 9.3; N, 3.3%, with spectroscopic data
identical to the racemate; (1S,2S,3S,aS)-29 (43 mg, 2.6%) as
a colourless oil; [a]2D3 +19.2 (c 0.26, CHCl3); mmax (film) 2956s,
1721s, 1602w, 1494w, 1453m, 1367s, 1146s, 700s; dH (400 MHz,
CDCl3) 0.57 (3H, d, J 6.8, CH(CH3ACH3B)), 0.94 (3H, d, J 6.8,
CH(CH3ACH3B)), 1.19 (3H, d, J 6.8, C(a)Me), 1.33 (1H, m,
C(4)HA), 1.45 (9H, s, OC(CH3)3) overlays 1.46 (1H, m, C(5)HA),
1.68–1.76 (3H, m, C(3)H, C(4)HB and C(5)HB), 2.06 (1H, sep-
tet of doublets, J 6.7, 4.3, CH(CH3)2), 2.69 (1H, app td, J 8.2,
4.1, C(1)H), 3.43 (1H, dd, J 9.1, 4.7, C(2)H), 3.72 and 3.89
(2 × 1H, AB system, JAB 16.0, NCH2Ph) overlays 3.88 (1H, q,
J 6.8, C(a)H), 7.21–7.49 (10H, m, Ph); dC (100 MHz, CDCl3)
16.4 (CH(CH3ACH3B)), 22.8 (CH(CH3ACH3B)), 23.0 (C(a)Me),
23.8 (C(5)), 27.6 (CH(CH3)2), 28.1 (OC(CH3)3), 30.9 (C(4)), 45.2
(C(3)), 51.0 (C(1) and NCH2Ph), 62.6 (C(2)), 66.4 (C(a)H), 79.7
(OC(CH3)3), 126.2 and 126.6 (p-Ph), 127.3, 127.8, 127.9 and
Preparation of tert-butyl (1S,2S,3S,aS)-3-benzyl-2-(N-benzyl-
N-a-methylbenzylamino)-cyclopentane-1-carboxylate 28 via
epimerisation
Following general procedure 6, a solution of (1R,2S,3S,aS)-
t
25 (117 mg, 0.25 mmol) in BuOH (10 ml) and THF (10 ml)
was treated with KOtBu and stirred at rt for 7 d. Purification
by flash chromatography on silica gel (2% Et2O:n-pentane)
gave (1S,2S,3S,aS)-28 (116 mg, quantitative) in >98% de as a
colourless oil; [a]D25 +21.2 (c 0.80, CHCl3); mmax (film) 3041s, 3019s,
2929s, 2874s, 1717s, 1602w, 1491s, 1451s, 1359s, 1248m, 1149s,
738m, 699s; dH (400 MHz, CDCl3) 1.30 (3H, d, J 6.4, C(a)Me)
overlays 1.34 (1H, m, C(4)HA), 1.48 (9H, s, OC(CH3)3), 1.57
(1H, m, C(4)HB), 1.71–1.82 (2H, m, C(5)H2), 2.14–2.21 (2H, m,
C(3)CHAHBPh and C(3)H), 2.94 (1H, m, C(1)H), 3.27 (1H, dd,
J 13.6, 3.6, C(3)CHAHBPh), 3.42 (1H, dd, J 8.4, 6.0, C(2)H),
3.83 and 3.91 (2 × 1H, AB system, JAB 16.0, NCH2Ph), 3.96 (1H,
q, J 6.4, C(a)H), 7.02–7.43 (15H, Ph); dC (100 MHz, CDCl3)
22.8 (C(a)Me), 29.2 and 29.5 (C(4) and C(5)), 28.6 (OC(CH3)3),
40.5 (C(3)CH2Ph), 44.5 (C(1)), 45.9 (C(3)), 53.3 (NCH2Ph),
57.1 (C(a)H), 70.3 (C(2)), 80.6 (OC(CH3)3), 126.2, 126.3 and
127.3 (p-Ph), 127.8, 128.1, 128.5, 128.7, 128.9 and 129.3 (o-,
t
m-Ph), 141.3, 144.2 and 144.9 (ipso-Ph), 175.6 (CO2 Bu); m/z
(APCI+) 470 (MH+, 100), 414 (MH+–C4H8, 55%); HRMS, found
470.3048; C32H40NO2 (MH+) requires 470.3059.
t
128.1 (o-, m-Ph), 143.7 and 145.4 (ipso-Ph), 176.4 (CO2 Bu);
Preparation of tert-butyl (1RS,2SR,3SR,aSR)-3-(1-methyl-
ethyl)-2-(N-benzyl-N-a-methylbenzylamino)-cyclopentane-1-
carboxylate 26
m/z (APCI+) 422 (MH+, 100%); HRMS, found 422.3068;
C28H40NO2 (MH+) requires 422.3059; (1S,2R,3R,aS)-32 (6 mg,
0.4%) as a crystalline solid, with full spectroscopic data for the
enantiomer, (1R,2S,3S,aR)-32, recorded below.
Following general procedure 4, n-BuLi (1.5 M, 0.96 ml,
1.44 mmol), (RS)-N-benzyl-N-a-methylbenzylamine (305 mg,
1.44 mmol) in THF (20 ml) and (RS)-17 (100 mg, 0.48 mmol) in
THF (2 ml) gave, after quenching with 2,6-di-tert-butylphenol
(317 mg, 1.54 mmol) in THF (5 ml), (1RS,2SR,3SR,aSR)-26,
Preparation of tert-butyl (1S,2S,3S,aS)-3-(1-methylethyl)-2-
(N-benzyl-N-a-methylbenzylamino)-cyclopentane-1-carboxylate
29 via epimerisation
(1SR,2SR,3SR,aSR)-29 and (1SR,2RS,3RS,aSR)-32 in
a
Following general procedure 6, a solution of (1R,2S,3S,aS)-26
(105 mg, 0.25 mmol) in tBuOH (10 ml) was treated with KOtBu
and heated at reflux for 3 h. Purification by flash chromato-
graphy on silica gel (2% Et2O:n-pentane) gave (1S,2S,3S,aS)-
29 (103 mg, quantitative) in >98% de as a colourless oil, with
spectroscopic data identical to that recorded above.
94.1:5.2:0.7 ratio. Purification by flash chromatography on
silica gel (2% Et2O:n-pentane) gave (1RS,2SR,3SR,aSR)-26
(145 mg, 72%) as a clear oil; mmax (film) 2961s, 1711s, 1603w,
1494m, 1454m, 1366m, 1261s, 1135s, 761m, 702s; dH (400 MHz,
CDCl3) 0.53 (3H, d, J 7.2, CH(CH3ACH3B)), 0.83 (3H, d, J 7.2,
CH(CH3ACH3B)), 1.16 (3H, d, J 6.8, C(a)Me) overlays 1.17 (1H,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4
3 3 4 9

View Article Online
Preparation of tert-butyl (1SR,2SR,3SR,aSR)-3-(1,1-dimethyl-
ethyl)-2-(N-benzyl-N-a-methylbenzylamino)-cyclopentane-1-
carboxylate 34
in tert-butanol and epimerised under thermodynamic condi-
tions in accordance with general procedure 6. Purification by
flash chromatography on silica gel (2% Et2O:n-pentane) gave
(1S,2S,3S)-34 (147 mg, quantitative) as a white crystalline solid;
mp 104–106 °C; [a]2D5 +18.1 (c 1.3, CHCl3), with spectroscopic
data identical to the racemate.
Following general procedure 4, n-BuLi (2.5 M, 1.20 ml,
3.0 mmol), (RS)-N-benzyl-N-a-methylbenzylamine (636 mg,
3.0 mmol) in THF (20 ml) and (RS)-19 (224 mg, 1.0 mmol) in
THF (2 ml) gave, after quenching with 2,6-di-tert-butylphenol
(317 mg, 1.54 mmol) in THF (5 ml), (1RS,2SR,3SR,aSR)-33
and (1SR,2SR,3SR,aSR)-34 in a 23.1:76.9 ratio. Purification
by flash chromatography on silica gel (2% Et2O:n-pentane)
gave the diastereoisomeric products (1RS,2SR,3SR,aSR)-33
and (1SR,2SR,3SR,aSR)-34 as an inseparable mixture (287 mg,
66%); selected NMR data for (1RS,2SR,3SR,aSR)-33 (assigned
from the diastereoisomeric mixture): dH (400 MHz, CDCl3) 0.66
(2.1H, s, C(3)C(CH3)3), 1.15 (0.69H, d, J 6.8, C(a)Me), 1.61
(2.1H, s, OC(CH3)3), 2.47 (0.23H, m, C(1)H), 3.42 (0.23H, dd, J
10.1, 7.4, C(2)H), 4.20 and 4.31 (2 × 0.23H, AB system, JAB 15.1,
NCH2Ph) overlays 4.17 (1H, q, J 6.8, C(a)H); dC (100 MHz,
CDCl3) 21.8 (C(a)Me), 26.2 (C(5)), 27.4 (C(3)C(CH3)3), 27.7
(OC(CH3)3), 30.6 (C(4)), 33.4 (C(3)C(CH3)3), 46.5 (C(3)),
50.3 (NCH2Ph), 52.8 (C(1)), 61.9 (C(2)), 65.5 (C(a)H), 80.3
(O(CH3)3), 145.2 and 146.0 (ipso-Ph), 175.6 (CO2tBu).
Preparation of (1R,2S,3R)-3-ethyl-2-aminocyclopentane-1-
carboxylic acid 44
Following general procedure 7, Pd(OH)2 on C (40 mg) was added
to a stirred degassed solution of (1R,2S,3R,aS)-24 (204 mg,
0.50 mmol) in MeOH (5 ml) and stirred under H2 (5 atm) over-
night. Filtration through Celite® and concentration in vacuo
gave the crude b-amino ester. Although this material was used
without purification, flash chromatography on silica gel (Et2O)
gave an analytical sample of tert-butyl (1R,2S,3R)-3-ethyl-2-
aminocyclopentane-1-carboxylate (73 mg, 69%) as a colourless
oil; [a]2D2 −44.7 (c 1.0, CHCl3); mmax (film) 3390br w, 2961s, 1722s,
1613w, 1462w, 1367m, 1153s; dH (400 MHz, CDCl3) 0.94 (3H, t,
J 7.3, CH2CH3), 1.12–1.22 (2H, m, CHAHBCH3 and C(4)HA),
1.47 (9H, s, OC(CH3)3), 1.57–1.63 (2H, m, C(3)H and C(4)HB),
1.88 (2H, br s, NH2) overlays 1.82–2.02 (3H, m, CHAHBCH3 and
C(5)H2), 2.80 (1H, app q, J 7.8, C(1)H), 3.07 (1H, m, C(2)H);
dC (100 MHz, CDCl3) 12.6 (CH2CH3), 25.9 (C(5)), 27.0 (C(4)),
28.2 (OC(CH3)3), 29.3 (CH2CH3), 49.4 (C(3)), 50.3 (C(1)), 60.0
The
mixture
of
(1RS,2SR,3SR,aSR)-33
and
(1SR,2SR,3SR,aSR)-34 (250 mg, 0.57 mmol) was re-dissolved
in tert-butanol and epimerised under thermodynamic condi-
tions in accordance with general procedure 6. Purification by
flash chromatography on silica gel (2% Et2O:n-pentane) gave
(1SR,2SR,3SR,aSR)-34 (246 mg, quantitative) in >98% de as a
white crystalline solid; mp 103–105 °C; elemental analysis, found
C, 79.9; H, 9.5; N, 3.2%; C29H41NO2 requires C, 80.0; H, 9.5; N,
3.2%; mmax (KBr) 3025w, 2968s, 2877m, 2798w, 1721s, 1600w,
1494m, 1452s, 1366s, 1148s, 849m, 742s, 707s; dH (400 MHz,
CDCl3) 0.87 (9H, s, C(3)C(CH3)3), 1.33 (3H, d, J 7.0, C(a)Me)
overlays 1.36 (1H, m, C(4)HA), 1.46 (9H, s, OC(CH3)3), 1.59 (1H,
m, C(5)HA), 1.70–1.84 (3H, m, C(3)H, C(4)HB and C(5)HB), 2.59
(1H, m, C(1)H), 3.59 and 3.99 (2 × 1H, AB system, JAB 15.7,
NCH2Ph), 3.73 (1H, dd, J 6.9, 2.9, C(2)H), 3.83 (1H, q, J 7.0,
C(a)H), 7.21–7.53 (10H, m, Ph); dC (100 MHz, CDCl3) 21.5
(C(a)Me), 27.3 (C(5)), 28.0 (C(3)C(CH3)3), 28.5 (OC(CH3)3),
31.2 (C(4)), 32.8 (C(3)C(CH3)3), 46.5 (C(3)), 50.8 (NCH2Ph),
54.8 (C(1)), 61.6 (C(2)), 63.9 (C(a)H), 79.9 (OC(CH3)3), 126.5
and 127.0 (p-Ph), 127.9, 128.1, 128.4 and 128.7 (o-, m-Ph),
t
(C(2)), 80.2 (OC(CH3)3), 173.9 (CO2 Bu); m/z (APCI+) 214
(MH+, 15), 158 (MH+–C4H8, 100%); HRMS, found 214.1808;
C12H24NO2 (MH+) requires 214.1807.
Following general procedure 8, TFA (5 ml) was added to
a solution of crude tert-butyl (1R,2S,3R)-3-ethyl-2-amino-
cyclopentane-1-carboxylate (100 mg, 0.47 mmol) at rt and
stirred for 16 h. Purification using Dowex® 50X8-200 resin
gave (1R,2S,3R)-44 (51 mg, 69% from 24) as a white solid; mp
202–204 °C (decomposes); [a]2D4 −32.3 (c 1.1, H2O); elemental
analysis, found C, 61.2; H, 9.6; N, 8.6%; C8H15NO2 requires
C, 61.1; H, 9.6; N, 8.9%; mmax (KBr) 3677–2360br s, 2956s,
2188m, 1644m, 1611m, 1566s, 1519s, 1414s, 1329m, 1308m,
1174m, 1132m, 845w, 745w; dH (400 MHz, D2O) 0.76 (3H, t,
J 7.4, CH2CH3), 1.11–1.22 (2H, m, CHAHBCH3 and C(4)HA),
1.38–1.44 (1H, m, CHAHBCH3), 1.64–1.69 (1H, m, C(5)HA),
1.81–1.96 (3H, m, C(3)H, C(4)HB and C(5)HB), 2.76 (1H, m,
C(1)H), 3.23 (1H, dd, J 6.6, 5.0, C(2)H); dC (100 MHz, CDCl3)
11.7 (CH2CH3), 26.8 (CH2CH3), 28.1 (C(5)), 28.5 (C(4)), 45.3
(C(3)), 47.3 (C(1)), 57.5 (C(2)), 181.1 (CO2H); m/z (APCI+) 158
(MH+, 80), 140 (MH+–NH3, 100%); HRMS, found 158.1180;
C8H16NO2 (MH+) requires 158.1181.
t
143.2 and 14.0 (ipso-Ph), 176.2 (CO2 Bu); m/z (APCI+) 436
(MH+, 100), 380 (MH+–C4H8, 15%); HRMS, found 436.3219;
C29H42NO2 (MH+) requires 436.3216.
Preparation of tert-butyl (1S,2S,3S,aS)-3-(1,1-dimethylethyl)-
2-(N-benzyl-N-a-methylbenzylamino)-cyclopentane-1-carboxy-
late 34 via kinetic resolution and subsequent epimerisation
Preparation of (1S,2S,3R)-3-ethyl-2-aminocyclopentane-1-
carboxylic acid hydrochloride 47
Followinggeneralprocedure5,n-BuLi(1.6M,0.44ml,0.70mmol),
(S)-N-benzyl-N-a-methylbenzylamine (148 mg, 0.70 mmol) in
THF (20 ml) and (RS)-19 (224 mg, 1.00 mmol) in THF (2 ml)
gave, after quenching with 2,6-di-tert-butylphenol (318 mg,
1.54 mmol) in THF (5 ml), (1R,2S,3S,aS)-33, (1S,2S,3S,aS)-34
and an unassigned mixture of (1S,2R,3R,aS):(1R,2R,3R,aS)-
35 in a 31.9:66.9:1.2 (33:34:35) ratio. The amines were sepa-
rated from the unused acceptor by dissolving the crude mixture
in n-pentane (25 ml) and passing HCl (g) through the mix-
ture. The pentane was decanted from the solid, neutralised
(NaHCO3) and concentrated in vacuo to give the crude acceptor,
which was purified by flash chromatography on silica gel (2%
Et2O:n-pentane) furnishing (R)-19 (90 mg, 40%) {[a]2D4 −32.9
(c 0.45, CHCl3)}, with spectroscopic data identical to the
racemate. The adducts (1R,2S,3S,aS)-33, (1S,2S,3S,aS)-34
and (1S,2R,3R,aS):(1R,2R,3R,aS)-35 were neutralised (KOH)
and purified by flash chromatography in the same manner as the
racemate, to give (1R,2S,3S,aS)-33 and (1S,2S,3S,aS)-34 as a
32.2:67.8 mixture (161 mg, 37%). The mixture of (1R,2S,3S)-
33 and (1S,2S,3S)-34 (150 mg, 0.34 mmol) was re-dissolved
Following general procedure 7, Pd(OH)2 on C (25 mg) was
added to a stirred degassed solution of (1S,2S,3R,aS)-27
(110 mg, 0.27 mmol) in MeOH (5 ml) and stirred under H2
(5 atm) overnight. Filtration through Celite® and concentration
in vacuo gave the crude b-amino ester, from which an analyti-
cal sample was purified by flash chromatography on silica gel
(Et2O), giving tert-butyl (1S,2S,3R)-3-ethyl-2-aminocyclopen-
tane-1-carboxylate as a colourless oil (26 mg); [a]2D2 +36.1 (c
0.50, CHCl3); mmax (film) 3387br w, 2957s, 1726s, 1459w, 1366m,
1154s; dH (400 MHz, CDCl3) 0.87 (3H, t, J 7.4, CH2CH3),
1.11–1.21 (1H, m, CHAHBCH3), 1.23–1.31 (1H, m, C(5)HA),
1.45 (9H, s, OC(CH3)3) overlays 1.42–1.47 (1H, m, C(3)H),
1.69 (2H, br s, NH2) overlays 1.63–1.71 (1H, m, CHAHBCH3),
1.77–1.91 (3H, m, C(4)H2 and C(5)HB), 2.37 (1H, app q, J 8.8,
C(1)H), 2.85 (1H, br t, J 8.8, C(2)H); dC (100 MHz, CDCl3) 12.4
(CH2CH3), 25.5 (CH2CH3), 26.1 (C(4)), 28.1 (OC(CH3)3), 28.5
(C(5)), 49.7 (C(3)), 54.3 (C(1)), 61.8 (C(2)), 80.2 (OC(CH3)3),
t
174.8 (CO2 Bu); m/z (ESI+) 214 (MH+, 100), 158 (MH+–C4H8,
70%); HRMS, found 214.1806; C12H24NO2 (MH+) requires
214.1807.
3 3 5 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4

View Article Online
TFA (5 ml) was added to a solution of crude tert-butyl
(1S,2S,3R)-3-ethyl-2-aminocyclopentane-1-carboxylate (60 mg,
0.28 mmol) at rt and stirred for 16 h, in accordance with general
procedure 9, furnishing (1S,2S,3R)-47 (31 mg, 73% from 27) as
a clear glass; [a]2D5 +10.9 (c 1.0, H2O); mmax (film) 3411br s, 3321–
2386br s, 2963s, 1716s, 1615m, 1516m, 1463w, 1412w, 1211s;
dH (400 MHz, D2O) 0.78 (3H, t, J 7.5, CH2CH3), 1.17 (1H, m,
CHAHBCH3), 1.32 (1H, m, C(4)HA), 1.53 (1H, m, CHAHBCH3),
1.74–1.93 (3H, m, C(3)H, C(4)HB and C(5)HA), 1.97–2.06 (1H,
m, C(5)HB), 2.86 (1H, app td, J 9.5, 7.8, C(1)H), 3.38 (1H,
app t, J 8.1, C(2)H); dC (100 MHz, D2O) 11.5 (CH2CH3), 25.2
(CH2CH3), 27.0 (C(5)), 28.5 (C(4)), 45.9 (C(3)), 48.4 (C(1)),
58.7 (C(2)), 177.4 (CO2H); m/z (ESI+) 158 (MH+, 100), 140
(MH+–NH3, 20%); HRMS, found 158.1182; C8H16NO2 (MH+)
requires 158.1181.
(c 1.2, CHCl3); mmax (film) 3391br w, 2971m, 1723s, 1493w,
1451w, 1367m, 1148s; dH (400 MHz, CDCl3) 1.36–1.42 (1H,
m, C(4)HA), 1.46 (9H, s, OC(CH3)3), 1.71–1.91 (3H, m, C(4)HB
and C(5)H2), 1.99 (2H, br s, NH2) overlays 1.92–2.01 (1H, m,
C(3)H), 2.49–2.56 (2H, m, CHAHBPh and C(1)H), 2.95 (1H, dd,
J 13.2, 5.6, CHAHBPh), 3.08 (1H, br t, J 8.4, C(2)H), 7.17–7.29
(5H, m, Ph); dC (100 MHz, CDCl3) 25.7 (C(5)), 28.1 (OC(CH3)3),
29.2 (C(4)), 39.7 (CH2Ph), 48.9 (C(3)), 53.1 (C(1)), 61.1 (C(2)),
80.6 (OC(CH3)3), 126.0 (p-Ph), 128.4 and 128.8 (o-, m-Ph),
t
140.7 (ipso-Ph), 171.3 (CO2 Bu); m/z (ESI+) 276 (MH+, 100), 220
(MH+–C4H8, 95%); HRMS, found 276.1964; C17H26NO2 (MH+)
requires 276.1964.
TFA (5 ml) was added to a solution of crude tert-butyl
(1S,2S,3S )-3-benzyl-2-aminocyclopentane-1-carboxylate
(80 mg, 0.29 mmol) at rt and stirred for 16 h, in accordance with
general procedure 9, furnishing (1S,2S,3S)-48 (49 mg, 77% from
28) as a white solid; mp 203–205 °C; [a]2D4 +13.9 (c 1.2, H2O);
mmax (KBr) 3397m, 3329–2403br s, 3126s, 2938s, 1708s, 1602w,
1484m, 1481m, 1453m, 1424s, 1283m, 1200s, 866m, 742s, 702s,
683s; dH (400 MHz, D2O) 1.37 (1H, m, C(4)HA), 1.67 (1H, m,
C(4)HB), 1.78 (1H, m, C(5)HA), 1.92–2.01 (1H, m, C(5)HB), 2.21
(1H, m, C(3)H), 2.48 (1H, dd, J 13.5, 9.7, CHAHBPh), 2.86 (1H,
dd, J 13.5, 5.1, CHAHBPh) overlays 2.89 (1H, m, C(1)H), 3.52
(1H, app t, J 7.7, C(2)H), 7.15–7.27 (5H, m, Ph); dC (100 MHz,
CDCl3) 26.9 (C(5)), 29.0 (C(4)), 38.2 (CH2Ph), 45.9 (C(3)), 48.5
(C(1)), 58.5 (C(2)), 126.9 (p-Ph), 129.1 and 129.4 (o-, m-Ph),
140.1 (ipso-Ph), 177.2 (CO2H); m/z (ESI+) 220 (MH+, 100), 202
(MH+–NH3, 55%); HRMS, found 220.1335; C13H18NO2 (MH+)
requires 220.1338.
Preparation of (1R,2S,3S)-3-benzyl-2-aminocyclopentane-1-
carboxylic acid 45
Following general procedure 7, Pd(OH)2 on C (50 mg) was added
to a stirred degassed solution of (1R,2S,3S,aS)-25 (235 mg,
0.50 mmol) in MeOH (5 ml) and stirred under H2 (5 atm) over-
night. Filtration through Celite® and concentration in vacuo
gave the crude b-amino ester. Although this material was used
without purification, flash chromatography on silica gel (Et2O)
gave an analytical sample of tert-butyl (1R,2S,3S)-3-benzyl-2-
aminocyclopentane-1-carboxylate (99 mg, 72%) as a colourless
oil; [a]2D2 −32.5 (c 1.0, CHCl3); elemental analysis, found C,
73.8; H, 8.7; N, 5.1%; C17H25NO2 requires C, 74.1; H, 9.2; N,
5.1%; mmax (film) 3389br w, 2973m, 1720s, 1603w, 1495w, 1453w,
1391w, 1366m, 1150s, 745w, 700m; dH (400 MHz, CDCl3) 1.22
(1H, m, C(4)HA), 1.39 (2H, br s, NH2), 1.47 (9H, s, OC(CH3)3),
1.81–1.88 (3H, m, C(4)HB and C(5)H2), 2.04 (1H, m, C(3)H),
2.47 (1H, dd, J 13.5, 8.9, CHAHBPh), 2.83–2.90 (2H, m, C(1)H
and CHAHBPh), 3.12 (1H, br t, J 7.4, C(2)H), 7.17–7.30 (5H, m,
Ph); dC (100 MHz, CDCl3) 26.0 (C(5)), 28.2 (OC(CH3)3), 29.6
(C(4)), 40.2 (CH2Ph), 49.2 (C(3)), 50.0 (C(1)), 59.8 (C(2)), 80.4
(OC(CH3)3), 125.8 (p-Ph), 128.3 and 128.9 (o-, m-Ph), 141.0
Preparation of (1R,2S,3S)-3-(1-methylethyl)-2-aminocyclo-
pentane-1-carboxylic acid 46
Following general procedure 7, Pd(OH)2 on C (40 mg) was added
to a stirred degassed solution of (1R,2S,3S,aS)-26 (200 mg,
0.48 mmol) in MeOH (5 ml) and stirred under H2 (5 atm) over-
night. Filtration through Celite® and concentration in vacuo gave
the crude b-amino ester. Although this material was routinely
used without purification, flash chromatography on silica gel
(Et2O) gave an analytical sample of tert-butyl (1R,2S,3S)-3-(1-
methylethyl)-2-aminocyclopentane-1-carboxylate (70 mg, 64%)
as a colourless oil; [a]D22 −20.0 (c 0.35, CHCl3); mmax (film) 3385br
w, 2958s, 2873m, 1723s, 1468w, 1392m, 1367s, 1249w, 1221w,
1152s; dH (400 MHz, CDCl3) 0.88 (3H, d, J 6.5, CH(CH3ACH3B)),
0.99 (3H, d, J 6.5, CH(CH3ACH3B)), 1.23 (1H, m, C(4)HA), 1.48
(9H, s, OC(CH3)3), 1.76 (2H, br s, NH2) overlays 1.60–1.93
(5H, m, CH(CH3)2, C(3)H, C(4)HB and C(5)H2), 2.72 (1H, m,
C(1)H), 3.30 (1H, dd, J 7.1, 5.7, C(2)H); dC (100 MHz, CDCl3)
19.2 (CH(CH3ACH3B)), 21.5 (CH(CH3ACH3B)), 26.4 (C(5)),
26.9 (C(4)), 28.1 (OC(CH3)3), 30.6 (CH(CH3)2), 51.3 (C(3)),
t
(ipso-Ph), 173.9 (CO2 Bu); m/z (APCI+) 276 (MH+, 100%);
HRMS, found 276.1954; C17H26NO2 (MH+) requires 276.1964.
Following general procedure 8, TFA (5 ml) was added to
a solution of crude tert-butyl (1R,2S,3S)-3-benzyl-2-amino-
cyclopentane-1-carboxylate (80 mg, 0.47 mmol) at rt and
stirred for 16 h. Purification using Dowex® 50X8-200 resin
gave (1R,2S,3S)-45 (45 mg, 72% from 25) as a white solid; mp
210–212 °C (decomposes); [a]2D4 −15.0 (c 0.50, H2O); elemental
analysis, found C, 70.9; H, 7.5; N, 6.7%; C13H17NO2 requires C,
71.1; H, 7.8; N, 6.4%; mmax (KBr) 3742–2362br s, 3065s, 2966s,
2362m, 2114w, 1619m, 1658s, 1497m, 1407s, 1314m, 1204w,
727s, 698s; dH (400 MHz, D2O) 1.30 (1H, m, C(4)HA), 1.62–1.80
(2H, m, C(4)HB and C(5)HA), 1.97 (1H, m, C(5)HB), 2.28 (1H,
m, C(3)H), 2.50 (1H, dd, J 13.6, 8.9, CHAHBPh), 2.73 (1H, dd, J
13.6, 6.6, CHAHBPh), 2.85 (1H, m, C(1)H), 3.32 (1H, dd, J 6.6,
5.3, C(2)H), 7.13–7.26 (5H, m, Ph); dC (100 MHz, D2O) 29.5
(C(5)), 30.0 (C(4)), 41.3 (CH2Ph), 47.1 (C(3)), 47.9 (C(1)), 58.7
(C(2)), 127.8 (p-Ph), 130.0 and 130.4 (o-, m-Ph), 141.5 (ipso-Ph),
181.9 (CO2H); m/z (APCI+) 220 (MH+, 100), 202 (MH+–NH3,
60%); HRMS, found 220.1340; C13H18NO2 (MH+) requires
220.1338.
t
54.9 (C(1)), 57.2 (C(2)), 80.3 (OC(CH3)3), 173.8 (CO2 Bu); m/z
(APCI+) 228 (MH+, 15), 172 (MH+–C4H8, 100%); HRMS, found
228.1954; C13H26NO2 (MH+) requires 228.1964.
Following general procedure 8, TFA (5 ml) was added to a
solution of crude tert-butyl (1R,2S,3S)-3-(1-methylethyl)-2-
aminocyclopentane-1-carboxylate (60 mg, 0.26 mmol) at rt and
stirred for 16 h. Purification using Dowex® 50X8-200 resin gave
(1R,2S,3S)-46 (26 mg, 61% from 26) as a white solid; mp 200–
202 °C (decomposes); [a]2D3 +11.7 (c 1.1, H2O); mmax (KBr) 3672–
2361br s, 3420m, 2958s, 2362w, 2125w, 1650m, 1575s, 1524m,
1469w, 1449w, 1414s, 1310m, 1207w, 1148m; dH (400 MHz,
D2O) 0.71 (3H, d, J 6.7, CH(CH3ACH3B)), 0.78 (3H, d, J 6.7,
CH(CH3ACH3B)), 1.30 (1H, m, C(4)HA), 1.50 (1H, app septet,
J 6.7, CH(CH3)3), 1.58–1.68 (1H, m, C(5)HA), 1.70–1.81 (2H,
m, C(3)H and C(4)HB), 1.85–1.94 (1H, m, C(5)HB), 2.67 (1H,
app td, J 10.4, 7.2, C(1)H), 3.40 (1H, dd, J 7.2, 3.4, C(2)H); dC
(100 MHz, D2O) 18.3 (CH(CH3ACH3B)), 20.6 (CH(CH3ACH3B)),
26.1 (C(4)), 28.6 (C(5)), 30.2 (CH(CH3)2), 48.2 (C(1)), 50.7
(C(3)), 55.4 (C(2)), 175.0 (CO2H); m/z (APCI+) 172 (MH+, 65),
154 (MH+–NH3, 100%); HRMS, found 172.1333; C9H18NO2
(MH+) requires 172.1338.
Preparation of (1S,2S,3S)-3-benzyl-2-aminocyclopentane-1-
carboxylic acid hydrochloride 48
Following general procedure 7, Pd(OH)2 on C (25 mg) was
added to a stirred degassed solution of (1S,2S,3S,aS)-28
(120 mg, 0.26 mmol) in MeOH (5 ml) and stirred under H2 (5
atm) overnight. Filtration through Celite® and concentration
in vacuo gave the crude b-amino ester, from which an analyti-
cal sample was purified by flash chromatography on silica gel
(Et2O), giving tert-butyl (1S,2S,3S)-3-benzyl-2-aminocyclo-
pentane-1-carboxylate as a colourless oil (33 mg); [a]2D3 +44.2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4
3 3 5 1

View Article Online
Preparation of (1S,2S,3S)-3-(1-methylethyl)-2-aminocyclo-
pentane-1-carboxylic acid hydrochloride 49
26.9 (C(CH3)3), 28.4 (C(5)), 32.1 (C(CH3)3), 50.5 (C(1)), 54.7
(C(3)), 55.7 (C(2)), 177.2 (CO2H); m/z (ESI+) 186 (MH+, 100%);
HRMS, found 186.1495; C10H20NO2 (MH+) requires 186.1494.
Following general procedure 7, Pd(OH)2 on C (25 mg) was
added to a stirred degassed solution of (1S,2S,3S,aS)-29
(80 mg, 0.19 mmol) in MeOH (5 ml) and stirred under H2
(5 atm) overnight. Filtration through Celite® and concentration
in vacuo gave the crude b-amino ester, from which an analyti-
cal sample was purified by flash chromatography on silica gel
(Et2O), giving tert-butyl (1S,2S,3S)-3-(1-methylethyl)-2-
aminocyclopentane-1-carboxylate as a colourless oil (18 mg);
[a]2D3 +30.6 (c 0.50, CHCl3); mmax (film) 3387br w, 2956s, 2875s,
1725s, 1365s, 1153s; dH (400 MHz, CDCl3) 0.87 (3H, d, J 6.6,
CH(CH3ACH3B)), 0.96 (3H, d, J 6.7, CH(CH3ACH3B)), 1.46 (9H,
s, OC(CH3)3) overlays 1.41–1.46 (1H, m, C(4)HA), 1.67–1.84
(4H, m, CH(CH3)2, C(3)H, C(4)HB and C(5)HA), 1.99 (2H, br s,
NH2) overlays 1.92–2.01 (1H, m, C(5)HB), 2.66 (1H, app q, J 8.4,
C(1)H), 3.26 (1H, br t, J 7.6, C(2)H); dC (100 MHz, CDCl3) 17.9
(CH(CH3ACH3B)), 21.7 (CH(CH3ACH3B)), 24.9 (CH(CH3)2),
26.8 (C(5)), 28.0 (OC(CH3)3), 28.7 (C(4)), 52.1 (C(1) and C(3)),
Preparation of tert-butyl (1S,2S,3S,aS)-3-(1-methylethyl)-2-
(N-a-methylbenzylamino)-cyclopentane-1-carboxylate 40
In accordance with the literature procedure,26 CAN (1.73 g,
3.15 mmol) and (1S,2S,3S,aS)-29 (632 mg, 1.5 mmol) in 5:1
MeCN–H2O (6 ml) at rt overnight gave, after purification by
flash chromatography on silica gel (20% Et2O:n-pentane),
(1S,2S,3S,aS)-40 (353 mg, 71%) as a colourless oil; [a]2D5 +32.6
(c 0.90, CHCl3); mmax (film) 2958s, 2871s, 1722s, 1455m, 1367m,
1277m, 1255m, 1147s, 761m, 701m; dH (400 MHz, CDCl3)
0.62 (3H, d, J 6.7, CH(CH3ACH3B)), 0.81 (3H, d, J 6.7,
CH(CH3ACH3B)), 1.34 (3H, d, J 6.7, C(a)Me), 1.41 (9H, s,
OC(CH3)3) overlays 1.38–1.42 (2H, m, C(3)H and C(4)HA),
1.57–1.68 (2H, m, CH(CH3)2 and C(4)HB), 1.73–1.81 (1H, m,
C(5)HA), 1.82–1.90 (1H, m, C(5)HB), 2.55 (1H, ddd, J 8.9, 8.9,
4.4, C(1)H), 2.86 (1H, dd, J 7.3, 4.9, C(2)H), 3.84 (1H, q, J
6.7, C(a)H), 7.19–7.31 (5H, m, Ph); dC (100 MHz, CDCl3) 18.1
(CH(CH3ACH3B)), 22.1 (CH(CH3ACH3B)), 25.0 (C(a)Me), 26.1
(C(4)), 28.0 (OC(CH3)3), 28.8 (C(5)), 29.0 (CH(CH3)2), 53.0
(C(1)), 54.5 (C(3)), 56.2 (C(a)H), 63.0 (C(2)), 79.8 (OC(CH3)3),
126.8 (p-Ph), 126.9 and 128.1 (o-, m-Ph), 145.5 (ipso-Ph), 175.8
t
57.6 (C(2)), 80.9 (OC(CH3)3), 173.8 (CO2 Bu); m/z (ESI+) 228
(MH+, 100), 172 (MH+–C4H8, 65%); HRMS, found 228.1963;
C13H26NO2 (MH+) requires 228.1964.
TFA (5 ml) was added to a solution of crude giving tert-butyl
(1S,2S,3S)-3-(1-methylethyl)-2-aminocyclopentane-1-carboxy-
late (40 mg, 0.18 mmol) at rt and stirred for 16 h, in accordance
with general procedure 9, furnishing (1S,2S,3S)-49 (20 mg, 69%
from 29) as a clear glass; [a]2D4 +14.8 (c 0.50, H2O); mmax (film)
3332–2386br s, 1709s, 1604w, 1492m, 1206s; dH (400 MHz,
D2O) 0.75 (3H, d, J 6.8, CH(CH3ACH3B)), 0.83 (3H, d, J 6.8,
CH(CH3ACH3B)), 1.45 (1H, m, C(4)HA), 1.63–1.86 (4H, m,
CH(CH3)2, C(3)H, C(4)HB and C(5)HA), 1.93–2.03 (1H, m,
C(5)HB), 2.85 (1H, app td, J 9.3, 7.6, C(1)H), 3.55 (1H, app t,
J 7.8, C(2)H); dC (100 MHz, D2O) 17.0 (CH(CH3ACH3B)), 21.0
(CH(CH3ACH3B)), 24.7 (CH(CH3)2), 27.5 (C(5)), 28.2 (C(4)),
50.4 (C(1) and C(3)), 56.6 (C(2)), 177.3 (CO2H); m/z (ESI+) 172
(MH+, 100), 154 (MH+–NH3, 90%); HRMS, found 172.1334;
C9H18NO2 (MH+) requires 172.1338.
t
(CO2 Bu); m/z (APCI+) 332 (MH+, 50), 276 (MH+–C4H8, 100),
172 (70), 105 (40%); HRMS, found 332.2592; C21H34NO2 (MH+)
requires 332.2590.
Preparation of tert-butyl (R)-3-(1-methylethyl)-cyclopentene-1-
carboxylate 17
Methyliodide(3ml)wasaddedneat, dropwise, to(1S,2S,3S,aS)-
40 (320 mg, 0.97 mmol) and the reaction mixture stirred for
2 d at rt. After the addition of NaHCO3 (aq, sat, 10 ml), the
mixture was extracted with Et2O (3 × 20 ml) and the combined
organic phases dried (MgSO4), filtered and concentrated in
vacuo to give tert-butyl (1S,2S,3S,aS)-3-(1-methylethyl)-2-(N-
methyl-N-a-methylbenzylamino)cyclopentane-1-carboxylate
as a yellow oil. This crude material (355 mg) was subsequently
dissolved in CHCl3 (5 ml) and a solution of mCPBA (50% by
mass, 415 mg) in CHCl3 (5 ml) added dropwise. After stirring
at rt overnight, NaHCO3 (aq, sat, 10 ml) was added and the
aqueous layer separated and extracted with CHCl3 (3 × 15 ml).
The combined organic phases were dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash chromatography on
silica gel (2% Et2O:n-pentane) gave (R)-17 (86 mg, 42% from
40) as a volatile oil; [a]2D5 +51.2 (c 0.75, CHCl3). The material was
judged to be >98% ee by chiral shift NMR spectroscopy using
4 eq by mass Eu(hfc)3, with spectroscopic data consistent with
that obtained for the racemate.
Preparation of (1S,2S,3S)-3-(1,1-dimethylethyl)-2-aminocyclo-
pentane-1-carboxylic acid hydrochloride 50
Following general procedure 7, Pd(OH)2 on C (25 mg) was
added to a stirred degassed solution of (1S,2S,3S,aS)-34
(75 mg, 0.17 mmol) in MeOH (5 ml) and stirred under H2
(5 atm) overnight. Filtration through Celite® and concentration
in vacuo gave the crude b-amino ester, from which an analyti-
cal sample was purified by flash chromatography on silica gel
(Et2O), giving tert-butyl (1S,2S,3S)-3-(1,1-dimethylethyl)-2-
aminocyclopentane-1-carboxylate as a colourless oil (15 mg);
[a]2D3 +34.2 (c 0.70, CHCl3); mmax (film) 3389br w, 2958 s, 2869s,
1724s, 1466w, 1389m, 1364s, 1149s; dH (400 MHz, CDCl3) 0.92
(9H, s, C(3)C(CH3)3), 1.46 (9H, s, OC(CH3)3), 1.50–1.60 (2H,
m, C(3)H and C(4)HA), 1.64–1.78 (2H, m, C(4)HB and C(5)HA),
1.80–1.88 (1H, m, C(5)HB), 2.41 (2H, br s, NH2) overlays
2.38–2.47 (1H, m, C(1)H), 3.25 (1H, br, C(2)H); dC (100 MHz,
CDCl3) 27.6 (C(5)), 27.9 (C(3)C(CH3)3), 28.1 (OC(CH3)3), 30.9
(C(4)), 32.6 (C(3)C(CH3)3), 46.1 (C(3)), 55.5 (C(1)), 57.2 (C(2)),
Preparation of tert-butyl (1R,2S,3S,aR)-3-(1-methylethyl)-2-
(N-benzyl-N-a-methylbenzylamino)-cyclopentane-1-carboxylate
32 and tert-butyl (1S,2S,3S,aR)-3-(1-methylethyl)-2-(N-benzyl-
N-a-methylbenzylamino)-cyclopentane-1-carboxylate 41
Following general procedure 4, n-BuLi (1.5 M, 0.72 mmol,
0.48 ml), (R)-N-benzyl-N-a-methylbenzylamine (153 mg,
0.72 mmol) in THF (5 ml) and (R)-17 (50 mg, 0.24 mmol) in THF
(1 ml) gave, after quenching with 2,6-di-tert-butylphenol (326 mg,
1.58 mmol) in THF (4 ml), (1R,2S,3S,aR)-32, (1S,2S,3S,aR)-41
and (1S,2R,3R,aR)-42 in an 88.0:11.1:0.9 ratio. Purification by
flash chromatography on silica gel (2% Et2O:n-pentane) and
subsequent recrystallisation from n-pentane gave a sample of
pure (1R,2S,3S,aR)-32 (29 mg, 29%) as a white crystalline solid;
mp 102–104 °C; [a]D24 −19.1 (c 0.50, CHCl3); mmax (KBr) 3028w,
2952s, 2881m, 2870m, 1710s, 1602w, 1454m, 1366s, 1213m,
1138s, 748s, 698s; dH (400 MHz, CDCl3) 0.11 (3H, d, J 6.7,
CH(CH3ACH3B)), 0.83 (3H, d, J 6.7, CH(CH3ACH3B)), 1.18–1.24
(1H, m, C(4)HA), 1.50 (3H, d, J 6.9, C(a)Me), 1.55 (9H, s,
t
80.3 (OC(CH3)3), 174.4 (CO2 Bu); m/z (ESI+) 242 (MH+, 100),
186 (MH+–C4H8, 95%); HRMS, found 242.2122; C14H28NO2
(MH+) requires 242.2120.
TFA (5 ml) was added to a solution of crude tert-butyl
(1S,2S,3S)-3-(1,1-dimethylethyl)-2-aminocyclopentane-1-
carboxylate (30 mg, 0.12 mmol) at rt and stirred for 16 h, in
accordance with general procedure 9, furnishing (1S,2S,3S)-50
(13 mg, 61% from 34) as a clear glass; [a]D24 +18.2 (c 0.50, H2O);
mmax (film) 3591–2384br s, 2917s, 2163br m, 1661s, 1516m, 1416m,
1371m, 1251w, 1203w; dH (400 MHz, D2O) 0.80 (9H, s, C(CH3)3),
1.51–1.62 (1H, m, C(4)HA), 1.68–1.85 (3H, m, C(3)H, C(4)HB
and C(5)HA), 1.88–1.98 (1H, m, C(5)HB), 2.88 (1H, m, C(1)H),
3.70 (1H, app t, J 6.3, C(2)H); dC (100 MHz, D2O) 26.7 (C(4)),
3 3 5 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4

View Article Online
OC(CH3)3) overlays 1.48–1.53 (1H, m, C(5)HA), 1.74–1.83 (3H,
m, CH(CH3)2, C(4)HB and C(5)HB), 2.36 (1H, m, C(3)H), 2.85
(1H, app td, J 6.9, 1.6, C(1)H), 2.92 (1H, dd, J 10.7, 6.8, C(2)H),
3.81 and 4.19 (2 × 1H, AB system, JAB 14.1, NCH2Ph), 4.01 (1H,
q, J 6.9, C(a)H) 7.17–7.40 (10H, m, Ph); dC (100 MHz, CDCl3)
14.1 and 14.2 (CH(CH3ACH3B) and C(a)Me), 20.0 (C(5)), 22.9
(CH(CH3ACH3B)), 26.4 (CH(CH3)2), 28.1 and 28.2 (OC(CH3)3
and C(4)), 44.3 (C(3)), 49.4 (C(1)), 50.4 (NCH2Ph), 56.1 (C(a)H),
63.3 (C(2)), 80.0 (OC(CH3)3), 126.5 and 126.6 (p-Ph), 127.7,
128.2, 128.3 and 128.8 (o-, m-Ph), 141.6 and 143.7 (ipso-Ph),
176.2 (CO2tBu); m/z (APCI+) 422 (MH+, 100%); HRMS, found
422.3058; C28H40NO2 (MH+) requires 422.3059.
spectroscopic data consistent with that obtained for the same
compound reported above.
Acknowledgements
The authors wish to thank AgrEvo and Pfizer for industrial
CASE awards (to R.M.P. and J.M.W., respectively) and New
College, Oxford for a Junior Research Fellowship (A.D.S.).
References and notes
1 For representative examples see K. Gademann, A. Hane,
M. Rueping, B. Jaun and D. Seebach, Angew. Chem. Int. Ed.,
2003, 42, 1534; D. Seebach, M. Overhand, F. N. M. Kuehnle and
B. Martinoni, Helv. Chim. Acta, 1996, 79, 913; D. Seebach, P. E.
Ciceri, M. Overhand, B. Jaun, D. Rigo, L. Oberer, U. Hommel,
R. Amstutz and H. Widmer, Helv. Chim. Acta, 1996, 79, 2043;
D. Seebach, K. Gademann, J. V. Schreiber, J. L. Matthews,
T. Hintermann, B. Jaun, L. Oberer, U. Hommel and H. Widmer,
Helv. Chim. Acta, 1997, 80, 2033; D. Seebach and J. L. Matthews,
Chem. Commun., 1997, 2015; D. Seebach, S. Abele, J. V. Schreiber,
B. Martinoni, A. K. Nussbaum, H. Schild, H. Schulz, H. Hennecke,
R. Woessner and F. Bitsch, Chimia, 1998, 52, 734.
2 For representative examples see A. M. Brueckner, P. Chakraborty,
S. H. Gellman and U. Diederichsen, Angew. Chem. Int. Ed., 2003,
42, 4395; B. R. Huck, J. D. Fisk, I. A. Guzei, H. A. Carlson
and S. H. Gellman, J. Am. Chem. Soc., 2003, 125, 9035; J. M.
Langenhan, I. A. Guzei and S. H. Gellman, Angew. Chem. Int.
Ed., 2003, 42, 2402; M. Schinnerl, J. K. Murray, J. M. Langenhan
and S. H. Gellman, Eur. J. Org. Chem., 2003, 4, 721; M. G. Woll,
J. D. Fisk, P. R. LePlae and S. H. Gellman, J. Am. Chem. Soc.,
2002, 124, 12447; R. P. Cheng, S. H. Gellman and W. F. DeGrado,
Chem. Rev., 2001, 101, 3219; Y. J. Chung, L. A. Christianson,
H. E. Stanger, D. R. Powell and S. H. Gellman, J. Am. Chem. Soc.,
1998, 120, 10555.
A mixed fraction of (1R,2S,3S,aR)-32 and (1S,2S,3S,aR)-41
(34 mg, 34%) as a colourless oil, was also obtained. This material
was subsequently re-dissolved in tert-butanol (5 ml) and epimer-
ised under thermodynamic conditions in accordance with gen-
eral procedure 6. Purification by flash chromatography on silica
gel (2% Et2O:n-pentane) gave (1S,2S,3S,aR)-41 in >98% de as
a colourless oil (33 mg, quantitative); [a]2D5 −0.93 (c 0.75, CHCl3);
mmax (film) 3086w, 3062w, 3029m, 2956s, 2872s, 1721s, 1602w,
1494m, 1453m, 1367s, 1274m, 1255m, 1148s, 749s, 733s, 698s;
dH (400 MHz, CDCl3) 0.26 (3H, d, J 6.8, CH(CH3ACH3B)), 0.81
(3H, d, J 6.8, CH(CH3ACH3B)), 1.27–1.32 (1H, m, C(4)HA), 1.36
(3H, d, J 6.8, C(a)Me), 1.40–1.44 (1H, m, C(5)HA), 1.52 (9H, s,
OC(CH3)3), 1.63–1.69 (1H, m, CH(CH3)2), 1.70–1.82 (3H, m,
C(3)H, C(4)HB and C(5)HB), 2.83 (1H, m, C(1)H), 3.34 (1H, dd,
J 9.3, 5.2, C(2)H), 3.69 and 3.80 (2 × 1H, AB system, JAB 14.2,
NCH2Ph), 3.90 (1H, q, J 6.8, C(a)H), 7.17–7.46 (10H, m, Ph);
dC (100 MHz, CDCl3) 13.2 (C(a)Me), 15.8 (CH(CH3ACH3B)),
22.9 (CH(CH3ACH3B)), 23.2 (C(5)), 27.0 (CH(CH3)2), 28.1
(OC(CH3)3), 31.0 (C(4)), 45.8 (C(1)), 50.5 (NCH2Ph), 51.0
(C(3)), 56.3 (C(a)H), 63.0 (C(2)), 79.9 (OC(CH3)3), 126.5 and
126.7 (p-Ph), 127.8, 127.9, 128.1 and 128.7 (o-, m-Ph), 141.5 and
3 G. P. Dado and S. H. Gellman, J. Am. Chem. Soc., 1994, 116, 1054;
D. H. Appella, L. A. Christianson, D. A. Klein, D. R. Powell,
X. Huang, J. J. Barchi and S. H. Gellman, Nature, 1997, 387, 381.
4 T. A. Martinek, G. K. Táth, E. Vass, M. Hollósi and F. Fülop,
Angew. Chem. Int. Ed., 2002, 41, 1718.
t
144.2 (ipso-Ph), 176.5 (CO2 Bu); m/z (ESI+) 422 (MH+, 100%);
HRMS, found 422.3057; C28H40NO2 (MH+) requires 422.3059.
5 A. Hayen, M. A. Schmitt, F. N. Ngassa, K. A. Thomasson and
S. H. Gellman, Angew. Chem., Int. Ed., 2004, 43, 505; S. De Pol,
C. Zorn, C. D. Klein, O. Zerbe and O. Reiser, Angew. Chem., Int.
Ed., 2004, 43, 511.
X-ray crystal structure determination for 32†
DatawerecollectedusinganEnraf-Nonius j-CCDdiffractometer
with graphite monochromated Cu–Ka radiation using standard
procedures at 190 K. The structure was solved by direct methods
(SIR92), all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at idealised
positions. The structure was refined using CRYSTALS.32
X-ray crystal structure data for 32 [C28H39NO2]: M =
421.62, monoclinic, space group P 1 21 1, a = 10.0382(3) Å,
b = 10.7600(3) Å, c = 11.6779(4) Å, V = 1261.05(7) Å3, Z =
2, l = 0.068 mm−1, colourless block, crystal dimensions =
0.1 × 0.1 × 0.1 mm. A total of 3011 unique reflections were
measured for 5 < h < 27 and 2299 reflections were used in the re-
finement. The final parameters were wR2 = 0.043 and R1 = 0.045
[I > 2r(I)]. Crystallographic data (excluding structure factors)
has been deposited with the Cambridge Crystallographic Data
Centre. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44(0)-1223-336033 or deposit@ccdc.cam.ac.uk].
6 For example see S. G. Davies and O. Ichihara, Tetrahedron: Asym-
metry, 1991, 2, 183; S. G. Davies, O. Ichihara and I. A. S. Walters,
Synlett, 1993, 461; S. G. Davies, N. M. Garrido, O. Ichihara
and I. A. S. Walters, Chem. Commun., 1993, 1153; S. G. Davies,
M. E. Bunnage and C. J. Goodwin, J. Chem. Soc., Perkin Trans. 1,
1993, 1375; S. G. Davies, M. E. Bunnage and C. J. Goodwin, Synlett,
1993, 731; S. G. Davies, O. Ichihara and I. A. S. Walters, Synlett, 1994,
117; S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1996, 7,
1919; S. G. Davies and O. Ichihara, Tetrahedron Lett., 1999, 40, 9313;
S. G. Davies and D. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 2629;
S. D. Bull, S. G. Davies and A. D. Smith, J. Chem. Soc., Perkin Trans.
1, 2001, 2931; S. D. Bull, S. G. Davies and A. D. Smith, Tetrahedron:
Asymmetry, 2001, 12, 2191; S. D. Bull, S. G. Davies, P. M. Roberts,
E. D. Savory and A. D. Smith, Tetrahedron, 2002, 58, 4629.
7 S. Bailey, S. G. Davies, A. D. Smith and J. M. Withey, Chem. Com-
mun., 2002, 2910; M. E. Bunnage, A. M. Chippendale, S. G. Davies,
R. M. Parkin, A. D. Smith and J. M. Withey, Org. Biomol. Chem.,
2003, 3698.
8 A. Horeau, Tetrahedron, 1975, 31, 1307.
9 This approach is valid on the assumption that there are no non-
linear effects operating in the reaction. For a review concerned with
non-linear effects in asymmetric synthesis see H. B. Kagan, Adv.
Synth. Catal., 2001, 343. For other manuscripts describing non-
linear effects and related topics in kinetic resolution reactions see
D. W. Johnson, Jr and D. A. Singleton, J. Am. Chem. Soc., 1999, 121,
9307; R. F. Ismagilov, J. Org. Chem., 1998, 63, 3772.
Preparation of tert-butyl (1R,2S,3S)-3-(1-methylethyl)-2-
aminocyclopentane-1-carboxylate 43 by hydrogenolysis of
(1R,2S,3S,aR)-32
Following general procedure 7, Pd(OH)2 on C (8 mg) was added
to a degassed solution of (1R,2S,3S,aR)-43 (20 mg, 0.05 mmol)
in MeOH (3 ml) and stirred under H2 (5 atm) overnight. Filtra-
tion through Celite®, concentration in vacuo and purification by
flash chromatography on silica gel (Et2O) gave (1R,2S,3S)-32
as a colourless oil (7 mg, 64%); [a]2D2 −18.1 (c 0.35, CHCl3), with
10 S. M. Brown, S. G. Davies and J. A. A. de Sousa, Tetrahedron:
Asymmetry, 1991, 2, 511; S. M. Brown, S. G. Davies and J. A. A. de
Sousa, Tetrahedron: Asymmetry, 1993, 4, 813; S. C. Case-Green,
J. F. Costello, S. G. Davies, N. Heaton, C. J. R. Hedgecock and
J. C. Prime, Chem. Commun., 1993, 1621; S. C. Case-Green,
J. F. Costello, S. G. Davies, N. Heaton, C. J. R. Hedgecock,
V. M. Humphries, M. R. Metzler and J. C. Prime, J. Chem. Soc.,
Perkin Trans 1, 1994, 933; S. P. Bew, S. G. Davies and S.-I. Fukuzawa,
Chirality, 2000, 12, 483.
† CCDC reference number 237688. See http://www.rsc.org/suppdata/
ob/b4/b407559e/ for crystallographic data in .cif or other electronic
format.
11 For the parallel kinetic resolutions of 5-alkyl-cyclopentene
carboxylates with a pseudoenantiomeric mixture of lithium amides
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4
3 3 5 3

View Article Online
1
see S. G. Davies, D. Díez, M. M. El Hammouni, N. M. Garrido,
A. C. Garner, M. J. C. Long, R. M. Morrison, A. D. Smith, M. J.
Sweet and J. M. Withey, Chem. Commun., 2003, 2410.
12 J. H. Babler and S. J. Sarussi, J. Org. Chem., 1987, 52, 3462.
13 D. Henderson, K. A. Richardson, R. J. K. Taylor and J. Saunders,
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14 X. Wang, J. F. Espinosa and S. H. Gellman, J. Am. Chem. Soc., 2000,
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15 A. Barco, S. Benetti and G. P. Pollni, Synthesis, 1973, 316.
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J. Wright, G. J. Drtina, R. A. Roberts and L. A. Paquette, J. Am.
Chem. Soc., 1988, 110, 5806.
17 Attempted alkylation of the mono-enolate of tert-butyl 2-oxo-
cyclopentene-1-carboxylate with 2-iodopropane also returned only
starting materials.
18 H. O. House, L. J. Czuba, M. Gall and H. D. Olmstead, J. Org.
Chem., 1969, 34, 2324.
19 L. A. Paquette, A. T. Hamme II, L. H. Kuo, J. Doyon and
R. Kreuzholz, J. Am. Chem. Soc., 1997, 119, 1242.
23 As shown by H NMR chiral shift experiments with commercially
available Eu(hfc)3 (Aldrich) and reference to an authentic racemic
sample.
24 Prepared by epimerisation of the major diastereoisomeric product 26
from kinetic resolution.
25 S. D. Bull, S. G. Davies, G. Fenton, A. W. Mulvaney, R. S. Prasad
and A. D. Smith, Chem. Commun., 2000, 337; S. D. Bull, S. G.
Davies, G. Fenton, A. W. Mulvaney, R. S. Prasad and A. D. Smith,
J. Chem. Soc., Perkin Trans. 1, 2000, 3765.
26 We have previously used this, and related procedures, to effect
a range of asymmetric transformations; see S. G. Davies and
G. D. Smyth, J. Chem. Soc., Perkin Trans. 1, 1996, 2467; S. G. Davies
and G. D. Smyth, Tetrahedron: Asymmetry, 1996, 7, 1005; S. G.
Davies and G. D. Smyth, Tetrahedron: Asymmetry, 1996, 7, 1001;
S. G. Davies, C. A. P. Smethurst, A. D. Smith and G. D. Smyth,
Tetrahedron: Asymmetry, 2000, 11, 2437.
27 As shown by 19F and 1H NMR spectroscopic analysis of the derived
methyl esters and subsequent derivatisation with both racemic and
99% ee Mosher’s acid chloride.
20 The syn-1,2-anti-2,3-arrangement within b-amino esters 20 and
21 and the anti-1,2-anti-2,3-arrangement within 22 and 23 were
assumed by analogy to that proven unambiguously in the 3-methyl
series; see ref. 7.
21 The relative configurations within the observed b-amino esters were
readily assigned by analogy to the selectivity observed in the related
(RS)-3-methyl substrate; see ref. 7 for full details.
22 A total of four diastereoisomeric compounds were identified in
the kinetic resolution crude reaction mixture in this case, with the
combined sum (by 1H NMR integration) of the two minor diastereo-
isomeric products being 1.2% of the total.
28 E. Stahl, Thin Layer Chromatography, Springer-Verlag, Berlin, 1969,
p. 873.
29 T. H. Chan, I. Paterson and J. Pinsonnault, Tetrahedron Lett., 1977, 15,
4183; M. Reetz and W. Maier, Angew. Chem., Int. Ed. Engl., 1978, 7, 48.
30 L. A. Paquette, K. Dahnke, J. Doyne, W. He, K. Wyant and
D. Friedrich, J. Org. Chem., 1991, 56, 6199.
31 C. M. Main, R. P. C. Cousins, G. Coumbarides and N. S. Simpkins,
Tetrahedron, 1990, 46, 523.
32 D. J. Watkin, C. K. Prout, J. R. Carruthers, P. W. Betteridge and
R. I. Cooper, CRYSTALS, 2001, Issue 11, Chemical Crystallogra-
phy Laboratory, Parks Road, Oxford.
3 3 5 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 3 7 – 3 3 5 4