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

View Article Online / Journal Homepage / Table of Contents for this issue

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,^aStephen G. Davies,*^bRichard M. Parkin,^bPaul M. Roberts,^b

Andrew D. Smith^band Jonathan M. Withey^b

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 KO^tBu 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 Seebach¹and Gell-

man.²For 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,³while 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).⁴The 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,⁸the 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.⁹If 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.⁶This 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

View Article Online

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) KO^tBu, BuOH, D, 3 h; (iii) Pd(OH)₂on 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,^10,11and 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 cyclopentanone¹⁸with TiCl₄and

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,¹²Dieckmann cyclisation¹³and

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

NaBH₄reduction to the alcohol, followed by either tosylation

and subsequent elimination, or treatment with PPh₃/diisopropyl

azodicarboxylate (DIAD)¹⁴gave 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,¹⁵with 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.¹⁶Subse-

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.²⁰Chromatographic 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 KO^tBu 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

View Article Online

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 KO^tBu 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) KO^tBu, BuOH, D, 3 h (R = Et);

(iv) KO^tBu, ^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.⁸Addition 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) KO^tBu, BuOH, D, 3 h (R = Et, Pr, Bu);

(iv) KO^tBu, ^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,²²with

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

View Article Online

(S)-11, (R)-12, (R)-17 and (S)-19 were also isolated in 36–43%

yield, and in >86 to >99 ± 1% ee,²³consistent 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)²⁴in 35% overall yield,

by chemoselective N-debenzylation to afford b-amino ester 40,²⁵

and subsequent N-methylation and N-oxidation/Cope elimina-

tion.²⁶The ee of (S)-17 was established to be >98% by ¹H NMR

chiral shift experiments in the presence of Eu(hfc)₃and 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

View Article Online

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) KO^tBu, ^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)₂on 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

View Article Online

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% ee²⁷after 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

View Article Online

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)₂on C, MeOH, H₂

(5 atm); (ii) TFA:DCM (1:1) then HCl, Et₂O; (iii) Dowex 50WX8-200;

(iv) KO^tBu, ^tBuOH, D, 3 h (R = Et, ⁱPr, ^tBu); (v) KO^tBu, ^tBuOH, rt, 7 d

(R = Bn).

reagent.²⁸Infrared 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

(d_H) 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: NaBH₄reduction 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

View Article Online

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; m_max(film) 1749s, 1721s,

1161m; major diastereoisomer: d_H(400 MHz, CDCl₃) 0.95 (3H,

t, J 7.5, CH₂CH₃), 1.22–1.42 (2H, m, C(4)H_Aand CH_AH_BCH₃),

1.47 (9H, s, OC(CH₃)₃), 1.83 (1H, m, CH_AH_BCH₃), 2.02–2.50

(4H, m, C(3)H, C(4)H_Band C(5)H₂), 3.03 (1H, dd, J 11.1, 8.3,

C(1)H); d_C(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 (CO₂Bu), 214.3 (C(2)); minor

diastereoisomer: d_H(400 MHz, CDCl₃) 0.89 (3H, t, J 7.4,

CH₂CH₃), 1.22–1.42 (2H, m, C(4)H_Aand CH_AH_BCH₃), 1.46

(9H, s, OC(CH₃)₃), 1.83 (1H, m, CH_AH_BCH₃), 2.02–2.50 (4H, m,

C(3)H, C(4)H_Band C(5)H₂), 3.15 (1H, m, C(1)H); d_C(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 (CO₂Bu), 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.³29–31 °C); d_H(200 MHz, CDCl₃)

1.45 (18H, s, OC(CH₃)₃), 1.56–1.73 (4H, m, C(3)H₂and C(4)H₂),

2.15–2.32 (4H, m, C(2)H₂and 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;

m_max(film) 1716s, 1146m; major diastereoisomer: d_H(400 MHz,

CDCl₃) 1.48 (9H, s, OC(CH₃)₃), 1.49 (1H, m, C(4)H_A), 1.99–2.40

(3H, m, C(4)H_Band C(5)H₂), 2.54 (1H, m, C(3)H), 2.60 (1H,

m, CH_AH_BPh), 3.02 (1H, dd, J 10.6, 8.5, C(1)H), 2.17 (1H, m,

CH_AH_BPh), 7.16–7.31 (5H, m, Ph); d_C(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 (CO₂^tBu), 215.7 (C(2)); minor

diastereoisomer: d_H(400 MHz, CDCl₃) 1.48 (9H, s, OC(CH₃)₃),

1.49 (1H, m, C(4)H_A), 1.86 (1H, m, C(5)H_A), 1.99–2.40 (3H, m,

C(3)H, C(4)H_Band C(5)H_B), 2.60 (1H, m, CH_AH_BPh), 3.17 (1H,

m, CH_AH_BPh), 3.20 (1H, m, C(1)H), 7.16–7.31 (5H, m, Ph); d_C

(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 (CO₂^tBu),

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.⁴80–85 °C, 2 mm Hg) gave the title compound

(32.1 g, 84%) as a colourless oil; d_H(200 MHz, CDCl₃) 1.45 (9H, s,

OC(CH₃)₃), 1.74–1.97 (1H, m, C(4)H_A), 2.05–2.33 (5H, m, C(3)H₂,

C(4)H_Band 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; d_H(200 MHz, CDCl₃) 0.84 (3H,

d, J 6.8, CH(CH_3ACH_3B)), 0.89 (3H, d, J 6.8, CH(CH_3ACH_3B)),

1.26 (3H, t, J 6.9, OCH₂CH₃), 1.80–2.70 (7H, m, C(3)H₂, C(4)H₂,

C(5)H₂and 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: d_H(200 MHz, CDCl₃) 1.00 (9H, s, C(CH₃)₃),

1.55–2.65 (5H, m, C(3)H, C(4)H₂and C(5)H₂), 3.08 (1H, dd, J

11.8, 8.2, C(1)H), 3.76 (3H, s, OCH₃); minor diastereoisomer:

d_H(200 MHz, CDCl₃) 0.98 (9H, s, C(CH₃)₃), 1.55–2.65 (5H, m,

C(3)H, C(4)H₂and 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: d_H(400 MHz, CDCl₃) 0.90 (3H,

d, J 6.8, CH(CH_3ACH_3B)), 1.07 (3H, d, J 6.8, CH(CH_3ACH_3B)),

1.29 (3H, m, OCH₂CH₃), 1.64 (1H, m, C(4)H_A), 2.01–2.40 (5H,

m, C(3)H, C(4)H_B, C(5)H₂and CH(CH₃)₂), 3.06 (1H, dd, J 11.4,

8.4, C(1)H), 4.20 (2H, m, OCH₂CH₃); minor diastereoisomer:

d_H(400 MHz, CDCl₃) 0.92 (3H, d, J 6.8, CH(CH_3ACH_3B)), 1.05

(3H, d, J 6.8, CH(CH_3ACH_3B)), 1.28 (3H, m, OCH₂CH₃), 1.64

(1H, m, C(4)H_A), 2.01–2.40 (5H, m, C(3)H, C(4)H_B, 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; m_max(film) 3473br s, 1705s,

1155m; major diastereoisomer: d_H(400 MHz, CDCl₃) 0.94 (3H,

t, J 7.4, CH₂CH₃), 1.15–1.22 (2H, m, C(4)H_Aand CH_AH_BCH₃),

1.45 (1H, m, C(5)H_A), 1.46 (9H, s, OC(CH₃)₃), 1.84 (1H, m,

CH_AH_BCH₃), 1.90–2.04 (3H, m, C(3)H, C(4)H_Band C(5)H_B),

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); d_C(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.⁸45 °C, 11 mm Hg) gave the title com-

pound (27.5 g, 74%) as a colourless oil; d_H(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)H₂and 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 (CO₂Bu); minor diastereoisomer: d_H(400 MHz, CDCl₃)

0.95 (3H, t, J 7.4, CH₂CH₃), 1.44 (1H, m, CH_AH_BCH₃), 1.47

(9H, s, OC(CH₃)₃), 1.50–1.71 (3H, m, C(3)H, C(4)H_Aand

CH_AH_BCH₃), 1.79–2.08 (3H, m, C(4)H_Band 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); d_C(50 MHz, CDCl₃) 12.7 (CH₂CH₃), 22.0

(C(5)), 25.2 (CH₂CH₃), 28.0 (OC(CH₃)₃and C(4)), 47.6 (C(3)),

t

50.1 (C(1)), 74.3 (C(2)), 81.0 (OC(CH₃)₃), 174.9 (CO₂Bu);

+

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.⁹95 °C, 45 mm Hg) gave the title compound

(7.1 g, 39%) as a colourless oil; d_H(200 MHz, CDCl₃) 0.96 (9H,

s, C(CH₃)₃), 1.50–2.50 (7H, m, C(2)H, C(3)H₂, C(4)H₂and

(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; m_max

(film) 1709s, 1631m, 1167m; d_H(400 MHz, CDCl₃) 0.94 (3H,

t, J 7.4, CH₂CH₃), 1.37 (1H, m, CH_AH_BCH₃), 1.49 (9H, s,

OC(CH₃)₃), 1.46–1.54 (2H, m, CH_AH_BCH₃and C(4)H_A), 2.12

(1H, dddd, J 13.0, 8.6, 8.6, 4.5, C(4)H_B), 2.48 (1H, m, C(5)H_A),

2.53 (1H, m, C(5)H_B), 2.70 (1H, m, C(3)H ), 6.61 (1H, app q,

J 2.0, C(2)H ); d_C(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: d_H(400 MHz, CDCl₃) 0.88 (3H,

d, J 6.6, CH(CH_3ACH_3B)), 0.97 (3H, d, J 6.6, CH(CH_3ACH_3B)),

1.24 (1H, m, C(4)H_A), 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)H_Band

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); d_C(50 MHz, CDCl₃) 14.0

(OCH₂CH₃), 20.0 (C(5)), 21.0 (C(4)), 26.7 (CH(CH_3ACH_3B)),

27.1 (CH(CH_3ACH_3B)), 30.7 (CH(CH₃)₂), 49.4 (C(3)), 54.5

(C(1)), 60.5 (OCH₂CH₃), 76.3 (C(2)), 174.7 (CO₂^tBu); m/z (CI⁺,

NH₃) 218 (MNH₄⁺, 5), 201 (MH⁺, 100), 183 (MH⁺–H₂O, 20%);

HRMS, found 201.1493; C₁₁H₂₁O₃(MH⁺) requires 201.1491.

t

+

(CO₂Bu); 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; m_max(film) 3471br s, 1704s

1154m; major diastereoisomer: d_H(400 MHz, CDCl₃) 1.28 (1H,

m, C(4)H_A), 1.48 (9H, s, OC(CH₃)₃), 1.89–1.99 (3H, m, C(3)H,

C(4)H_Band C(5)H_A), 2.31 (1H, m, C(5)H_B), 2.46 (1H, dd, J

13.6, 9.0, CH_AH_BPh), 2.78–2.85 (2H, m, CH_AH_BPh 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); d_C(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 (CO₂^tBu); minor diastereoisomer: d_H(400 MHz,

CDCl₃) 1.46 (9H, s, OC(CH₃)₃), 1.68–1.81 (2H, m, C(3)H and

C(4)H_A), 1.89–2.10 (3H, m, C(4)H_Band C(5)H₂), 2.64 (2H, m,

C(1)H and CH_AH_BPh), 2.94 (1H, dd, J 13.5, 8.1, CH_AH_BPh),

3.26 (1H, br s, OH), 4.15 (1H, app t, J 3.4, C(2)H), 7.15–7.31

(5H, m, Ph); d_C(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;

m_max(film) 1716s, 1634m; d_H(400 MHz, CDCl₃) 0.90 (3H, d, J 7.1,

CH(CH_3ACH_3B)), 0.94 (3H, d, J 7.1, CH(CH_3ACH_3B)), 1.30 (3H,

t, J 7.1, CH₂CH₃), 1.57–1.67 (2H, m, CH(CH₃)₂and C(4)H_A),

2.07 (1H, dddd, J 13.0, 8.6, 8.6, 4.3, C(4)H_B), 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); d_C(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; d_H(200 MHz, CDCl₃) 0.90 (3H, d, J 7.0, CH(CH_3ACH_3B)),

0.94 (3H, d, J 7.0, CH(CH_3ACH_3B)), 1.56–1.73 (2H, m,

CH(CH₃)₂and C(4)H_A), 2.08 (1H, dddd, J 13.0, 8.5, 8.5, 4.5,

C(4)H_B), 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; m_max(film) 1709s, 1633m, 1171s; d_H(400 MHz,

CDCl₃) 0.90 (3H, d, J 6.7, CH(CH_3ACH_3B)), 0.94 (3H, d, J 6.7,

CH(CH_3ACH_3B)), 1.50 (9H, s, OC(CH₃)₃), 1.54–1.64 (2H, m,

CH(CH₃)₂and C(4)H_A), 2.05 (1H, dddd, J 13.0, 8.7, 8.7, 4.3,

C(4)H_B), 2.44–2.60 (3H, m, C(3)H and C(5)H₂), 6.64 (1H, app

q, J 2.0, C(2)H); d_C(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 (CO₂^tBu); 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%; C₁₇H₂₂O₂requires C, 79.0; H, 8.6%;

m_max(film) 1707s, 1629m, 1167m; d_H(400 MHz, CDCl₃) 1.49

(9H, s, OC(CH₃)₃), 1.61 (1H, m, C(4)H_A), 2.09 (1H, dddd, J

13.0, 8.8, 8.8, 4.5, C(4)H_B), 2.49 (1H, m, C(5)H_A), 2.56 (1H,

m, C(5)H_B), 2.65 and 2.77 (2H, ABX system, J_AB13.5, J_AX

8.0, J_BX7.3, 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); d_C(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 (CO₂Bu); 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; m_max(film) 3485br s, 1716s and

t

+

(CO₂Bu); 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; m_max(film) 3507br s,

1716s; major diastereoisomer: d_H(400 MHz, CDCl₃) 1.03 (9H, s,

C(CH₃)₃), 1.43 (1H, br s, OH), 1.53 (1H, m, C(4)H_A), 1.68–1.86

(3H, m, C(3)H, C(4)H_Band C(5)H_A), 2.13 (1H, m, C(5)H_B), 2.52

(1H, m, C(1)H), 3.69 (3H, s, OCH₃), 4.48 (1H, m, C(2)H); d_C

(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): d_H(400 MHz, CDCl₃) 0.88 (3H, t, J 7.5, CH₂CH₃),

1.03 (1H, m, CH_AH_BCH₃), 1.13 (1H, m, C(4)H_A), 1.58 (9H, s,

OC(CH₃)₃), 1.67–1.81 (2H, m, C(5)H_Aand CH_AH_BCH₃), 1.91

(1H, m, C(5)H_B), 2.07 (1H, m, C(4)H_B), 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, J_AB13.9,

N(CH₂Ph)₂), 7.21–7.42 (10H, m, Ph); d_C(100 MHz, CDCl₃) 12.3

(CH₂CH₃), 27.2 and 27.4 (CH₂CH₃and 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 (CO₂^tBu).

+

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%; C₂₆H₃₅NO₂requires C, 79.4; H, 9.0; N, 3.6%; m_max(KBr)

3059s, 3028s, 2974s, 2873s, 1717s, 1603m, 1495m, 1452m,

1363s, 1254m, 1145s, 1072m, 965m, 845m, 751s; d_H(400 MHz,

CDCl₃) 0.84 (1H, t, J 7.4, CH₂CH₃), 1.09 (1H, m, CH_AH_BCH₃),

1.32 (1H, m, C(4)H_A), 1.50 (9H, s, OC(CH₃)₃), 1.72–1.87 (5H,

m, CH_AH_BCH₃, C(3)H, C(4)H_Band 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, J_AB13.8, N(CH₂Ph)₂), 7.21–7.39 (10H,

m, Ph); d_C(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; d_H

(400 MHz, CDCl₃) 0.90 (9H, s, C(CH₃)₃), 1.58–1.77 (1H, m,

C(4)H_A), 1.97 (1H, dddd, J 13.1, 8.8, 8.8, 4.4, C(4)H_B), 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; d_H(400 MHz, CDCl₃) 0.91 (9H, s,

C(CH₃)₃), 1.73–1.80 (1H, m, C(4)H_A), 2.01 (1H, dddd, J 13.2,

8.8, 8.8, 4.4, C(4)H_B), 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; m_max(film) 1710s,

1634m, 1168s; d_H(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)H_A), 2.01 (1H, dddd, J

13.2, 8.8, 8.8, 4.4, C(4)H_B), 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); d_C(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 (CO₂Bu); 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): d_H(400 MHz,

CDCl₃) 1.19 (1H, m, C(4)H_A), 1.59 (9H, s, OC(CH₃)₃), 1.70

(1H, m, C(5)H_A), 1.87–1.92 (2H, m, C(4)H_Band C(5)H_B), 2.19

(1H, dd, J 13.6, 10.4, C(3)CH_ACH_BPh), 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)CH_AH_BPh), 3.85 and 3.98 (2 × 2H, AB system, J_AB14.0,

N(CH₂Ph)₂), 7.10–7.45 (15H, m, Ph); d_C(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 (CO₂^tBu).

t

+

144.5 (C(2)), 165.3 (CO₂Bu); 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; m_max(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; d_H(400 MHz, CDCl₃) 1.36 (1H, m, C(4)H_A),

1.51 (1H, s, OC(CH₃)₃), 1.59 (1H, m, C(4)H_B), 1.80–1.84 (2H,

m, C(5)H₂), 2.15–2.22 (2H, m, C(3)CH_AH_BPh and C(3)H),

2.96 (1H, m, C(1)H), 3.13 (1H, dd, J 13.6, 4.2, C(3)CH_AH_BPh),

3.26 (1H, dd, J 8.4, 7.2, C(2)H), 3.59 and 3.85 (2 × 2H,

AB system, J_AB13.7, N(CH₂Ph)₂), 7.04–7.44 (15H, Ph); d_C

(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]²_D⁴−68.3, (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]²_D³−125.3 (c 1.1, CHCl₃),

with spectroscopic data identical to the racemate.

t

176.9 (CO₂Bu); 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; d_H(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, J_AB13.2,

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]²_D⁴+52.9 (c 1.0, CHCl₃)},

and (S)-enantiomer (186 g, 90%) {[a]²_D³−53.1 (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 KO^tBu

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]²_D⁵+21.2

(c 0.80, CHCl₃); m_max(film) 2959s, 1720s, 1493m, 1454m, 1367m,

1154s, 700m; d_H(400 MHz, CDCl₃) 0.83 (3H, t, J 7.4, CH₂CH₃),

1.16 (1H, m, CH_AH_BCH₃), 1.20 (1H, d, J 6.8, C(a)Me) overlays

1.21 (1H, m, C(4)H_A), 1.43 (9H, s, OC(CH₃)₃), 1.67–1.70 (4H,

m, C(3)H, C(4)H_Band C(5)H₂), 1.73 (1H, m, CH_AH_BCH₃), 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, J_AB15.8, NCH₂Ph) overlays 3.87 (1H, q, J

6.8, C(a)H), 7.20–7.44 (10H, m, Ph); d_C(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 (CO₂Bu); 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%; C₂₇H₃₇NO₂requires C, 79.6; H, 9.2; N, 3.4%;

m_max(film) 2965s, 1719s, 1493m, 1454m, 1366s, 1145s, 700s; d_H

(400 MHz, CDCl₃) 0.82 (3H, t, J 7.2, CH₂CH₃), 0.89–0.98 (1H,

m, CH_AH_BCH₃), 1.00–1.09 (1H, m, C(4)H_A), 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)H_A), 1.73 (1H, m, C(5)H_B), 1.86 (1H, m, CH_AH_BCH₃), 1.99

(1H, m, C(4)H_B), 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, J_AB15.6, NCH₂Ph) overlays 4.17 (1H, q,

J 6.8, C(a)H), 7.20–7.49 (10H, m, Ph); d_C(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; m_max(film) 3061w, 3026m, 2973s,

2870w, 1718s, 1602w, 1494m, 1453m, 1366s, 1146s, 700s; d_H

(400 MHz, CDCl₃) 1.10 (1H, m, C(4)H_A), 1.27 (3H, d, J 6.8,

C(a)Me), 1.57 (9H, s, OC(CH₃)₃) overlays 1.58 (1H, m, C(5)H_A),

1.71–1.84 (2H, m, C(4)H_Band C(5)H_B), 2.06 (1H, dd, J 13.2,

11.2, C(3)CH_AH_BPh), 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)CH_AH_BPh), 4.08 and 4.33 (2 × 1H, AB system, J_AB

16.0, NCH₂Ph) overlays 4.30 (1H, q, J 6.8, C(a)H), 6.98–7.63

(15H, m, Ph); d_C(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 (CO₂Bu); 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)H_A), 1.39–1.44 (1H, m, C(5)H_A), 1.55 (9H, s, OC(CH₃)₃),

t

Ph), 176.3 (CO₂Bu); m/z (APCI⁺) 470 (MH⁺, 100%); HRMS,

1.68–1.80 (2H, m, C(4)H_Band C(5)H_B), 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, J_AB16.4, NCH₂Ph) over-

lays 4.23 (1H, q, J 6.8, C(a)H), 7.21–7.49 (10H, m, Ph); d_C

(100 MHz, CDCl₃) 15.1 (CH(CH_3ACH_3B)), 21.3 (C(5)), 22.3

(CH(CH_3ACH_3B)), 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]²_D⁴−74.2 (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]²_D³−45.1 (c 1.0, CHCl₃); elemental analysis, found C, 81.6; H,

8.4; N, 3.0%; C₃₂H₃₉NO₂requires C, 81.8; H, 8.4; N, 3.0%, with

spectroscopic data identical to the racemate.

t

(ipso-Ph), 176.0 (CO₂Bu); 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]²_D⁴−48.3 (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]²_D³−89.5 (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]²_D³+19.2 (c 0.26, CHCl₃); m_max(film) 2956s,

1721s, 1602w, 1494w, 1453m, 1367s, 1146s, 700s; d_H(400 MHz,

CDCl₃) 0.57 (3H, d, J 6.8, CH(CH_3ACH_3B)), 0.94 (3H, d, J 6.8,

CH(CH_3ACH_3B)), 1.19 (3H, d, J 6.8, C(a)Me), 1.33 (1H, m,

C(4)H_A), 1.45 (9H, s, OC(CH₃)₃) overlays 1.46 (1H, m, C(5)H_A),

1.68–1.76 (3H, m, C(3)H, C(4)H_Band C(5)H_B), 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, J_AB16.0, NCH₂Ph) overlays 3.88 (1H, q,

J 6.8, C(a)H), 7.21–7.49 (10H, m, Ph); d_C(100 MHz, CDCl₃)

16.4 (CH(CH_3ACH_3B)), 22.8 (CH(CH_3ACH_3B)), 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 KO^tBu 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); m_max(film) 3041s, 3019s,

2929s, 2874s, 1717s, 1602w, 1491s, 1451s, 1359s, 1248m, 1149s,

738m, 699s; d_H(400 MHz, CDCl₃) 1.30 (3H, d, J 6.4, C(a)Me)

overlays 1.34 (1H, m, C(4)H_A), 1.48 (9H, s, OC(CH₃)₃), 1.57

(1H, m, C(4)H_B), 1.71–1.82 (2H, m, C(5)H₂), 2.14–2.21 (2H, m,

C(3)CH_AH_BPh and C(3)H), 2.94 (1H, m, C(1)H), 3.27 (1H, dd,

J 13.6, 3.6, C(3)CH_AH_BPh), 3.42 (1H, dd, J 8.4, 6.0, C(2)H),

3.83 and 3.91 (2 × 1H, AB system, J_AB16.0, NCH₂Ph), 3.96 (1H,

q, J 6.4, C(a)H), 7.02–7.43 (15H, Ph); d_C(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 (CO₂Bu); 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 (CO₂Bu);

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 KO^tBu

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; m_max(film) 2961s, 1711s, 1603w,

1494m, 1454m, 1366m, 1261s, 1135s, 761m, 702s; d_H(400 MHz,

CDCl₃) 0.53 (3H, d, J 7.2, CH(CH_3ACH_3B)), 0.83 (3H, d, J 7.2,

CH(CH_3ACH_3B)), 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]²_D⁵+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): d_H(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, J_AB15.1,

NCH₂Ph) overlays 4.17 (1H, q, J 6.8, C(a)H); d_C(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 (CO₂^tBu).

Preparation of (1R,2S,3R)-3-ethyl-2-aminocyclopentane-1-

carboxylic acid 44

Following general procedure 7, Pd(OH)₂on 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]²_D²−44.7 (c 1.0, CHCl₃); m_max(film) 3390br w, 2961s, 1722s,

1613w, 1462w, 1367m, 1153s; d_H(400 MHz, CDCl₃) 0.94 (3H, t,

J 7.3, CH₂CH₃), 1.12–1.22 (2H, m, CH_AH_BCH₃and C(4)H_A),

1.47 (9H, s, OC(CH₃)₃), 1.57–1.63 (2H, m, C(3)H and C(4)H_B),

1.88 (2H, br s, NH₂) overlays 1.82–2.02 (3H, m, CH_AH_BCH₃and

C(5)H₂), 2.80 (1H, app q, J 7.8, C(1)H), 3.07 (1H, m, C(2)H);

d_C(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%; C₂₉H₄₁NO₂requires C, 80.0; H, 9.5; N,

3.2%; m_max(KBr) 3025w, 2968s, 2877m, 2798w, 1721s, 1600w,

1494m, 1452s, 1366s, 1148s, 849m, 742s, 707s; d_H(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)H_A), 1.46 (9H, s, OC(CH₃)₃), 1.59 (1H,

m, C(5)H_A), 1.70–1.84 (3H, m, C(3)H, C(4)H_Band C(5)H_B), 2.59

(1H, m, C(1)H), 3.59 and 3.99 (2 × 1H, AB system, J_AB15.7,

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); d_C(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 (CO₂Bu); 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]²_D⁴−32.3 (c 1.1, H₂O); elemental

analysis, found C, 61.2; H, 9.6; N, 8.6%; C₈H₁₅NO₂requires

C, 61.1; H, 9.6; N, 8.9%; m_max(KBr) 3677–2360br s, 2956s,

2188m, 1644m, 1611m, 1566s, 1519s, 1414s, 1329m, 1308m,

1174m, 1132m, 845w, 745w; d_H(400 MHz, D₂O) 0.76 (3H, t,

J 7.4, CH₂CH₃), 1.11–1.22 (2H, m, CH_AH_BCH₃and C(4)H_A),

1.38–1.44 (1H, m, CH_AH_BCH₃), 1.64–1.69 (1H, m, C(5)H_A),

1.81–1.96 (3H, m, C(3)H, C(4)H_Band C(5)H_B), 2.76 (1H, m,

C(1)H), 3.23 (1H, dd, J 6.6, 5.0, C(2)H); d_C(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 (CO₂Bu); 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]²_D⁴−32.9

(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)₂on 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]²_D²+36.1 (c

0.50, CHCl₃); m_max(film) 3387br w, 2957s, 1726s, 1459w, 1366m,

1154s; d_H(400 MHz, CDCl₃) 0.87 (3H, t, J 7.4, CH₂CH₃),

1.11–1.21 (1H, m, CH_AH_BCH₃), 1.23–1.31 (1H, m, C(5)H_A),

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, CH_AH_BCH₃),

1.77–1.91 (3H, m, C(4)H₂and C(5)H_B), 2.37 (1H, app q, J 8.8,

C(1)H), 2.85 (1H, br t, J 8.8, C(2)H); d_C(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 (CO₂Bu); 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]²_D⁵+10.9 (c 1.0, H₂O); m_max(film) 3411br s, 3321–

2386br s, 2963s, 1716s, 1615m, 1516m, 1463w, 1412w, 1211s;

d_H(400 MHz, D₂O) 0.78 (3H, t, J 7.5, CH₂CH₃), 1.17 (1H, m,

CH_AH_BCH₃), 1.32 (1H, m, C(4)H_A), 1.53 (1H, m, CH_AH_BCH₃),

1.74–1.93 (3H, m, C(3)H, C(4)H_Band C(5)H_A), 1.97–2.06 (1H,

m, C(5)H_B), 2.86 (1H, app td, J 9.5, 7.8, C(1)H), 3.38 (1H,

app t, J 8.1, C(2)H); d_C(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); m_max(film) 3391br w, 2971m, 1723s, 1493w,

1451w, 1367m, 1148s; d_H(400 MHz, CDCl₃) 1.36–1.42 (1H,

m, C(4)H_A), 1.46 (9H, s, OC(CH₃)₃), 1.71–1.91 (3H, m, C(4)H_B

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, CH_AH_BPh and C(1)H), 2.95 (1H, dd,

J 13.2, 5.6, CH_AH_BPh), 3.08 (1H, br t, J 8.4, C(2)H), 7.17–7.29

(5H, m, Ph); d_C(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 (CO₂Bu); 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]²_D⁴+13.9 (c 1.2, H₂O);

m_max(KBr) 3397m, 3329–2403br s, 3126s, 2938s, 1708s, 1602w,

1484m, 1481m, 1453m, 1424s, 1283m, 1200s, 866m, 742s, 702s,

683s; d_H(400 MHz, D₂O) 1.37 (1H, m, C(4)H_A), 1.67 (1H, m,

C(4)H_B), 1.78 (1H, m, C(5)H_A), 1.92–2.01 (1H, m, C(5)H_B), 2.21

(1H, m, C(3)H), 2.48 (1H, dd, J 13.5, 9.7, CH_AH_BPh), 2.86 (1H,

dd, J 13.5, 5.1, CH_AH_BPh) 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); d_C(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)₂on 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]²_D²−32.5 (c 1.0, CHCl₃); elemental analysis, found C,

73.8; H, 8.7; N, 5.1%; C₁₇H₂₅NO₂requires C, 74.1; H, 9.2; N,

5.1%; m_max(film) 3389br w, 2973m, 1720s, 1603w, 1495w, 1453w,

1391w, 1366m, 1150s, 745w, 700m; d_H(400 MHz, CDCl₃) 1.22

(1H, m, C(4)H_A), 1.39 (2H, br s, NH₂), 1.47 (9H, s, OC(CH₃)₃),

1.81–1.88 (3H, m, C(4)H_Band C(5)H₂), 2.04 (1H, m, C(3)H),

2.47 (1H, dd, J 13.5, 8.9, CH_AH_BPh), 2.83–2.90 (2H, m, C(1)H

and CH_AH_BPh), 3.12 (1H, br t, J 7.4, C(2)H), 7.17–7.30 (5H, m,

Ph); d_C(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)₂on 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); m_max(film) 3385br

w, 2958s, 2873m, 1723s, 1468w, 1392m, 1367s, 1249w, 1221w,

1152s; d_H(400 MHz, CDCl₃) 0.88 (3H, d, J 6.5, CH(CH_3ACH_3B)),

0.99 (3H, d, J 6.5, CH(CH_3ACH_3B)), 1.23 (1H, m, C(4)H_A), 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)H_Band C(5)H₂), 2.72 (1H, m,

C(1)H), 3.30 (1H, dd, J 7.1, 5.7, C(2)H); d_C(100 MHz, CDCl₃)

19.2 (CH(CH_3ACH_3B)), 21.5 (CH(CH_3ACH_3B)), 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 (CO₂Bu); 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]²_D⁴−15.0 (c 0.50, H₂O); elemental

analysis, found C, 70.9; H, 7.5; N, 6.7%; C₁₃H₁₇NO₂requires C,

71.1; H, 7.8; N, 6.4%; m_max(KBr) 3742–2362br s, 3065s, 2966s,

2362m, 2114w, 1619m, 1658s, 1497m, 1407s, 1314m, 1204w,

727s, 698s; d_H(400 MHz, D₂O) 1.30 (1H, m, C(4)H_A), 1.62–1.80

(2H, m, C(4)H_Band C(5)H_A), 1.97 (1H, m, C(5)H_B), 2.28 (1H,

m, C(3)H), 2.50 (1H, dd, J 13.6, 8.9, CH_AH_BPh), 2.73 (1H, dd, J

13.6, 6.6, CH_AH_BPh), 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); d_C(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 (CO₂Bu); 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]²_D³+11.7 (c 1.1, H₂O); m_max(KBr) 3672–

2361br s, 3420m, 2958s, 2362w, 2125w, 1650m, 1575s, 1524m,

1469w, 1449w, 1414s, 1310m, 1207w, 1148m; d_H(400 MHz,

D₂O) 0.71 (3H, d, J 6.7, CH(CH_3ACH_3B)), 0.78 (3H, d, J 6.7,

CH(CH_3ACH_3B)), 1.30 (1H, m, C(4)H_A), 1.50 (1H, app septet,

J 6.7, CH(CH₃)₃), 1.58–1.68 (1H, m, C(5)H_A), 1.70–1.81 (2H,

m, C(3)H and C(4)H_B), 1.85–1.94 (1H, m, C(5)H_B), 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); d_C

(100 MHz, D₂O) 18.3 (CH(CH_3ACH_3B)), 20.6 (CH(CH_3ACH_3B)),

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)₂on 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]²_D³+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)₂on 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]²_D³+30.6 (c 0.50, CHCl₃); m_max(film) 3387br w, 2956s, 2875s,

1725s, 1365s, 1153s; d_H(400 MHz, CDCl₃) 0.87 (3H, d, J 6.6,

CH(CH_3ACH_3B)), 0.96 (3H, d, J 6.7, CH(CH_3ACH_3B)), 1.46 (9H,

s, OC(CH₃)₃) overlays 1.41–1.46 (1H, m, C(4)H_A), 1.67–1.84

(4H, m, CH(CH₃)₂, C(3)H, C(4)H_Band C(5)H_A), 1.99 (2H, br s,

NH₂) overlays 1.92–2.01 (1H, m, C(5)H_B), 2.66 (1H, app q, J 8.4,

C(1)H), 3.26 (1H, br t, J 7.6, C(2)H); d_C(100 MHz, CDCl₃) 17.9

(CH(CH_3ACH_3B)), 21.7 (CH(CH_3ACH_3B)), 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,²⁶CAN (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]²_D⁵+32.6

(c 0.90, CHCl₃); m_max(film) 2958s, 2871s, 1722s, 1455m, 1367m,

1277m, 1255m, 1147s, 761m, 701m; d_H(400 MHz, CDCl₃)

0.62 (3H, d, J 6.7, CH(CH_3ACH_3B)), 0.81 (3H, d, J 6.7,

CH(CH_3ACH_3B)), 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)H_A),

1.57–1.68 (2H, m, CH(CH₃)₂and C(4)H_B), 1.73–1.81 (1H, m,

C(5)H_A), 1.82–1.90 (1H, m, C(5)H_B), 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); d_C(100 MHz, CDCl₃) 18.1

(CH(CH_3ACH_3B)), 22.1 (CH(CH_3ACH_3B)), 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 (CO₂Bu); 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]²_D⁴+14.8 (c 0.50, H₂O); m_max(film)

3332–2386br s, 1709s, 1604w, 1492m, 1206s; d_H(400 MHz,

D₂O) 0.75 (3H, d, J 6.8, CH(CH_3ACH_3B)), 0.83 (3H, d, J 6.8,

CH(CH_3ACH_3B)), 1.45 (1H, m, C(4)H_A), 1.63–1.86 (4H, m,

CH(CH₃)₂, C(3)H, C(4)H_Band C(5)H_A), 1.93–2.03 (1H, m,

C(5)H_B), 2.85 (1H, app td, J 9.3, 7.6, C(1)H), 3.55 (1H, app t,

J 7.8, C(2)H); d_C(100 MHz, D₂O) 17.0 (CH(CH_3ACH_3B)), 21.0

(CH(CH_3ACH_3B)), 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

(CO₂Bu); 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]²_D⁵+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)₂on 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]²_D³+34.2 (c 0.70, CHCl₃); m_max(film) 3389br w, 2958 s, 2869s,

1724s, 1466w, 1389m, 1364s, 1149s; d_H(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)H_A), 1.64–1.78 (2H, m, C(4)H_Band C(5)H_A),

1.80–1.88 (1H, m, C(5)H_B), 2.41 (2H, br s, NH₂) overlays

2.38–2.47 (1H, m, C(1)H), 3.25 (1H, br, C(2)H); d_C(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); m_max(KBr) 3028w,

2952s, 2881m, 2870m, 1710s, 1602w, 1454m, 1366s, 1213m,

1138s, 748s, 698s; d_H(400 MHz, CDCl₃) 0.11 (3H, d, J 6.7,

CH(CH_3ACH_3B)), 0.83 (3H, d, J 6.7, CH(CH_3ACH_3B)), 1.18–1.24

(1H, m, C(4)H_A), 1.50 (3H, d, J 6.9, C(a)Me), 1.55 (9H, s,

t

80.3 (OC(CH₃)₃), 174.4 (CO₂Bu); 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);

m_max(film) 3591–2384br s, 2917s, 2163br m, 1661s, 1516m, 1416m,

1371m, 1251w, 1203w; d_H(400 MHz, D₂O) 0.80 (9H, s, C(CH₃)₃),

1.51–1.62 (1H, m, C(4)H_A), 1.68–1.85 (3H, m, C(3)H, C(4)H_B

and C(5)H_A), 1.88–1.98 (1H, m, C(5)H_B), 2.88 (1H, m, C(1)H),

3.70 (1H, app t, J 6.3, C(2)H); d_C(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)H_A), 1.74–1.83 (3H,

m, CH(CH₃)₂, C(4)H_Band C(5)H_B), 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, J_AB14.1, NCH₂Ph), 4.01 (1H,

q, J 6.9, C(a)H) 7.17–7.40 (10H, m, Ph); d_C(100 MHz, CDCl₃)

14.1 and 14.2 (CH(CH_3ACH_3B) and C(a)Me), 20.0 (C(5)), 22.9

(CH(CH_3ACH_3B)), 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 (CO₂^tBu); 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]²_D⁵−0.93 (c 0.75, CHCl₃);

m_max(film) 3086w, 3062w, 3029m, 2956s, 2872s, 1721s, 1602w,

1494m, 1453m, 1367s, 1274m, 1255m, 1148s, 749s, 733s, 698s;

d_H(400 MHz, CDCl₃) 0.26 (3H, d, J 6.8, CH(CH_3ACH_3B)), 0.81

(3H, d, J 6.8, CH(CH_3ACH_3B)), 1.27–1.32 (1H, m, C(4)H_A), 1.36

(3H, d, J 6.8, C(a)Me), 1.40–1.44 (1H, m, C(5)H_A), 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)H_Band C(5)H_B), 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, J_AB14.2,

NCH₂Ph), 3.90 (1H, q, J 6.8, C(a)H), 7.17–7.46 (10H, m, Ph);

d_C(100 MHz, CDCl₃) 13.2 (C(a)Me), 15.8 (CH(CH_3ACH_3B)),

22.9 (CH(CH_3ACH_3B)), 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 (CO₂Bu); 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)₂on 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]²_D²−18.1 (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://ww w .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,

Synthesis, 1983, 996.

14 X. Wang, J. F. Espinosa and S. H. Gellman, J. Am. Chem. Soc., 2000,

122, 4821.

15 A. Barco, S. Benetti and G. P. Pollni, Synthesis, 1973, 316.

16 K. Sisido, K. Utimoto and T. Isida, J. Org. Chem., 1964, 29, 2781;

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

Article Doi

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

DOI: 10.1039/b407559e

Source and publish data:

Authors:

Article abstract of DOI:10.1039/b407559e

Full text of DOI:10.1039/b407559e

Products guided by the article

R&D Labs maybe for 821766-77-2

Relevant to this article

Hot Product