Kinetic resolution and parallel kinetic resolution of methyl (±)-5-alkyl-cyclopentene-l-carboxylates for the asymmetric synthesis of 5-alkyl-cispentacin derivatives

Article abstract of DOI:10.1039/b506339f

Conjugate addition of lithium dibenzylamide to methyl 5-isopropyl, 5-phenyl- and 5-tert-butyl-cyclopentene-1-carboxylates occurs with high levels of substrate control (>88% de), with preferential addition to the face of the cyclic α,β-unsaturated acceptor

Full text of DOI:10.1039/b506339f

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A R T I C L E
Kinetic resolution and parallel kinetic resolution of methyl
( )-5-alkyl-cyclopentene-1-carboxylates for the asymmetric
synthesis of 5-alkyl-cispentacin derivatives
Stephen G. Davies,* A. Christopher Garner, Marcus J. C. Long, Rachel M. Morrison,
Paul M. Roberts, Edward D. Savory, Andrew D. Smith, Miles J. Sweet and Jonathan M. Withey
The Department of Organic Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, UK OX1 3TA. E-mail: steve.davies@chem.ox.ac.uk
Received 6th May 2005, Accepted 1st June 2005
First published as an Advance Article on the web 30th June 2005
Conjugate addition of lithium dibenzylamide to methyl 5-isopropyl, 5-phenyl- and 5-tert-butyl-cyclopentene-
1-carboxylates occurs with high levels of substrate control (>88% de), with preferential addition to the face of the
cyclic a,b-unsaturated acceptor anti- to the stereodirecting 5-alkyl substituent. Treatment of a range of methyl
( )-5-alkyl-cyclopentene-1-carboxylates with both lithium ( )-N-benzyl-N-a-methylbenzylamide and lithium
( )-N-3,4-dimethoxybenzyl-N-a-methylbenzylamide indicates significant enantiorecognition in their mutual kinetic
resolutions, with preferential addition anti- to the 5-alkyl substituent, giving the 1,2-syn-1,5-anti-arrangement
(E >16) after enolate protonation anti- to the amino functionality. The kinetic resolution of a range of methyl
( )-5-alkyl-cyclopentene-1-carboxylates with lithium (S)-N-benzyl-N-a-methylbenzylamide, and their efficient
parallel kinetic resolution with a pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-a-methylbenzylamide and
lithium (R)-N-3,4-dimethoxybenzyl-N-a-methylbenzylamide are also demonstrated, giving a range of
5-alkyl-cispentacin derivatives in >98% de and high ee after N-deprotection.
cyclopentene-1-carboxylates. Extensive work by Villie´ras et al.
Introduction
has demonstrated that these materials may be prepared effi-
The simple cyclic b-amino acid (1R,2S)-2-aminocyclopentane-
ciently via the copper catalysed conjugate addition of Grig-
carboxylic acid (cispentacin) has recently attracted considerable
nard reagents to 5-acetoxy-cyclopentene-1-carboxylates, fol-
synthetic attention,1 with a number of efficient methodologies
lowed by elimination to give the required 5-alkyl-cyclopentene-
having been developed for its synthesis in enantiomerically en-
carboxylates.10 Following this strategy,11 the known methyl ester
riched form.2 We have recently reported routes3 to 3-substituted
1 was acetylated to generate 5-acetoxy methyl ester 2 in 84%
analogues of cispentacin in homochiral form,4 and we wished
i
yield. Subsequent addition of MeMgCl, PrMgCl, PhMgBr,
to extend the application of lithium amide conjugate addition
tBuMgCl and mesityl magnesium bromide, respectively, to 2 in
methodology5 to allow the asymmetric synthesis of a range of 5-
the presence of CuI gave the corresponding methyl ( )-5-alkyl-
cyclopentene-1-carboxylates 3–7 in good yields (Scheme 1).
alkyl-cispentacins, which have received only limited attention in
the literature.6 Previous investigations from this laboratory con-
cerning the kinetic resolution3 and parallel kinetic resolution7
of ( )-3-alkyl-cyclopentene-1-carboxylates have demonstrated
that a full understanding of the observed stereoselectivity in
these systems is best achieved by initially evaluating the level
of substrate control upon conjugate addition of an achiral
lithium amide to the chiral ( )-acceptor. For those substrates
offering high facial selectivity upon conjugate addition, the
levels of enantiorecognition between the substrate and chiral
lithium amides may be evaluated through their mutual kinetic
Scheme 1 Reagents and conditions: (i) pyridine, Ac2O, 0 ◦C; (ii) CuI,
resolution [addition of ( )-acceptor to an excess of a ( )-lithium
◦
i
THF, then (a) MeMgCl, CuI, THF, −35 C; (b) PrMgCl, CuI, THF,
amide]. This approach,8 in which the effects of mass action are
eliminated, allows the magnitude of the stereoselectivity factor
(E) for the reaction to be calculated independent of the reaction
conversion, as it is generally identical to the diastereoselectivity
observed in the reaction.9 If high enantiorecognition is seen
between the reacting partners, then efficient kinetic resolution
and parallel kinetic resolution in these systems may be expected,
and readily achieved. We detail herein the extension of this
methodology to the kinetic and parallel kinetic resolutions of
a range of ( )-5-alkyl-cyclopentene-1-carboxylates.
−70 ◦C; (c) PhMgBr, CuI, THF, −50 C; (d) BuMgCl, CuI, THF,
◦
t
−60 ◦C; (e) mesitylmagnesium bromide, CuI, THF, −35 ◦C.
Evaluation of substrate control: conjugate addition of lithium
dibenzylamide
With a series of methyl ( )-5-alkyl-cyclopentene-1-carboxylates
3–7 in hand, the level of substrate control they exert upon conju-
gate addition of lithium dibenzylamide was evaluated, as a guide
for predicting the extent of enantiorecognition upon reaction
with a chiral lithium amide. Conjugate addition of lithium diben-
zylamide to ( )-5-tert-butyl-6 gave methyl (1RS,2SR,5SR)-
2-dibenzylamino-5-tert-butyl-cyclopentane-1-carboxylate 14 in
>98% de and in 80% yield as a single diastereoisomer after chro-
matographic purification (Scheme 2). The relative configuration
within (1RS,2SR,5SR)-14 was assigned from 1H NMR NOE dif-
ference experiments, consistent with the cyclopentane b-amino
Results and discussion
Preparation of a range of methyl
( )-5-alkyl-cyclopentene-1-carboxylates
Initial investigations were directed towards the preparation
of multigram quantities of a range of methyl ( )-5-alkyl-
2 7 6 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5
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 5
©

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ester preferentially adopting an envelope conformation with the
5-tert-butyl group occupying a pseudo-equatorial position. A
6.4% enhancement from C(1)H to C(2)H indicated that these
protons have a syn relationship, while the 9.1% enhancement
from C(1)H to the 5-tert-butyl group, as compared to the
1.9% enhancement from C(1)H to C(5)H, is consistent with an
anti-relationship between the 5-tert-butyl group and the C(1)-
carboxylate. However, conjugate addition of lithium dibenzy-
lamide to ( )-5-methyl-3 proceeded with complete consumption
of starting material to give a mixture of products, containing
a 78 : 22 mixture of the partially separable 1,2-syn-1,5-anti-
and 1,2-syn-1,5-syn-diastereoisomers 8 : 9 in 50% overall yield
after chromatography. The relative configurations within both 8
and 9 were confirmed by 1H NMR NOE difference or NOESY
analysis, with the 1,2-syn-1,5-anti-arrangement within the major
diastereoisomer 8 consistent with that observed in the 5-tert-
butyl diastereoisomer 14 (Fig. 1.) This product distribution is
consistent with the 5-methyl substituent of ( )-3 conferring
moderate facial control while the bis-a-branched 5-tert-butyl
group of ( )-6 confers excellent facial control in the conjugate
addition step. To elucidate the steric requirement of C(5)
substitution needed to afford high stereocontrol in these systems,
the conjugate addition of lithium dibenzylamide to ( )-5-iso-
propyl 4 and ( )-5-phenyl 5 was assessed. The crude product
mixtures arising from these reactions indicated consumption of
starting material, and contained predominantly one b-amino
ester diastereoisomer in each case (diastereoisomer ratio >90 :
<10; configuration within minor diastereoisomer assigned by
analogy to 9). These crude product mixtures were contaminated
with a number of unidentified products, presumably arising
from either competitive 1,2-addition or c-deprotonation that
precluded accurate determination of the reaction stereoselec-
tivity. Purification gave (1RS,2SR,5RS)-5-isopropyl-10 in 59%
isolated yield and (1RS,2SR,5SR)-5-phenyl-12 in 42% isolated
yield. The 1,2-syn-1,5-anti-relationship within b-amino esters 10
Scheme 2 Reagents and conditions: (i) lithium dibenzylamide, THF,
−78 ◦C then NH4Cl(aq)
.
planar s-cis conformation,12 and during conjugate addition the
5-alkyl stereodirecting group may adopt either a pseudoaxial
or pseudoequatorial position. Assuming that the conformation
with an a-branched 5-alkyl substituent in the pseudoequato-
rial position is destabilised by 1,2-steric interactions with the
adjacent ester, the preferred conformation of the cyclopentene-
1-carboxylate places the 5-alkyl substituent in a pseudoaxial
position. In this position, the substituent provides a large facial
bias as it projects effectively over one face of the acceptor, and
addition of lithium dibenzylamide occurs preferentially anti-
to this stereocontrolling pseudoaxial substituent. Preferential
protonation of the intermediate enolate anti- to the adjacent
2-amino group13 then affords the 1,2-syn-1,5-anti-configuration
observed within the major diastereoisomers (Fig. 2.)
1
and 12, confirmed in each case by H NMR NOE analysis, is
consistent with the sense of induction observed in the 5-tert-
butyl diastereoisomer 14, and is indicative of high stereocontrol
occurring in the conjugate addition step (Scheme 2).
Fig. 2 Proposed model for selectivity observed upon lithium dibenzy-
lamide addition to methyl ( )-5-alkyl-cyclopentene-1-carboxylates and
subsequent protonation.
Having demonstrated that conjugate addition of lithium
dibenzylamide to a-branched 5-alkyl cyclopentene-1-carboxy-
lates proceeds with high levels of substrate control, the extent of
enantiorecognition between ( )-esters 3–7 and chiral lithium
amides was next investigated through their mutual kinetic
resolution.
Fig. 1 Selected 1H NMR NOESY and 1H NMR NOE difference
enhancements for b-amino esters ( )-9 and ( )-14.
The high 1,2-syn-1,5-anti-selectivity noted in these reactions
Enantiorecognition studies: mutual kinetic resolution of
( )-5-alkyl-cyclopentene-1-carboxylates 3–7 with lithium
( )-N-benzyl-N-a-methylbenzylamide and lithium
( )-N-3,4-dimethoxybenzyl-N-a-methylbenzylamide
i
(R = Pr, Ph, tBu) indicates that the presence of an a-branched
substituent in the 5-position of cyclopentene-1-carboxylates
leads to good levels of substrate control upon conjugate addition
of lithium dibenzylamide. This 1,2-syn-1,5-anti-arrangement
may be rationalised using the following model. Lithium amides
are known to add to a,b-unsaturated acceptors in the conjugated
To evaluate the potential of ( )-5-alkyl-cyclopentene-1-carb-
oxylates 3–7 to undergo kinetic and parallel kinetic resolutions
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5
2 7 6 3

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upon reaction with homochiral lithium amides, their mu-
tual kinetic resolution with both lithium ( )-N-benzyl-N-a-
methylbenzylamide and lithium ( )-N-3,4-dimethoxybenzyl-
N-a-methylbenzylamide was investigated. In these reactions,
four diastereoisomeric products 17–20 are possible assuming
exclusive protonation anti- to the amino group upon conjugate
addition (Fig. 3.)13 Under these constraints, if both reaction
components show high stereodirecting capabilities, the major
product is predicted to have the 1,2-syn-1,5-anti-configuration
corresponding to 17 (‘matched’ with respect to each compo-
nent) and a high E value may be expected. However, if the
stereodirecting capability of one of the components is greater
than the other, either diastereoisomer 19 or 20 (arising from
‘matched’ and ‘mismatched’ selectivity with respect to one of
each of the reaction components) may be formed, resulting in a
loss of selectivity and a reduction in the E value.
Scheme 3 Reagents and conditions: (i) ( )-16, THF, −78 ◦C then
NH4Cl(aq)
.
purification and recrystallisation. Additionally, conjugate ad-
dition of lithium amide ( )-16 to ( )-5-tert-butyl 6 and ( )-
5-mesityl 7 proceeded with high selectivity, giving essentially
a single b-amino ester diastereoisomer in each case (ratio of
major : minor >99 : <1). Chromatographic purification gave
(1RS,2SR,5SR,aSR)-5-tert-butyl 27 as a single diastereoisomer
in 85% yield, and (1RS,2SR,5SR,aSR)-5-mesityl 29 as a single
diastereoisomer in 73% yield, consistent with E >99 in both
reactions (Scheme 4). As high enantiorecognition is observed in
each of these processes (E >16), the configuration at C(2) within
the major diastereoisomers relative to the N-a-methylbenzyl
stereocentre was assigned by analogy with the stereoselectivity
observed during addition of lithium amide 16 to a,b-unsaturated
acceptors,14 with the configuration at C(5) and C(1) determined
relative to C(2) by 1H NMR NOE difference analysis. The
relative (1RS,2SR,5SR,aSR)-configurations within the 5-phenyl
and 5-mesityl b-amino esters 25 and 29 respectively were con-
firmed unambiguously by single crystal X-ray structure analysis
in each case (Fig. 4), while the 1,2-syn-1,5-anti-arrangement of
the minor diastereoisomer series was confirmed by analysis of
the products arising from kinetic resolution (vide supra).
Fig. 3 Possible diastereoisomeric b-amino ester products obtained
upon addition of lithium ( )-N-benzyl-N-a-methylbenzylamide 16
to methyl ( )-5-alkyl-cyclopentene-1-carboxylates (assuming exclusive
protonation anti- to the amino group).
Initial investigations concentrated upon the mutual kinetic
resolution of ( )-5-methyl 3, which showed only moderate levels
of substrate control upon addition of lithium dibenzylamide.
Conjugate addition of lithium ( )-amide 16 to ( )-5-methyl
3 gave an 80 : 20 mixture of the partially separable di-
astereoisomers 21 : 22 in 60% overall yield after chromatography.
The relative 1,2-syn-1,5-anti- and 1,2-syn-1,5-syn-configurations
within 21 and 22 respectively were confirmed by 1H NMR
NOESY analysis. In both cases, the configuration at C(2) relative
to the N-a-methylbenzyl stereocentre was predicated upon the
assumption that the stereodirecting ability of the lithium amide
dominates the low control exerted by the substrate and was
assigned by analogy with previous models developed to explain
the high stereoselectivity observed during addition of lithium
amide 16 to a,b-unsaturated acceptors.14 This product distribu-
tion is consistent with low levels of enantiorecognition between
( )-16 and ( )-3 (E = 4), indicating that the ( )-5-methyl 3 is
not suitable for either kinetic or parallel kinetic resolution with
enantiomerically pure lithium amides (Scheme 3).
The mutual kinetic resolution of the methyl a-branched 5-
substituted cyclopentene-1-carboxylates that showed high sub-
strate control upon conjugate addition of lithium dibenzylamide
was next investigated. Addition of lithium ( )-N-benzyl-N-
a-methylbenzylamide 16 to ( )-5-isopropyl 4 gave a 96.5 :
3.5 mixture of b-amino esters (1RS,2SR,5RS,aSR)-23 and
(1SR,2RS,5SR,aSR)-24 (E >25), giving 23 in 84% yield and
94% de after purification. Similarly, addition of lithium amide
( )-16 to ( )-5-phenyl 5 gave a 94 : 6 mixture of b-amino esters
(1RS,2SR,5SR,aSR)-25 and (1SR,2RS,5RS,aSR)-26 (E > 16),
giving 25 as a single diastereoisomer after chromatographic
Scheme 4 Reagents and conditions: (i) ( )-16, THF, −78 ◦C then
NH4Cl(aq)
.
Close inspection of the product distributions in these re-
actions indicates a change in relative configuration of the
minor diastereoisomers from the 1,2-syn-1,5-syn-arrangement
upon addition of lithium dibenzylamide to the 1,2-syn-1,5-
anti-arrangement upon addition of chiral lithium amide 16.
It is apparent from these data that lithium dibenzylamide
is not an ideal achiral model for an evaluation of substrate
stereocontrol conferred by the acceptor upon lithium amide
conjugate addition. This led to the evaluation of lithium N-
benzyl-N-isopropylamide as an alternative achiral amide in this
reaction manifold. The incorporation of an a-branched sub-
stituent in this achiral model was expected to mimic better the
steric bias of lithium N-benzyl-N-a-methylbenzylamide. Thus,
2 7 6 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5

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Scheme 6 Reagents and conditions: (i) ( )-32, THF, −78 ◦C then
NH4Cl(aq)
.
the addition of lithium amide ( )-16, with single crystal X-ray
structure analysis of the C(5)-Ph-b-amino ester 34 confirming
this analysis unambiguously (Fig. 5).
Fig.
4
Chem3D representation of the X-ray crystal structures
of 5-Ph-(1RS,2SR,5SR,aSR)-25 and 5-mesityl-(1RS,2SR,5SR,aSR)-29
(some H atoms omitted for clarity).
conjugate addition of lithium N-benzyl-N-isopropylamide to
( )-5-isopropyl 4 gave a single product, furnishing 1,2-syn-
1,5-anti-b-amino ester 31 in >98% de and 81% isolated yield,
indicating that ( )-5-isopropyl 4 provides high substrate control
in the conjugate addition manifold. This is consistent with the
1,2-syn-1,5-anti-arrangement of both diastereoisomers observed
upon addition of the chiral lithium amide ( )-16 to ( )-5-
isopropyl 4 (Scheme 5).
Fig. 5 Chem3D representation of the X-ray crystal structure of
5-Ph-(1RS,2SR,5SR,aSR)-35 (some H atoms omitted for clarity).
The epimerisation of 1,2-syn-2-aminocyclopentane-1-car-
boxylates and 1,2-syn-2,3-anti-3-alkyl-2-aminocyclopentane-1-
carboxylates to the corresponding thermodynamic 1,2-anti-2-
aminocyclopentane-1-carboxylates upon treatment with tBuOK
t
in BuOH–THF has previously been demonstrated within this
Scheme 5 Reagents and conditions: (i) lithium N-benzyl-N-isopropyl-
amide, THF, −78 ◦C then NH4Cl(aq)
.
laboratory and utilised for the preparation of transpentacin and
its 3-alkyl derivatives.3 Further investigations were then directed
toward the possible epimerisation of the C(1)-stereogenic centre
within the 1,2-syn-1,5-anti-b-amino esters 14, 21, 35 and 37 to
their corresponding 1,2-anti-1,5-syn-b-amino esters. Treatment
of dibenzyl-b-amino ester 14 with NaOMe in MeOH for
one week returned only starting material, while treatment of
N-a-methylbenzyl-b-amino esters 5-Me 21, 5-Ph 35 and 5-tBu
37 with tBuOK in tBuOH–THF at reflux indicated consumption
of starting material with extensive decomposition in each case.
The reason for the failure of these 5-alkyl-cyclopentane b-
amino esters to epimerise, unlike the facile epimerisation in the
analogous 3-alkyl cyclopentane b-amino esters, is unknown.
However, it may be that epimerisation is disfavoured as the
C(1)H proton is held in a conformation approximately coplanar
with the carbonyl carbon as observed in the solid state (see
Having demonstrated that a-branched 5-substituted cyclo-
pentene-1-carboxylates undergo efficient mutual kinetic resolu-
tion with lithium ( )-amide 16, their mutual kinetic resolution
with lithium ( )-N-3,4-dimethoxybenzyl-N-a-methylbenzyl-
amide 32 was evaluated, giving similar results to those observed
for lithium amide ( )-16 (Scheme 6). Thus, addition of lithium
amide ( )-31 to ( )-5-isopropyl 4 and ( )-5-phenyl 5 gave a
mixture of b-amino esters 33 : 34 and 35 : 36 respectively
in a 96.5 : 3.5 ratio and 96 : 4 ratio (E >25 and E >20
respectively). Addition of lithium amide ( )-32 to ( )-5-tert-
butyl 6 and ( )-5-mesityl 7 gave essentially a single b-amino
ester diastereoisomer in each case (ratio of major : minor >99 :
<1, E >99). In each case, the configuration within the major
diastereoisomer was assumed by analogy to those identified for
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5
2 7 6 5

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Figs. 4 and 5). These results demonstrate that conjugate
additions of lithium ( )-N-benzyl-N-a-methylbenzylamide and
lithium ( )-N-3,4-dimethoxybenzyl-N-a-methylbenzylamide to
5-alkyl-cyclopentene-1-carboxylates with an a-branched sub-
stituent proceed with significant enantiorecognition and with
preferential protonation anti- to the neighbouring amino group.
Kinetic resolution of methyl ( )-5-isopropyl-, ( )-5-phenyl- and
( )-5-tert-butyl-cyclopentene-1-carboxylates 4–6
Having assessed the degree of enantiorecognition between ( )-
5-alkyl acceptors 3–7 and ( )-lithium amides 16 and 32, the
kinetic resolution of 4–6 with homochiral lithium amide (S)-
16 was investigated. In test scale reactions, a range of 0.5 to
1.0 equivalents of lithium amide (S)-16 were added to ( )-5-
tert-butyl 6, with the reaction proceeding to approximately 50%
conversion after two hours with the use of 0.8 equivalents of (S)-
16. Using this reaction as a basis, addition of 0.8 equivalents of
lithium amide (S)-16 to ( )-5-tert-butyl 6 on a preparative scale
gave, at 53% conversion, b-amino ester (1R,2S,5S,aS)-27 in 88%
de and in 42% isolated yield, arising from the expected ‘matched’
combination of the homochiral lithium amide and ( )-acceptor.
Resolved (S)-5-tert-butyl 6 was isolated in 41% yield and in
>97 ee,15 consistent with E >50.16 Similarly, conjugate addition
of 0.9 equivalents of (S)-16 to ( )-5-isopropyl 4 gave, at 34%
conversion, (1R,2S,5R,aS)-23 in 80% de and in 21% isolated
yield. The resolved acceptor (S)-5-isopropyl 4 was isolated in
61% yield and 44% ee,15 consistent with E >19. Furthermore,
addition of 0.8 equivalents of lithium (S)-16 to ( )-5-phenyl
5 gave, at 56% conversion, b-amino ester (1R,2S,5S,aS)-25
in 76% de and in 48% isolated yield, with crystallisation of
the diastereoisomeric mixture giving the major diastereoisomer
(1R,2S,5S,aS)-25 in >98% de and in 28% overall yield. The
resolved acceptor (S)-5-phenyl-5 was also isolated in 30% yield
and 97% ee,15 consistent with E >25 (Scheme 7).
Scheme 8 Reagents and conditions: (i) (S)-16 (3.0 eq), THF, −78 ◦C
then NH4Cl(aq)
.
amide (S)-16. This indicates that the 5-tert-butyl group, not
the lithium amide, is the dominating factor in the competitive
stereocontrol in the kinetic resolution reaction. The assigned
configurations within the 5-tert-butyl diastereoisomers were
further correlated through N-deprotection by hydrogenolysis.
Treatment of the 94 : 6 mixture of (1R,2S,5S,aS)-27 and
(1S,2R,5R,aS)-28 (arising from kinetic resolution, 88% de) and
(1S,2R,5R,aS)-28 (arising from the mismatched addition, >98%
de) with Pd(OH)2 on C under 5 atm H2 gave the enantiomeric
primary b-amino esters (1R,2S,5S)-41 in >98% de, 95% yield
and 88 1% ee17 {[a]D −7.0 (c 1.8, CHCl3)} and (1S,2R,5R)-
24
41 in >98% de, 88% yield and 98 1% ee17 {[a]D +9.5 (c 1.0,
24
CHCl3)}. As the de of the primary b-amino ester (1R,2S,5S,aS)-
27 formed in the kinetic resolution reaction (88% de) is equal to
the ee of the b-amino ester (1R,2S,5S)-41 (88 1% ee), it follows
that (1S,2R,5R,aS)-28 is the minor diastereoisomer formed in
the kinetic resolution protocol (Scheme 9).
Scheme 7 Reagents and conditions: (i) (S)-16, THF, −78 ◦C then
Scheme 9 Reagents and conditions: (i) Pd(OH)2 on C, MeOH, H2 (5
atm).
NH4Cl(aq)
.
With the kinetic resolution of 4–6 achieved, the configuration
of the minor b-amino ester diastereoisomer arising in these
protocols was investigated in the 5-tert-butyl series, through
the ‘mismatched’ reaction pairing of lithium amide (S)-16 and
the resolved homochiral acceptor (S)-6 (>97% ee). Conjugate
addition of lithium amide (S)-16 to (S)-5-tert-butyl 6 gave
(1S,2R,5R,aS)-28 in >95% de and in 56% isolated yield as a
single diastereoisomer (>98% de), with identical spectroscopic
properties to that of the minor diastereoisomer arising from the
kinetic resolution reaction. The relative configuration within
b-amino ester 28 was verified by 1H NMR NOE difference
experiments (Scheme 8).
Having determined the configuration of the minor di-
astereoisomer arising from the kinetic resolution reaction, N-
deprotection of the mixture of diastereoisomeric 5-isopropyl b-
amino esters 23 : 24 (80% de) and the 5-phenyl b-amino ester
25 (>98% de) by hydrogenolysis gave 5-isopropyl (1R,2S,5R)-
42 in 60% yield and >98% de and 5-phenyl (1R,2S,5S)-43 in
quantitative yield and >98% de respectively. Derivatisation to
the Mosher’s amides allowed unambiguous ee determination in
each case, with the ee of 5-isopropyl (1R,2S,5R)-42 assessed
as 81
1% ee and that of 5-phenyl (1R,2S,5S)-43 as 98
1% ee (Scheme 10). Further deprotection of b-amino esters 41–
43 to the corresponding b-amino acids 44–46 was achieved by
treatment of 41–43 with aqueous HCl at reflux and subsequent
ion exchange chromatography, giving the corresponding b-
amino acids 44–46 in >98% de. Deprotection of 5-isopropyl b-
amino ester 42 to the corresponding acid could also be achieved
The (1S,2R,5R,aS)-configuration within b-amino ester 28
is consistent with conjugate addition of lithium amide (S)-16
occurring anti- to the 5-tert-butyl group to the Re face of the
acceptor, contrary to the expected Si face selectivity of lithium
2 7 6 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5

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Scheme 11 Reagents and conditions: (i) (S)-16 (1.5 eq), (R)-32 (1.5 eq),
THF, −78 ◦C then NH4Cl(aq)
.
diastereoselectivities observed in these reactions were identical
(within experimental error) to those observed in the mutual
kinetic resolution of the corresponding substrates, consistent
with the two pseudoenantiomeric lithium amides having com-
plementary selectivities and effectively eliminating the effects of
mass action in these reactions (Scheme 12). High selectivity was
observed in the parallel kinetic resolution of ( )-5-mesityl 7,
giving a 50 : 50 mixture of b-amino esters N-benzyl 29 : N-3,4-
dimethoxybenzyl 39 in 98 1% de in each case (E >65) with
chromatography affording the readily separable b-amino esters
29 and 39 in 45% and 41% yield respectively. Parallel kinetic
resolution of ( )-5-isopropyl-4 and ( )-5-phenyl-5 also gave
the corresponding N-benzyl : N-3,4-dimethoxybenzyl b-amino
esters, 23 : 33 and 25 : 35 respectively, each in 93 1% de (E >32).
In the 5-isopropyl series, chromatographic purification gave N-
benzyl-b-amino ester 23 and N-3,4-dimethoxybenzyl-b-amino
ester 33 in an identical 30% yield and 93 1% de in each case.
In the 5-phenyl series, chromatography furnished N-benzyl-
b-amino ester 25 in 43% yield and N-3,4-dimethoxybenzyl-
Scheme 10 Reagents and conditions: (i) Pd(OH)2 on C, MeOH, H2 (5
atm); (ii) 20% HCl (aq), D; (iii) Dowex 50W-X8.
under basic conditions by treatment with LiOH in THF :
H2O, giving 44·HCl in >98% de after acidification with HCl,
confirming that 1,2-syn- to 1,2-anti-epimerisation does not occur
under basic reaction conditions.
Although high selectivity is observed upon kinetic resolution
of ( )-4–6 with lithium amide (S)-16, further investigations
considered the use of two pseudoenantiomeric lithium amides in
a parallel kinetic resolution. This was predicted to eliminate the
inherent sensitivity of the product stereoselectivity to conversion
as each kinetic resolution would stop automatically at 50%
conversion, giving the products with improved selectivity and
in higher ee.
b-amino ester 35 in 38% yield and in 93
1% de in each
case. Further purification of b-amino esters 25 and 35 by
crystallisation allowed their isolation as single diastereoisomers
(Scheme 12).
Parallel kinetic resolution of methyl ( )-5-isopropyl-,
( )-5-phenyl-, ( )-5-tert-butyl- and ( )-5-mesityl-
cyclopentene-1-carboxylates 4–7
Previous investigations from this laboratory have shown that a
50 : 50 mixture of lithium (S)-N-benzyl-N-a-methylbenzylamide
16 and (R)-N-3,4-dimethoxybenzyl-N-a-methylbenzylamide 32
constitute an optimal pseudoenantiomeric mixture for the
parallel kinetic resolution18 of ( )-3-alkyl-cyclopentene-1-
carboxylates.7 The application of this protocol for the effi-
cient parallel kinetic resolution of ( )-5-alkyl-cyclopentene-
1-carboxylates was investigated initially for ( )-5-tert-butyl-
acceptor 6. ( )-6 (1 eq) was treated with a 50 : 50 mixture
of lithium amides (S)-16 (98% ee,19 1.5 eq) and (R)-32 (98%
ee,19 1.5 eq) followed by protonation of the intermediate b-
amino enolates with NH4Cl(aq), to afford a 50 : 50 mixture of
b-amino esters (1R,2S,5S,aS)-27 and (1S,2R,5R,aR)-37 in 98
1% de in each case, consistent with E >65 for each process.
The high polarity of the N-3,4-dimethoxybenzyl-b-amino ester
37 facilitated its simple chromatographic separation from N-
benzyl b-amino ester 27, giving 27 in 39% yield and 37 in 35%
yield, and in 98 1% de in each case (Scheme 11).
Similar results were observed upon addition of the pseu-
doenantiomeric mixture of amides (S)-16 : (R)-32 to the ( )-
5-isopropyl-, ( )-5-phenyl- and ( )-5-mesityl-cyclopentene-1-
carboxylates 4, 5 and 7 respectively, with a 50 : 50 mixture
of the corresponding N-benzyl-b-amino ester and the N-3,4-
dimethoxybenzyl-b-amino ester obtained in each case. The
Scheme 12 Reagents and conditions: (i) (S)-16 (1.5 eq), (R)-32 (1.5 eq),
THF, −78 ◦C then NH4Cl(aq)
.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5
2 7 6 7

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With a range of differentially protected pseudoenantiomeric
b-amino esters in hand from this parallel kinetic resolution
protocol, N-deprotection of a series of model substrates to the
corresponding primary b-amino esters was investigated. Direct
hydrogenolysis of the 5-isopropyl- and 5-tert-butyl-2-N-benzyl-
N-a-methylbenzylamino esters 23 and 27 (93 1% de and 98
1% de respectively) gave the corresponding primary b-amino
esters C(5)-isopropyl 42 and C(5)-tert-butyl 41 in 45% and 75%
yield, in >98% de in each case, and in 91 1% ee and 96%
1% ee respectively.17 These data indicate that, as expected in
the 5-isopropyl case, the de of the b-amino ester from parallel
kinetic resolution corresponds to the ee of the primary amine
upon hydrogenolysis, consistent with the minor diastereoisomer
arising in this resolution protocol being mismatched with respect
to the lithium amide. N-Deprotection of the 5-isopropyl-, 5-
tert-butyl- and 5-mesityl-2-N-3,4-dimethoxybenzyl-esters 33, 37
Conclusion
In conclusion, conjugate addition of lithium dibenzylamide
to 5-isopropyl-, 5-phenyl- and 5-tert-butylcyclopentene-1-
carboxylates occurs with high levels of substrate control, with
preferential addition of lithium dibenzylamide to the face
of the cyclic a,b-unsaturated acceptor anti- to the stereodi-
recting 5-alkyl substituent. The reaction of a range of ( )-
5-alkyl-acceptors 4–7 with both lithium ( )-N-benzyl-N-a-
methylbenzylamide and lithium ( )-N-3,4-dimethoxybenzyl-
N-a-methylbenzylamide indicates significant enantiorecogni-
tion in their mutual kinetic resolution (E >32). Subse-
quently, the kinetic resolution of a range ( )-5-alkyl-esters 4–
6 with lithium (S)-N-benzyl-N-a-methylbenzylamide 16, and
the parallel kinetic resolution of ( )-5-alkyl-esters 4–7 with
a pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-a-
methylbenzylamide 16 and lithium (R)-N-3,4-dimethoxybenzyl-
N-a-methylbenzylamide 32 have been demonstrated, giving a
range of 5-alkyl-cispentacin derivatives in >98% de and high
ee after deprotection. The further application of this highly
efficient methodology to allow the stereoselective preparation of
a range of novel molecular architectures for secondary structural
analysis and bioactivity studies is currently underway.
and 39 (92
1% de, >98% de and >98% de respectively)
required a two step procedure, with chemoselective oxidative
N-3,4-dimethoxybenzyl deprotection with DDQ giving the
corresponding secondary b-amino esters 47, 48 and 49 (70–
71% yield, 95
1% de, >98% de and >98% de respectively
after purification). Subsequent hydrogenolysis gave the primary
b-amino esters 42, 41 and 50 in 60–85% yield, in >98% de in
each case after purification, and in 95 1% ee, 97% 1% ee
and 97% 1% ee respectively (Scheme 13).17
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 hexanes and was titrated against diphenylacetic acid
prior to use. Unless otherwise noted, all other reagents were
used as supplied without further purification. 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 Dragendorff’s
reagent.20 Infra red spectra were recorded as thin films or KBr
discs using a Perkin-Elmer PARAGON 1000 FT-IR spectrom-
1
eter, with selected peaks reported in cm−1. H and 13C NMR
spectra were recorded on Varian Gemini 200 (1H 200 MHz, 13
C
50 MHz), Bruker DPX-200 (1H 200 MHz, 13C 50 MHz), Bruker
DPX-400 and AVANCE AV-400 (1H 400 MHz, 13C 100 MHz), or
Bruker AMX-500 (1H 500 MHz, 13C 125 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 instrument (APCI or ESI). 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 resolution of 5000 full-width half-
height. Positive ion spectra were calibrated 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 polarimeter,
using a path length of 10 cm, in spectroscopic grade solvents
(Aldrich), with concentrations (c) given in g/100 cm3, solvent
and temperature as recorded. Melting points were recorded
on a Gallenkamp Hot Stage apparatus and are uncorrected.
Elemental analyses were performed by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford.
General procedure 1: Grignard additions. CuI was added to a
stirred solution of methyl 5-acetoxy-cyclopentene-1-carboxylate
Scheme 13 Reagents and conditions: (i) Pd(OH)2 on C, MeOH, H2 (5
atm), rt; (ii) DDQ (2.1 eq), DCM : H2O (3 : 1), rt.
2 7 6 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5

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2 in THF at (a) −35 ◦C, (b) −50 ◦C, (c) −60 ◦C or (d)
−70 ◦C. After five minutes, a solution of the requisite Grignard
reagent was added dropwise; saturated aqueous NH4Cl solution
was added after a further three hours. The organic layer was
separated and the aqueous layer was extracted with ether. The
combined organic extracts were washed with saturated aqueous
brine solution, dried, filtered and concentrated in vacuo.
column chromatography (49 : 1 pentane–ether), ( )-3 (2.04 g,
76%) as a colourless oil; dH(400 MHz, CDCl3) 1.14 (3H, d, J
6.9, C(5)HCH3), 1.53–1.60 (1H, m, C(4)HA), 2.13–2.23 (1H,
m, C(4)HB), 2.34–2.43 (1H, m, C(3)HA), 2.47–2.57 (1H, m,
C(3)HB), 2.95–3.05 (1H, m, C(5)H), 3.74 (3H, s, OCH3), 6.73–
6.75 (1H, m, C(2)H); dC(100 MHz, CDCl3) 19.9 (C(5)HCH3),
31.4 (C(4)), 32.2 (C(3)), 38.8 (C(5)), 51.2 (OCH3), 140.9 (C(1)),
143.4 (C(2)), 165.7 (C O); vmax/cm−1 (film) 1720 (C O); m/z
=
=
General procedure 2: Lithium amide additions to a,b-un-
saturated esters. n-BuLi was added dropwise to a stirred
solution of the requisite amine or mixture of amines in THF
at −78 ◦C. After thirty minutes, a solution of the requisite
acceptor in THF at −78 ◦C was added via cannula and the
reaction mixture was stirred for a further two hours before
the addition of saturated aqueous NH4Cl solution. The organic
layer was separated and the aqueous layer was extracted with
DCM. The combined organic extracts were dried, filtered and
the solvent was removed in vacuo. The residue was partitioned
between 10% aqueous citric acid solution and DCM, and the
combined organic extracts were washed with saturated aqueous
NaHCO3 solution and saturated aqueous brine solution, dried,
filtered, and concentrated in vacuo. The following work-up
procedure was further employed for standard kinetic resolution
reactions: the crude reaction product was then dissolved in
pentane and saturated with gaseous HCl at 0 ◦C; the pentane was
decanted from the resultant hydrochloride salt and neutralised
by dropwise addition of saturated aqueous K2CO3 solution;
the aqueous layer was separated and extracted with DCM; the
combined organic extracts were dried, filtered and concentrated
in vacuo to furnish the resolved acceptor; the hydrochloride
salt was neutralised with saturated aqueous K2CO3 solution,
extracted with DCM, dried, filtered and concentrated in vacuo.
(CI+) 158 (MNH4 , 75%), 141 (100); HRMS C8H13O2 requires
+
141.0918, found 141.0916.
Preparation of methyl ( )-5-isopropyl-cyclopentene-1-car-
boxylate 4. Following General procedure 1(d), CuI (0.15 g,
0.79 mmol), ( )-2 (2.90 g, 15.8 mmol) in THF (60 mL) and
iPrMgCl (2.0 M in THF, 15.8 mL) gave, after purification by
column chromatography (49 : 1 pentane–ether), ( )-4 (1.73 g,
65%) as a colourless oil; dH(400 MHz, CDCl3) 0.70 (3H, d, J
6.9, CH(CH3)A(CH3)B), 0.92 (3H, d, J 6.9, CH(CH3)A(CH3)B),
1.74–1.84 (1H, m, C(4)HA), 1.86–1.98 (1H, m, C(4)HB), 2.11–
2.24 (1H, m, CH(CH3)2), 2.35–2.53 (2H, m, C(3)H2), 2.93–3.01
(1H, m, C(5)H), 3.72 (3H, s, OCH3), 6.77–6.91 (1H, m, C(2)H);
dC(100 MHz, CDCl3) 16.2, 21.3 (CH(CH3)2), 23.8 (C(4)), 29.1
(CH(CH3)2), 32.4 (C(3)), 50.0 (C(5)), 51.2 (OCH3), 138.6 (C(1)),
144.3 (C(2)), 165.9 (C O); vmax/cm−1 (film) 1720 (C O); m/z
(CI+) 169 (MH+, 100%); HRMS C10H17O2 requires 169.1235,
found 169.1229.
=
=
Preparation of methyl ( )-5-phenyl-cyclopentene-1-car-
boxylate 5. Following General procedure 1(b), CuI (0.15 g,
0.79 mmol), ( )-2 (2.94 g, 16.0 mmol) in THF (60 mL) and
PhMgBr (1.0 M in THF, 31.9 mL) gave, after purification by
column chromatography (49 : 1 pentane–ether), ( )-5 (2.38 g,
74%) as a colourless oil; dH(400 MHz, CDCl3) 1.90–2.01 (1H, m,
C(4)HA), 2.48–2.61 (2H, m, C(3)HA, C(4)HB), 2.63–2.78 (1H,
m, C(3)HB), 3.63 (3H, s, OCH3), 4.13–4.21 (1H, m, C(5)H),
7.00–7.04 (1H, m, C(2)H), 7.16–7.34 (5H, m, Ph); dC(100 MHz,
CDCl3) 32.2 (C(3)), 34.1 (C(4)), 50.1 (C(5)), 51.3 (OCH3),
126.2 (Php), 127.0, 128.4 (Pho,m), 139.2 (C(1)), 144.9 (Phipso),
General procedure 3: Hydrogenolysis. Pd(OH)2/C was added
to a vigorously stirred solution of the requisite amine in degassed
MeOH at room temperature and placed under a hydrogen
atmosphere. After twenty four hours, the reaction mixture was
R
filtered through Celiteꢀ or basic alumina, washed with MeOH,
and concentrated in vacuo.
145.1 (C(2)), 165.2 (C O); vmax/cm−1 (film) 1717 (C O); m/z
=
=
(CI+) 220 (MNH4 , 100%), 203 (96); HRMS C13H15O2 requires
+
General procedure 4: Deprotection of N-3,4-dimethoxybenzyl-
amine derivatives. The adduct was dissolved in 5 : 1 DCM–
water, and DDQ was added. The reaction was stirred at room
temperature for two days before addition of saturated aqueous
NaHCO3 solution. The organic layer was separated and the
aqueous layer was extracted with DCM. The combined organic
extracts were washed with saturated aqueous brine solution,
dried, filtered, and concentrated in vacuo.
203.1069, found 203.1072.
Preparation of methyl ( )-5-tert-butyl-cyclopentene-1-car-
boxylate 6. Following General procedure 1(c), CuI (0.16 g,
0.81 mmol), ( )-2 (3.00 g, 16.3 mmol) in THF (60 mL) and
tBuMgCl (1.0 M in THF, 32.6 mL) gave, after purification
by column chromatography (49 : 1 pentane–ether), ( )-6
(2.53 g, 85%) as a colourless oil; dH(400 MHz, CDCl3) 0.85
(9H, s, C(CH3)3), 1.89–2.06 (2H, m, C(4)H2), 2.26–2.47 (2H, m,
C(3)H2), 2.81–2.87 (1H, m, C(5)H), 3.71 (3H, s, OCH3), 6.72–
6.76 (1H, m, C(2)H); dC(100 MHz, CDCl3) 27.5 (C(CH3)3 and
C(4)), 32.6 (C(3)), 35.5 (C(CH3)3), 51.2 (OCH3), 53.9 (C(5)),
Preparation of methyl ( )-5-acetoxy-cyclopentene-1-carboxy-
late 2. Acetic anhydride (9.29 mL, 98.5 mmol) was added
dropwise to a stirred solution of 1 (7.00 g, 49.2 mmol) and
pyridine (5.97 mL, 73.9 mmol) in DCM (5 mL) at room
temperature. After 3 hours, the mixture was diluted with
ether (30 mL), washed consecutively with 10% aqueous CuSO4
solution (2 × 100 mL) and brine (100 mL), dried, filtered and
concentrated in vacuo. The residue was purified by column
chromatography (10 : 1 pentane–EtOAc) to give ( )-2 (7.60 g,
84%) as a colourless oil; dH(400 MHz, CDCl3) 1.81–1.91 (1H,
m, C(4)HA), 1.99 (3H, s, OCOCH3), 2.29–2.49 (2H, m, C(4)HB,
C(3)HA), 2.58–2.69 (1H, m, C(3)HB), 3.70 (3H, s, OCH3), 5.90–
5.97 (1H, m, C(5)H), 7.04–7.08 (1H, m, C(2)H); dC(100 MHz,
CDCl3) 21.1 (OCOCH3), 31.1 (C(4)), 31.2 (C(3)), 51.5 (OCH3),
138.8 (C(1)), 144.2 (C(2)), 167.3 (C O); vmax/cm−1 (film) 1721
(C O); m/z (CI ) 183 (MH , 100%); HRMS C11H19O2 requires
183.1389, found 183.1385.
=
+
+
=
Preparation of methyl ( )-5-mesityl-cyclopentene-1-car-
boxylate 7. Following General procedure 1(a), CuI (0.30 g,
1.5 mmol), ( )-2 (1.10 g, 5.9 mmol) in THF (30 mL) and
mesityl MgBr (1.0 M in THF, 11.8 mL) gave, after purification
by column chromatography (49 : 1 pentane–ether), ( )-7 (1.30 g,
89%) as a white solid; dH(400 MHz, CDCl3) 1.90–2.04 (1H, m,
C(4)HA), 2.19 (3H, s, Ar(CH3)o), 2.23 (3H, s, Ar(CH3)o), 2.42
(3H, s, Ar(CH3)p), 2.45–2.56 (1H, m, C(3)HA), 2.57–2.82 (2H,
m, C(3)HB, C(4)HB), 3.60 (3H, s, CO2CH3), 4.59–4.67 (1H, m,
C(5)H), 6.75 (1H, s, Ar), 6.90 (1H, q, J 6.1, C(2)H), 6.84 (1H, s,
Ar); dC(100 MHz, CDCl3) 20.0 (Ar(CH3)o), 20.7 (Ar(CH3)o),
21.3 (Ar(CH3)p), 29.7 (C(4)), 32.6 (C(3)), 45.4 (C(5)), 51.3
=
77.2 (C(5)), 134.7 (C(1)), 150.0 (C(2)), 163.9, 170.5 (C O);
v
+
+
max/cm−1 (film) 1728 (C O), 1637 (C O); m/z (CI ) 185 (MH ,
=
=
100%), 125 (88); HRMS C9H13O4 requires 185.0816, found
185.0814.
Preparation of methyl ( )-5-methyl-cyclopentene-1-carboxy-
late 3. Following General procedure 1(a), CuI (0.18 g,
0.96 mmol), ( )-2 (3.54 g, 19.2 mmol) in THF (60 mL) and
MeMgCl (3.0 M in THF, 12.8 mL) gave, after purification by
(CO2CH3), 73.0 (C(1)), 129.0, 130.9, 135.2, 136.0 (Ar), 142.8
+
(C(2)), 165.4 (C O); vmax/cm−1 (KBr) 1711 (C O); m/z (ESI )
=
=
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5
2 7 6 9

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245 (MH+, 100%); HRMS C16H21O2 requires 245.1542, found
245.1539; mp 66–68 ◦C.
THF (2 mL) gave, after purification by column chromatography
(99 : 1 pentane–ether), (1RS,2SR,5SR)-14 (0.33 g, 80%) as a
colourless oil; dH(400 MHz, CDCl3) 0.82 (9H, s, C(CH3)3), 1.19–
1.33 (1H, m, C(4)HA), 1.65–1.82 (2H, m, C(3)HA, C(4)HB),
1.83–1.97 (1H, m, C(3)HB) 2.28–2.37 (1H, m, C(5)H), 2.91
(1H, dd, J 8.6, J 5.4, C(1)H), 3.06–3.16 (1H, m, C(2)H), 3.63
(2H, d, J 14.4, N(CHA)2), 3.74 (3H, s, OCH3), 3.79 (2H, d, J
14.4, N(CHB)2), 7.19–7.33 (10H, m, Ph); dC(100 MHz, CDCl3)
25.8 (C(4)), 27.1 (C(CH3)3), 29.5 (C(3)), 32.6 (C(CH3)3), 48.8
(C(1)), 51.6 (OCH3), 53.1 (C(5)), 56.2 (N(CH2)2), 67.6 (C(2)),
Preparation of methyl (1RS,2SR,5SR)-5-methyl-2-(N,N-di-
benzylamino)cyclopentane-1-carboxylate 8 and methyl (1SR,
2RS,5SR)-5-methyl-2-(N,N-dibenzylamino)cyclopentane-1-car-
boxylate 9. Following General procedure 2, n-BuLi (6.23 mmol)
and dibenzylamine (2.10 g, 6.23 mmol) in THF (20 mL) and
( )-3 (0.50 g, 3.57 mmol) in THF (6 mL) gave, after purification
by column chromatography (99.9 : 1 pentane–ether), a mixture
of 8 : 9 (600 mg, 50%) as a colourless oil. (1RS,2SR,5SR)-8:
dH(500 MHz, CDCl3) 0.99 (3H, d, J 6.8, C(5)CH3), 1.03–1.15
(1H, m, C(4)HA), 1.75–1.85 (1H, m, C(3)HA), 1.90–2.04 (2H,
m, C(3)HB, C(4)HB), 2.44–2.53 (1H, m, C(5)H), 2.58 (1H,
t, J 9.1, C(1)H), 3.53–3.57 (1H, m, C(2)H), 3.64 (4H, ABq,
J 14.0, N(CH2)2), 3.76 (3H, s, OCH3), 7.19–7.34 (10H, m,
Ph); dC(125 MHz, CDCl3) 20.8 (C(5)CH3), 26.5 (C(4)), 32.7
(C(3)), 36.8 (C(3)), 51.3 (C(1)), 55.7 (N(CH2)2), 56.0 (C(2)), 64.2
=
126.6 (Php), 128.0, 128.5 (Pho,m), 139.9 (Phipso), 176.6 (C O);
+
+
=
v
max/cm−1 (film) 1732 (C O); m/z (APCI ) 380 (MH 100%);
HRMS C25H34NO2 requires 380.2590, found 380.2577.
Mutual kinetic resolution for the preparation of methyl
(1RS,2SR,5SR,aSR)-5-methyl-2-(N-benzyl-N-a-methylbenzyl-
amino)cyclopentane-1-carboxylate 21 and methyl (1RS,2SR,
5RS,aSR)-5-methyl-2-(N-benzyl-N-a-methylbenzylamino)cyclo-
pentane-1-carboxylate 22. Following General procedure 2,
n-BuLi (6.23 mmol) and ( )-N-benzyl-N-a-methylbenzylamine
(2.5 g, 6.23 mmol) in THF (20 mL) and ( )-3 (0.50 g,
3.57 mmol) in THF (6 mL) gave, after purification by column
chromatography (99.9 : 1 pentane–ether), a mixture of 21 :
22 (750 mg, 60%) as a colourless oil. (1RS,2SR,5SR,aSR)-21:
dH(400 MHz, CDCl3) 0.92 (3H, d, J 6.2, C(5)CH3), 0.99–1.04
(1H, m, C(4)HA), 1.30 (3H, d, J 4.3, C(a)CH3), 1.69–1.72
(1H, m, C(3)HB), 1.93–2.03 (1H, m, C(3)H2), 2.37–2.45 (2H,
m, C(1)H, C(5)H), 3.45–3.49 (1H, m, C(2)H), 3.70 (3H, s,
OCH3), 3.82 (2H, dd, J 6.2, 3.2, CH2Ph), 3.98 (1H, d, J 4.3,
C(a)H), 7.20–7.40 (10H, m, Ph); dC(125 MHz, CDCl3) 14.1
(C(a)CH3), 20.5 (C(5)CH3), 29.1 (C(4)), 32.9 (C(3)), 36.8 (C(1)),
51.2 (OCH3), 51.7 (CH2Ph) 56.4 (C(a)), 61.7 (C(2)), 126.4,
127.6, 127.9, 127.9, 128.2 (Pho,m,p), 141.3, 143.4 (Phipso), 174.7
(OCH3), 126.5, 127.9, 128.4, 139.9 (Ph), 174.7 (C O); vmax/cm−1
=
+
+
=
(film) 1743 (C O); m/z (ESI ) 338 (MH , 100%); HRMS
C22H28NO2 requires 338.2120, found 338.2116. (1SR,2RS,5SR)-
9: dH(500 MHz, CDCl3) 0.99 (3H, d, J 6.4, (C(3)CH3), 1.19–1.37
(2H, m, C(4)H2), 1.73–1.92 (2H, m, C(3)H2), 2.04–2.12 (1H,
m, C(5)H), 2.44 (1H, t, J 9.9, C(1)H), 3.59 (4H, ABq, J 13.9,
NCH2)2), 3.62–3.65 (1H, m, C(2)H), 3.69 (3H, s, OCH3),
7.20–7.35 (10H, m, Ph); dC(125 MHz, CDCl3) 19.0 (C(5)CH3),
24.8 (C(4)), 32.5 (C(3)), 37.8 (C(5)), 51.3 (C(1)), 54.3 (N(CH2)2),
54.8 (C(2)), 65.2 (OCH3), 126.6, 127.9, 128.4, 139.9 (Ph), 176.0
+
+
(C O); vmax/cm−1 (film) 1731 (C O); m/z (ESI ) 338 (MH ,
=
=
100%); HRMS C22H28NO2 requires 338.2120, found 338.2128.
Preparation of methyl (1RS,2SR,5RS)-5-isopropyl-2-(N,N-
dibenzylamino)cyclopentane-1-carboxylate 10. Following Gen-
eral procedure 2, n-BuLi (2.38 mmol) and dibenzylamine
(0.46 mL, 2.38 mmol) in THF (10 mL) and ( )-4 (0.20 g,
1.19 mmol) in THF (2 mL) gave, after purification by column
chromatography (99 : 1 pentane–ether), (1RS,2SR,5RS)-10
(0.25 g, 59%) as a colourless oil; dH(400 MHz, CDCl3) 0.86
(6H, app t, J 7.1, CH(CH3)2), 1.11–1.26 (1H, m, C(4)HA), 1.38–
1.51 (1H, m, CH(CH3)2), 1.67–1.78 (1H, m, C(3)HA), 1.83–
1.98 (2H, m, C(3)HB, C(4)HB), 2.16–2.27 (1H, m, C(5)H), 2.83
(1H, dd, J 8.9, J 6.5, C(1)H), 3.24–3.34 (1H, m, C(2)H), 3.70
(4H, ABq, J 14.2, N(CH2)2), 3.75 (3H, s, OCH3), 7.18–7.39
(10H, m, Ph); dC(100 MHz, CDCl3) 20.1, 21.0 (CH(CH3)2), 28.4
(C(4)), 28.5 (C(3)), 33.3 (CH(CH3)2), 49.6 (C(5)), 51.5 (OCH3),
51.7 (C(1)), 56.2 (N(CH2)2), 66.6 (C(2)), 126.6 (Php), 128.0,
(C O); vmax/cm−1 (film) 1730 (C O); m/z (ESI ) 338 (MH ,
100%); HRMS C23H30NO2 requires 352.2277, found 352.2274.
(1RS,2SR,5RS,aSR)-22: dH(400 MHz, CDCl3) 0.92 (3H, d, J
7.0, C(5)CH3), 1.34 (3H, d, J 6.8, C(a)CH3), 1.54–1.63 (1H,
m, C(4)HA), 2.00–2.11 (2H, m, C(3)HA, C(4)HB), 2.12–2.19
(1H, m, C(5)H), 2.86 (1H, t, J 6.0, C(1)H), 2.26–3.31 (1H, m,
C(2)H), 3.63 (3H, s, OCH3), 3.70 (1H, d, J 16.8, NCHA), 3.79
(1H, d, J 16.8, NCHB), 4.17 (1H, q, J 7.0, C(a)H), 7.16–7.42
(10H, m, Ph); dC(125 MHz, CDCl3) 15.4 (C(a)CH3), 16.0
(C(5)CH3), 27.6 (C(4)), 29.8 (C(3)), 34.8 (C(5)), 50.6 (C(1)),
51.5(OCH3), 51.7 (NCH2), 57.7 (C(a)), 65.4 (C(2)), 126.1,
126.4, 126.5, 127.7, 127.8, 127.9, 128.2, 128.9, 129.6 (Pho,m,p),
+
+
=
=
142.7, 143.0 (Phipso), 173.6 (C O); vmax/cm−1 (film) 1732 (C O);
m/z (ESI+) 338 (MH+, 100%); HRMS C23H30NO2 requires
352.2277, found 352.2268.
=
=
128.5 (Pho,m), 140.0 (Phipso), 175.9 (C O); vmax/cm−1 (film) 1732
(C O); m/z (APCI ) 366 (MH , 100%); HRMS C24H32NO2
requires 366.2417, found 366.2433.
=
+
+
=
Mutual kinetic resolution for the preparation of methyl
(1RS,2SR,5RS,aSR)-5-isopropyl-2-(N-benzyl-N-a-methylbenzyl-
amino)cyclopentane-1-carboxylate 23. Following General pro-
cedure 2, n-BuLi (2.38 mmol), ( )-N-benzyl-N-a-methylbenzyl-
amine (0.50 g, 2.38 mmol) in THF (10 mL) and ( )-4 (0.20 g,
1.19 mmol) THF (2 mL) gave, after purification by column
chromatography (99 : 1 pentane–EtOAc), (1RS,2SR,5RS,aSR)-
23 (0.29 g, 84%) as a colourless oil; dH(400 MHz, CDCl3)
0.79 (3H, d, J 5.6, CH(CH3)A(CH3)B), 0.81 (3H, d, J 5.6,
CH(CH3)A(CH3)B), 0.84–0.98 (1H, m, CH(CH3)2), 1.01–1.14
(1H, m, C(4)HA), 1.35 (3H, d, J 6.8 C(a)CH3), 1.43–1.68 (1H,
m, C(3)HA), 1.80–1.96 (2H, m, C(3)HB, C(4)HB), 2.07–2.15
(1H, m, C(5)H), 2.62 (1H, dd, J 9.4, J 6.6, C(1)H), 3.21–3.27
(1H, m, C(2)H), 3.72 (3H, s, OCH3), 3.75 (1H, d, J 14.6,
NCHA), 3.88 (1H, d, J 14.6, NCHB), 4.08 (1H, q, J 6.8, C(a)H),
7.19–7.44 (10H, m, Ph); dC(100 MHz, CDCl3) 15.0 (C(a)CH3),
20.1 (CH(CH3)2), 28.3 (C(4)), 29.9 (C(3)), 33.1 (CH(CH3)2),
49.4 (C(5)), 51.4, 51.7, 52.1 (C(1), NCH2, OCH3), 56.9 (C(a)),
63.8 (C(2)), 126.4, 126.6 (Php), 127.7, 127.9, 128.0, 128.1 (Pho,m),
Preparation of methyl (1RS,2SR,5SR)-5-phenyl-2-(N,N-di-
benzylamino)-cyclopentane-1-carboxylate 12. Following Gen-
eral procedure 2, n-BuLi (1.98 mmol) and dibenzylamine
(0.38 mL, 1.98 mmol) in THF (10 mL) and ( )-5 (0.20 g,
0.99 mmol) in THF (2 mL) gave, after purification by column
chromatography (99 : 1 pentane–ether), (1RS,2SR,5SR)-12
(0.17 g, 42%) as a colourless oil; dH(400 MHz, CDCl3) 1.61–
1.70 (1H, m, C(4)HA) 1.92–2.16 (1H, m, C(3)HA), 2.04–2.16
(1H, m, C(3)HB), 2.22–2.31 (1H, m, C(4)HB), 3.15 (1H, app t, J
9.0, C(1)H), 3.68 (2H, d, J 14.5, N(CHA)2), 3.74 (3H, s, OCH3)
overlays 3.63–3.78 (2H, m, C(2)H, C(5)H), 3.80 (2H, d, J 14.5,
N(CHB)2), 7.15–7.40 (15H, m, Ph); dC(100 MHz, CDCl3) 27.1
(C(4)), 33.2 (C(3)), 47.9 (C(5)), 51.6 (C(2)), 56.0 (N(CH2)2),
65.0 (OCH3), 126.3, 126.7, 127.1, 127.4, 128.1, 128.5 (Pho,m,p),
143.6, 144.7 (Phipso), 174.2 (C O); vmax/cm−1 (film) 1736 (C O);
m/z (APCI+) 400 (MH+, 100%); HRMS C27H30NO2 requires
400.2272, found 400.2277.
=
=
Preparation of methyl (1RS,2SR,5SR)-5-tert-butyl-2-(N,N-
dibenzylamino)cyclopentane-1-carboxylate 14. Following Gen-
eral procedure 2, n-BuLi (2.20 mmol), dibenzylamine (0.42 mL,
2.20 mmol) in THF (10 mL) and ( )-6 (0.20 g, 1.10 mmol) in
141.9, 143.1 (Phipso), 176.2 (C O); vmax/cm−1 (film) 1729 (C O);
m/z (APCI+) 380 (MH+, 100%); HRMS C25H34NO2 requires
380.2584, found 380.2590.
=
=
2 7 7 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5

View Article Online
Mutual kinetic resolution for the preparation of methyl
(1RS,2SR,5SR,aSR)-5-phenyl-2-(N-benzyl-N-a-methylbenzyl-
amino)cyclopentane-1-carboxylate 25. Following General
procedure 2, n-BuLi (1.98 mmol), ( )-N-benzyl-N-a-methyl-
benzylamine (0.42 g, 1.98 mmol) in THF (10 mL) and
( )-5 (0.20 g, 0.99 mmol) in THF (2 mL) gave, after
purification by column chromatography (99 : 1 pentane–
EtOAc), (1RS,2SR,5SR,aSR)-25 (0.29 g, 75%) as a pale yellow
solid; dH(400 MHz, CDCl3) 1.43 (3H, d, J 6.8, C(a)CH3),
1.58–1.67 (1H, m, C(4)HA), 1.90–1.97 (1H, m, C(3)HA),
2.15–2.29 (2H, m, C(3)HB, C(4)HB), 3.04 (1H, dd, J 9.8, J
8.5, C(1)H), 3.61–3.68 (2H, m, C(2)H, C(5)H), 3.76 (3H, s,
OCH3), 4.00 (2H, app s, NCH2), 4.11 (1H, q, J 6.8, C(a)H),
7.15–7.54 (15H, m, Ph); dC(100 MHz, CDCl3) 14.4 (C(a)CH3),
29.6 (C(3)), 33.3 (C(4)), 48.0 (C(5)), 51.6, 52.0 (NCH2, OCH3),
56.2 (C(1)), 57.4 (C(a)), 62.5 (C(2)), 126.3, 126.7, 126.8 (Php),
127.9, 128.0, 128.1, 128.2, 128.3, 128.4 (Pho,m), 141.3, 143.4,
d, J 6.7, C(a)CH3), 1.67–1.79 (1H, m, C(3)HA), 1.86–2.13
(3H, m, C(3)HB, C(4)H2), 2.17 (6H, s, 2 × Ar(CH3)o), 2.24
(3H, s, Ar(CH3)p), 3.10 (1H, dd, J 6.9, 1.8, C(1)H), 3.69
(3H, s, CO2CH3), 3.67–3.73 (1H, m, C(2)H), 3.88 (1H, d, J
15.3, CHAHBPh), 3.95 (1H, d, J 15.3, CHAHBPh), 4.08–4.16
(2 × 1H, m, C(a)H, C(5)H), 6.71–7.51 (12H, m, Ar, Ph);
dC(100 MHz, CDCl3) 14.5 (C(a)CH3), 20.6 (2 × Ar(CH3)o), 20.8
(Ar(CH3)p), 29.9 (C(3)), 30.8 (C(4)), 42.3 (C(5)), 45.4 (C(1)),
51.6 (CO2CH3), 51.7 (CH2Ph), 57.0 (C(a)), 64.0 (C(2)), 126.6,
126.7, 127.9, 128.1, 128.2, 130.0, 135.5, 136.6, 141.6, 141.6 (Ph,
+
Ar), 176.5 (C O); vmax/cm−1 (film) 1726 (C O); m/z (ESI )
456 (MH+, 100%); HRMS C31H38NO2 requires 456.2903, found
456.2895; mp 142–144 ◦C.
=
=
X-Ray crystal structure determination for 29. Data were
collected using an Enraf-Nonius j-CCD diffractometer with
graphite monochromated Mo–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.21
144.6 (Phipso), 174.6 (C O); vmax/cm−1 (film) 1731 (C O); m/z
(APCI+) 414 (MH+ 100%); mp 79–81 ◦C; anal. C28H31NO2
requires C, 81.3; H, 7.6; N, 3.4; found C, 81.2; H, 7.5; N, 3.4%.
=
=
X-Ray crystal structure determination for 25. Data were
collected using an Enraf-Nonius j-CCD diffractometer with
graphite monochromated Mo–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.21
X-Ray crystal structure data for 29 [C31H37NO2]: M = 455.64,
˚
orthorhombic, space group P 21 21 21, a = 9.4415(1) A, b =
3
˚
˚
˚
15.0875(2) A, c = 18.2970(3) A, V = 2606.38(6) A , Z = 4, l =
0.071 mm−1, colourless plate, crystal dimensions = 0.3 × 0.4 ×
0.5 mm. A total of 3327 unique reflections were measured for
5 < h < 27 and 2898 reflections were used in the refinement. The
final parameters were wR2 = 0.044 and R1 = 0.038 [I > 3r(I)].
CCDC reference number 237686.†
X-Ray crystal structure data for 25 [C28H31NO2]: M = 413.56,
˚
monoclinic, space group P 1 21/c 1, a = 10.0421(2) A, b =
3
Preparation of methyl (1RS,2SR,5RS)-5-isopropyl-2-(N-
benzyl-N-isopropylamino)cyclopentane-1-carboxylate 31. Fol-
lowing General procedure 2, n-BuLi (1.1 mL, 1.75 mmol),
N-benzyl-N-isopropylamine (0.26 g, 1.8 mmol), and ( )-4
(0.10 g, 0.60 mmol) in THF (3 mL) gave, after purification by
column chromatography (99 : 1 petrol–ether), (1RS,2SR,5RS)-
31 (152 mg, 81%) as a clear oil; dH (CDCl3, 400 MHz)
0.85 (6H, app t, J 6.3, C(5)CH(CH3)2), 0.96 (3H, d, J 6.6,
NCH(CH3)A), 1.10 (3H, d, J 6.6, NCH(CH3)B), 1.21–1.28 (1H,
m, C(4)HA), 1.39–1.48 (1H, m, C(5)CH), 1.62–1.69 (1H, m,
C(3)HA), 1.75–1.89 (2H, m, C(3)HB, C(4)HB), 2.05–2.13 (1H,
m, C(5)H), 2.72 (1H, dd, J 6.2, 2.9, C(2)H), 3.1 (1H, sept,
J 6.5, NCH(CH3)2), 3.30–3.40 (1H, m, C(1)H), 3.67 (2H, s,
CH2Ph), 3.69 (3H, s, CO2CH3), 7.17–7.33 (5H, m, Ph); dC
(CDCl3, 100 MHz) 18.7 (NCH(CH3)A), 19.1 (NCH(CH3)B), 22.5
(C(3)CH(CH3)2), 28.4 (C(4)), 31.2 (C(5)), 33.5 (C(3)CH), 50.1
(C(3)), 50.2 (NCH(CH3)2), 51.3 (CO2CH3), 51.5 (CH2Ph), 53.2
(C(2)), 60.3 (C(1)), 120.1, 121.1, 123.2, 140.3 (Ar, Ph), 175.2
˚
˚
˚
9.1315(2) A, c = 25.1731(8) A, V = 2299.2(1) A , Z = 4, l =
0.074 mm−1, colourless plate, crystal dimensions = 0.2 × 0.4 ×
0.6 mm. A total of 5082 unique reflections were measured for
1 < h < 27 and 3301 reflections were used in the refinement. The
final parameters were wR2 = 0.078 and R1 = 0.087 [I > 1r(I)].
CCDC reference number 237689.†
Mutual kinetic resolution for the preparation of methyl
(1RS,2SR,5SR,aSR)-5-tert-butyl-2-(N-benzyl-N-a-methylbenzyl-
amino)cyclopentane-1-carboxylate 27. Following General pro-
cedure 2, n-BuLi (2.20 mmol), ( )-N-benzyl-N-a-methylbenzyl-
amine (0.46 g, 2.20 mmol) in THF (10 mL) and ( )-6 (0.20 g,
1.10 mmol) in THF (2 mL) gave, after purification by column
chromatography (99 : 1 pentane–EtOAc), (1RS,2SR,5SR,aSR)-
27 (0.35 g, 81%) as a pale yellow solid; dH(400 MHz, CDCl3)
0.74 (9H, s, CH(CH3)3), 1.09–1.19 (1H, m, C(4)HA), 1.35 (3H,
d, J 7.1, C(a)CH3), 1.57–1.63 (1H, m, C(3)HA), 1.65–1.72 (1H,
m, C(4)HB) 1.81–1.92 (1H, m, C(3)HB), 2.19–2.20 (1H, m,
C(5)H), 2.65–2.69 (1H, m, C(1)H), 3.02–3.09 (1H, m, C(2)H),
3.64 (1H, d, J 15.0, NCHA) 3.72 (3H, s, OCH3), 3.90 (1H, d,
J 15.0, NCHB), 4.14 (1H, q, J 6.8, C(a)H), 7.18–7.42 (10H,
m, Ph); dC(100 MHz, CDCl3) 15.6 (C(a)CH3), 25.5 (C(4)),
27.0 (C(CH3)3), 30.2 (C(3)), 32.5 (C(CH3)3), 49.1 (C(1)), 51.5,
51.6, (OCH3, NCH2), 52.7 (C(5)), 57.3 (C(a)), 65.0 (C(2)),
126.3, 126.7 (Php), 127.9, 127.9, 128.0, 128.1 (Pho,m), 142.2,
+
+
(C O); vmax/cm−1 1733 (C O); m/z (ESI ) 318 (MH , 100%);
=
=
HRMS C20H32NO2 requires 318.2433, found 318.2434.
Mutual kinetic resolution for the preparation of methyl
(1RS,2SR,5RS,aSR)-5-isopropyl-2-(N-3,4-dimethoxybenzyl-N-
a-methylbenzylamino)cyclopentane-1-carboxylate 33. Follow-
ing General procedure 2, n-BuLi (0.70 mL, 1.75 mmol),
( )-N-3,4-dimethoxybenzyl-N-a-methylbenzylamine (0.48 g,
1.8 mmol), and ( )-4 (0.10 g, 0.60 mmol) in THF (10 mL) gave,
after purification by column chromatography (5 : 1 petrol–ether),
(1RS,2SR,5RS,aSR)-33 (220 mg, 84%) as a colourless oil;
dH(400 MHz, CDCl3) 0.79 (3H, d, J 7.2, CH(CH3)A(CH3)B), 0.82
(3H, d, J 7.2, CH(CH3)A(CH3)B), 0.99–1.40 (1H, m, CH(CH3)2),
1.33–1.38 (1H, m, C(4)HA), 1.34 (3H, d, J 8.4, C(a)CH3), 1.63–
1.71 (1H, m, C(3)HA), 1.80–2.01 (2H, m, C(3)HB, C(4)HB),
2.03–2.15 (1H, m, C(5)H), 2.62 (1H, dd, J 4.3, 2.0, C(1)H),
3.14–3.32 (1H, m, C(2)H), 3.66 (3H, s, CO2CH3), 3.72 (1H,
d, J 15.1, CHAHBAr), 3.79 (1H, d, J 15.1, CHAHBAr), 3.86
(3H, s, C6H3(OCH3)A), 3.93 (3H, s, C6H3(OCH3)B), 4.09 (1H, q,
J 6.9, C(a)H), 6.70–7.48 (8H, m, Ph, Ar); dC(100 MHz, CDCl3)
15.3 (C(a)CH3), 20.4, 20.9 (CH(CH3)2), 27.3 (CH(CH3)2), 28.4
(C(4)), 29.9 (C(3)), 51.3 (C(5)), 51.4 (CH2Ar), 51.5 (C(1)),
52.2 (CO2CH3), 55.8, 55.8 (C6H3(OCH3)2), 56.6 (C(a)), 63.6
142.6 (Phipso), 176.9 (C O); vmax/cm−1 (film) 1722 (C O);
m/z (APCI+) 394 (MH+ 100%); HRMS C26H36NO2 requires
394.2738, found 394.2746; mp 57–59 ◦C; anal. C26H35NO2
requires C, 79.35; H, 9.0; N, 3.6; found C, 79.1; H, 8.5; N, 3.5%.
=
=
Mutual kinetic resolution for the preparation of methyl
(1RS,2SR,5SR,aSR)-5-mesityl-2-(N-benzyl-N-a-methylbenzyl-
amino)cyclopentane-1-carboxylate 29. Following General
procedure 2, n-BuLi (0.24 mL, 0.59 mmol), ( )-N-benzyl-N-
a-methylbenzylamine (128 mg, 0.60 mmol), and ( )-7 (50 mg,
0.20 mmol) in THF (10 mL) gave, after purification by column
chromatography (49 : 1 petrol–ether), (1RS,2SR,5SR,aSR)-29
(73 mg, 82%) as a white solid; dH(400 MHz, CDCl3) 1.40 (3H,
† See http://dx.doi.org/10.1039/[b506339f] for crystallographic data in
CIF or other electronic format.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5
2 7 7 1

View Article Online
(C(2)), 110.7, 111.5, 119.8, 125.3, 126.5, 127.8, 127.9, 134.3,
lowing General procedure 2, n-BuLi (0.24 mL, 0.59 mmol),
( )-N-3,4-dimethoxybenzyl-N-a-methylbenzylamine (169 mg,
0.60 mmol), and ( )-7 (50 mg 0.20 mmol) in THF (10 mL)
gave, after purification by column chromatography (5 : 1
petrol–ether), (1RS,2SR,5SR,aSR)-39 (73.6 mg, 70%) as a
white solid; dH(400 MHz, CDCl3) 1.38 (3H, d, J 6.8, C(a)CH3),
1.65–2.10 (4H, m, C(3)H2, C(4)H2), 2.19 (6H, s, 2 × Ar(CH3)o),
2.22 (3H, s, Ar(CH3)p), 3.12 (1H, t, J 3.5, C(1)H), 3.61 (3H, s,
CO2CH3), 3.63–3.71 (1H, m, C(2)H), 3.75 (1H, d, J 15.1,
CHAHBAr), 3.78 (3H, s, C6H3(OCH3)A), 3.86 (1H, d, J 15.1,
CHAHBAr), 3.95 (3H, s, C6H3(OCH3)B), 4.10–4.21 (2H, m,
C(5)H, C(a)H), 6.71–7.50 (10H, m, Ph, Ar); dC(100 MHz,
CDCl3) 14.6 (C(a)CH3), 20.6 (Ar(CH3)p), 20.8 (2 × Ar(CH3)o),
30.0 (C(4)), 30.6 (C(3)), 42.3 (C(5)), 51.4 (CH2Ar), 51.6
(CO2CH3), 51.9 (C(1)), 55.9, 56.0 (C6H3(OCH3)2), 56.0 (C(a)),
64.0 (C(2)), 110.8, 111.3, 11.6, 120.0, 126.7, 127.8, 128.0, 128.1,
143.2, 147.6, 148.9 (Ar, Ph), 176.1 (C O); vmax/cm−1 (film)
=
+
+
=
1717 (C O); m/z (ESI ) 440 (MH , 100%); HRMS C27H37NO4
requires 440.2791, found 440.2791.
Mutual kinetic resolution for the preparation of methyl
(1RS,2SR,5SR,aSR)-5-phenyl-2-(N-3,4-dimethoxybenzyl-N-a-
methylbenzylamino)cyclopentane-1-carboxylate 35. Following
General procedure 2, n-BuLi (0.60 mL, 1.49 mmol), ( )-N-3,4-
dimethoxybenzyl-N-a-methylbenzylamine (410 mg, 1.5 mmol),
and ( )-5 (100 mg, 0.50 mmol) in THF (10 mL) gave, after
purification by column chromatography (5 : 1 petrol–ether),
(1RS,2SR,5SR,aSR)-35 (210 mg, 93%) as a pale yellow solid;
dH(400 MHz, CDCl3) 1.34 (3H, d, J 6.6, C(a)CH3), 1.50–1.62
(1H, m, C(4)HA), 1.83–1.93 (1H, m, C(3)HA), 2.10–2.23 (2H, m,
C(3)HB, C(4)HB), 2.97 (1H, t, J 9.3, C(1)H), 3.50–3.62 (1H, m,
C(5)H), 3.60–3.68 (1H, m, C(2)H), 3.80 (3H, s, CO2CH3) 3.86
(1H, d, J 15.8, CHAHBAr), 3.87 (3H, s, C6H3(OCH3)A), 3.93
(3H, s, C6H3(OCH3)B), 3.95 (1H, d, J 15.8, CHAHBAr), 4.03
(1H, q, J 6.6, C(a)H), 6.79–7.43 (13H, m, Ar, Ph); dC(100 MHz,
CDCl3) 14.0 (C(a)CH3), 29.2 (C(4)), 33.4 (C(3)), 47.9 (C(5)),
51.8 (CH2Ar), 51.4 (CO2CH3), 55.9, 56.0 (C6H3(OCH3)2), 56.3
(C(a)), 56.5 (C(1)), 62.1 (C(2)), 126.2, 126.7, 126.7, 127.9, 128.0,
103.1, 134.1, 135.5, 136.5, 137.4, 143.3, 147.8, 149.0 (Ar, Ph),
+
176.3 (C O); vmax/cm−1 (KBr) 1730 (C O); m/z (ESI ) 537
(MNa+, 100%); HRMS C33H42NO4 requires 516.3114, found
516.3109; mp 52–54 ◦C.
=
=
Kinetic resolution for the preparation of methyl (1R,2S,5R,aS)-
5-isopropyl-2-(N-benzyl-N-a-methylbenzylamino)cyclopentane-
1-carboxylate 23 and methyl (S)-5-isopropylcyclopentene-
1-carboxylate 4. Following General procedure 2, n-BuLi
(3.68 mmol), (S)-N-benzyl-N-a-methylbenzylamine (0.78 g,
3.68 mmol) in THF (125 mL) and ( )-4 (0.69 g, 4.08 mmol)
in THF (25 mL) gave (1R,2S,5R,aS)-23 (0.32 g, 21%) with
=
128.2, 128.3, 128.4, 141.3, 143.4, 144.6 (Ar, Ph), 174.6 (C O);
v
+
+
max/cm−1 (KBr) 1727 (C O); m/z (ESI ) 474 (MH , 100%);
=
mp 110–112 ◦C; anal. C30H35NO4 requires C, 76.1; H, 7.5; N,
3.0; found C, 75.8; H, 7.4; N, 2.9%.
X-Ray crystal structure determination for 35. Data were
collected using an Enraf-Nonius j-CCD diffractometer with
graphite monochromated Mo–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.21
24
identical properties to those reported above and [a]D −57.5 (c
1.0 in CHCl3); and (S)-4 (0.42 g, 61%) with identical properties
24
to those reported above and [a]D −7.8 (c 1.9 in CHCl3).
Kinetic resolution for the preparation of methyl (1R,2S,5S,aS)-
5-phenyl-2-(N-benzyl-N-a-methylbenzylamino)cyclopentane-1-
carboxylate 25 and methyl (S)-5-phenylcyclopentene-1-
carboxylate 5. Following General procedure 2, n-BuLi
(5.57 mmol), (S)-N-benzyl-N-a-methylbenzylamine (1.18 g,
5.57 mmol) in THF (125 mL) and ( )-5 (1.41 g, 6.96 mmol)
in THF (25 mL) gave (1R,2S,5S,aS)-25 (1.33 g, 48%) with
X-Ray crystal structure data for 35 [C30H35NO4]: M = 473.61,
˚
orthorhombic, space group P 21 21 21, a = 8.6059(1) A, b =
3
˚
˚
˚
11.6484(1) A, c = 25.9199(3) A, V = 2598.34(5) A , Z = 4, l =
0.080 mm−1, colourless block, crystal dimensions = 0.2 × 0.2 ×
0.2 mm. A total of 3316 unique reflections were measured for
5 < h < 27 and 2742 reflections were used in the refinement. The
final parameters were wR2 = 0.038 and R1 = 0.032 [I > 3r(I)].
CCDC reference number 237685.†
24
identical properties to those reported above and [a]D −29.7 (c
0.9 in CHCl3); and (S)-5 (0.42 g, 30%) with identical properties
24
to those reported above and [a]D +125.6 (c 1.5 in CHCl3).
Kinetic resolution for the preparation of methyl (1R,2S,5S,aS)-
5-tert-butyl-2-(N-benzyl-N-a-methylbenzylamino)cyclopentane-
1-carboxylate 27 and methyl (S)-5-tert-butylcyclopentene-
1-carboxylate 6. Following General procedure 2, n-BuLi
(10.8 mmol), (S)-N-benzyl-N-a-methylbenzylamine (2.28 g,
10.8 mmol) in THF (125 mL) and ( )-6 (2.46 g, 13.5 mmol)
in THF (25 mL) gave (1R,2S,5S,aS)-27 (2.22 g, 42%) with
Mutual kinetic resolution for the preparation of methyl
(1RS,2SR,5SR,aSR)-5-tert-butyl-2-(N-3,4-dimethoxybenzyl-N-
a-methylbenzylamino)cyclopentane-1-carboxylate 37. Follow-
ing General procedure 2, n-BuLi (0.66 mL, 1.64 mmol),
( )-N-3,4-dimethoxybenzyl-N-a-methylbenzylamine (400 mg,
1.65 mmol), ( )-6 (100 mg, 0.55 mmol) in THF (10 mL)
gave, after purification by column chromatography (5 : 1
petrol–ether), (1RS,2SR,5SR,aSR)-37 (200 mg, 81%) as a
yellow oil; dH(400 MHz, CDCl3) 0.75 (9H, s, C(CH3)3),
1.08–1.22 (1H, m, C(4)HA), 1.35 (3H, d, J 6.8, C(a)CH3),
1.56–1.66 (1H, m, C(3)HA), 1.66–1.77 (1H, m, C(4)HB),
1.83–1.99 (1H, m, C(3)HB), 2.15–2.25 (1H, m, C(5)H), 2.68
(1H, dd, J 5.3, 2.2, C(1)H), 3.03–3.08 (1H, m, C(2)H), 3.60
(1H, d, J 29.2, CHAHBAr), 3.68 (3H, s, CO2CH3), 3.83
(1H, d, J 29.2, CHAHBAr), 3.86 (3H, s, C6H3(OCH3)A), 3.93
(3H, s, C6H3(OCH3)B), 4.14 (1H, q, J 6.8, C(a)H), 6.75–7.44
(8H, m, Ph, Ar); dC(100 MHz, CDCl3) 15.3 (C(a)CH3), 25.6
(C(4)), 27.03 (C(CH3)3), 30.1 (C(3)), 32.5 (C(CH3)3), 49.1
(C(1)), 51.2 (CH2Ar), 51.4 (CO2CH3), 52.7 (C(5)), 55.8, 55.9
(C6H3(OCH3)2), 57.0 (C(a)), 64.9 (C(2)), 109.5, 110.7, 119.6,
126.7, 127.9, 128.4, 142.7, 147.5, 148.8, 150.0 (Ph, Ar), 176.9
24
identical properties to those reported above and [a]D −74.6 (c
0.9 in CHCl3); and (S)-6 (1.02 g, 41%) with identical properties
24
to those reported above and [a]D +9.1 (c 1.3 in CHCl3).
Preparation of methyl (1S,2R,5R,aS)-5-tert-butyl-2-(N-
benzyl-N-a-methylbenzylamino)cyclopentane-1-carboxylate 28.
Following General procedure 2, n-BuLi (3.29 mmol), (S)-N-
benzyl-N-a-methylbenzylamine (0.70 g, 3.29 mmol) in THF
(10 mL) and (S)-6 (0.20 g, 1.10 mmol) in THF (2 mL) gave,
after purification by column chromatography (99 : 1 pentane–
EtOAc), (1S,2R,5R,aS)-28 (0.24 g, 56%) as a colourless oil;
dH(400 MHz, CDCl3) 0.85 (9H, s, C(CH3)3), 1.17–1.37 (2H, m,
C(3)HA, C(4)HA), 1.43 (3H, d, J 7.0, C(a)CH3), 1.55–1.68 (2H,
m, C(3)HB, C(4)HB), 2.16–2.22 (1H, m, C(5)H), 2.89 (1H, dd, J
8.8, J 5.5, C(1)H), 3.32–3.38 (1H, m, C(2)H), 3.65 (1H, d, J 15.0,
NCHAHB) 3.71 (3H, s, OCH3), 3.77 (1H, d, J 15.0, NCHAHB),
4.12 (1H, q, J 6.9, C(a)H), 7.17–7.40 (10H, m, Ph); dC(100 MHz,
CDCl3) 13.3 (C(a)CH3), 25.9 (C(4)), 27.1 (C(CH3)3), 30.3 (C(3)),
32.6 (C(CH3)3), 49.7 (C(1)), 51.5 (OCH3), 52.7 (NCH2), 53.0
(C(5)), 56.7 (C(a)), 65.1 (C(2)), 126.2, 126.3 (Php), 127.7, 127.8,
+
+
(C O); vmax/cm−1 (film) 1729 (C O); m/z (ESI ) 454 (MH ,
100%), 476 (82); anal. C28H39NO4 requires C, 74.1; H, 8.7; N,
3.1; found C, 73.6; H, 8.3; N, 3.2%.
=
=
Mutual kinetic resolution for the preparation of methyl
(1RS,2SR,5SR,aSR)-5-mesityl-2-(N-3,4-dimethoxybenzylamine-
N-a-methylbenzylamino)cyclopentane-1-carboxylate 39. Fol-
127.9, 128.1 (Pho,m), 141.7, 143.3 (Phipso), 176.8 (C O); vmax/cm−1
(film) 1732 (C O); m/z (APCI ) 394 (MH , 100%); HRMS
=
+
+
=
2 7 7 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5

View Article Online
stretch), 2000–3100 (NH3 ); m/z (APCI+) 172 (MH+, 100%);
24
+
C26H36NO2 requires 394.2747, found 394.2746; [a]D −39.6 (c
24
1.0 in CHCl3).
HRMS C9H18NO2 requires 172.1341, found 172.1338; [a]D
+9.6 (c 1.0, H2O, HCl).
Preparation of methyl (1R,2S,5S)-5-tert-butyl-2-aminocyclo-
pentane-1-carboxylate 41. Following General procedure 3,
(1R,2S,5S,aS)-27 (1.13 g, 2.87 mmol) and Pd(OH)2/C (0.56 g)
under H2 (5 atm) in MeOH (10 mL) gave (1R,2S,5S)-41
(0.55 g, 95%) as a colourless oil; dH(400 MHz, CDCl3) 0.79
(9H, s, C(CH3)3), 1.26–1.36 (1H, m, C(4)HA), 1.52–1.61 (1H,
m, C(3)HA), 1.71–1.79 (1H, m, C(4)HB), 1.81–1.88 (1H, m,
C(3)HB), 2.29 (1H, app q, J 8.4, C(5)H), 2.44 (2H, s, NH2), 2.69
(1H, app t, J 8.0, C(1)H), 3.36–3.42 (1H, m, C(2)H), 3.65 (3H, s,
OCH3); dC(100 MHz, CDCl3) 25.3 (C(4)), 27.1 (C(CH3)3), 32.5
(C(CH3)3), 35.4 (C(3)), 50.2 (C(1)), 51.5, (OCH3), 52.7 (C(5)),
Preparation of (1R,2S,5S)-5-phenyl-2-aminocyclopentane-1-
carboxylate 45. A solution of 43 (0.25 g, 1.14 mmol) in 20%
aqueous HCl solution (20 mL) was heated at reflux (100 ◦C) for
16 hours, and then concentrated in vacuo. Purification by ion
exchange chromatography (Dowex 50W-X8) gave 45 (0.16 g,
69%) as a white solid; dH(400 MHz, D2O, HCl) 1.71–1.85 (2H,
m, C(3)HA and C(4)HA), 2.12–2.19 (1H, m, C(3)HB), 2.30–
2.38 (1H, m, C(4)HB), 3.12 (1H, dd, J 11.1, J 7.3, C(1)H),
3.33–3.42 (1H, m, C(2)H), 3.94–4.01 (1H, m, C(5)H), 7.10–
7.29 (5H, m, Ph); dC(100 MHz, D2O, HCl) 30.7, 31.9 (C(3) and
C(4)), 48.3 (C(2)), 53.0, 53.5 (C(1) and (C(5)), 127.6, 127.7,
56.1 (C(2)), 175.7 (C O); vmax/cm−1 (film) 1730 (C O), 3378
(N–H); m/z (APCI+) 200 (MH+, 100%); HRMS C11H22NO2
=
=
129.3 (Pho−,m,p), 142.1 (Phipso), 175.6 (C O); vmax/cm−1 (KBr)
=
24
requires 200.1656, found 200.1651; [a]D −7.0 (c 1.8 in CHCl3).
+
−
1404 (CO2 stretch), 1494 (NH3 bend), 1558 (CO2 stretch),
+
1652 (NH3 bend), 2955, 3027 (C–H stretch and N–H stretch),
Preparation of methyl (1S,2R,5R)-5-tert-butyl-2-aminocyclo-
pentane-1-carboxylate 41. Following General procedure 3,
(1S,2R,5R,aS)-28 (152 mg, 0.39 mmol) and Pd(OH)2/C (75 mg)
under H2 (5 atm) in MeOH (5 mL) gave (1S,2R,5R)-41 (68 mg,
88%) as a colourless oil with identical properties to those
2000–3100 (NH3 ); m/z (APCI+) 206 (MH+, 100%); HRMS
+
C12H16NO2 requires 206.1181, found 206.1182; mp 200 ◦C
24
(decomp.); [a]D +76.3 (c 1.2, H2O, HCl); anal. C12H15NO2
requires C, 70.2; H, 7.4; N, 6.8; found C, 69.7; H, 7.5; N, 6.6%.
24
reported above and [a]D +9.5 (c 1.0 in CHCl3).
Preparation of (1R,2S,5S)-5-tert-butyl-2-aminocyclopentane-
1-carboxylate 46. A solution of 41 (0.25 g, 1.25 mmol) in 20%
aqueous HCl solution (20 mL) was heated at reflux (100 ◦C) for
16 hours, and then concentrated in vacuo. Purification by ion
exchange chromatography (Dowex 50W-X8) gave 46 (0.16 g,
68%) as a white solid; dH(400 MHz, D2O, HCl) 0.76 (9H, s,
C(CH3)3), 1.45–1.53 (1H, m, C(4)HA), 1.72–1.85 (2H, m, C(3)HA
and C(4)HB), 1.99–1.92 (1H, m, C(3)HB), 2.23 (1H, app q, J 8.5,
C(5)H), 2.82 (1H, app t, J 7.6, C(1)H), 3.63 (1H, app t, J 6.7,
C(2)H); dC(100 MHz, D2O, HCl) 24.5 (C(4)), 26.7 (C(CH3)3),
30.7 (C(CH3)3), 32.6 (C(3)), 47.3 (C(1)), 52.9 (C(5)), 54.1 (C(2)),
Preparation of methyl (1R,2S,5R)-5-isopropyl-2-aminocyclo-
pentane-1-carboxylate 42. Following General procedure 3,
(1R,2S,5R,aS)-23 (282 mg, 0.77 mmol) and Pd(OH)2/C
(141 mg) under H2 (5 atm) in MeOH (5 mL) gave, after
purification by column chromatography (1 : 1 pentane–ether)
(1R,2S,5R)-42 (86 mg, 60%) as a colourless oil; dH(400 MHz,
CDCl3) 0.84 (6H, d, J 6.6, CH(CH3)2), 0.91–1.29 (1H, m,
C(4)HA), 1.41–1.55 (2H, m, C(3)HA, CH(CH3)2), 1.68–1.93 (2H,
m, C(3)HB, C(4)HB), 2.16–2.24 (1H, m, C(5)H), 2.60 (1H, app
t, J 8.3, C(1)H), 3.46–3.54 (1H, m, C(2)H), 3.68 (3H, s, OCH3);
dC(100 MHz, CDCl3) 20.0, 21.0 (CH(CH3)2), 27.7 (C(4)), 32.6
(CH(CH3)2), 35.7 (C(3)), 48.7 (C(5)), 51.4, (OCH3), 53.6 (C(1)),
177.8 (C O); vmax/cm−1 (KBr) 1401 (CO2− stretch), 1512 (NH3
bend), 1540 (CO2 stretch), 1646 (NH3 bend), 2965 (C–H
+
=
−
+
55.7 (C(2)), 175.3 (C O); vmax/cm−1 (film) 1731 (C O), 2871,
2955, (C–H), 3379 (N–H); m/z (APCI+) 186 (MH+, 90%), 154
(100); HRMS C10H20NO2 requires 186.1497, found 186.1494;
stretch and N–H stretch), 2000–3100 (NH3 ); m/z (APCI+)
+
=
=
186 (MH+, 100%); HRMS C10H20NO2 requires 186.1487, found
186.1494; mp 207 ◦C (decomp.); [a]D +7.9 (c 1.1, H2O, HCl).
24
24
[a]D −2.6 (c 0.7 in CHCl3).
Parallel kinetic resolution for the preparation of methyl
(1R,2S,5R,aS)-5-isopropyl-2-(N-benzyl-N-a-methylbenzylamino)-
cyclopentane-1-carboxylate 23 and methyl (1S,2R,5S,aR)-
5-isopropyl-2-(N-3,4-dimethoxybenzyl-N-a-methylbenzylamino)-
cyclopentane-1-carboxylate 33. Following General procedure
2, n-BuLi (5.37 mmol), ( )-4 (0.30 g, 1.79 mmol), (S)-
N-benzyl-N-a-methylbenzylamine (567 mg, 2.67 mmol),
(R)-N-3,4-dimethoxybenzyl-N-a-methylbenzylamine (711 mg,
2.67 mmol) in THF (10 mL) gave, after purification by
Preparation of methyl (1R,2S,5S)-5-phenyl-2-aminocyclo-
pentane-1-carboxylate 43. Following General procedure 3,
(1R,2S,5S,aS)-25 (0.67 g, 1.67 mmol) and Pd(OH)2/C (0.33 g)
under H2 (5 atm) in MeOH (10 mL) gave (1R,2S,5S)-43 (0.39 g,
100%) as a colourless oil; dH(400 MHz, CDCl3) 1.29–1.62 (4H,
m, C(4)HA, C(3)HA, NH2), 1.88–2.01 (1H, m, C(3)HB), 2.06–
2.18 (1H, m, C(4)HB), 2.95 (1H, dd, J 10.1, J 7.2, C(1)H), 3.37
(3H, s, OCH3), 3.64 (1H, s, C(2)H), 3.78–3.85 (1H, m, C(5)H),
7.13–7.30 (5H, m, Ph); dC(100 MHz, CDCl3) 32.9 (C(4)), 36.3
(C(3)), 46.6 (C(5)), 51.2 (OCH3), 55.7 (C(2)), 58.8 (C(1)), 128.0
chromatography (99
: 1 petrol–ether), (1R,2S,5R,aS)-23
(203 mg, 30%) as a colourless oil with identical properties to
(Php), 128.2, 128.4 (Pho,m), 145.1 (Phipso), 173.4 (C O); vmax/cm−1
=
24
those reported above and [a]D −45.0 (c 0.7 in CHCl3); and
+
+
=
(film) 1728 (C O), 3369 (N–H); m/z (APCI ) 206 (MH , 100%);
(1S,2R,5S,aR)-33 (236 mg, 30%) with identical properties to
24
HRMS C13H18NO2 requires 220.1331, found 220.1338; [a]D
24
those reported above and [a]D +45.1 (c 0.7 in CHCl3).
+7.8 (c 0.8 in CHCl3).
Preparation of (1R,2S,5R)-5-isopropyl-2-aminocyclopentane-
1-carboxylate 44. A solution of 42 (71.6 mg, 0.39 mmol) in
20% aqueous HCl solution (10 mL) was heated at reflux (100 ◦C)
for 16 hours, and then concentrated in vacuo. Purification by ion
exchange chromatography (Dowex 50W-X8) gave 44 (30 mg,
37%) as a white solid; dH(400 MHz, D2O, HCl) 0.74 (3H, d,
J 6.8, CH(CH3)A), 0.78 (3H, d, J 6.8, CH(CH3)B), 1.34–1.42
(1H, m, C(4)HA), 1.52–1.59 (1H, m, C(3)HA), 1.67–1.74 (1H,
m, CH(CH3)2), 1.79–1.87 (1H, m, C(4)HB), 1.96–2.03 (1H,
m, C(3)HB), 2.07–2.13 (1H, m, C(5)H), 2.75 (1H, dd, J 8.7,
J 7.4, C(1)H), 3.71 (1H, app q, J 6.5, C(2)H); dC(100 MHz,
D2O, HCl) 18.7, 20.5 (CH(CH3)2), 25.6 (C(4)), 30.4 (C(3)), 31.2
Parallel kinetic resolution for the preparation of methyl
(1R,2S,5S,aS)-5-phenyl-2-(N-benzyl-N-a-methylbenzylamino)-
cyclopentane-1-carboxylate 25 and methyl (1S,2R,5R,aR)-
5-phenyl-2-(N-3,4-dimethoxybenzyl-N-a-methylbenzylamino)-
cyclopentane-1-carboxylate 35. Following General procedure
2, n-BuLi (4.46 mmol), (S)-N-benzyl-N-a-methylbenzylamine
(472 mg, 2.23 mmol), (R)-N-3,4-dimethoxybenzyl-N-a-
methylbenzylamine (606 mg, 2.23 mmol), and ( )-5 (300 mg,
1.49 mmol) in THF (10 mL) gave, after purification by
chromatography (99 : 1 pentane–ether), (1R,2S,5S,aS)-25
(264 mg, 43%) as a pale yellow solid with identical properties
24
to those reported above and [a]D −35.1 (c 1.0 in CHCl3), mp
◦
=
(CH(CH3)2), 49.1 (C(1) and C(5)), 53.7 (C(2)), 177.3 (C O);
78–79 C; and (1S,2R,5R,aR)-35 (260 mg, 38%) with identical
−
+
24
v
max/cm−1 (KBr) 1400 (CO2 stretch), 1511 (NH3 bend), 1542
properties to those reported above and [a]D +3.4 (c 0.7 in
(CO2− stretch), 1647 (NH3+ bend), 2964 (C–H stretch and N–H
CHCl3).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5
2 7 7 3

View Article Online
Parallel kinetic resolution for the preparation of methyl
(1R,2S,5S,aS)-5-tert-butyl-2-(N-benzyl-N-a-methylbenzylamino)-
cyclopentane-1-carboxylate 27 and methyl (1S,2R,5R,aR)-
5-tert-butyl-2-(N-3,4-dimethoxybenzyl-N-a-methylbenzylamino)-
cyclopentane-1-carboxylate 37. Following General procedure
2, n-BuLi (1.64 mmol), (S)-N-benzyl-N-a-methylbenzylamine
(519 mg, 2.46 mmol), (R)-N-3,4-dimethoxybenzyl-N-a-
methylbenzylamine (667 mg, 2.46 mmol), and ( )-6 (300 mg,
1.64 mmol) in THF (10 mL) gave, after purification by
column chromatography (99 : 1 petrol–ether), (1R,2S,5S,aS)-27
(254 mg, 39%) as a pale yellow oil with identical properties to
2.20–2.31 (1H, m, C(5)H), 2.81 (1H, dd, J 6.6, 2.3, C(1)H),
2.89–3.00 (1H, m, C(2)H), 3.72 (3H, s, CO2CH3), 3.79 (1H, q, J
6.7, C(a)H), 7.21–7.33 (5H, m, Ph); dC(100 MHz, CDCl3) 24.9
(C(a)CH3), 25.3 (C(4)), 27.2 (C(CH3)3), 32.5 (C(CH3)3), 33.8
(C(3)), 48.3 (C(5)), 51.4 (CO2CH3), 54.0 (C(1)), 56.5 (C(a)), 60.6
(C(2)), 126.5, 126.8, 128.3, 146.0 (Ph), 176.6 (C O); vmax/cm−1
=
+
+
=
(film) 2361 (C O), 3380 (N–H); m/z (ESI ) 304 (MH , 100%);
24
HRMS C19H30NO2 requires 304.2277, found 304.2281; [a]D
+34.2 (c 1.0 in CHCl3).
Preparation of methyl (1S,2R,5R,aR)-5-mesityl-2-(N-a-
methylbenzylamino)cyclopentane-1-carboxylate 49. Following
General procedure 4, (1S,2R,5R,aR)-39 (200 mg, 0.39 mmol)
and DDQ (176 mg, 0.78 mmol) in 5 : 1 DCM–water solution
(20 mL) gave, after purification by column chromatography (4 : 1
pentane–ether), (1S,2R,5R,aR)-49 (74 mg, 71%) as a colourless
oil; dH(400 MHz, CDCl3) 1.33 (3H, d, J 6.6, C(a)CH3), 1.69–
1.84 (2H, m, C(3)HA, C(4)HA), 1.88–2.02 (2H, m, C(3)HB,
C(4)HB), 2.26 (3H, s, Ar(CH3)p), 2.30 (6H, s, 2 × Ar(CH3)o),
3.36 (1H, t, J 8.6, C(1)H), 3.50–3.56 (1H, m, C(2)H), 3.73 (3H, s,
CO2CH3), 3.82 (1H, q, J 5.5, C(a)H), 4.13–4.18 (1H, m, C(5)H),
6.84 (2H, s, Ar), 7.24–7.45 (5H, m, Ph); dC(100 MHz, CDCl3)
20.7 (Ar(CH3)p), 21.0 (2 × Ar(CH3)o), 24.7 (C(a)CH3), 29.4
(C(4)), 34.6 (C(3)), 43.2 (C(5)), 51.3 (C(1)), 51.5 (CO2CH3),
56.8 (C(a)), 60.5 (C(2)), 126.7, 126.8, 126.9, 127.0, 128.4, 128.4,
24
those reported above and [a]D −80.0 (c 0.7 in CHCl3); and
(1S,2R,5R,aR)-37 (253 mg, 35%) with identical properties to
24
those reported above and [a]D +72.1 (c 0.7 in CHCl3).
Parallel kinetic resolution for the preparation of methyl
(1R,2S,5S,aS)-5-mesityl-2-(N-benzyl-N-a-methylbenzylamino)-
cyclopentane-1-carboxylate 29 and methyl (1S,2R,5R,aR)-
5-mesityl-2-(N-3,4-dimethoxybenzyl-N-a-methylbenzylamino)-
cyclopentane-1-carboxylate 39. Following General procedure
2, n-BuLi (3.69 mmol), (S)-N-benzyl-N-a-methylbenzylamine
(389 mg, 184 mmol), (R)-N-3,4-dimethoxybenzyl-N-a-
methylbenzylamine (500 mg, 184 mmol), and ( )-7 (300 mg,
1.23 mmol) in THF (10 mL) gave, after purification by
column chromatography (99 : 1 petrol–ether), (1R,2S,5S,aS)-29
(280 mg, 45%) with identical properties to those reported
130.1, 135.5, 136.5, 146.0 (Ph, Ar), 176.1 (C O); vmax/cm−1 (film)
=
24
+
+
above and [a]D −23.1 (c 0.7 in CHCl3); and (1S,2R,5R,aR)-39
=
1732 (C O); m/z (ESI ) 366 (MH , 100%); HRMS C23H30NO2
24
(265 mg, 41%) with identical properties to those reported above
requires 366.2432, found 366.2432; [a]D +43.1 (c 1.0 in CHCl3).
24
and [a]D +24.0 (c 0.7 in CHCl3).
Preparation of methyl (1S,2R,5S)-5-isopropyl-2-aminocyclo-
pentane-1-carboxylate 42. Following General procedure 3,
(1S,2R,5S,aR)-47 (100 mg, 0.34 mmol) and Pd(OH)2/C (20 mg)
under H2 (5 atm) in MeOH (5 mL) gave (1S,2R,5S)-42 (45 mg,
75%) as a colourless oil with identical properties to those
Preparation of methyl (1R,2S,5R)-5-isopropyl-2-aminocyclo-
pentane-1-carboxylate 42. Following General procedure 3,
(1R,2S,5R,aS)-23 (250 mg, 0.68 mmol) and Pd(OH)2/C
(150 mg) under H2 (5 atm) in MeOH (5 mL) gave (1R,2S,5R)-42
(57 mg, 45%) as a colourless oil with identical properties to those
24
reported above and [a]D +3.6 (c 1.1 in CHCl3).
24
reported above and [a]D −3.2 (c 0.7 in CHCl3).
Preparation of methyl (1S,2R,5R)-5-tert-butyl-2-aminocyclo-
pentane-1-carboxylate 41. Following General procedure 3,
(1S,2R,5R,aR)-48 (100 mg, 0.3 mmol) and Pd(OH)2/C (80 mg)
under H2 (5 atm) in MeOH (10 mL) gave (1S,2R,5R)-41 (39 mg,
60%) as a colourless oil with identical properties to those
Preparation of methyl (1R,2S,5S)-5-tert-butyl-2-aminocyclo-
pentane-1-carboxylate 41. Following General procedure 3,
(1R,2S,5S,aS)-27 (150 mg, 0.38 mmol) and Pd(OH)2/C (80 mg)
under H2 (5 atm) in MeOH (10 mL) gave (1R,2S,5S)-41 (52 mg,
70%) as a colourless oil with identical properties to those
24
reported above and [a]D +7.6 (c 1.2 in CHCl3).
24
reported above and [a]D −7.5 (c 1.0 in CHCl3).
Preparation of methyl (1S,2R,5R)-5-mesityl-2-aminocyclo-
pentane-1-carboxylate 50. Following General procedure 3,
(1S,2R,5R,aR)-49 (100 mg, 0.27 mmol) and Pd(OH)2/C (50 mg)
under H2 (5 atm) in MeOH (10 mL) gave (1S,2R,5R)-50 (20 mg,
85%) as a colourless oil; dH(400 MHz, CDCl3) 1.85–2.02 (2H,
m, C(3)HA, C(4)HA), 2.21–2.33 (2H, m, C(3)HB, C(4)HB), 2.24
(3H, s, Ar(CH3)p), 2.37 (6H, m, 2 × Ar(CH3)o), 3.53 (1H,
dd, J 6.7, 3.5, C(1)H), 3.62 (3H, s, CO2CH3), 3.85–4.05 (1H,
m, C(2)H), 4.28 (1H, q, J 10.2, C(5)H), 6.82 (2H, s, Ar);
dC(100 MHz, CDCl3) 20.6 (Ar(CH3)p), 21.2 (2 × Ar(CH3)o), 28.9
(C(3)), 34.6 (C(4)), 41.1 (C(5)), 51.9 (CO2CH3), 52.8 (C(1)), 55.8
Preparation of methyl (1S,2R,5S,aR)-5-isopropyl-2-(N-a-
methylbenzylamino)cyclopentane-1-carboxylate 47. Following
General procedure 4, (1S,2R,5S,aR)-33 (200 mg, 0.46 mmol) and
DDQ (144 mg, 1.02 mmol) in 5 : 1 DCM–water (20 mL) gave,
after purification by column chromatography (4 : 1 petrol–ether),
(1S,2R,5S,aR)-47 (93 mg, 80%) as a colourless oil; dH(400 MHz,
CDCl3) 0.80 (3H, d, J 16.1, CH(CH3)A(CH3)B), 0.85 (3H, d, J
16.1, CH(CH3)A(CH3)B), 0.98–1.13 (1H, m, C(4)HA), 1.13 (3H,
d, J 7.0, C(a)CH3), 1.35–1.48 (1H, m, CH(CH3)2), 1.49–1.64
(1H, m, C(3)HA), 1.70–1.84 (2H, m, C(3)HB, C(4)HB), 2.04–
2.17 (1H, m, C(5)H), 2.71 (1H, dd, J 6.8, 1.8, C(1)H), 3.01–
3.12 (1H, m, C(2)H), 3.75 (3H, s, CO2CH3), 3.77 (1H, q, J
6.8, C(a)H), 7.22–7.36 (5H, m, Ph); dC(100 MHz, CDCl3) 20.2,
21.0 (CH(CH3)2)), 27.9 (C(4)), 33.0 (C(a)CH3), 33.9 (C(3)), 50.6
(C(5)), 51.5 (C(1)), 52.0 (CO2CH3), 56.6 (C(a)), 59.9 (C(2)),
(C(2)), 130.1, 135.4, 135.6, 136.7 (Ar), 174.1 (C O); vmax/cm−1
=
+
+
=
(film) 1729 (C O), 3384 (N–H); m/z (ESI ) 262 (MH , 100%);
24
HRMS C16H24NO2 requires 262.1807, found 262.1811; [a]D
+7.2 (c 1.0 in CHCl3).
125.8, 126.7, 126.9, 128.1, 128.4 (Ph), 176.3 (C O); vmax/cm−1
=
+
+
Acknowledgements
=
(film) 1728 (C O); m/z (ESI ) 290 (MH , 100%); HRMS
24
C18H28NO2 requires 290.2120, found 290.2120; [a]D +107.7 (c
The authors wish to thank the Rhodes Trust for a Scholarship
(M. J. S.) and New College, Oxford for a Junior Research
Fellowship (A. D. S.).
0.7 in CHCl3).
Preparation of methyl (1S,2R,5R,aR)-5-tert-butyl-2-(N-a-
methylbenzylamino)cyclopentane-1-carboxylate 48. Following
General procedure 4, (1S,2R,5R,aR)-37 (200 mg, 0.46 mmol) and
DDQ (200 mg, 0.92 mmol) in 5 : 1 DCM–water (20 mL) gave,
after purification by column chromatography (5 : 1 ether–petrol),
(1S,2R,5R,aR)-48 (92 mg, 70%) as a colourless oil; dH(400 MHz,
CDCl3) 0.78 (9H, s, C(CH3)3), 1.13–1.18 (1H, m, C(4)HA), 1.26
(3H, d, J 6.3, C(a)CH3) 1.50–1.71 (3H, m, C(4)HB, C(3)H2),
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 6 2 – 2 7 7 5
2 7 7 5