Cyclic β-amino acid derivatives: Synthesis via lithium amide promoted tandem asymmetric conjugate addition-cyclisation reactions

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

A R T I C L E

Cyclic b-amino acid derivatives: synthesis via lithium amide promoted

tandem asymmetric conjugate addition–cyclisation reactions

Stephen G. Davies,*^aDavid D´ıez,^bSara H. Dominguez,^bNarciso M. Garrido,^b

Dennis Kruchinin,^aPaul D. Price^aand Andrew D. Smith^a

^aDepartment of Organic Chemistry, University of Oxford, Chemical Research Laboratory,

Mansﬁeld Road, Oxford, OX1 3TA, UK. E-mail: steve.davies@chem.ox.ac.uk

^bDepartamento de Qu´ımica Orga´nica, Universidad de Salamanca, Plaza de los Ca´ıdos 1-5,

37008, Salamanca, Spain

Received 7th January 2005, Accepted 1st February 2005

First published as an Advance Article on the web 2nd March 2005

The product distribution upon conjugate addition of homochiral lithium N-benzyl-N-a-methylbenzylamide to

dimethyl-(E,E)-nona-2,7-dienedioate can be controlled to give either the cyclic 1,2-anti-1,6-anti-b-amino ester

(derived from conjugate addition and intramolecular enolate cyclisation) or the acyclic bis-b-amino ester derivative

(derived from double conjugate addition) in high de. The introduction of a protected nitrogen functionality into the

diester skeleton facilitates, after conjugate addition and intramolecular enolate cyclisation, the asymmetric

construction of piperidines in high de; variation in the N-protecting group indicates that the highest stereoselectivity

is observed with a-branched N-substituents. Tandem conjugate addition–aldol reactions can also be achieved

stereoselectively, with lithium amide conjugate addition to e- and f-oxo-a,b-unsaturated esters giving the

corresponding ﬁve and six membered cyclic b-amino esters in high de. N-deprotection by hydrogenolysis of the

products arising from these reactions furnishes a range of polyfunctionalised transpentacin and transhexacin

derivatives in high de and ee.

Introduction

Synthetic design in organic chemistry demands efﬁciency in

terms of minimisation of the number of steps required for

the preparation of molecules of structural complexity. Tan-

dem reaction sequences permit relatively complex structures

to be constructed in a small number of synthetic steps.¹

Within this area, the conjugate addition of a nucleophile to

an a,b-unsaturated system and intramolecular cyclisation of

the resultant enolate onto an internal electrophilic site has

been studied extensively as a method for the stereocontrolled

construction of three- to seven-membered cyclic systems from

acyclic precursors.²A variety of synthetic protocols have been

Fig. 1 Conjugate addition and cyclisation for the synthesis of the

developed that use this strategy for the preparation of enantio-

stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylate.

merically pure cyclic derivatives.³In this area, Yamamoto et al.

have previously demonstrated that addition of achiral lithium

N-benzyl-N-trimethylsilylamide to dimethyl-(E,E)-nona-2,7-

dienedioate facilitates tandem conjugate addition and diastere-

tuted carbocyclic pentacin and hexacin derivatives that would

be of interest as scaffolds for synthetic peptide design and for

incorporation into novel b-peptide architectures.⁹Furthermore,

the incorporation of a protected nitrogen functionality within

the acceptor framework would lead, after conjugate addition

and cyclisation, to the synthesis of homochiral piperidines

(Fig. 2).

oselective intramolecular cyclisation,⁴while conjugate addition

to the enantiomerically pure dimethyl ester derivative promotes

the transformation in a diastereo- and enantioselective fashion.⁵

Previous work from this laboratory has demonstrated exten-

sively that the conjugate addition of homochiral lithium amides

derived from a-methylbenzylamine to a,b-unsaturated esters

allows the highly diastereoselective preparation of N-protected

b-amino esters.⁶This methodology has been extended recently

to the conjugate addition and concomitant intramolecular

cyclisation of diester derivatives of (E,E)-octa-2,6-dienedioic

acid, allowing the preparation of the stereoisomers of

2-amino-5-carboxymethyl-cyclopentane-1-carboxylate 3–6 in

enantiomerically pure form (Fig. 1).⁷

In order to demonstrate further the versatility of this lithium

amide methodology, a study concerned with the compatability

of a range of e- and f-functionalised a,b-unsaturated esters

to participate in conjugate addition–cyclisation reactions was

undertaken.⁸It was envisaged that lithium amide conjugate

addition and subsequent intramolecular cyclisation of the in situ-

formed b-amino enolate onto either an a,b-unsaturated ester or

aldehyde functionality would give rise to a range of polysubsti-

Fig. 2 Proposed conjugate addition–cyclisation reactions for the

synthesis of the pentacin, hexacin and piperidine derivatives.

1 2 8 4

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

T h i s j o u r n a l i s

T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5

©

View Article Online

We report herein our full results in this area, in which we

delineate the scope and limitations of this methodology, part of

which has been communicated previously.¹⁰

Results and discussion

Lithium amide addition to (E,E)-nona-2,7- and (E,E)-deca-2,8-

dienedioate esters; promoting tandem conjugate addition–

cyclisation or double conjugate addition reactions

Initial studies concentrated upon the propensity for lithium

amides to promote the conjugate addition and cyclisation

of a range of diester derivatives of (E,E)-nona-2,7-dienedioic

acid. Addition of dimethyl, diethyl, di-tert-butyl or di-3-pentyl-

(E,E)-nona-2,7-dienedioate 8–11 to lithium (S)-N-benzyl-N-a-

methylbenzylamide (7, 1.6 eq.) gave, in each case, the corre-

sponding 1,2-anti-1,6-anti-cyclic b-amino esters 12–15 as the

sole reaction products in >95% de and in 72–84% yield after

puriﬁcation (Scheme 1). The relative conﬁguration within b-

amino ester 12 was assigned using ¹H NMR spectroscopic

analysis, using a combination of coupling constant analysis and

NOESY experiments. The absolute conﬁguration at C(2) within

12 was assigned relative to the N-a-methylbenzyl stereocentre

by analogy with previous authenticated models developed

to explain the stereoselectivity observed during addition of

lithium amide (S)-7 to a,b-unsaturated acceptors,¹¹while the

conﬁguration at C(1) is consistent with the established anti-

alkylation preference of lithium (Z)-b-amino enolates.¹²The

1,2-anti-1,6-anti-arrangement within b-amino esters 13–15 was

assigned by analogy to 12, and was veriﬁed independently by ¹H

NMR analysis in each case.

Scheme 2 Reagents and conditions: (i) lithium (R)-N-benzyl-N-a-

methylbenzylamide (7, 12 eq.), THF, −78 ^◦C.

Having shown that the product distribution upon lithium

amide addition to (E,E)-nona-2,7-dienedioate esters can be

biased towards either the conjugate addition–cyclisation or

diaddition reaction manifolds, lithium amide addition to a

homologous (E,E)-deca-2,8-dienedioic acid derivative was in-

vestigated. Addition of lithium amide (R)-7 (1.2 eq.) to di-

3-pentyl-(E,E)-deca-2,8-dienedioate 17 gave, at approximately

45% conversion, mono b-amino ester 18 in 42% isolated yield

and >95% de, while addition of diester 17 to an excess of

lithium amide (R)-7 (10 eq.) gave the bis-b-amino ester 19 as

the sole reaction product in 67% isolated yield and >95% de.

Furthermore, addition of lithium amide (S)-7 to the mono-

b-amino ester 18 gave the meso-di-b-amino ester 20 in >95%

de and 71% yield (Scheme 3). Comparison of the ratio of

products arising from the additions of 2,7-dienedioate 8 and

2,8-dienedioate 17 to an excess of lithium amide indicates that

intermolecular conjugate addition can compete effectively with

intramolecular cyclisation for formation of the six-membered

carbocycle, but that bis-addition is favoured upon addition to

the deca-2,8-dienoate. This product ratio presumably reﬂects the

relative rates of cyclisation to form the six and seven membered

rings, respectively, or that the reaction is reversible.

Scheme 1 Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-

methylbenzylamide (7, 1.6 eq.), THF, −78 ^◦C.

It was envisaged that an alternative reaction manifold may be

realised in this system if, following initial lithium amide conju-

gate addition to dimethyl-(E,E)-nona-2,7-dienedioate, the rate

of a second intermolecular lithium amide conjugate addition

could compete effectively with the intramolecular cyclisation of

the in situ formed b-amino enolate. In order to bias the system

toward the di-addition reaction manifold, addition of dienoate 8

to a large excess of lithium amide (R)-7 (12 eq.) was investigated,

giving a separable 40 : 60 mixture of the 1,2-anti-1,6-anti-cyclic b-

amino ester 12 (>95% de) to the bis-b-amino ester 16 (>95% de),

in 26 and 44% isolated yields, respectively, after chromatography

(Scheme 2).

Scheme 3 Reagents and conditions: (i) lithium (R)-N-benzyl-N-a-

methylbenzylamide (7, 1.2 eq.), THF, −78 ^◦C; (ii) lithium (R)-N-

benzyl-N-a-methylbenzylamide (7, 10 eq.), THF, −78 ^◦C; (iii) lithium

(S)-N-benzyl-N-a-methylbenzylamide (7, 4 eq.), THF, −78 ^◦C.

Having shown that tandem conjugate addition–cyclisation al-

lows the effective stereoselective synthesis of six-membered car-

bocycles, the extension of this methodology for the preparation

of piperidine derivatives was investigated. It was envisaged that

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

1 2 8 5

View Article Online

lithium amide conjugate addition to a 2,7-dienoate containing a

protected nitrogen at C(5) and subsequent intramolecular cycli-

sation would proceed to give a functionalised piperidine skele-

ton. N-benzyl protection was initially chosen, as it was envisaged

that global N-deprotection of the b-amino piperidine product

could be realised by hydrogenolysis. The desired N-benzyl

protected dienoate for this protocol, methyl-(E,E)-4-(N-benzyl-

N-methoxycarbonylallylamino)-but-2-enoate 22, was prepared

by a simple two step procedure. Based upon a literature

protocol,¹³benzylamine (2 eq.) was added to a solution of methyl

4-bromocrotonate to give the known N-benzyl amino ester 21

in 76% yield. Subsequent treatment of 21 with excess methyl 4-

bromocrotonate in the presence of NEt₃gave the desired diester

22 in 60% yield (Scheme 4).

linear N-methyl and N-allyl protected diesters 28 and 29, and the

a-branched N-tert-butyl and the known (R)-N-a-methylbenzyl

protected diesters 30 and 31 were therefore prepared by standard

procedures (Scheme 6).

Scheme 4 Reagents and conditions: (i) BnNH₂(2 eq.), DCM, rt;

(ii) methyl 4-bromocrotonate (2 eq.), NEt₃, DCM, rt.

Addition of diester 22 to lithium amide (S)-7 (1.2 eq.) gave a

partially separable 89 : 11 mixture of two diastereoisomers 23

and 24 (78% de) in 76% overall yield. The relative conﬁguration

within both diastereoisomers 23 and 24 was elucidated through

Scheme 6 Reagents and conditions: (i) RNH₂(2 eq.), DCM, rt; (ii)

1

methyl 4-bromocrotonate (2 eq.), NEt(ⁱPr)₂, DCM, rt.

a combination of DQF-COSY, NOE difference and H NMR

coupling constant analysis, which were consistent with the

piperidine skeleton adopting a chairlike conformation, with the

N-alkyl group assumed to occupy an equatorial position.¹⁴The

absolute conﬁguration at C(3) within 23 and 24 was assigned

relative to the N-a-methylbenzyl stereocentre by analogy with

the model developed previously to explain the stereoselectivity

observed during conjugate addition of lithium amide 7 to

a,b-unsaturated acceptors, allowing the (3R,4S,5S,aS)- and

(3R,4S,5R,aS)-conﬁgurations within 23 and 24 to be derived

(Scheme 5).

Investigations initially focused upon the addition of N-methyl

and N-allyl diesters 28 and 29 to lithium amide (S)-7. Treatment

of N-methyl 28 with lithium amide (S)-7 (1.2 eq.) gave an

89 : 11 mixture of diastereoisomers 32 : 33 (78% de), with

chromatographic puriﬁcation allowing the isolation of 32 in

67% yield and 33 in 5% yield and in >98% de in each case.

Similarly, addition of N-allyl 29 to lithium amide (S)-7 (1.2

eq.) gave an 89 : 11 mixture of diastereoisomers 34 : 35, with

chromatographic puriﬁcation allowing the isolation of 34 in 81%

yield. Furthermore, treatment of N-tert-butyl 30 with lithium

amide (S)-7 (1.2 eq.) gave a 95 : 5 mixture of diastereoisomers 36 :

37 (90% de), giving 36 and 37 in 77 and 4% yields, respectively,

after puriﬁcation (Scheme 7).¹⁵

Scheme 5 Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-

methylbenzylamide (7, 1.2 eq.), THF, −78 ^◦C.

The stereoselectivity observed upon conjugate addition–

cyclisation of N-benzyl protected diester 22 is signiﬁcantly lower

than the selectivity (>95% de) observed in the analogous carbo-

cyclic analogue. Notably, the 89 : 11 mixture of diastereoisomers

23 and 24 (78% de) that are epimeric at C(5) is consistent with

the expected high stereocontrol upon lithium amide conjugate

addition, but incomplete stereocontrol in the C–C bond forming

cyclisation step of the reaction. The effect of changing the

nature of the N-protecting group within the diester upon the

stereoselectivity of the cyclisation reaction was next investigated,

with a range of diesters containing linear and a-branched N-

protecting groups used to probe this reaction manifold. The

Scheme 7 Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-

methylbenzylamide (7, 1.2 eq.), THF, −78 ^◦C.

1 2 8 6

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

View Article Online

Treatment of the homochiral branched (R)-N-a-methylbenzyl

protected diester 31 with lithium amide (S)-7 was next investi-

gated, giving a separable 93 : 7 mixture of diastereoisomers 38

and 39 (86% de), isolated in 65 and 4% yield, respectively. To

test if this level of stereoselectivity was a result of “matched”

double diastereoinduction operating in the reaction,¹⁶addition

of diester (R)-31 to the enantiomeric lithium amide (R)-7 was

evaluated, which also gave a 93 : 7 mixture of diastereoisomers

(86% de). Puriﬁcation yielded the major diastereoisomer 40

in 83% isolated yield and >98% de (Scheme 8). Analysis

of the product distributions arising from conjugate addition–

cyclisation of the N-containing diesters 22 and 28–31 indicate

that increased branching in the N-protecting group has a small

positive effect upon the stereoselectivity of the reaction. Notably

the linear N-methyl, N-allyl and N-benzyl protected dienoates

give an 89 : 11 mixture of diastereoisomers (78% de) upon

cyclisation, while the N-tert-butyl protected dienoate gives the

highest diastereoselectivity upon cyclisation, giving a 95 : 5

mixture of diastereoisomers (90% de).

Fig. 3 Proposed transition state models for conjugate addition–

cyclisation reactions.

reaction optimisation and prepared in three steps by a modiﬁed

literature procedure from d-valerolactone.^6bAddition of 41

to lithium amide (S)-7 (1.6 eq.) returned starting material,

although addition to an excess of lithium amide (S)-7 (2.4

eq.) gave the uncyclised b-amino-f-aldehyde ester (3S,aS)-42

in 69% isolated yield and in >98% de. Having shown that

conjugate addition to 41, but not cyclisation of the resultant

b-amino enolate was feasible at −78 ^◦C, the effect of raising

the reaction temperature to promote the cyclisation reaction

was investigated.¹⁹Addition of ester 41 to lithium amide (S)-7

◦

at −78 C and subsequent warming to −20 C gave a 27 : 73

mixture of b-amino ester 42 (>98% de) to the cyclic 1,2-syn-1,6-

anti-b-amino ester 43 (>98% de). Chromatographic puriﬁcation

allowed the isolation of (3S,aS)-42 in 23% yield, and the amino

alcohol (1R,2S,6S,aS)-43 in 31% yield and >98% de. The low

isolated yield of amino alcohol 43 was ascribed to decomposition

during chromatography, so in situ protection of the alcohol was

investigated. In this manner, acetylation of the crude reaction

product, followed by chromatography gave aldehyde 42 in 21%

yield (>98% de) and the 1,2-syn-1,6-anti-acetate (1R,2S,6S,aS)-

44 in 58% yield and >98% de (Scheme 9). An authentic sample

of acetate 44 was also prepared from the puriﬁed alcohol 43 in

94% yield. The (1R,2S,6S,aS) conﬁguration within both cyclic

b-amino esters 43 and 44 was assigned on the basis of NMR

spectroscopic analysis and NOE difference analysis relative to

the assumed sense of asymmetric induction at C(6) arising from

lithium amide conjugate addition.

Subsequent studies were concerned with the analogous cy-

clisation upon lithium amide addition to tert-butyl-(E)-6-oxo-

hex-2-enoate 45, which was prepared in three steps from c-

valerolactone. Addition of 45 to a solution of lithium amide (S)-7

(2.4 eq.) at −78 ^◦C gave a 57 : 43 mixture of b-amino-e-aldehyde

ester 46 and the 1,2-syn-1,5-anti-cyclic b-amino ester 47, with

puriﬁcation giving 46 in 54% yield (>98% de) and 47 in 18% yield

(>98% de). Warming the reaction to −20 ^◦C after initial addition

of 45 to lithium amide (S)-7 at −78 ^◦C gave a 9 : 91 mixture of 46 :

47, furnishing 46 in 7% yield (>98% de) and cyclic b-amino ester

47 in 66% yield (>98% de), with subsequent O-acetylation of 47

giving the 1,2-syn-1,5-anti-acetate 48 in 97% yield (Scheme 10).

The relative conﬁguration within 48 was conﬁrmed by NOE

Scheme 8 Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-

methylbenzylamide (7, 1.2 eq.), THF, −78 ^◦C.

The diastereoselectivity observed in the tandem conjugate

addition–cyclisation reactions of the 2,7-carbocyclic dienoates

8–11 and the analogous N-containing systems 22 and 28–

31 is consistent with the initially formed lithium (Z)-b-amino

enolate¹⁷arising from conjugate addition occupying a pseudo-

equatorial position in a chair-like transition state. Subsequent

intramolecular reaction with the tethered a,b-unsaturated sys-

tem preferentially in a pseudo-equatorial position gives the 1,2-

anti-1,6-anti arrangement (carbocyclic system) or 3,4-anti-4,5-

anti arrangement (piperidine system) of the major diastereoiso-

mer. The minor 3,4-anti-4,5-syn arrangement of the piperidine

diastereoisomer is presumably formed via the tethered a,b-

unsaturated system occupying a pseudo-axial position in the

transition state (Fig. 3).¹⁸

Conjugate addition and cyclisation onto e- and f-oxo-a,b-

unsaturated esters

To extend further the scope of this methodology, the lithium

amide promoted conjugate addition and cyclisation of e- and

f-oxo-a,b-unsaturated esters was investigated. tert-Butyl-(E)-

7-oxohept-2-enoate (41) was chosen as a model system for

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

1 2 8 7

View Article Online

Fig. 4 Proposed transition state for tandem cyclisation of ﬁve and six

membered aldehydes.

bocyclic b-amino esters 13 and 14 (>98% de) by hydrogenolysis

gave the corresponding amino esters 51 and 52 in >98% de

and in 96% yield in each case, with ester hydrolysis under basic

or acidic conditions, respectively, and subsequent puriﬁcation by

Dowex ion exchange chromatography, giving the b-amino diacid

53 (>98% de) in 74 and 71% yield, respectively (Scheme 11).

Scheme 9 Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-

methylbenzylamide (7, 2.4 eq.), THF, −78 ^◦C, 2 h; (ii) lithium

(S)-N-benzyl-N-a-methylbenzylamide (7, 2.4 eq.), THF, −78 ^◦C, 2 h

then −20 ^◦C, 2 h; (iii) Ac₂O, DMAP, pyridine, DCM, rt, 5 h.

difference analysis, with the absolute conﬁguration assumed

relative to the known sense of asymmetric induction at C(5)

arising from lithium amide addition.

Scheme 11 Reagents and conditions: (i) Pd(OH)₂/C, MeOH, H₂

(5 atm); (ii) LiOH, THF : H₂O, rt then DOWEX ion exchange

chromatography; (iii) TFA : DCM (1 : 1), rt then DOWEX ion exchange

chromatography.

The differential and global deprotection of the N-benzyl

and N-allyl protected piperidine b-amino esters 34 and 23 was

next investigated. The ability to deprotect selectively the N-allyl

functionality within b-amino ester 34 using palladium catalysis²⁰

allowed the selective unmasking of the piperidine nitrogen,

giving 54 in 93% yield and >98% de and >98% ee.²¹Global N-

deprotection of N-benzyl piperidine 23 was readily achieved by

hydrogenolysis, giving 55 in 92% yield (>98% de) (Scheme 12).

Further studies were directed toward deprotection and func-

tionalisation of the products arising from conjugate addition to

the e- and f-oxo-a,b-unsaturated esters. It was envisaged that

deprotection of both the uncyclised b-amino-e- or f-oxo esters

42 and 46 and cyclised b-amino ester products 43, 44, 47 and

48 arising from these reactions would furnish useful scaffolds

for incorporation into pseudopeptides. While b-amino-e- and

f-oxo esters 42 and 46 may be prepared selectively by conjugate

addition in reasonable yield at low temperature, an alternative,

selective synthesis of these products was investigated that would

prove amenable to large scale synthesis. Thus, addition of a,b-

unsaturated esters 56 and 57 to an excess of lithium amide (S)-7

gave the corresponding b-amino-e- and f-alcohols 58 and 59

in 79 and 82% yield and in >98% de, with Swern oxidation

giving the aldehydes 46 and 42 in 87 and 91% yield respectively.

Subsequent treatment of 46 and 42 with Pd(OH)₂on C under

H₂(5 atm) gave (S)-homoproline tert-butyl ester 60 and (S)-

homopipecolic acid tert-butyl ester 61 in 96 and 86% yield

respectively (Scheme 13).

Scheme 10 Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-

methylbenzylamide (7, 2.4 eq.), THF, −78 ^◦C, 2 h; (ii) lithium

(S)-N-benzyl-N-a-methylbenzylamide (7, 2.4 eq.), THF, −78 ^◦C, 2 h

then −20 ^◦C, 2 h; (iii) Ac₂O, pyridine, DMAP, DCM, rt.

With the relative 1,2-syn-1,6-anti- and 1,2-syn-1,5-anti-

conﬁguration of the cyclic products 43 and 47 elucidated,

possible transition states for their formation can be postulated.

Diastereoselective conjugate addition of lithium amide (S)-7 to

41 and 45 is assumed to generate the corresponding lithium (Z)-

b-amino enolates. Allowing lithium chelation between the eno-

late oxygen and remote aldehyde, the bicyclic transition states

49 and 50 are consistent with the observed stereoselectivity.

Minimization of 1,3-allylic strain predicts preferential alkylation

anti-to the C(3)-amino functionality of the b-amino enolate

in each case, with intramolecular aldol reaction proceeding

via either a chair (six ring) or envelope (ﬁve ring) transition

state. Assuming that the large C(3)-amino group occupies an

equatorial position within the transition state, the aldehyde

offers preferentially its Re face to nucleophilic attack (Fig. 4).

Deprotection reactions: asymmetric synthesis of

polyfunctionalised transpentacin and transhexacin derivatives

Having demonstrated that both tethered aldehyde and a,b-

unsaturated ester functional groups may participate in conjugate

addition–cyclisation reactions, deprotection of the polyfunc-

tionalised scaffolds was investigated. N-deprotection of the car-

Finally, deprotection of the cyclic b-amino esters 43, 44,

47 and 48 derived from tandem conjugate addition and in-

tramolecular aldol reaction was investigated. In the pentacin

1 2 8 8

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

View Article Online

Scheme 14 Reagents and conditions: (i) Pd(OH)₂/C, MeOH, H₂

(5 atm); (ii) TFA : DCM (1 : 1), rt then DOWEX ion exchange

chromatography.

Scheme 12 Reagents and conditions: (i) Pd(PPh₃)₄, 1,3-dimethylbarbi-

turic acid, DCM, rt; (ii) Pd(OH)₂on C, MeOH, H₂(5 atm).

of a range of natural products is under investigation in our

laboratory.

Experimental

General experimental

All reactions involving organometallic or other moisture-

sensitive reagents were performed under an atmosphere of dry

nitrogen using standard vacuum line techniques. All glassware

was ﬂame-dried and allowed to cool under vacuum. In all cases,

the reaction diastereoselectivity was assessed by peak integration

1

in the H NMR spectrum of the crude reaction mixture. THF

and Et₂O were distilled from sodium–benzophenone ketyl under

an atmosphere of dry nitrogen. DCM was distilled from CaH₂

under dry nitrogen, all other solvents were used as supplied

(analytical or HPLC grade) without prior puriﬁcation. n-

Butyllithium (BuLi) was used as a solution in hexane and

was titrated against diphenylacetic acid prior to use. DIBAL-

H was used as supplied (Aldrich), as a 1.0 M solution in

hexane. Allylamine was distilled from and stored over potassium

hydroxide pellets. All other reagents were used as supplied, with-

out further puriﬁcation. Unless otherwise stated, all aqueous

solutions were saturated, and all organic layers were dried with

MgSO₄. Column chromatography was performed on silica gel

(Kieselgel 60) or basic alumina. TLC was performed on Merck

plates, aluminium sheets coated with silica gel 60 F₂₅₄. Plates were

visualized either by UV light (254 nm), iodine, Dragendorff’s

reagent,²²ammonium molybdate (7% in 10% ethanolic sulfuric

acid) or 1% aqueous KMnO₄. Nuclear magnetic resonance

(NMR) spectra were recorded on Varian Gemini 200 (¹H:

200 MHz), Bruker AM-200 (¹H:200 MHz and ¹³C:50.3 MHz),

Bruker DPX-400 (¹H:400 MHz and ¹³C:100.6 MHz), or Bruker

AM-500 (¹H:500 MHz and ¹³C:125.78 MHz) spectrometers

in the deuterated solvents stated. All chemical shifts (d_H) are

reported in parts per million (ppm) and are referenced to the

residual solvent peak. Coupling constants (J) are measured in

Hz and are calculated using a ﬁrst order approximation. Carbon

chemical shifts (d_C) are quoted in ppm and are referenced

using residual solvent signals. Proton and carbon assignment

was performed with the aid of COSY and DQF-COSY to

Scheme 13 Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-

methylbenzylamide (7, 3.5 eq.), THF, −78 ^◦C; (ii) (COCl)₂, DMSO,

Et₃N, −78 ^◦C, 1 h, then rt, 30 min; (iii) Pd(OH)₂on C, MeOH, H₂

(5 atm).

series, N-deprotection of 47 and 48 by hydrogenolysis gave

the corresponding 2-hydroxy- or 2-acetoxy protected b-amino

esters 62 and 63, with subsequent ester hydrolysis and pu-

riﬁcation by Dowex ion exchange chromatography giving 2-

hydroxy-transpentacin 64 and 2-acetoxy-transpentacin 65 in

high yield and >98% de in each case. Similarly, in the hexacin

series, N-deprotection of 43 and 44 by hydrogenolysis gave the

corresponding b-amino esters 66 and 67 (>98% de) with ester

hydrolysis and Dowex ion exchange chromatography giving 2-

hydroxy-transhexacin 68 and 2-acetoxy-transhexacin 69 in high

yield and >98% de (Scheme 14). As enantiomerically pure

lithium (S)-N-benzyl-N-a-methylbenzylamide 7 was used to

initiate the formation of 43, 44, 47 and 48, and the subsequent

deprotection steps proceeded without epimerisation, an ee of

>98% was ascribed to the b-amino acids 64, 65, 68 and 69.

In conclusion, we have demonstrated that the conjugate addi-

tion of homochiral lithium amides and subsequent intramolecu-

lar cyclisation of the in situ-formed lithium (Z)-b-amino enolate

onto an a,b-unsaturated ester or aldehyde functionality gives

access to a range of polysubstituted carbocyclic transhexacin,

transpentacin and piperidine derivatives. The application of

this methodology to the synthesis of a range of scaffolds for

incorporation into pseudopeptides and for the total synthesis

1

establish the H–¹H coupling and APT, HMQC and HMBC

1

to establish the H–¹³C coupling. NOE spectra were obtained

on the Bruker DRX-500 (500 MHz) spectrometer. Infrared

spectra were recorded on a Perkin-Elmer 1750 IR Fourier

Transform spectrophotometer using either KBr disc (KBr) or

as thin ﬁlm (ﬁlm). Selected peaks are reported in cm⁻¹. Low

resolution mass spectra (m/z) were recorded on VG Masslab

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

1 2 8 9

View Article Online

20–250 or Micromass Platform 1 spectrometers and high-

resolution mass spectra (HRMS) on a Micromass Autospec 500

OAT spectrometer. Techniques used were chemical ionisation

(CI, NH₃), atmospheric pressure chemical ionisation (APCI)

using partial puriﬁcation by HPLC with methanol : acetonitrile

: water (40 : 40 : 20) as eluent or electrospray ionisation (ESI).

Major peaks are listed with intensities quoted as percentages of

the base peak. Optical rotations were recorded on a Perkin-

Elmer 241 polarimeter, using a path length of 10 cm, with

concentrations (c) given in g/100 mL solvent and temperature as

recorded. Values are quoted in units of 10⁻¹deg cm²g⁻¹. Melting

points were recorded on a Leica VMTG Galen III apparatus

and are uncorrected. Elemental analysis was performed by the

microanalysis service of the Inorganic Chemistry Laboratory,

Oxford.

via column chromatography on silica (1 : 5, Et₂O : pentane)

gave 8 as a clear oil (1.43 g, 54%) with spectroscopic properties

consistent with the literature;²³d_H(400 MHz, CDCl₃) 1.62–1.64

(2H, m, C(5)H₂), 2.24 (4H, dt, J_4,311.5, J_4,56.1, C(4)H₂and

C(6)H₂), 3.72 (6H, s, 2x CO₂CH₃), 5.85 (2H, dt, J_2,313.0, J_2,4

1.1, C(2)H and C(8)H), 6.95 (2H, td, J_3,213.0, J_3,46.1, C(3)H

and C(7)H).

Preparation of diethyl-(2E,7E)-2,7-nonadienedioate (9)

Following the general procedure 3, glutaraldehyde (40% w/w,

3.0 mL, 12.7 mmol), ethyl triphenylphosphoranylidene acetate

(6.30 mL, 31.8 mmol) and EtOH (5 mL) gave the crude reaction

product as a yellow oil. Puriﬁcation via column chromatography

on silica (1 : 5, Et₂O : pentane) gave 9 as a clear oil (678 mg, 81%)

with spectroscopic properties consistent with the literature;²⁴d_H

(400 MHz, CDCl₃) 1.29 (6H, t, J_{1 ,2}

m, C(5)H₂), 2.21 (4H, app q, J_4,3;4,56.6, C(4)H₂and C(6)H₂),

4.19 (4H, q, J_{2 ,1}7.1, 2x CH₂CH₃), 5.85 (2H, d, J_2,315.6, C(2)H

ꢀ

7.1, 2x CH₂CH₃), 1.64 (2H,

General procedure 1a (standard addition) and 1b (inverse

addition) for lithium amide reaction

ꢀ

n-BuLi was added dropwise to a stirred solution of secondary

amine in THF at −78 ^◦C under N₂atmosphere and the resulting

solution stirred for 30 min. Subsequently (a) a solution of the

a,b-unsaturated ester in THF at −78 ^◦C was added dropwise to

the lithium amide solution via cannula and stirred at −78 ^◦C for

2 h before addition of saturated aqueous NH₄Cl and warming

to rt or (b) the lithium amide solution was added dropwise

via cannula to a solution of the a,b-unsaturated ester in THF

at −78 ^◦C and stirred at −78 ^◦C for 2 h before addition

of saturated aqueous NH₄Cl and warming to rt. The crude

reaction mixture was partitioned between DCM and brine and

the organics concentrated in vacuo. This residue was partitioned

between DCM and 10% citric acid solution, organic layer

washed in succession with aqueous NaHCO₃solution and brine,

dried and concentrated in vacuo before puriﬁcation via column

chromatography.

and C(8)H), 6.92 (2H, dt, J_3,215.6, J_3,46.6, C(3)H and C(7)H).

Preparation of di-tert-butyl-(2E,7E)-2,7-nonadienedioate (10)

Following the general procedure 2, phosphorane (5.0 g, 13.3

mmol), glutaraldehyde (25% w/w, 5.0 mL, 53.2 mmol) and

THF (150 mL) were reacted to afford the crude product as a

colourless oil. Puriﬁcation via column chromatography on silica

(1 : 5, Et₂O : pentane) furnished 10 (2.57 g, 65%) as a white

solid; mp 61–63 ^◦C (Et₂O); v_max(ﬁlm) 1654, 1706; d_H(400 MHz,

CDCl₃) 1.48 (18H, s, 2x C(CH₃)₃), 1.61–1.63 (2H, m, C(5)H₂),

2.30–2.33 (4H, m, C(4)H₂and C(6)H₂), 5.76 (2H, d, J_2,315.6,

C(2)H and C(8)H), 6.83 (2H, dt, J_3,215.5, J_3,46.9, C(3)H and

C(7)H); d_C(100 MHz, CDCl₃), 28.1 2x(C(CH₃)₃), 29.7 (C(5)H₂),

30.3 (C(4)H₂and C(6)H₂), 80.2 2x(C(CH₃)₃), 123.8 (C(2)H and

C(8)H), 145.8 (C(3)H and C(7)H), 165.8 2x(CO); m/z (CI⁺)

300.2333 (C₁₇H₃₂NO₄⁺. Requires 300.2331); 300 (MNH₄⁺, 27%),

244 (72).

General procedure 2

Phosphorus ylide was added portion-wise to a stirred solution of

the aldehyde in DCM at rt and left stirring for 16 h. The resultant

solution was then diluted with DCM, dried and concentrated in

vacuo before puriﬁcation via column chromatography.

Preparation of methyl-(1S,2S,6S,aS)-2-N-benzyl-N-a-

methylbenzylamino-6-(methyloxycarbonylmethyl)-

cyclohexanecarboxylate (12)

Following the general procedure 1a, n-BuLi (1.6 M, 2.0 mL,

3.22 mmol), (S)-N-benzyl-N-a-methylbenzylamine (0.70 mL,

3.34 mmol) in THF (8 mL) and diester 8 (0.48 g, 2.0 mmol)

in THF (5 mL) gave the crude reaction product as a red oil.

Puriﬁcation via column chromatography on silica (1 : 4, Et₂O :

pentane) gave 12 (0.65 g, 72%) as a clear oil; [a]²_D⁴−4.1 (c 1.00,

CHCl₃); v_max(ﬁlm) 2974, 1738, 1435, 1028; d_H(400 MHz, CDCl₃)

0.80–0.92 (1H, m, C(4)H_AH_B), 1.20–1.30 (1H, m, C(3)H_AH_B),

1.36 (3H, d, J 6.9, C(a)CH₃), 1.25–1.40 (1H, m, C(5)H_AH_B),

1.60–1.70 (1H, m, C(4)H_AH_B), 1.68–1.80 (1H, m, C(3)H_AH_B),

1.92–2.05 (3H, m, C(5)H_AH_B, C(6)H and CH_AH_BCO₂), 2.10–

2.18 (1H, m, CH_AH_BCO₂), 2.29 (1H, dd, J_1,29.8, J_1,69.2,

C(1)H), 3.02 (1H, td, J_1,2;1,69.8, J_1,63.6, C(2)H), 3.40, 3.59

(3H, s, 2x CO₂CH₃), 3.72 (1H, AB d, J_A,B12.8, CH_AH_BPh), 3.82

(1H, AB d, J_A,B12.8, CH_AH_BPh), 3.96 (1H, q, J 6.9, C(a)H),

7.13–7.32 (10H, m, 2x o/m/p-Ph); d_C(100 MHz, CDCl₃) 16.1

(C(a)CH₃), 24.5 (C(3)H₂), 28.5 (C(5)H₂), 30.1 (C(4)H₂), 37.3

(C(6)H₂), 39.4 (C(6)CH₂), 49.9 (CH₂Ph), 51.2 (CO₂CH₃), 51.4

General Procedure 3

The requisite phosphonoacetate was added dropwise to a

solution of glutaraldehyde followed by 6.5 M aqueous K₂CO₃

solution (5 eq.). The reaction mixture was stirred at rt for 16 h

and then extracted with ether. The combined organic extracts

were washed with brine, dried, ﬁltered and concentrated in vacuo

before puriﬁcation via column chromatography.

General Procedure 4

Pd(OH)₂/C was added to a solution of substrate in degassed

MeOH and the resultant suspension stirred under hydrogen (5

atm) for 16 h. The reaction mixture was then ﬁltered through

R

celite^ꢀ(eluent MeOH), concentrated in vacuo, and the residue

puriﬁed via column chromatography on activated basic alumina.

General Procedure 5

ꢀ

(CO₂CH₃), 54.5 (C(1)H), 56.8 (C(a)H), 58.6 (C(2)H), 126.4,

A 1 : 1 mixture of TFA–DCM solution was added dropwise

to the requisite substrate at 0 ^◦C. Solution was then vigorously

stirred for 16 h at rt, after which the mixture was concentrated

in vacuo, and puriﬁed via ion-exchange chromatography.

126.7, 127.7, 127.9, 129.1 2x(o/m/p-Ph), 140.6, 144.1 (i-Ph),

172.4 (CH₂CO₂), 174.1 (C(1)CO₂); m/z (CI⁺) 424.2490 (MH⁺,

C₂₆H₃₄NO₄requires 424.2488); 423 (M⁺, 7), 250 (25), 146 (30),

105 (90), 91 (100), 79 (25).

Preparation of dimethyl-(2E,7E)-2,7-nonadienedioate (8)

Preparation of ethyl-(1S,2S,6S,aS)-2-N-benzyl-N-a-

methylbenzylamino-6-(ethyloxycarbonylmethyl)-

cyclohexanecarboxylate (13)

Following the general procedure 3, glutaraldehyde (40% w/w,

3.0 mL, 12.7 mmol), methyl triphenylphosphoranylidene acetate

(6.75 g, 31.9 mmol) and K₂CO₃solution (5 M, 12.8 mL, 64.0

mmol) gave the crude reaction product as yellow oil. Puriﬁcation

Following the general procedure 1a, n-BuLi (1.6 M in hex-

ane, 1.0 mL, 1.61 mmol), (S)-N-benzyl-N-a-methylbenzylamine

1 2 9 0

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

View Article Online

ꢀ

(0.35 mL, 1.67 mmol) in THF (5 mL) and diester 9 (0.25 g,

1.0 mmol) in THF (5 mL) gave the crude reaction product as a

red oil. Puriﬁcation via column chromatography on silica (1 :

4, Et₂O : pentane) gave 13 (0.49 g, 82%) as a red oil; [a]_D²⁴

−5.1 (c 1.00, CHCl₃); (Found: C, 74.3; H, 8.2; N, 3.2. Calc.

for C₂₈H₃₇NO₄: C, 73.4; H, 8.2; N, 3.2%); v_max(ﬁlm) 1730,

1736, 2859, 2978; d_H(400 MHz, CDCl₃) 0.84–0.97 (1H, m,

J_{1 ,2}6.2, 2x CH(CH₂CH₃)₂), 7.15–7.40 (10H, m, 2x o/m/p-

ꢀ

Ph); d_C(100 MHz, CDCl₃) 9.4, 9.5 2x (CH(CH₂CH₃)₂), 19.5

(C(a)CH₃), 24.6 (C(3)H₂), 25.2, 25.3, 26.4 2x(CH(CH₂CH₃)₂),

28.1 (C(5)H₂), 30.9 (C(4)H₂), 38.0 (C(6)H), 39.7 (C(6)CH₂), 49.7

(CH₂Ph), 54.7 (C(1)H), 60.4 (C(a)H), 60.9 (C(2)H), 76.6, 76.9

2x(CH(CH₂CH₃)₂), 126.5, 126.6, 127.6, 127.8, 129.1 2x(o/m/p-

Ph), 141.6, 144.4 2x(i-Ph), 171.6, 174.2 2x(CO₂); m/z (CI⁺)

536.3724 (MH⁺, C₃₄H₅₀NO₄requires 536.3740); 539 (12%), 538

(68), 536 ((MH)⁺, 100);

C(5)H_AH_B), 1.15 (3H, t, J_{1 ,2}

ꢀ

7.0, CH₂CH₃), 1.21 (3H, t, J_{1 ,2}

ꢀ

7.0, CH₂CH₃), 1.21–1.40 (2H, m, C(5)H_AH_Band C(3)H_AH_B),

1.39 (3H, d, J 6.9, C(a)CH₃), 1.70–1.81 (2H, m, C(4)H₂), 1.90–

2.06 (3H, m, C(3)H_AH_B, C(6)H and C(6)CH_AH_B), 2.15–2.22

(1H, m, C(6)CH_AH_B), 2.25 (1H, app t, J_1,2;1,69.5, C(1)H), 3.08–

3.10 (1H, m, C(2)H), 3.70 (1H, AB d, J_A,B12.9, CH_AH_BPh),

3.89 (1H, AB d, J 12.9, CH_AH_BPh), 3.89–3.91 (1H, m, C(a)H),

Preparation of dimethyl-(3R,aR,7R,a^ꢀR)-3,7-bis-N-benzyl-N-a-

methylbenzylamino-nonadioate (16)

Following the general procedure 1b, (R)-N-benzyl-N-a-

methylbenzylamine (1.2 g, 5.5 mmol) in THF (10 mL), n-BuLi

(3.4 mL, 5.4 mmol) and diene 8 (98 mg, 0.46 mmol) in THF

(1 mL) gave, after puriﬁcation via column chromatography

on silica (1 : 24, EtOAc : pentane), 12 (50 mg, 26%) as

a colourless oil; [a]²_D⁶+3.9 (c 1.86 CHCl₃); Further elution

furnished diester 16 (128 mg, 44%) as a colourless oil; [a]²_D⁶+7.5

(c 2.00, CHCl₃); v_max(ﬁlm) 702, 1152, 1204, 1377, 1452, 1738,

2949; d_H(400 MHz, CDCl₃): 1.21–1.32 (2H, m, C(5)H₂), 1.36

(6H, d, J 7.0, C(a)CH₃), 1.45–1.65 (4H, m, C(4)H₂and C(6)H₂),

2.02 (2H, dd, J_A,B14.6, J_2,38.2, C(2)H_AH_Band C(8)H_AH_B), 2.08

(2H, dd, J_B,A14.6, J_2,34.8, C(2)H_AH_Band C(8)H_AH_B), 3.34–

3.38 (2H, m, C(3)H and C(7)H), 3.54 (6H, s, 2x CO₂CH₃),

3.57 (2H, AB d, J_A,B14.8, CH_AH_BPh), 3.78 (2H, AB d, J_A,B

14.8, CH_AH_BPh), 3.86 (2H, q, J 7.0, C(a)H), 7.21–7.42 (20H,

m, 4x o/m/p-Ph); d_C(50 MHz, CDCl₃) 19.9 (C(a)CH₃), 24.9

(C(5)H₂), 34.1 (C(4)H₂and C(6)H₂), 36.8 (C(2)H₂and C(8)H₂),

50.2 (CH₂Ph), 51.0 2x(CO₂CH₃), 54.7 (C(3)H and C(7)H), 58.2

(C(a)H), 126.6, 126.9, 128.0, 128.1, 128.3 4x(o/m/p-Ph), 141.7,

143.6 4x(i-Ph), 173.1 2x(CO₂Me); m/z (EI⁺) 635.3862 (MH⁺,

ꢀ

3.95–4.13 (4H, m, CH₂CH₃and CH₂CH₃), 7.13–7.50 (10H, m,

2x o/m/p-Ph); d_C(100 MHz, CDCl₃) 14.0, 14.2 2x(CH₂CH₃),

16.6 (C(a)CH₃), 24.6 (C(4)H₂), 28.4 (C(5)H₂), 30.9 (C(6)H₂),

37.5 (C(3)H), 39.5 (C(6)CH₂), 50.0 (CH₂Ph), 54.4, 57.1, 59.0

(C(1)H, C(2)H, C(a)H), 60.1, 60.2 2x(CH₂CH₃) 126.4, 126.7,

127.7, 128.0, 129.2 2x(o/m/p-Ph), 140.8, 144.2 2x(i-Ph), 172.1,

174.0 2x(CO₂); m/z (CI⁺) 452.2807 (MH⁺, C₃₄H₃₈NO₄requires

452.2801); 455 (12%), 454 (21), 452 ((MH)⁺, 100), 348 (12).

Preparation of tert-butyl-(1S,2S,6S,aS)-2-N-benzyl-N-a-

methylbenzylamino-6-(tert-butyloxycarbonylmethyl)-

cyclohexanecarboxylate (14)

Following the general procedure 1a, n-BuLi (2.5 M, 1.11 mL,

2.77 mmol), (S)-N-benzyl-N-a-methylbenzylamine (0.60 mL,

2.86 mmol) in THF (10 mL) and diester 10 (0.50 g, 1.79 mmol)

in THF (8 mL) gave the crude reaction product. Puriﬁcation via

column chromatography on silica (1 : 10, EtOAc : pentane)

furnished 14 (710 mg, 78%) as a clear oil; [a]²_D⁴−4.5 (c

1.35, CHCl₃); v_max(ﬁlm) 1602, 1727, 2933, 2976, 3062; d_H

(400 MHz, CDCl₃) 0.90 (1H, app q, J_5,4;5,69.5, C(5)H_AH_B),

1.21–1.24 (1H, m, C(4)H_AH_B), 1.39 (3H, d, J 6.9, C(a)CH₃),

C₄₁H₅₁O₄N₂requires 635.3849); 635 ((MH)⁺, 100%), 561 (8),

+

424 (12).

ꢀ

1.41 (9H, s, C(CH₃)₃), 1.48 (9H, s, C(CH₃)₃), 1.45–1.50 (1H,

Preparation of di-3-pentyl-(3R,aR,8E)-3-N-benzyl-N-a-

m, C(6)CH_AH_B), 1.61–1.72 (2H, m, C(5)H_AH_B, C(6)CH_AH_B),

1.72–1.79 (1H, m, C(4)H_AH_B), 1.84–1.93 (2H, m, C(3)H_AH_B,

C(6)H), 2.10 (1H, app t, J_1,2;1,68.7, C(1)H), 2.23 (1H, app q,

J_3,4;3,56.5, C(3)H_AH_B), 3.06 (1H, dt, J_2,18.7, J_2,33.1, C(2)H),

3.71 (1H, AB d, J_A,B13.3, CH_AH_BPh), 3.78 (1H, AB d, J_A,B

13.3, CH_AH_BPh), 3.81 (1H, q, J 6.9, C(a)H), 7.13–7.39 (10H,

m, 2x o/m/p-Ph); d_C(125 MHz, CDCl₃) 21.0 (C(a)CH₃), 25.1

(C(4)H₂), 28.3, 28.6 2x(C(CH₃)₃), 29.1 (C(5)H₂), 30.9 (C(3)H₂),

38.8 (C(6)H), 40.8 (C(6)CH₂), 50.1 (CH₂Ph), 55.4 (C(1)H), 58.7

(C(a)H), 60.9 (C(2)H), 80.6, 80.7 2x (C(CH₃)₃), 126.9, 128.2

2x(p-Ph), 128.4, 128.5, 128.9, 129.2, 129.5 2x(o/m-Ph), 141.9,

144.8 2x(i-Ph), 172.0, 174.3 2x(CO₂); m/z (CI⁺) 508.3413 (MH⁺,

methylbenzylamino-dec-8-enedioate (18)

Following the general procedure 1b, (R)-N-benzyl-N-a-

methylbenzylamine (352 mg, 1.7 mmol) in THF (15 mL), n-

BuLi (0.9 mL, 1.4 mmol) and diene 17 (430 mg, 1.27 mmol) in

THF (2 mL), gave after chromatographic puriﬁcation on silica

(1 : 49, EtOAc : pentane), 18 (295 mg, 42%) as a colourless

oil; [a]²_D⁶+6.2 (c 2.62, CHCl₃); v_max(ﬁlm) 700, 1460, 1500, 1640,

1714, 3000–2800; d_H(400 MHz, CDCl₃) 0.81 (6H, t, J_{3 ,2}

ꢀ

7.4,

7.4, CH(CH₂CH₃)₂), 1.33

ꢀ

CH(CH₂CH₃)₂), 0.85 (6H, t, J_{3 ,2}

ꢀ

(3H, d, J 7.0, C(a)CH₃), 1.48–1.52 (8H, m, 2x CH(CH₂CH₃)₂),

1.60 (6H, m, C(4)H₂and C(5)H₂and C(6)H₂), 1.96 (1H, dd,

J_2,214.6, J_2,33.0, C(2)H_AH_B), 2.04 (1H, dd, J_2,214.6, J_2,36.0,

C(2)H_AH_B), 2.17 (2H, app q, J 6.9, C(7)H₂), 3.31–3.35 (1H,

m, C(3)H), 3.50 (1H, AB d, J 15.0, CH_AH_BPh), 3.81 (1H,

AB d, J 15.0, CH_AH_B), 3.81 (1H, q, J 7.0, C(a)H), 4.67

C₃₂H₄₆NO₄requires 508.3427); (EI⁺) 530 (21%), 508 ((MH)⁺,

+

100).

Preparation of 3-pentyl-(1S,2S,6S,aS)-2-N-benzyl-N-a-

methylbenzylamino-6-(pent-3-yloxycarbonylmethyl)-

cyclohexanecarboxylate (15)

(1H, quin, J_{1 ,2}

ꢀ

6.8, CH(CH₂CH₃)₂), 4.82 (1H, quin, J_{1 ,2}6.8,

ꢀ

CH(CH₂CH₃)₂), 5.81 (1H, d, J_9,815.6, C(9)H), 6.95 (1H, dt,

J_8,915.6, J_8,76.9, C(8)H), 7.22–7.43 (10H, m, 2x o/m/p-Ph);

d_C(50 MHz, CDCl₃) 9.5 (CH(CH₂CH₃)₂), 20.7 (C(a)CH₃), 26.3

(C(4)H₂), 26.5 2x(CH(CH₂CH₃)₂), 27.8 (C(5)H₂), 32.1 (C(6)H₂),

33.4 (C(7)H₂), 36.6 (C(2)H₂), 50.2 (CH₂Ph), 53.9 (C(3)H), 58.6

(C(a)H), 76.4 2x(CH(CH₂CH₃)₂), 121.7 (C(9)H), 126.6, 126.9,

127.8, 128.0, 128.2 2x(o/m/p-Ph), 141.9, 143.2 2x(i-Ph), 148.8

(C(8)H), 166.6, 172.6 2x(CO₂); m/z (EI⁺) 549.3837 (MH⁺,

C₃₅H₅₁O₄N⁺requires 549.3818); (CI⁺) 549 ((MH)⁺. 60%), 420

(12), 352 (30), 262 (35), 181 (70), 105 (100).

Following the general procedure 1a, (S)-N-benzyl-N-a-

methylbenzylamine (239 mg, 2.1 mmol) in THF (10 mL), n-BuLi

(1.25 mL, 2.0 mmol) and diene 11 (219 mg, 0.67 mmol) in THF (2

mL) gave, after puriﬁcation via column chromatography on silica

(1 : 24, EtOAc : pentane), 15 (303 mg, 84%) as a colourless oil;

[a]²_D⁶−2.5 (c 1.35, CHCl₃); v_max(ﬁlm) 750, 912, 1030, 1260, 1465,

1732, 2971; d_H(400 MHz, CDCl₃) 0.75–0.82 (1H, m, C(4)H_AH_B),

0.83 (6H, t, J_{3 ,2}

ꢀ

7.4, CH(CH₂CH₃)₂), 0.91 (3H, t, J_{3 ,2}

ꢀ

7.4,

CH(CH₂CH₃)), 0.93 (3H, t, J_{3 ,2}

ꢀ

7.4, CH(CH₂CH₃)^ꢀ), 1.12–1.30

(2H, m, C(3)H_AH_Band C(5)H_AH_B) 1.32 (3H, d, J 6.9, C(a)CH₃),

1.45–1.75 (11H, m, C(3)H_AH_B, C(4)H_AH_B, C(5)H_AH_Band 2x

CH(CH₂CH₃)₂), 1.92–2.08 (2H, m, C(6)H and C(6)H_AH_B),

2.14 (1H, app t, J_1,2;1,610.6, C(1)H), 2.27 (1H, d, J_B,A11.8,

C(6)H_AH_B), 3.16 (1H, td, J_2,1;2,310.6, J_2,33.3, C(2)H), 3.74

(2H, s, CH₂Ph), 4.04 (1H, q, J 6.9, C(a)H), 4.68, 4.69 (1H, quin,

Preparation of di-3-pentyl-(3R,aR,8R,a^ꢀR)-3,8-bis-N-benzyl-N-

a-methylbenzylamino-decadioate (19)

Following the general procedure 1a, (R)-N-benzyl-N-a-

methylbenzylamine (1.81 g, 8.6 mmol) in THF (20 mL), n-BuLi

(5.3 mL, 8.6 mmol) and diester 17 (290 mg, 0.86 mmol) in

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

1 2 9 1

View Article Online

THF (1 mL) gave, after chromatographic puriﬁcation on silica

(1 : 19, EtOAc : pentane), 19 (427 mg, 67%) as a colourless

oil; [a]²_D⁶+7.1 (c 0.86, CHCl₃); v_max(ﬁlm) 903, 964, 1460, 1493,

with spectroscopic properties consistent with the literature;²⁶d_H

(400 MHz, CDCl₃) 3.24–3.26 (4H, m, 2x C(4)H₂), 3.61 (2H, s,

CH₂Ph), 3.75 (6H, s, 2x CO₂CH₃), 6.06 (2H, d, J_2,315.7, 2x

C(2)H), 6.95 (2H, dt, J_3,215.7, J_3,45.8, C(3)H), 7.30–7.40 (5H,

m, o/m/p-Ph).

1726, 1807, 1948, 1975, 2971; d_H(400 MHz, CDCl₃) 0.82 (6H, t,

ꢀ

J_{3 ,2}

ꢀ

7.4, CH(CH₂CH₃)₂), 0.86 (6H, t, J_{3 ,2}

ꢀ

7.4, CH(CH₂CH₃)₂),

1.20–1.30 (4H, m, C(5)H₂and C(6)H₂), 1.33 (6H, d, J 7.0, 2x

C(a)CH₃), 1.42–1.75 (12H, m, 2x CH(CH₂CH₃)₂, C(4)H₂and

C(7)H₂), 1.97 (4H, m, C(2)H₂and C(9)H₂), 3.35–3.38 (2H, m,

C(3)H and C(8)H), 3.49 (2H, AB d, J 15.0, CH_AH_BPh), 3.81

(2H, AB d, J 15.0, CH_AH_BPh), 3.82 (2H, q, J 7.0, 2x C(a)H),

Preparation of (3R,4R,5S,aS)- and (3R.4R,5R,aS)-1-benzyl-3-

(N-benzyl-N-a-methylbenzylamino)-4-methoxycarbonyl-5-

methoxycarbonylmethyl-piperidine (23 and 24)

Following the general procedure 1a, n-BuLi (2.5 M, 0.3 mL,

0.76 mmol), (S)-N-benzyl-N-a-methylbenzylamine (170 mg,

0.80 mmol) in THF (3 mL) and diene 22 (200 mg, 0.67 mmol) in

THF (5 mL) gave, after puriﬁcation via column chromatography

on silica (1 : 3, Et₂O : pentane), a partially separable mixture of

diastereoisomers (261 mg, 76% overall). The least polar fraction

gave piperidine 24 (15 mg, 5%) as a colourless oil; [a]²_D³+14.5 (c

0.75, CHCl₃); v_max(ﬁlm) 2948, 1737, 1170; d_H(400 MHz, CDCl₃)

1.33 (3H, d, J 6.9, C(a)CH₃), 1.97 (1H, br d, C(6)H_ax), 2.05 (1H,

t, J_2,1;2,310.7, C(2)H_ax), 2.49–2.67 (5H, m, C(4)H_ax, C(5)H_eq,

C(6)H_eq, and C(1^ꢀ)H₂), 2.95–2.96 (1H, m, C(2)H_eq), 3.35–3.49

(3H, m, C(3)H and CH₂Ph^ꢀ), 3.50, 3.55 (3H, s, 2x CO₂CH₃),

3.67 (1H, AB d, J_A,B14.5, CH_AH_BPh), 3.78 (1H, AB d, J_A,B

14.5, CH_AH_BPh), 4.05 (1H, q, J 6.9, C(a)H), 7.16–7.34 (15H,

m, 3x o/m/p-Ph); d_C(100 MHz, CDCl₃) 18.4 (C(a)CH₃), 33.0

(C(1^ꢀ)H₂), 33.4 (C(5)H), 49.4 (C(4)H), 49.5 (CH₂Ph), 51.2, 51.4

2x(CO₂CH₃), 53.9 (C(3)H), 55.6 (C(2)H₂), 57.2, (C(6)H₂), 58.7

(C(a)H), 62.6 (CH₂Ph^ꢀ), 126.5, 126.6, 126.9, 127.1, 127.7, 127.8,

128.0, 128.1, 128.2, 128.4, 128.6 3x(o/m/p-Ph), 138.6, 141.0,

144.2 3x(i-Ph), 173.4, 173.6 2x(CO₂); m/z (CI⁺) 527 (5%), 515

((MH)⁺, 100).

4.69 (2H, quin, J_{1 ,2}6.7, 2x CH(CH₂CH₃)₂), 7.23–7.46 (20H, m,

ꢀ

4x o/m/p-Ph); d_C(50 MHz, CDCl₃) 9.6 (CH(CH₂CH₃)₂), 20.4

(C(a)CH₃), 26.4 (CH(CH₂CH₃)₂), 27.4 (C(5)H₂and C(6)H₂),

33.9 (C(4)H₂and C(7)H₂), 37.0 (C(2)H₂and C(9)H₂), 50.2

2x(CH₂Ph), 54.3 (C(3)H and C(8)H), 58.4 2x(C(a)H), 76.4

2x(CH(CH₂CH₃)₂), 126.6, 126.9. 127.9, 128.2 4x(o/m/p-Ph),

141.9, 143.2 4x(i-Ph), 172.6 2x(CO₂); m/z (EI⁺) 761.5251 (MH⁺,

C₅₀H₆₉O₄N₂requires 761.5257); 762 ((MH₂)⁺, 100%), 747 (6),

+

631 (8).

Preparation of di-3-pentyl-(3R,aR,8S,a^ꢀS)-3,8-bis-N-benzyl-N-

a-methylbenzylamino-decadioate (20)

Following the general procedure 1a, (S)-N-benzyl-N-a-

methylbenzylamine (127 mg, 0.6 mmol) in THF (5 mL), n-

BuLi (0.4 mL, 0.6 mmol) and diester 17 (82 mg, 0.4 mmol) in

THF (1 mL) gave, after chromatographic puriﬁcation on silica

(1 : 49, EtOAc : pentane), 20 (82 mg, 71%) as a colourless

oil; [a]²_D⁶−0.3 (c 0.86, CHCl₃); v_max(ﬁlm) 903, 964, 1460,

1493, 1726, 1807, 1948, 1975, 2971, 3020, 3060, 3080; d_H

(200 MHz, CDCl₃) 0.80 (6H, t, J_{3 ,2}

ꢀ

7.4, CH(CH₂CH₃)₂), 0.87

Further elution furnished the major piperidine diastereoiso-

mer 23 (210 mg, 61%) as a colourless oil; [a]²_D³+11.0 (c 1.00,

CHCl₃); v_max(ﬁlm) 1737, 1159; d_H(400 MHz, CDCl₃) 1.24 (3H,

d, J 6.9, C(a)CH₃), 1.73 (1H, m, C(6)H_ax), 1.99 (1H, app t,

J_{2ax,2eq;2ax,3ax}10.8, C(2)H_ax), 2.07 (1H, dd, J_A,B15.7, J_A,58.3,

C(1^ꢀ)H_AH_B), 2.21 (1H, dd, J_B,A15.7, J_B,52.9, C(1^ꢀ)H_AH_B), 2.33–

2.38 (2H, m, C(4)H_axand C(5)H_ax), 2.93 (1H, ddd, J_6eq,6ax11.3,

(6H, t, J_{3 ,2}7.4, CH(CH₂CH₃)₂), 1.20–1.30 (4H, m, C(5)H₂

ꢀ

and C(6)H₂), 1.33 (6H, d, J 7.0, 2x C(a)CH₃), 1.42–1.75 (8H,

m, 2x CH(CH₂CH₃)₂), C(4)H₂and C(7)H₂), 1.97 (4H, m,

C(2)H₂and C(9)H₂), 3.30–3.43 (2H, m, C(3)H and C(8)H),

3.49 (2H, AB d, J 15.0, CH_AH_BPh), 3.81 (2H, AB d, J 15.0,

CH_AH_BPh), 3.82 (2H, q, J 7.0, 2x C(a)H), 4.69 (2H, quin,

J_{1 ,2}6.7, 2x CH(CH₂CH₃)₂), 7.23–7.46 (20H, m, 4x o/m/p-

ꢀ

J

_6eq,5ax3.4, J_6eq,2eq1.4, C(6)H_eq), 3.10 (1H, ddd, J_2eq,2ax10.8, J_2eq,3ax

Ph); d_C(50 MHz, CDCl₃) 9.5 (CH(CH₂CH₃)₂), 20.4 (C(a)CH₃),

26.3 (CH(CH₂CH₃)₂), 27.3 (C(5)H₂and C(6)H₂), 33.7 (C(4)H₂

and C(7)H₂), 37.0 (C(2)H₂and C(9)H₂), 50.2 (CH₂Ph), 54.2

(C(3)H and C(8)H), 58.3 (C(a)H), 76.4 (CH(CH₂CH₃)₂), 126.5,

126.7, 127.9, 128.2 4x(o/m/p-Ph), 141.9, 143.1 4x(i-Ph), 172.6

2.6, J_2eq,6eq1.4, C(2)H_eq), 3.26–3.30 (1H, m, C(3)H_ax), 3.42–3.45

(4H, m, CO₂CH₃and CH_AH_BPh^ꢀ), 3.57–3.60 (4H, m, CO₂CH₃

and CH_AH_BPh^ꢀ), 3.66 (1H, AB d, J 13.5, CH_AH_BPh), 3.88

(1H, AB d, J 13.5, CH_AH_BPh), 3.95 (1H, q, J 6.9, C(a)H),

7.18–7.40 (15H, m, 3x o/m/p-Ph); d_C(100 MHz, CDCl₃) 15.9

(C(a)CH₃), 35.8 (C(5)H), 36.8 (C(1^ꢀ)H₂), 50.0 (CH₂Ph), 51.4,

51.5 2x(CO₂CH₃), 52.8 (C(4)H), 56.6, 56.7 (C(3)H and C(a)H),

55.0, 58.2, 62.5 (C(2)H₂, C(6)H₂and CH₂Ph^ꢀ), 126.5, 126.8,

127.1, 127.8, 128.0, 128.3, 129.1 3x(o/m/p-Ph), 138.3, 140.4,

143.7 3x(i-Ph), 172.0, 173.6 2x(CO₂); m/z (CI⁺) 515.2912 (MH⁺,

2x(CO₂); m/z (EI⁺) 761.5252 (MH⁺, C₅₀H₆₉O₄N₂requires

+

761.5257); 762 ((MH₂)⁺, 100%), 550 (5).

Preparation of (E)-methyl-4-(N-benzylamino)-but-2-enoate (21)

Benzylamine (4.28 g, 40.0 mmol) was added dropwise to a stirred

solution of methyl 4-bromocrotonate (3.07 g, 20.0 mmol) and

stirred at rt under nitrogen for 3 h before being washed with

aqueous saturated NaHCO₃solution. The resultant solution

was extracted with DCM, dried and concentrated in vacuo and

the residue puriﬁed via column chromatography on silica (1 : 4,

Et₂O : pentane) to give the 21 (3.10 g, 76%) as a colourless oil

with spectroscopic properties consistent with the literature; d_H

(200 MHz, CDCl₃) 1.44 (1H, br s, NH), 3.44 (2H, dd, J_4,35.4,

J_4,21.8, C(4)H₂), 3.75 (3H, s, CO₂CH₃), 3.82 (2H, s, CH₂Ph),

6.05 (1H, dt, J_2,315.7, J_2,41.8, C(2)H), 7.04 (1H, dt, J_3,215.7,

J_3,45.4, C(3)H), 7.24–7.35 (5H, m, o/m/p-Ph).²⁵

C₃₂H₃₈N₂O₄requires 515.2910); 537 (10%), 515 ((MH)⁺, 100).

+

Preparation of methyl-(E)-4-allylamino-but-2-enoate (25)

Methyl 4-bromocrotonate (9.6 mL, 70 mmol) was added to a

solution of allylamine (4.68 mL, 63.0 mmol) in DCM (50 mL)

at 0 ^◦C, followed by NEt₃(10.0 mL, 71.5 mmol) and stirred

overnight before the addition of saturated aqueous K₂CO₃

solution. The resultant solution was extracted with DCM,

dried and concentrated in vacuo. After puriﬁcation via column

chromatography (1 : 5, Et₂O : pentane) on silica, the more

polar mono-ester 25 (3.71 g, 38%) was isolated as an orange

oil; (Found C, 62.3; H, 8.7; N, 8.8. Calc. for C₈H₁₃NO₂:

C, 61.9; H, 8.4; N, 9.0%); v_max(ﬁlm) 1659, 1724, 3311; d_H

(400 MHz, CDCl₃) 3.25 (2H, d, J 8.7, NCH_2−allyl), 3.41 (2H,

dd, J_4,35.4, J_4,21.7, C(4)H₂), 3.74 (3H, CO₂CH₃), 5.11 (1H,

dd, J 14.5, 1.2, CHCH_cisH_{trans−allyl}), 5.19 (1H, dd, J 14.5, 1.5,

C(3)H_cisH_{trans−allyl}), 5.81–5.92 (1H, m, NCH₂CH_allyl), 6.00 (1H,

dd, J_2,314.4, J_2,41.7, C(2)H), 6.99 (1H, dt, J_3,214.4, J_3,45.4,

C(3)H); d_C(100 MHz, CDCl₃) 49.5 (C(4)H₂), 51.5 (CO₂CH₃),

51.7 (NCH_2−allyl), 116.3 (CHCH_2−allyl), 121.1 (C(2)H), 136.3

Preparation of dimethyl-(E,E)-4-(N-benzyl-N-

methoxycarbonylallylamino)-but-2-enoate (22)

Methyl 4-bromocrotonate (1.3 mL, 10.7 mmol) was added to

a solution of methyl-(E)-4-(N-benzylamino)-but-2-enoate 21

(2.0 g, 9.8 mmol) in DCM (15 mL) at 0 ^◦C, followed by

triethylamine (3.1 mL, 20.0 mmol) and stirred overnight. After

puriﬁcation via column chromatography on silica (1 : 5, Et₂O :

pentane), diene 22 was isolated as an orange oil (1.77 g, 60%)

1 2 9 2

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

View Article Online

(CHCH_2−allyl), 146.9 (C(3)H), 166.9 (CO₂); m/z (CI⁺) 156.1011

Preparation of methyl-(2E,2^ꢀE)-4-(N-allyl-N-

methoxycarbonylallylamino)-but-2-enoate (29)

(MH⁺, C₈H₁₄NO₂requires 156.1024); (EI⁺) 156 ((MH)⁺,

+

100%), 114 (61).

Methyl-(E)-4-bromocrotonate (0.25 mL, 3.52 mmol) was added

dropwise to methyl-(E)-4-allylamino-but-2-enoate 25 (500 mg,

3.2 mmol) in DCM (10 mL) at 0 ^◦C and allowed to warm to rt

overnight before the addition of saturated aqueous K₂CO₃solu-

tion. The resultant solution was extracted with DCM, dried and

concentrated in vacuo. Puriﬁcation via column chromatography

on silica (1 : 8, Et₂O : pentane) furnished diester 29 (0.81 g, 98%)

as a yellow oil with spectroscopic properties same as above.

Diester 29 was isolated as the least polar component (5.13 g,

32%) as a yellow oil; v_max(ﬁlm) 1660, 1726, 3069; d_H(400 MHz,

CDCl₃) 3.09 (2H, d, J 16.3, NCH_2−allyl), 3.22 (4H, dd, J_4,3

15.7, J_4,21.5, 2x C(4)H₂), 3.71 (6H, s, 2x CO₂CH₃), 5.16 (1H,

dd, J 13.6, 1.5, CHCH_cisH_{trans−allyl}), 5.19 (1H, dd, J 13.6, 1.5,

CHCH_cisH_{trans−allyl}), 5.71–5.88 (1H, m, CHCH_2−allyl), 6.03 (2H,

dd, J_2,315.7, J_2,41.5, 2x C(2)H), 6.91 (2H, dt, J_3,215.7, J_3,45.8,

2x C(3)H); d_C(100 MHz, CDCl₃) 51.6 (CO₂CH₃), 54.4 (C(4)H₂),

57.0 (NCH_2−allyl), 118.2 (CHCH_2−allyl), 122.6 (C(2)H), 134.8

(CHCH_2−allyl), 145.8 (C(3)H), 166.7 (CO₂); m/z (CI⁺) 254.1397

Preparation of methyl-(2E,2^ꢀE)-4-(N-tert-butyl-N-

methoxycarbonylallylamino)-but-2-enoate (30)

(MH⁺, C₁₃H₂₀NO₄requires 254.1392); (EI⁺) 255 (34%), 254

+

((MH)⁺, 100).

Methyl 4-bromocrotonate (2.46 g, 11.7 mmol) was added

dropwise to a stirred solution of amino ester 27 (1.0 g, 5.8 mmol)

and DIPEA (0.83 g, 6.4 mmol). The mixture was placed under

nitrogen in DCM (20 mL) at rt and left to stir overnight. This

solution was partitioned between aqueous saturated NaHCO₃

and DCM, organic layers dried and concentrated in vacuo. The

residue was puriﬁed via column chromatography on silica (1 : 4,

Et₂O : pentane) and then recrystallised (Et₂O : hexane) to give

the diester 30 (1.46 g, 92%) as white solid; mp 48–49 ^◦C (Et₂O :

hexane); v_max(KBr) 1160, 1660, 1723, 2886, 2977; d_H(400 MHz,

CDCl₃) 1.08 (9H, s, C(CH₃)₃), 3.30 (4H, dd, J_4,35.7, J_4,21.6,

C(4)H₂), 3.72 (6H, s, 2x CO₂CH₃), 5.98 (2H, dt, J_2,315.6, J_2,41.6,

C(2)H), 6.94 (2H, dt, J_3,215.6, J_3,45.7, C(3)H); d_C(100 MHz,

CDCl₃) 27.4 (C(CH₃)₃), 50.5 (CO₂CH₃), 51.4 (C(4)H₂), 55.1

(C(CH₃)₃), 121.2 (C(2)H), 149.0 (C(3)H), 168.9 (CO₂); m/z

Preparation of (2E,aR)-methyl 4-(N-a-methylbenzylamino)-

but-2-enoate (26)

(R)-N-Benzyl-N-a-methylbenzylamine (88.5 mL, 66.0 mmol)

was added dropwise to a solution of methyl 4-bromocrotonate

(5.26 mL, 33.0 mmol) and stirred at rt under nitrogen for 3 h

before being washed with aqueous saturated NaHCO₃solution.

The resultant solution was extracted with DCM, dried and

concentrated in vacuo, and the residue puriﬁed via column

chromatography on silica (1 : 2, Et₂O : pentane) to give the ester

26 (6.3 g, 87%) as a colourless oil with spectroscopic properties

consistent with the literature; [a]²_D³+61.9 (c 1.00, CHCl₃); (lit.

ent.,²⁷[a]_D²³−48.5 (c 1.00, CHCl₃)); d_H(200 MHz, CDCl₃) 1.37

(3H, d, J 6.6, C(a)CH₃), 1.53 (1H, br s, NH), 3.26 (2H, dd, J_4,3

5.5, J_4,21.8, C(4)H₂), 3.75 (3H, s, CO₂CH₃), 3.81 (1H, q, J 6.6,

C(a)H), 5.98 (1H, dt, J_2,315.8, J_2,41.8, C(2)H), 6.99 (1H, dt, J_3,2

15.8, J_3,45.5, C(3)H), 7.23–7.39 (5H, m, o/m/p-Ph).

+

(CI⁺) 292.1513 (MNa⁺. C₁₄H₂₁NaNO₄requires 292.1525); 292

(80%), 270 ((MH)⁺, 40), 214 (100).

Preparation of methyl-(2E,2^ꢀE,aR)-4-(N-a-methylbenzyl-N-

methoxycarbonylallylamino)-but-2-enoate (31)

Methyl 4-bromocrotonate (1.5 mL, 9.2 mmol) was added

dropwise to a stirred solution of ester 26 (1.0 g, 4.6 mmol)

in DCM (5 mL) at 0 ^◦C followed by the dropwise addition

of NEt₃(0.63 mL, 4.6 mmol). The solution was allowed to

warm slowly to rt overnight before being partitioned between

aqueous saturated NaHCO₃solution and DCM, organic layers

combined, dried and concentrated in vacuo. The residue was

puriﬁed via column chromatography on silica (1 : 4, Et₂O :

pentane) to give diester 31 (0.85 g, 58%) as a colourless oil;

[a]²_D³+157.7 (c 1.00, CHCl₃); v_max(ﬁlm) 1172, 1659, 1724, 2821,

2951; d_H(200 MHz, CDCl₃) 1.36 (3H, d, J 6.8, C(a)CH₃), 3.10–

3.37 (4H, m, C(4)H₂), 3.74 (6H, s, 2x CO₂CH₃), 3.85 (1H, q,

J 6.8, C(a)H), 6.01 (2H, dt, J_2,315.8, J_2,41.6, C(2)H), 6.97

(2H, dt, J_3,215.8, J_3,45.7, C(3)H), 7.22–7.35 (5H, m, o/m/p-

Ph); d_C(50 MHz, CDCl₃) 17.1 (C(a)CH₃), 51.1 (C(4)H₂), 51.4

(CO₂CH₃), 59.2 (C(a)H), 122.2 (C(2)H), 127.1 (p-Ph), 127.3,

128.3 (o/m-Ph), 142.9 (i-Ph), 146.7 (C(3)H), 166.5 2x(CO₂);

m/z (CI⁺) 318.1704 (MH⁺, C₁₈H₂₄NO₄⁺requires 318.1705); 340

(10%), 318 ((MH)⁺, 20), 214 (100).

Preparation of (E)-methyl 4-(N-tert-butylamino)-but-2-

enoate (27)

tert-Butyl amine (5.9 mL, 55.7 mmol) was added dropwise to

a stirred solution of methyl 4-bromocrotonate (3.9 mL, 27.9

mmol) under nitrogen at rt and left to stir overnight. The

products were partitioned between aqueous saturated NaHCO₃

solution and DCM, organic layers dried and concentrated in

vacuo. The residue was puriﬁed via column chromatography on

silica (1 : 3, Et₂O : pentane) to furnish the ester 27 (3.85 g,

81%) as a yellow oil, with spectroscopic properties consistent

with these quoted in the literature;²⁸d_H(200 MHz, CDCl₃) 1.08

(9H, s, C(CH₃)₃), 3.38 (2H, dd, J_4,35.2, J_4,21.6, C(4)H₂), 3.72

(3H, s, CO₂CH₃), 6.01 (1H, dt, J_2,315.6, J_2,41.6, C(2)H), 7.05

(1H, dt, J_3,215.6, J_3,45.2, C(3)H).

Preparation of methyl-(2E,2^ꢀE)-4-(N-methyl-N-

methoxycarbonylallylamino)-but-2-enoate (28)

Methylamine (2.0 M, 27.9 mL, 55.7 mmol) was added dropwise

to a stirred solution of methyl 4-bromocrotonate (3.9 mL,

27.9 mmol) at 0 ^◦C under nitrogen. After 30 min the mixture was

warmed to rt and left to stir for 5 h. Aqueous saturated NaHCO₃

solution was added, solution partitioned between brine and

DCM, organic layers dried and concentrated in vacuo. The

residue was puriﬁed via column chromatography on silica gel

(1 : 2, Et₂O : pentane) to give the diene 28 (1.77 g, 51%) as a

colourless oil; v_max(ﬁlm) 1660, 1727, 2793, 2950; d_H(200 MHz,

CDCl₃) 2.26 (3H, s, NCH₃), 3.16 (4H, dd, J_4,36.0, J_4,21.6,

C(4)H₂), 3.75 (6H, s, 2x CO₂CH₃), 5.99 (2H, dt, J_2,315.7,

J_2,41.6, C(2)H), 6.95 (2H, dt, J_3,215.7, J_3,46.0, C(3)H); d_C

(100 MHz, CDCl₃) 42.4 (NCH₃), 51.4 (C(4)H₂), 58.0 (CO₂CH₃),

122.9 (C(2)H), 145.7 (C(3)H), 166.7 (CO₂); m/z (CI⁺) 228.1231

(MH⁺, C₁₁H₁₈NO₄⁺requires 228.1236); 250 (60%), 228 ((MH)⁺,

100).

Preparation of (3R,4R,5S,aS)- and (3R,4R,5R,aS)-1-methyl-3-

(N-benzyl-N-a-methylbenzylamino)-4-methoxycarbonyl-5-

methoxycarbonylmethyl-piperidine (32 and 33)

Following the general procedure 1a, n-BuLi (2.5 M, 3.4 mmol,

1.4 mL), (S)-N-benzyl-N-a-methylbenzylamine (0.75 g, 3.5

mmol) in THF (5 mL) and diene 28 (0.50 g, 2.2 mmol) in THF (10

mL) gave, after puriﬁcation via chromatography on silica (1 : 2,

Et₂O : pentane) a separable mixture of diastereoisomers (0.69 g,

72%). The minor piperidine diastereoisomer 33 was isolated

as a 11 : 1 mixture of piperidine 33 (51 mg, 5%) colourless

oil and starting material 28; v_max(ﬁlm) 1171, 1737, 2947; d_H

(400 MHz, CDCl₃) 1.41 (3H, d, J 7.0, C(a)CH₃), 1.90 (1H, dd,

J_6ax,6eq11.5, J_6ax,5eq2.1, C(6)H_ax), 1.97 (1H, app t, J_{2ax,2eq;2ax,3ax}

10.8, C(2)H_ax), 2.20 (3H, s, NCH₃), 2.50–2.63 (5H, m, C(4)H_ax,

C(5)H_eq, C(6)H_eq, and C(1^ꢀ)H₂), 2.91 (1H, dd, J_2eq,2ax10.8, J_2eq,3ax

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

1 2 9 3

View Article Online

3.4, C(2)H_eq), 3.39 (1H, td, J_{3ax,2ax;3ax,4ax}11.2, J_3ax,2eq4.1, C(3)H_ax),

3.48, 3.62 (3H, s, 2x CO₂CH₃), 3.79 (2H, AB q, J 14.5, CH₂Ph),

4.07 (1H, q, J 7.0, C(a)H), 7.19–7.33 (10H, m, 2x o/m/p-

Ph); d_C(100 MHz, CDCl₃) 18.2 (C(a)CH₃), 33.0 (C(1^ꢀ)H₂),

33.3 (C(5)H), 46.6 (NCH₃), 48.8 (C(4)H), 49.6 (CH₂Ph), 51.3,

51.5 2x(CO₂CH₃), 53.3 (C(3)H), 58.1 (C(2)H₂), 58.5 (C(a)H),

59.7 (C(6)H₂), 125.5, 125.7, 127.0, 127.8, 127.9, 128.0, 128.1,

128.4 (o/m/p-Ph), 141.0, 144.2 2x(i-Ph), 173.4, 173.7 2x(CO₂);

m/z (CI⁺) 439.2603 (MH⁺, C₂₆H₃₅N₂O₄⁺requires 439.2597); 461

(75%), 439 ((MH)⁺, 40).

Further elution gave the major product piperidine 32 (0.64 g,

67%) as a colourless oil; [a]²_D³+14.4 (c 1.00, CHCl₃); v_max(ﬁlm)

1736, 2845, 2947; d_H(400 MHz, CDCl₃) 1.37 (3H, d, J 7.0,

C(a)CH₃), 1.56 (1H, app t, J_{6ax,6eq;6ax,5ax}10.9, C(6)H_ax), 2.01 (1H,

mers (0.68 g, 81%). The minor piperidine diastereoisomer 37

was isolated as an 8 : 1 mixture of piperidine 37 (36 mg,

4%) and starting material 30 as a colourless oil; v_max(ﬁlm)

1168, 1737, 2805, 2970; d_H(400 MHz, CDCl₃) 0.94 (9H, s,

C(CH₃)₃), 1.39 (3H, d, J 7.0, C(a)CH₃), 1.94 (1H, dd, J_6eq,6ax11.7,

J_6eq,5eq2.4, C(6)H_ax), 2.02 (1H, app t, J_{2ax,2eq;2ax,3ax}10.7, C(2)H_ax),

2.42–2.47 (2H, m, C(5)H_eqand C(1^ꢀ)H_A), 2.54 (1H, dd, J_4ax,3ax

11.7, J_4ax,5eq4.5, C(4)H_ax), 2.67 (1H, dd, J_B,A17.8, J_B,510.0,

C(1^ꢀ)H_B), 2.84 (1H, dt, J_6eq,6ax11.7, J_{6eq,5eq;6eq,2eq}2.5, C(6)H_eq),

3.05 (1H, ddd, J_2eq,2ax10.7, J_2eq,3ax4.1, J_2eq,6eq2.3, C(2)H_eq), 3.24

(1H, ddd, J_3ax,4ax11.7, J_3ax,2ax10.7, J_3ax,2eq4.1, C(3)H), 3.51,

3.62 (3H, s, 2x CO₂CH₃), 3.78 (2H, AB q, J 14.5, CH₂Ph),

4.09 (1H, q, J 7.0, C(a)H), 7.20–7.29 (10H, m, 2x o/m/p-

Ph); d_C(100 MHz, CDCl₃) 18.8 (C(a)CH₃), 26.1 (C(CH₃)₃),

32.7 (C(1^ꢀ)H₂), 33.3 (C(5)H), 48.6 (C(2)H₂), 49.3 (CH₂Ph), 50.1

(C(4)H), 50.4 (C(6)H₂), 51.1, 51.3 2x(CO₂CH₃), 53.1 (C(CH₃)₃),

55.2 (C(3)H), 59.4 (C(a)H), 126.6, 127.7, 127.9, 128.5 2x(o/m/p-

Ph), 141.4, 144.3 2x(i-Ph), 173.7, 173.9 2x(CO₂); m/z (CI⁺)

app t, J_{2ax,2eq;2ax,3ax}11.0, C(2)H_ax), 2.05 (1H, dd, J

9.2, C(1^ꢀ)H_A), 2.20 (1H, dd, J_{1 B,1 A}

15.7, J_{1 B,5}

2.27–2.32 (5H, m, C(4)H and C(5)H and NCH₃), 2.86 (1H, dd,

_6eq,6ax16.9, J_6eq,5ax2.8, C(6)H_eq), 3.08 (1H, dd, J_2eq,2ax11.6, J_2eq,3ax

ꢀ

_{1 A,1 B}15.7, J_{1 A,5}

ꢀ

3.2, C(1^ꢀ)H_B),

J

481.3068 (MH⁺, C₂₉H₄₁N₂O₄requires 481.3066); 503 (20%),

+

2.0, C(2)H_eq), 3.28–3.34 (1H, m, C(3)H), 3.39, 3.62 (3H, s, 2x

CO₂CH₃), 3.68 (1H, AB d, J 13.8, CH_AH_BPh), 3.92 (1H, AB d,

J 13.8, CH_AH_BPh), 3.96 (1H, q, J 7.0, C(a)H), 7.17–7.35 (10H,

m, 2x o/m/p-Ph); d_CNMR (100 MHz, CDCl₃) 15.9 (C(a)CH₃),

35.7 (NCH₃), 36.7 (C(1^ꢀ)H₂), 46.4 (C(5)H), 50.1 (CH₂Ph), 51.5,

51.6 2x(CO₂CH₃), 52.2 (C(4)H), 56.3 (C(3)H), 56.7 (C(a)H),

58.2 (C(2)H₂), 59.8 (C(6)H₂), 126.6, 126.8 2x(p-Ph) 127.8, 128.1,

129.0 2x(o/m-Ph), 140.4, 143.6 2x(i-Ph), 171.9, 173.5 2x(CO₂);

m/z (CI⁺) 439.2601 (MH⁺, C₂₆H₃₅N₂O₄⁺requires 439.2597); 461

(70%), 439 ((MH)⁺, 50).

481 ((MH)⁺, 100).

Further elution furnished the major piperidine diastereoiso-

mer 36 (0.65 g, 77%) as a colourless oil; [a]²_D¹+16.1 (c 1.00,

CHCl₃); v_max(ﬁlm) 1171, 1738, 2806; d_H(400 MHz, CDCl₃) 1.08

(9H, s, C(CH₃)₃), 1.40 (3H, d, J 7.0, C(a)CH₃), 1.66 (1H, app t,

J 10.5, C(6)H_ax), 2.04 (1H, app t, J_{2ax,2eq;2ax,3ax}10.5, C(2)H_ax), 2.08

(1H, dd, J_A,B15.7, J_A,58.8, C(1^ꢀ)H_A), 2.19–2.32 (3H, m, C(5)H_eq,

C(4)H and C(1^ꢀ)H_B), 3.10 (1H, br d, C(6)H_eq), 3.22–3.29 (2H, m,

C(2)H_eqand C(3)H), 3.42, 3.62 (3H, s, 2x CO₂CH₃), 3.70 (1H,

AB d, J 13.7, CH_AH_BPh), 3.93 (1H, AB d, J 13.7, CH_AH_BPh),

4.00 (1H, q, J 7.0, C(a)H), 7.17–7.37 (10H, m, 2x o/m/p-

Ph); d_C(100 MHz, CDCl₃) 16.2 (C(a)CH₃), 26.1 (C(CH₃)₃),

36.4 (C(5)H), 37.0 (C(1^ꢀ)H₂), 48.8 (CH₂Ph), 50.0 (C(2)H₂), 51.0

(C(6)H₂), 51.3, 51.5 2x(CO₂CH₃), 53.3 (C(4)H), 53.7 (C(CH₃)₃),

57.0 (C(3)H), 57.9 (C(a)H), 126.5, 126.8, 127.8, 128.0, 129.1

2x(o/m/p-Ph), 140.7, 143.8 2x(i-Ph), 172.1, 173.8 2x(CO₂); m/z

Preparation of (3S,4S,5S,aS)-1-allyl-3-(N-benzyl-N-a-

methylbenzylamino)-4-methoxycarbonyl-5-

methoxycarbonylmethyl-piperidine (34)

Following the general procedure 1a, n-BuLi (2.5 M, 5.8 mL,

14.5 mmol), (S)-N-benzyl-N-a-methylbenzylamine (3.13 mL,

15.0 mmol) in THF (17 mL) and diester 29 (2.54 g, 10.0 mmol)

in THF (10 mL) gave the crude reaction product 34 in (78%

de) after 2 h. Puriﬁcation via column chromatography on silica

(3 : 10, Et₂O : pentane) gave the piperidine 34 (3.76 g, 81%)

as a yellow oil; [a]_D²³+14.9 (c 2.23, CHCl₃); v_max(ﬁlm) 1634,

1731, 2765; d_H(400 MHz, CDCl₃) 1.36 (3H, d, J 6.8, C(a)CH₃),

1.56–1.66 (1H, m, C(6)H_AH_B), 1.94 (1H, dd, J_2ax,2eq11.0, J_2ax,3eq

2.0, C(2)H_AH_B), 2.04 (1H, dd, J_A,B15.8, J_A,58.9, CH_AH_BCO₂),

2.20 (1H, dd, J_B,A15.8, J_B,53.0, CH_AH_BCO₂), 2.24–2.36 (2H, m,

C(4)H, C(5)H), 2.88 (1H, dd, J_6ax,5ax12.1, J_6ax,6eq1.4, C(6)H_AH_B),

(CI⁺) 481.3061 (MH⁺, C₂₉H₄₁N₂O₄requires 481.3066); 503

+

(100%), 481 ((MH)⁺, 90).

Preparation of (3R,4R,5S,aR,a^ꢀS)- and

(3R,4R,5R,aR,a^ꢀS)-1-a-methylbenzyl-3-(N-benzyl-

N-a^ꢀ-methylbenzylamino)-4-methoxycarbonyl-5-

methoxycarbonylmethyl-piperidine (38 and 39)

Following the general procedure 1a, n-BuLi (1.6 M, 0.8 mL,

1.3 mmol), (R)-N-benzyl-N-a-methylbenzylamine (0.28 g,

1.3 mmol) in THF (3 mL) and diester 31 (0.35 mg, 1.1 mmol)

in THF (5 mL) gave, after puriﬁcation via column chromato-

graphy on silica (1 : 3, Et₂O : pentane), a separable mixture of

diastereoisomers (0.36 g, 69% overall). The least polar fraction

gave 39 (18 mg, 4%) as a colourless oil; [a]²_D³+18.0 (c 0.90,

CHCl₃); m_max(ﬁlm) 1171, 1732, 1738, 2949, 3028; d_H(400 MHz,

CDCl₃) 1.24 (3H, d, J 6.7, C(a)CH₃), 1.35 (3H, d, J 7.0,

=

2.94 (1H, dd, J_A,B13.5, J_A,CH10.1, CH_AH_B(CH CH₂)), 3.04

(1H, dd, J_B,A13.5, J_B,CH9.9, CH_AH_B(CH CH₂)), 3.15 (1H,

=

dd, J_2eq,2ax11.0, J_2eq,3eq1.4, C(2)H_AH_B), 3.26 (1H, dt, J_3eq,4ax

7.4, J_3eq,2ax;2.0, C(3)H), 3.39 (3H, s, CO₂CH₃), 3.61 (3H, s,

CO₂CH₃), 3.66 (1H, AB d, J 13.8, CH_AH_BPh), 3.91 (1H,

ꢀ

AB d, J 13.8, CH_AH_BPh), 3.98 (1H, q, J 6.8, C(a)H), 5.18

=

(1H, dd, J 4.1, 1.1, CH_cisH CH), 5.21 (1H, dd, J 10.0, 1.1,

=

CH H CH), 5.69–5.92 (1H, m, CH CH₂), 7.13–7.43 (10H,

tr

ꢀ

C(a)CH₃), 1.88 (1H, dd, J_6ax,6eq11.7, J_6ax,5eq1.7, C(6)H_ax), 1.98

m, o/m/p-Ph); d_C(100 MHz, CDCl₃) 15.9 (C(a)CH₃), 35.6

(C(5)H), 36.8 (CH₂CO₂), 50.1 (CH₂Ph), 51.4, 51.6 2x(CO₂CH₃),

52.7 (C(4)H), 55.4 (C(2)H), 56.4 (C(3)H), 56.7 (C(a)H), 57.9

(C(6)H₂), 61.5 (CH₂CH CH₂), 118.0 (CH CH₂), 126.6, 126.9

2x(p-Ph), 127.8, 128.1, 129.1, 129.4 2x(o/m-Ph), 140.5, 143.6

(1H, app t, J 10.7, C(2)H_ax), 2.42–2.67 (5H, m, C(4)H_ax, C(5)H_eq,

C(6)H_eq, and C(1^ꢀ)H₂), 3.02 (1H, dd, J_2eq,2ax10.5, J_2eq,3ax2.3,

C(2)H_eq), 3.32–3.39 (2H, m, C(3)H and C(a)H), 3.50, 3.55

(2 × 3H, s, CO₂CH₃), 3.74 (2H, ABq, J 14.5, NCH₂), 4.07

(1H, q, J 7.0, C(a)H^ꢀ), 7.19–7.35 (15H, m, o/m/p-Ph); d_C

(100 MHz, CDCl₃) 18.3, 18.6 2x(C(a)CH₃), 32.8 (C(1^ꢀ)H₂), 33.4

(C(5)H), 49.4, 51.6 (C(2)H₂and C(6)H₂), 49.6 (C(4)H), 51.2,

51.4 2x(CO₂CH₃), 54.5 (C(3)H), 55.1 (NCH₂), 63.7 2x(C(a)H),

126.6, 126.8, 127.3, 127.7, 127.9, 128.1, 128.3, 128.6 (o/m/p-

Ph), 141.2, 144.0, 144.2 3x(i-Ph), 173.5, 173.6 2x(CO₂CH₃);

m/z (CI⁺) 529.3076 (MH⁺, C₃₃H₄₁N₂O₄⁺requires 529.3066); 551

(25%), 529 ((MH)⁺,100).

=

+

=

2x(i-Ph), 151.4 (CH CH₂), 171.9, 173.5 2x(CO₂); m/z (CI )

+

465.2749 (MH⁺, C₂₈H₃₇N₂O₄requires 465.2753); (EI⁺) 523

(36%), 466 (29), 465 ((MH)⁺, 100).

Preparation of (3R,4R,5S,aS)- and (3R,4R,5R,aS)-1-tert-butyl-

3-(N-benzyl-N-a-methylbenzylamino)-4-methoxycarbonyl-5-

methoxycarbonylmethyl-piperidine (36 and 37)

Following the general procedure 1a, n-BuLi (2.5 M, 2.0 mmol,

0.8 mL), (S)-N-benzyl-N-a-methylbenzylamine (0.44 g, 2.1

mmol) in THF (5 mL) and diester 30 (0.50 g, 1.7 mmol) in THF

(10 mL) gave, after puriﬁcation via column chromatography on

silica (1 : 2, Et₂O : pentane) a separable mixture of diastereoiso-

The major diastereoisomer 38 was next eluted, and isolated

as a colourless oil (0.35 g, 65%); [a]²_D³+48.6 (c 1.00, CHCl₃);

m_max(ﬁlm) 1737, 2949; d_H(400 MHz, CDCl₃) 1.25 (3H, d, J

ꢀ

7.0, C(a)CH₃), 1.37 (3H, d, J 6.7, C(a)CH₃), 1.70–1.76 (1H,

m, C(6)H_ax), 2.00–2.09 (2H, m, C(1^ꢀ)H_Aand C(2)H_ax), 2.15

1 2 9 4

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

View Article Online

(1H, dd, J_{1 B,1 A}

ꢀ

15.0, J_{1 B,5}

ꢀ

3.2, C(1^ꢀ)H_B), 2.28–2.35 (2H, m,

C(2)H_AH_B), 2.30 (2H, dt, J_6,57.8, J_6,71.6 C(6)H₂), 3.30–3.32

(1H, m, C(3)H), 3.50 (2H, AB d, J_A,B15.0, CH₂Ph), 3.84 (1H, q,

J 4.9, C(a)H), 7.35–7.52 (10H, m, 2x o/m/p-Ph), 9.71 (1H, br s,

CHO); d_C(100 MHz, CDCl₃) 19.4 (C(5)H₂), 20.7 (C(a)CH₃),

28.0 (C(CH₃)₃), 32.8 (C(4)H₂), 43.6 (C(6)H₂), 50.1 (CH₂Ph),

53.4 (C(3)H), 58.5 (C(a)CH₃), 65.9 (C(2)H₂), 80.2 (C(CH₃)₃),

126.7, 127.0 2x(p-Ph), 127.9, 128.0, 128.2, 128.3 2x(o/m-Ph),

141.7, 143.0 2x(i-Ph), 172.0 (CO₂), 202.7 (CHO); m/z (CI⁺)

410.2710 (MH⁺, C₂₆H₃₆NO₃⁺requires 410.2695); 411 (27%), 410

((MH)⁺, 100), 354 (52), 249 (26).

C(4)H and C(5)H), 2.86 (1H, ddd, J_6eq,6ax11.4, J_6eq,5ax3.4, J_6eq,2eq

1.7, C(6)H_eq), 3.14 (1H, ddd, J_2eq,2ax10.9, J_2eq,3ax3.8, J_2eq,6eq1.7,

C(2)H_eq), 3.25 (1H, m, C(3)H), 3.43, 3.55 2x(3H, s, CO₂CH₃×

2), 3.58–3.65 (2H, m, NCH_Aand C(a)H), 3.88 (1H, d, J 13.7,

NCH_AH_B), 3.95 (1H, q, J 7.0, C(a)H), 7.19–7.40 (15H, m,

o/m/p-Ph); d_C(100 MHz, CDCl₃) 15.9, 17.1 2x(C(a)CH₃),

35.9 (C(5)H), 36.9 (C(1^ꢀ)H₂), 50.0 (NCH₂), 51.0 (C(2)H₂), 51.4,

51.5 2x(CO₂CH₃) 53.1 (C(4)H), 55.4 (C(6)H₂), 56.6 (C(3)H)

56.9 (C(a)H^ꢀ), 62.9 (C(a)H), 126.5, 126.8, 126.9, 127.5, 127.8,

128.1, 128.2, 129.1 3x(o/m/p-Ph), 140.5, 143.6, 143.8 3x(i-Ph),

+

172.1, 173.8 2x(CO₂); m/z (CI⁺) 529.3060 (MH⁺, C₃₃H₄₁N₂O₄

Preparation of tert-butyl-(1R,2S,6S,aS)-2-hydroxy-6-(N-

benzyl-N-(a-methylbenzylamino)cyclohexanoate (43)

requires 529.3066); 551 (25%), 529 ((MH)⁺,100), 425 (10).

Following the general procedure 1a, n-BuLi (2.5 M, 0.5 mL,

1.2 mmol), (S)-N-benzyl-N-a-methylbenzylamine (0.24 mL,

1.2 mmol) in THF (7 mL) and ester 41 (100 mg, 0.5 mmol)

in THF (7 mL) were allo_◦wed to react for 2 h. The solution

was then warmed to −20 C for 2 h, and following the work-

up procedure gave the crude reaction product as a brown oil.

Puriﬁcation via column chromatography (1 : 5, Et₂O : pentane)

on silica gave the cyclic ester 43 (52 mg, 31%, >98% de) as a

more polar component as a colorless oil; [a]²_D⁴+10.4 (c 1.00,

CHCl₃); (Found: C, 75.8; H, 8.9; N, 2.9. Calc. for C₂₆H₃₅NO₃:

C, 76.2; H, 8.7; N, 3.4%); v_max(ﬁlm) 1602, 1703, 2248, 2866,

2935, 2974, 3027, 3480; d_H(500 MHz, CDCl₃) 1.19 (1H, app t,

J_{4ax,5eq;4ax,3ax}9.2, C(4)H_AH_B), 1.40 (3H, d, J 6.9, C(a)CH₃), 1.41–

1.45 (1H, m, C(4)H_AH_B), 1.48 (9H, s, C(CH₃)₃), 1.51–1.53 (1H,

m, C(3)H_AH_B), 1.81–1.84 (3H, m, C(5)H₂, C(3)H_AH_B), 2.45 (1H,

dd, J_1ax,6ax9.9, J_1ax,2eq3.9, C(1)H), 3.44 (1H, app. dt, J_{6ax,1ax;6ax,5ax}

9.9, J_6ax,5eq3.3, C(6)H), 3.73 (1H, AB d, J 14.2, CH_AH_BPh),

3.84 (1H, AB d, J 14.1, CH_AH_BPh), 4.01 (1H, q, J 6.9,

C(a)H), 4.08 (1H, br s, C(2)H), 7.14–7.42 (10H, m, 2x o/m/p-

Ph); d_C(100 MHz, CDCl₃) 17.8 (C(a)CH₃), 19.4 (C(4)H₂),

28.1 (C(CH₃)₃), 28.8 (C(5)H₂), 31.2 (C(3)H₂), 49.7 (CH₂Ph),

53.0 (C(1)H), 54.2 (C(6)H), 58.7 (C(a)H), 68.0 (C(2)H), 81.2

(C(CH₃)₃), 126.5, 126.6, 127.8, 127.9, 128.3, 129.0 2x(o/m/p-

Ph), 141.3, 144.2 2x(i-Ph), 175.3 (CO₂); m/z (CI⁺) 410.2694

Preparation of (3S,4S,5R,aR,a^ꢀR)-1-N-a-methylbenzyl-3-(N-

benzyl-N-a^ꢀ-methylbenzylamino)-4-methoxycarbonyl-5-

methoxycarbonylmethyl-piperidine (40)

Following the general procedure 1a, n-BuLi (1.6 M, 0.5 mL,

0.7 mmol), (R)-N-benzyl-N-a-methylbenzylamine (161 mg, 0.8

mmol) in THF (3 mL) and diester 31 (0.20 g, 0.6 mmol) in THF

(5 mL) gave, after puriﬁcation via column chromatography on

silica (1 : 3, Et₂O : pentane) piperidine 40 (0.28 g, 83%) as

a colourless oil; [a]_D²³−8.5 (c 1.00, CHCl₃); v_max(ﬁlm) 1737,

2971; d_H(400 MHz, CDCl₃) 1.14 (3H, d, J 7.0, C(a)CH₃),

ꢀ

1.37 (3H, d, J 6.7, C(a)CH₃), 1.63 (1H, app t, J_{6ax,6eq;6ax,5ax}

10.6, C(6)H_ax), 1.87 (1H, t, J 10.9, C(2)H_ax), 2.09 (1H, dd,

J_{1 A,1 B}

ꢀ

15.7, J_{1 B,5}

ꢀ

8.8, C(1^ꢀ)H_A), 2.22 (1H, dd, J_{1 B,1 A}

ꢀ

15.7, J_{1 B,5}

ꢀ

3.6, C(1^ꢀ)H_B), 2.29–3.38 (2H, m, C(4)H and C(5)H), 3.09–

3.20 (3H, m, C(6)H_eq, C(2)H_eqand C(3)H), 3.43 (4H, m,

CO₂CH₃and C(a)H^ꢀ), 3.51 (1H, AB d, J 13.6, CH_AH_BPh), 3.63

(3H, s, CO₂CH₃), 3.84 (1H, AB d, J 13.6, CH_AH_BPh), 3.90

(1H, q, J 7.0, C(a)H), 7.18–7.42 (15H, m, 3x o/m/p-Ph); d_C

(100 MHz, CDCl₃) 15.2, 20.2 2x(C(a)CH₃), 36.0 (C(5)H), 37.0

(C(1^ꢀ)H₂), 49.9 (CH₂Ph), 51.4, 51.6 2x(CO₂CH₃), 52.9 (C(4)H),

53.3 (C(2)H₂), 54.8 (C(6)H₂), 56.3 (C(3)H) 56.7 (C(a)H), 64.2

(C^ꢀ(a)H), 126.5, 126.7, 126.8, 126.9, 127.0, 127.4, 127.8, 128.0,

128.1, 128.3, 128.5, 129.1 3x(o/m/p-Ph), 140.5, 143.7, 144.0

3x(i-Ph), 172.1, 173.7 2x(CO₂); m/z (CI⁺) 529.3069 (MH⁺,

(MH⁺, C₂₆H₃₆NO₃requires 410.2695); (EI⁺) 411 (34%), 410

+

((MH)⁺, 100).

C₃₃H₄₁N₂O₄requires 529.3066); 551 (25%), 529 ((MH)⁺,100),

+

This reaction also gave amino ester 42 as a less polar fraction

(62 mg, 23%, >98% de), with spectroscopic data consistent with

that reported above; [a]²_D⁴−2.8 (c 0.96, CHCl₃).

424 (10).

Preparation of tert-butyl-(2E)-7-oxohept-2-enoate (41)

PCC (0.30 g, 1.3 mmol) was added to a solution of alcohol 57

(0.10 g, 0.50 mmol) and NaOAc (0.11 g, 1.3 mmol) in DCM

(10 mL) at 0 ^◦C. After 2 h Et₂O was added and the resultant

solution concentrated in vacuo, partitioned between water and

DCM, organic layers dried and re-concentrated in vacuo after

being passed through a pad of silica (eluent Et₂O), aldehyde 41

(54 mg, 56%) was obtained as a colourless oil with spectroscopic

data consistent with that quoted in the literature;²⁹d_H(400 MHz,

CDCl₃) 1.49 (9H, s, C(CH₃)₃), 1.82–1.86 (2H, m, C(5)H₂), 2.24–

2.26 (2H, m, C(4)H₂), 2.49 (2H, t, J_6,56.0, C(6)H₂), 5.77 (1H, d,

J_2,315.6, C(2)H), 6.83 (1H, dt, J_3,215.6, J_3,47.0, C(3)H), 9.79

(1H, s, COH).

Preparation of tert-butyl-(1R,2S,6S,aS)-2-acetoxy-6-(N-

benzyl-N-(a-methylbenzylamino)cyclohexanoate (44)

Following the general procedure 1a, n-BuLi (2.5 M, 0.5 mL,

1.2 mmol), (S)-N-benzyl-N-a-methylbenzylamine (0.24 mL,

1.2 mmol) in THF (7 mL) and acceptor 41 (100 mg, 0.5 mmol)

in THF (7 mL), followed by subsequent warming to −20 ^◦C

for 2 h and work up gave the crude reaction product containing

amino esters 42 and 43. Acetic anhydride (2.0 mL, 21.7 mmol)

followed by pyridine (2.0 mL, 30.0 mmol) and DMAP (5 mg,

0.04 mmol) were added to this crude reaction mixture at rt

in DCM (10 mL). After 16 h stirring, mixture was diluted

with Et₂O, washed with aqueous saturated CuSO₄solution and

brine, dried and concentrated in vacuo. Puriﬁcation via column

chromatography (1 : 10, Et₂O : pentane) on silica gave the

more polar fraction acetate 44 (114 mg, 58%, >98% de) as a

viscous green oil; [a]_D²⁴+9.8 (c 1.00, CHCl₃); v_max(ﬁlm) 1602,

1741, 2256, 2869, 2934, 3035; d_H(400 MHz, CDCl₃) 1.17–

1.21 (1H, app d, J_3ax,2eq2.9, C(3)H_AH_B), 1.24–1.32 (1H, m,

C(4)H_AH_B), 1.30–1.39 (1H, m, C(5)H_AH_B), 1.40 (3H, d, J 6.8,

C(a)CH₃), 1.47 (9H, s, C(CH₃)₃), 1.48–1.52 (2H, m, C(4)H_AH_B

and C(5)H_AH_B), 1.66 (1H, br d, J_3ax,4ax12.0, C(3)H_AH_B), 2.04

(3H, s, CH₃CO₂), 2.14 (1H, dd, J_1ax,6ax10.2, J_1ax,2eq2.9, C(1)H),

3.50–3.54 (1H, m, C(6)H), 3.59 (1H, AB d, J 12.2, CH_AH_BPh),

3.81 (1H, AB d, J 14.7, CH_AH_BPh), 4.18 (1H, q, J 6.8, C(a)H),

5.26–5.31 (1H, m, C(2)H), 7.13–7.38 (10H, m, 2x o/m/p-

Ph); d_C(100 MHz, CDCl₃) 19.8 (C(a)CH₃), 20.4 (C(4)H₂),

Preparation of tert-butyl-(3S,aS)-3-(N-benzyl-N-

(a-methylbenzylamino)-7-oxoheptanoate (42)

Following the general procedure 1a, n-BuLi (2.5 M, 0.9 mL,

2.3 mmol), (S)-N-benzyl-N-a-methylbenzylamine (0.5 mL, 2.5

mmol) in THF (5 mL) and a,b-unsaturated ester 41 (100 mg,

0.50 mmol) in THF (6 mL) gave the crude reaction mixture as

a brown oil. After puriﬁcation via column chromatography on

silica (1 : 5, EtOAc : pentane), amino ester 41 (107 mg, 69%)

was obtained as a colorless oil; [a]²_D⁴−2.9 (c 0.85, CHCl₃); v_max

(ﬁlm) 1601, 1724, 2816, 2975, 3427; d_H(400 MHz, CDCl₃) 1.22–

1.27 (1H, m, C(4)H_AH_B), 1.33 (3H, d, J 4.9, C(a)CH₃), 1.40

(9H, s, C(CH₃)₃), 1.50–1.53 (1H, m, C(4)H_AH_B), 1.70–1.74 (2H,

m, C(5)H₂), 1.85–1.89 (1H, m, C(2)H_AH_B), 1.98–2.04 (1H, m,

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

1 2 9 5

View Article Online

21.2 (CH₃CO₂), 27.0 (C(5)H₂), 28.0 (C(CH₃)₃), 29.9 (C(3)H₂),

48.6 (CH₂Ph), 52.8 (C(1)H), 57.0 (C(6)H), 63.0 (C(a)H), 70.5

(C(2)H), 79.9 (C(CH₃)₃), 126.6, 126.4 2x(p-Ph), 127.7, 127.8,

127.9, 128.6, 128.7 2x(o/m-Ph), 142.3, 144.3 2x(i-Ph), 170.1,

170.9 2x(CO₂); m/z (CI⁺) 452.2795 (MH⁺, C₂₈H₃₈NO₄⁺requires

452.2801); (EI⁺) 474 (15%), 453 (34), 452 ((MH)⁺, 100).

Less polar aldehyde 42 (56 mg, 23%, >98% de) was isolated

as a colorless oil with spectroscopic data consistent with that

reported above; [a]²_D⁴−3.3 (c 0.78, CHCl₃).

(1H, m, C(2)H), 4.20–4.22 (1H, m, C(5)H), 7.12–7.50 (10H,

m, 2x o/m/p-Ph); d_C(100 MHz, CDCl₃) 17.9 (C(a)CH₃), 24.5

(C(4)H₂), 28.2 (C(CH₃)₃), 33.8 (C(3)H₂), 36.2 (C(1)H), 52.8

(CH₂Ph), 53.1 (C(2)H), 61.4 (C(a)CH₃), 72.7 (C(5)H), 83.9

(C(CH₃)₃), 126.6, 126.9 2x(p-Ph), 127.8, 127.9, 128.1, 128.2,

128.6 2x(o/m-Ph), 143.7, 144.6 2x(i-Ph), 195.1 (CO₂); m/z

(CI⁺) 396.2538 (MH⁺, C₂₅H₃₄NO₃requires 396.2539); (EI⁺)

+

397 (34%), 396 ((MH)⁺, 100).

Using the effect of temperature on the reaction: following the

general procedure 1, n-BuLi (2.5 M, 0.3 mL, 0.6 mmol), (S)-

N-benzyl-N-a-methylbenzylamine (0.14 mL, 0.7 mmol) in THF

(5 mL) and a,b-unsaturated ester 45 (50 mg, 0.3 mmol) in THF

(5 mL) were reacted at −78 ^◦C. After 2 h, the reaction was

warmed to −20 ^◦C, stirred for further 2 h. After puriﬁcation via

column chromatography (1 : 10, Et₂O : pentane) on silica, alde-

hyde 46 (8 mg, 7%) was isolated as a colorless oil (>98% de) with

spectroscopic data consistent to that above; [a]²_D⁴−5.9 (c 1.00,

CHCl₃); After further elution, cyclic ester 47 (59 mg, 66%) was

obtained as a colourless oil and (>98% de) with spectroscopic

data consistent with that above; [a]²_D⁴+3.4 (c 1.15, CHCl₃).

Alternatively, acetic anhydride (2.0 mL, 21.7 mmol) followed

by pyridine (2.0 mL, 30.0 mmol) and DMAP (5 mg, 0.04 mmol)

were added to the cyclic b-amino ester 42 (75 mg, 0.2 mmol)

in DCM (10 mL) and stirred under nitrogen at rt. After 16 h,

mixture was partitioned between Et₂O and aqueous saturated

CuSO₄solution and brine, organic layer dried and concentrated

in vacuo. Puriﬁcation via column chromatography on silica (1 :

10, Et₂O : pentane) gave acetate 44 (77 mg, 94%, >98% de) as

a viscous green oil with spectroscopic data consistent with that

reported above; [a]²_D⁴+8.9 (c 0.96, CHCl₃).

Preparation of tert-butyl-(E)-6-oxohex-2-enoate (45)

Preparation of tert-butyl-(1R,2S,5S,aS)-2-acetoxy-5-(N-

benzyl-N-(a-methylbenzylamino)-cyclopentanoate (48)

PCC (0.30 g, 1.3 mmol) was added to a solution of alcohol 56

(0.10 g, 0.5 mmol) and NaOAc (0.11 g, 1.3 mmol) in DCM

(10 mL) at 0 ^◦C. After 2 h Et₂O was added and the resultant

solution concentrated in vacuo, re-dissolved in DCM, dried and

concentrated in vacuo after being passed through a pad of silica

(eluent Et₂O) to furnish aldehyde 45 (54 mg, 56%) as a colourless

oil; v_max(ﬁlm) 1634, 1728, 2718; d_H(400 MHz, CDCl₃) 1.43

(9H, s, C(CH₃)₃), 2.43–2.46 (2H, m, C(4)H₂), 2.56–2.58 (2H, m,

C(5)H₂), 5.72 (1H, dt, J_2,315.6, J_2,41.9, C(2)H), 6.81 (1H, dt, J_3,2

15.6, J_3,46.7, C(3)H), 9.83 (1H, s, CHO); d_C(100 MHz, CDCl₃)

28.3 (C(CH₃)₃), 30.3 (C(5)H₂), 31.7 (C(4)H₂), 62.3 (C(6)H₂),

62.6 (C(CH₃)₃), 123.6 (C(2)H), 146.8 (C(3)H), 173.1 (CO₂),

Following the general procedure 1a, n-BuLi (2.5 M, 0.3 mL,

0.6 mmol), (S)-N-benzyl-N-a-methylbenzylamine (0.14 mL,

0.7 mmol) in THF (5 mL) and a,b-unsaturated ester 45 (50 mg,

◦

0.3 mmol) in THF (5 mL) were reacted at −78 C. After 2 h,

the reaction was warmed to −20 ^◦C and stirred for a further

2 h before work up. Acetic anhydride (2.0 ml, 21.7 mmol)

followed by pyridine (2.0 mL, 30.0 mmol) and DMAP (5 mg,

0.04 mmol) were added to this crude reaction mixture at rt

in DCM (10 mL). After 16 h stirring, mixture was diluted

with Et₂O, washed with aqueous saturated CuSO₄solution and

brine, dried and concentrated in vacuo. After puriﬁcation via

column chromatography (1 : 10, Et₂O : pentane) on silica,

acetate 48 (88 mg, 94%) was isolated as a white crystalline

+

203.1 (CHO); m/z (GCMS, CI⁺) 185.1178 (MH⁺, C₁₀H₁₇O₃

requires 185.1176); (GCMS, CI⁺) 208 (44%), 185 ((MH⁺), 100).

◦

Preparation of tert-butyl-(3S,aS)-3-(N-benzyl-N-(a-

methylbenzylamino)-6-oxohexanoate (46) and (1R,2S,5S,aS)-

2-hydroxy-5-(N-benzyl-N-(a-methylbenzylamino)-

cyclopentanoate (47)

solid; mp 152–153 C (DCM : heptane); [a]²_D⁴+6.7 (c 1.21,

CHCl₃); v_max(KBr) 1493, 1602, 1740, 2931, 2974, 3028, 3641;

d_H(400 MHz, CDCl₃) 1.31 (3H, d, J 6.5, C(a)CH₃), 1.39 (9H, s,

C(CH₃)₃), 1.61–1.64 (1H, m, C(3)H_AH_B), 1.71–1.74 (1H, m,

C(4)H_AH_B), 1.81–1.93 (2H, m, C(3)H_AH_B, C(4)H_AH_B), 1.96

(3H, s, CH₃CO₂), 2.88 (1H, app t, J_{1ax,6ax;1ax,2ax}4.4, C(1)H),

3.71 (1H, AB d, J 14.3, CH_AH_BPh), 3.74 (1H, AB d, J 14.6,

CH_AH_BPh), 3.89 (1H, q, J 6.5, C(a)H), 3.94 (1H, app q,

J_{2ax,3ax;2ax,3eq}8.1, C(2)H), 5.20–5.25 (1H, m, C(5)H), 7.18–7.43

(10H, m, 2x o/m/p-Ph); d_C(100 MHz, CDCl₃) 17.7 (C(a)CH₃),

21.1 (CH₃CO₂), 28.0 (C(CH₃)₃), 30.3 (C(3)H₂), 30.9 (C(4)H₂),

50.0 (CH₂Ph), 52.2 (C(1)H), 60.0 (C(a)H), 61.7 (C(2)H), 75.1

(C(5)H), 80.3 (C(CH₃)₃), 126.6, 126.7 2x(p-Ph), 127.6, 127.8,

128.0, 128.2, 128.3, 128.6 2x(o/m-Ph), 141.9, 144.4 2x(i-Ph),

Following the general procedure 1a, n-BuLi (2.5 M, 0.3 mL,

0.6 mmol), (S)-N-benzyl-N-a-methylbenzylamine (0.14 mL,

0.7 mmol) in THF (5 mL) and acceptor 45 (50 mg, 0.3 mmol)

in THF (5 mL) were reacted together to give the crude reaction

product as a brown oil. Puriﬁcation via column chromatography

(1 : 20, Et₂O : pentane) on silica gave 46 (58 mg, 54%) as

a colourless oil; [a]_D²⁴−6.6 (c 1.12, CHCl₃); v_max(ﬁlm) 1601,

1723, 2718, 2931, 2975, 3027, 3061; d_H(400 MHz, CDCl₃)

1.34 (3H, d, J 6.9, C(a)CH₃), 1.49 (9H, s, C(CH₃)₃), 1.68–

1.70 (2H, m, C(4)H₂), 1.82–1.85 (2H, m, C(2)H₂), 2.61 (1H,

170.4, 170.5 2x(CO₂); m/z (CI⁺) 438.2648 (MH⁺, C₂₇H₃₆NO₄

+

dt, J_5,46.5, J_{5 ,4}

ꢀ

4.2 C(5)H_AH_B), 2.73 (1H, dt, J_5,46.6, J_{5 ,4}

ꢀ

requires 438.2644); (EI⁺) 460 (60%), 438 ((MH)⁺, 100).

4.0, C(5)H_AH_B), 3.33–3.34 (1H, m, C(3)H), 3.50 (1H, AB

d, J 14.6, CH_AH_BPh), 3.69 (1H, AB d, J 14.9, CH_AH_BPh),

3.72 (1H, obst q, C(a)H), 7.22–7.40 (10H, 2x o/m/p-Ph), 9.76

(1H, br s, CHO); d_C(100 MHz, CDCl₃) 19.2 (C(a)CH₃), 26.0

(C(4)H₂), 28.0 (C(CH₃)₃), 37.2 (C(2)H₂), 42.4 (C(5)H₂), 50.0

(CH₂Ph), 52.8 (C(a)H), 57.7 (C(3)H), 81.6 (C(CH₃)₃), 126.8,

127.0 2x(p-Ph), 127.9, 128.0, 128.1, 128.2, 128.4 2x(o/m-Ph),

142.4, 144.1 2x(i-Ph), 186.1 (CO₂), 204.0 (CHO); m/z (CI⁺)

428.2807 (MH⁺+MeOH. C₂₆H₃₉NO₄⁺requires 428.2801); (EI⁺)

429 (28%), 428 (100), 396 ((MH)⁺, 10).

The more polar cyclic ester 47 (29 mg, 18%) was obtained

as a colorless oil; [a]_D²⁴+3.2 (c 1.15, CHCl₃); v_max(ﬁlm) 1622,

1698, 2875, 2890, 3463; d_H(400 MHz, CDCl₃) 1.32 (3H, d,

J 6.9, C(a)CH₃), 1.44 (9H, s, C(CH₃)₃), 1.70–1.75 (2H, m,

C(4)H_AH_B, C(3)H_AH_B), 1.74–1.77 (1H, m, C(4)H_AH_B), 1.92–

1.94 (1H, m, C(3)H_AH_B), 2.70 (1H, dd, J_1ax,6ax8.0, J_1ax,2ax4.4,

C(1)H), 3.69 (1H, AB d, J 14.6, CH_AH_BPh), 3.74 (1H, AB d,

J 14.7, CH_AH_BPh), 3.84 (1H, q, J 6.9, C(a)CH₃), 3.83–3.85

Alternatively, Ac₂O (0.07 mL, 0.76 mmol) followed by pyri-

dine (0.03 mL, 0.5 mmol) and DMAP (5 mg, 0.04 mmol) were

added to a stirred solution of alcohol 47 (150 mg, 0.4 mmol) at

rt in DCM (5 mL). After 16 h of stirring, the reaction mixture

was diluted with Et₂O, partitioned between aqueous saturated

CuSO₄solution and DCM, and the organic layer dried and

concentrated in vacuo. After column chromatography (1 : 2, Et₂O

: pentane) on silica, acetate 48 (158 mg, 97%) was isolated as a

white crystal_◦line solid with spectroscopic properties as above;

mp 151–152 C (DCM : heptane); [a]²_D⁴+6.7 (c 1.21, CHCl₃).

Preparation of (1S,2S,6S)-1-ethylcarboxylate-2-amino-6-

ethylcyclohexane-ethanoate (51)

Following the general procedure 4, Pd(OH)₂/C (0.1 g, 46%

w/w), b-amino ester 13 (0.22 g, 0.5 mmol) and MeOH (5 mL)

gave the cyclic ester 51 (0.12 g, 96%) as a clear oil without

further puriﬁcation; [a]²_D⁴+4.0 (c 0.51, CHCl₃); v_max(ﬁlm) 1727,

1 2 9 6

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

View Article Online

3373, 3428; d_H(400 MHz, CDCl₃) 1.11 (1H, app t, J_{3ax,4ax;3ax,2ax}

10.2, C(3)H_AH_B), 1.24, 1.29 (3H, t, J 6.9, 2x CH₂CH₃), 1.39

(1H, m, C(4)H_AH_B), 1.63 (1H, m, C(5)H_AH_B), 1.80 (2H, m,

C(3)H_AH_Band C(4)H_AH_B), 2.03 (2H, br d, J 13.6, C(2)NH₂),

2.12 (1H, m, C(6)CH_AH_B), 2.29 (1H, m, C(5)H_AH_B), 2.41 (1H,

m, C(6)CH_AH_B), 2.54 (1H, app t, J_{1ax,2ax;1ax,6eq}7.7, C(1)H), 3.03

(1H, m, C(2)H), 3.42 (1H, m, C(6)H), 4.08 (2H, q, J 6.9,

between DCM and brine, organic layers combined, dried and

concentrated in vacuo. Puriﬁcation via column chromatography

on silica (1 : 3, Et₂O : pentane) gave the piperidine 54 (0.79 g,

93%) as an orange oil; [a]²_D⁴−3.2 (c 0.81, CHCl₃); v_max(ﬁlm)

1638, 1734, 2941, 3341; d_H(400 MHz, CDCl₃) 1.36 (3H, d, J 7.0,

C(a)CH₃), 1.99 (1H, obst dd, J_A,B10.2, J_A,54.1, C(5)CH_AH_B),

2.06–2.20 (3H, m, C(5)H, C(6)H_AH_Band C(5)CH_AH_B), 2.41

(1H, app t, J_{4ax,3ax;4ax,5ax}6.5, C(4)H), 2.64 (1H, app t, J_{2ax,2eq;2ax.3ax}

11.9, C(2)H_AH_B), 3.02–3.09 (2H, m, C(6)H_AH_B, C(3)H), 3.31

(1H, dd, J_2eq,2ax11.9, J_2eq,3ax4.1, C(2)H_AH_B), 3.43 (3H, s,

ꢀ

CH₂CH₃), 4.27 (2H, q, J 6.9, CH₂CH₃); d_C(100 MHz, CDCl₃)

ꢀ

14.0 (CH₂CH₃), 14.2 (CH₂CH₃), 23.1 (C(4)H₂), 29.4 (C(5)H₂),

30.4 (C(3)H₂), 33.5 (C(2)HN), 36.1 (C(6)CH₂), 52.4 (C(1)CO₂),

52.6 (C(6)H), 60.2 (CH₂CH₃), 62.1 (CH₂CH₃), 171.6 (CO₂Et),

172.4 (CO₂Et^ꢀ); m/z (CI⁺) 258.1711 (MH⁺, C₁₃H₂₄NO₄⁺requires

258.1705); 258 ((MH)⁺, 100%), 212 (50).

ꢀ

CO₂CH₃), 3.64 (3H, s, CO₂CH₃), 3.71 (1H, AB d, J 13.8,

CH_AH_BPh), 3.92 (1H, AB d, J 13.8, CH_AH_BPh), 3.99 (1H, q, J

7.0, C(a)H), 7.16–7.39 (10H, m, 2x o/m/p-Ph); d_C(125 MHz,

CDCl₃) 15.9 (C(a)CH₃), 36.5 (C(5)CH₂), 37.8 (C(5)H), 49.9

(C(6)H₂), 50.4 (C(2)H₂), 51.4, 51.5 2x(CO₂CH₃), 51.7 (CH₂Ph),

53.0 (C(4)H), 56.3 (C(a)H), 57.4 (C(3)H), 126.5, 126.8 2x(p-Ph),

127.8, 127.9, 128.0, 128.2, 128.4, 128.5, 128.9 2x(o/m-Ph), 140.3,

143.6 2x(i-Ph), 171.9, 173.2 2x(CO₂); m/z (CI⁺) 425.2450 (MH⁺,

Preparation of (1S,2S,6S)-1-tert-butyl-carboxylate-2-amino-6-

tert-butylcyclohexane-ethanoate (52)

Following the general procedure 4, Pd(OH)₂/C (40 mg, 10%

w/w), b-amino ester 14 (0.40 g, 0.8 mmol) and MeOH (5 mL)

gave the cyclic ester 52 (0.24 g, 96%) as a clear oil without further

puriﬁcation; [a]²_D⁴+4.1 (c 1.00, CHCl₃); v_max(ﬁlm) 1726, 2876,

2954, 3012, 3379; d_H(400 MHz, CDCl₃) 1.00 (1H, dq, J_5ax,6ax4.9,

C₂₅H₃₃N₂O₄requires 425.2440); (EI⁺) 604 (7%), 483 (10), 425

+

((MH)⁺, 100).

Preparation of (3S,4S,5S)-3-amino-4-methoxycarbonyl-5-

methylethanoate-piperidine (55)

J_5ax,4eq2.0, C(5)H_AH_B), 1.12 (1H, app q, J_4,3;4,52.0, C(4)H_AH_B),

ꢀ

1.32–1.38 (1H, m, C(4)H_AH_B), 1.41 (9H, s, C(CH₃)₃), 1.48

ꢀ

(9H, s, C(CH₃)₃), 1.48–1.53 (1H, m, C(3)H_AH_B), 1.71 (1H, dq,

Following the general procedure 4, Pd(OH)₂/C (100 mg, 40%

w/w), protected piperidine 23 (250 mg, 0.5 mmol) and MeOH

(5 mL) gave the piperidine 55 (89 mg, 85%) as a clear oil without

further puriﬁcation; [a]²_D⁴−5.21 (c 0.94, CHCl₃); v_max(ﬁlm) 1651,

1732, 2955, 3360; d_H(400 MHz, CDCl₃) 1.25 (3H, br s, NH

and NH₂), 1.96 (1H, app t, J_2,36.9, C(5)CH_AH_B), 2.09–2.42

(5H, m, C(5)CH_AH_B, C(6)H₂, C(5)H, C(4)H), 2.94 (1H, dt, J_3,4

10.2, J_3,24.5, C(3)H), 3.11–3.18 (2H, m, C(2)H₂), 3.64 (3H, s,

J_5eq,6eq4.9, J_5eq,4eq2.0, C(5)H_AH_B), 1.82 (1H, app t, J_{6eq,1ax;6eq,1A}

3.6, C(6)H), 1.94 (1H, q, J_{2ax,1ax;2ax,3ax}8.8, C(2)H), 2.00 (1H,

q, J_A,6;A,B11.1, C(6)CH_AH_B), 2.12–2.18 (1H, m, C(3)H_AH_B),

2.24 (1H, dd, J_B,A11.1, J_B,68.7, C(6)CH_AH_B), 2.81–2.89 (1H,

m, C(1)H); d_C(100 MHz, CDCl₃) 24.6 (C(4)H₂), 28.5, 28.6

2x(C(CH₃)₃), 31.0 (C(5)H₂), 35.2 (C(6)H), 35.4 (C(3)H₂), 37.0

(C(2)H), 40.7 (C(5)CH₂), 53.1 (C(1)H), 80.8, 81.4 2x(C(CH₃)₃),

172.0, 174.1 2x(CO₂); m/z (CI⁺) 314.2345 (MH⁺, C₁₇H₃₂NO₄

CO₂CH₃), 3.71 (3H, s, CO₂CH₃); d_C(100 MHz, CDCl₃) 36.6

+

ꢀ

requires 314.2331); (EI⁺) 336 (52%), 314 (MH⁺, 100).

(C(5)H), 50.5 (C(4)H), 50.6 (C(6)H₂), 51.62, 51.64 (CO₂CH₃and

ꢀ

CO₂CH₃), 51.7 (C(3)H), 54.3 (C(2)H₂), 57.6 (C(5)CH₂), 172.0,

+

173.9 2x(CO₂CH₃); m/z (CI⁺) 231.1346 (MH⁺, C₁₀H₁₉N₂O₄

Preparation of (1S,2S,6S,aS)-1-carboxyl-2-amino-6-ethanoate-

cyclohexanoic acid (53)

requires 231.1345); 461 (33%), 339 (38), 231 ((MH)⁺, 100), 273

(34).

Following the general procedure 5, b-amino ester 52 (75 mg,

0.24 mmol) and TFA–DCM (5 mL) gave the cyclic ester 53

(34 mg, 71%) as a yellow solid after ion exchange chromato-

graphy (Dowex 50WX8-200, 1 M NH₄OH_(aq)eluent); (Found

C, 53.7; H, 7.5; N, 6.9. Calc. for C₉H₁₅NO₄: C, 53.7; H, 7.5;

N, 7.0%); mp 169–171 ^◦C (MeOH); [a]²_D⁴−0.8 (c 0.50, MeOH);

v_max(ﬁlm) 1645, 2502, 3369; d_H(400 MHz, MeOD) 1.04 (1H, br

d, J_4,3;4,57.1, C(4)H_AH_B), 1.11–1.24 (1H, m, C(5)H_AH_B), 1.31–

1.42 (2H, m, C(6)H, C(5)H_AH_B), 1.48–1.56 (1H, m, C(4)H_AH_B),

1.71–1.99 (2H, m, C(3)H₂), 2.10 (1H, dd, J_A,B11.1, J_A,64.3,

C(6)CH_AH_B), 2.19–2.26 (2H, m, C(6)CH_AH_B, C(2)H), 2.32 (1H,

dd, J_1ax,2ax8.6, J_1ax,6eq6.3, C(1)H), 2.81 (2H, br s, NH₂); d_C

(100 MHz, MeOD) 12.1 (C(4)H₂), 22.2 (C(5)H₂), 29.1 (C(3)H₂),

35.9 (C(6)H), 51.6 (C(6)CH₂), 52.0 (C(1)H), 56.3 (C(2)H), 176.1,

178.4 2x(CO₂); m/z (CI⁺) 265.1160 (MH⁺, C₁₁H₁₈N₂O₄Na⁺

required 265.1164); (EI⁺) 267 (21%), 265 ((MH)⁺, 100).

Alternatively, b-amino ester 52 (100 mg, 0.39 mmol) was

dissolved in 1 : 1 THF : aqueous 5 M LiOH solution and stirred

overnight, after which the solution was neutralised with 1 M

HCl and concentrated in vacuo. Puriﬁcation via ion exchange

chromatography (Dowex 50WX8-200, 1 M NH₄OH_(aq)eluent)

gave 53 (76 mg, 74%) as a yellow solid with spectroscopic

properties same as above.

Preparation of tert-butyl-(2E)-6-hydroxyhex-2-enoate (56)

n-BuLi (1.6 M in hexane, 14.1 mL, 22.5 mmol) was added

dropwise to a solution of tert-butyl triphenylphosphoranylidene

acetate (5.80 g, 23.0 mmol) in THF (15 mL) under N₂and

stirred at −78 ^◦C. After 30 min a solution of c-lactone (1.8 mL,

◦

20.9 mmol) in THF (5 mL) at −78 C was added via cannula

followed by the dropwise addition of DIBAL-H (1.0 M in

hexane, 20.5 mL, 20.5 mmol). The solution was then warmed

to rt and stirred overnight, before the addition of aqueous

sodium potassium tartrate solution; the resultant solution was

partitioned between EtOAc and 0.5 M HCl, the organic layer

washed with aqueous saturated K₂CO₃solution and brine, dried

and concentrated in vacuo to furnish the crude product 56 in 86%

de. Puriﬁcation by column chromatography on silica (1 : 1, Et₂O

: pentane) gave alcohol 56 (1.92 g, 49%, 89% de) as a colorless

oil; v_max(ﬁlm) 1457, 1653, 1715, 2934, 2980, 3428; d_H(400 MHz,

CDCl₃) 1.47 (9H, s, C(CH₃)₃), 1.72 (2H, tt, J_5,47.2, J_5,66.5,

C(5)H₂), 2.28 (2H, dt, J_4,57.2, J_4,36.0, C(4)H₂), 3.66 (2H, t, J_6,5

6.5, C(6)H₂), 5.78 (1H, d, J_2,315.1, C(2)H), 6.84 (1H, dt, J_3,2

15.1, J_3,46.0, C(3)H); d_C(100 MHz, CDCl₃) 28.1 (C(CH₃)₃),

28.3 (C(5)H₂), 31.0 (C(4)H₂), 62.0 (C(6)H₂), 62.5 (C(CH₃)₃),

123.5 (C(2)H), 147.0 (C(3)H), 173.1 (CO₂); m/z (GCMS, CI⁺)

187.1335 (MH⁺, C₁₀H₁₉O₃⁺requires 187.1334); (GCMS, CI⁺)

204 (60%), 187 ((MH⁺), 100).

Preparation of (3S,4S,5S,aS)-3-(N-benzyl-N-(a-

methylbenzylamino)-4-methoxycarbonyl-5-(methylethanoate)-

piperidine (54)

Preparation of tert-butyl-(2E)-7-hydroxyhept-2-enoate (57)

Tetrakis–palladium Pd(PPh₃)₄(31.1 mg, 0.20 mmol) was added

to a solution of N-allyl-piperidine 34 (0.93 g, 2.0 mmol) and

1,3-dimethylbarbituric acid (0.93 g, 6.0 mmol) in DCM (20 mL)

followed by vigorous stirring. After 16 h saturated aqueous

K₂CO₃was added, and the resultant solution partitioned

n-BuLi (2.5 M in hexane, 8.9 mL, 22.2 mmol) was added

dropwise to a solution of tert-butyl triphenylphosphoranylidene

◦

acetate (5.54 g, 22.0 mmol) in THF (15 mL) at −78 C. After

30 min a solution of d-valerolactone (1.9 mL, 20.0 mmol) in

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

1 2 9 7

View Article Online

THF (5 mL) at −78 ^◦C was added via cannula followed by the

dropwise addition of DIBAL-H (1.0 M in hexane, 19.6 mL,

19.6 mmol). The solution was then warmed to rt overnight,

before the addition of saturated aqueous sodium potassium

tartrate solution; the resultant solution was partitioned between

EtOAc and 0.5 M HCl, organic layer partitioned between aque-

ous saturated K₂CO₃solution and brine, dried and concentrated

in vacuo. Puriﬁcation via column chromatography on silica (1 : 1,

Et₂O : pentane) gave alcohol 57 as a clear oil (1.42 g, 36%, 92%

de) with spectroscopic properties consistent with those quoted

in the literature;^6bd_H(400 MHz, CDCl₃) 1.49 (9H, s, C(CH₃)₃),

1.58–1.61 (4H, m, C(5)H₂and C(6)H₂), 2.23 (2H, dt, J_4,35.7,

the alcohol 58 (0.43 g, 1.3 mmol) via cannula in DCM (5 mL).

After further stirring for 20 min, NEt₃(1.1 mL, 7.6 mmol) was

added, reaction stirred for 30 min and allowed to reach rt over

another 30 min, extracted with DCM, washed with brine and

concentrated in vacuo. Residue was re-dissolved in Et₂O, washed

with aqueous saturated NaHCO₃and brine solutions, dried and

re-concentrated in vacuo to afford the aldehyde 46 (0.37 g, 87%)

as a colourless oil after passing through a pad of silica (eluent

Et₂O) with spectroscopic data consistent with that above; [a]_D²⁴

−6.1 (c 1.00, CHCl₃).

Preparation of tert-butyl-(3S,aS)-3-(N-benzyl-N-(a-

methylbenzylamino)-7-oxoheptanoate (42)

J

_4,55.6, C(4)H₂), 3.67 (2H, t, J_7,66.2, C(7)H₂), 5.78 (1H, dt, J_3,2

15.4, J_3,45.6, C(3)H), 6.86 (1H, d, J_2,315.4, C(2)H), 7.37 (1H, s,

CH₂OH).

Anhydrous DMSO (0.14 mL, 1.95 mmol) was added to a

solution of oxalyl chloride (0.9 mL, 1.0 mmol) in DCM (5 mL)

at −78 ^◦C and stirred for 20 min followed by the addition of

alcohol 59 (0.20 g, 0.5 mmol) via cannula in DCM (5 mL).

After further stirring for 20 min, NEt₃(0.4 mL, 2.9 mmol) was

added, reaction stirred for 30 min and allowed to reach rt over

another 30 min, extracted with DCM, washed with brine, con-

centrated, re-dissolved in Et₂O, washed with aqueous saturated

NaHCO₃and brine solutions, dried and concentrated in vacuo

to afford the aldehyde 42 (182 mg, 91%) as a colourless oil after

column chromatography (eluent Et₂O) with spectroscopic data

consistent with that above; [a]²_D⁵−2.8 (c 1.00, CHCl₃).

Preparation of tert-butyl-(3S,aS)-3-(N-benzyl-N-(a-

methylbenzylamino)-6-hydroxyhexanoate (58)

Following the general procedure 1, n-BuLi (2.5 M, 5.6 mL,

13.9 mmol), (S)-N-benzyl-N-a-methylbenzylamine (3.0 mL,

14.1 mmol) in THF (8 mL) and alcohol 56 (0.75 g, 4.0 mmol)

in THF (8 mL) gave the crude reaction product. Puriﬁcation via

column chromatography (1 : 5, Et₂O : pentane) on silica gave

58 (1.27 g, 79%) as a colourless oil; [a]²_D⁴−12.6 (c 1.23, CHCl₃);

v_max(ﬁlm) 1723, 3415; d_H(400 MHz, CDCl₃) 1.32 (3H, d, J 6.8,

C(a)CH₃), 1.36–1.38 (1H, m, C(4)H_AH_B), 1.39 (9H, s, C(CH₃)₃),

1.48–1.50 (1H, m, C(4)H_AH_B), 1.63–1.66 (1H, m, C(5)H_AH_B),

1.81–1.83 (1H, m, C(5)H_AH_B), 1.90–1.92 (2H, m, C(2)H₂), 3.31–

3.33 (1H, m, C(3)H), 3.49 (1H, AB d, J 14.9, CH_AH_BPh), 3.54–

3.57 (2H, m, C(6)H₂), 3.80 (1H, AB d, J 14.9, CH_AH_BPh), 3.81

(1H, q, J 6.8, C(a)H), 7.20–7.43 (10H, 2x o/m/p-Ph); d_C

(100 MHz, CDCl₃) 20.5 (C(a)CH₃), 28.0 (C(CH₃)₃), 29.6

(C(5)H₂), 30.0 (C(4)H₂), 37.3 (C(2)H₂), 50.1 (CH₂Ph), 53.2

(C(3)H), 58.3 (C(a)H), 62.6 (C(6)H₂), 80.2 (C(CH₃)₃), 126.7,

127.0 2x(p-Ph), 127.9, 128.0, 128.1, 128.2, 128.5 2x(o/m-Ph),

141.7, 142.8 2x(i-Ph), 172.4 (CO₂); m/z (CI⁺) 398.2695 (MH⁺,

Preparation of tert-butyl-(S)-pyrrolidin-2-ylacetate (60)

Following the general procedure 4, Pd(OH)₂/C (0.1 g, 0.5 eq.

w/w), b-amino ester 46 (221 mg, 0.60 mmol) and MeOH (5 mL)

gave the cyclic ester 60 (109 mg, 96%) with spectroscopic

properties consistent with the literature as a clear oil without

further puriﬁcation; [a]²_D⁴−1.5 (c 1.00, CHCl₃);³⁰d_H(400 MHz,

CDCl₃) 1.32–1.41 (1H, m, C(3)H_AH_B), 1.41 (9H, s, C(CH₃)₃),

1.70–1.76 (2H, m, C(4)H₂), 1.89–1.93 (1H, m, C(3)H_AH_B), 2.42

(2H, app d, J_AB,56.5, CH₂CO₂), 2.90 (1H, dt, J_5,AB7.9, J_5,47.7,

C(5)H_AH_B), 3.03 (1H, dt, J_5,AB;5,47.9, 7.7, C(5)H_AH_B), 3.38–3.42

(1H, m, C(2)H).

+

C₂₅H₃₆NO₃requires 398.2695); (EI⁺) 421 (51%), 398 ((MH)⁺,

100).

Preparation of tert-butyl-(S)-piperidine-2-acetate (61)

Preparation of tert-butyl-(3S,aS)-3-(N-benzyl-N-(a-

Following the general procedure 4, Pd(OH)₂/C (50 mg, 40%

w/w), b-amino ester 42 (120 mg, 0.29 mmol) and MeOH (5 mL)

gave the crude cyclic ester 61 as a yellow oil. Puriﬁcation

via column chromatography on silica (4 : 6 : 0.1, Et₂O :

pentane : NEt₃) gave 61 as a yellow oil (78 mg, 86%) with

spectroscopic properties consistent with the literature;^6b[a]_D²⁴

+5.1 (c 0.92, CHCl₃); (lit.,^6b[a]_D²⁶+8.3 (c 1.35 CHCl₃); d_H

(400 MHz, CDCl₃) 1.11–1.18 (1H, m, C(5)H_AH_B), 1.21–1.49

(2H, m, C(4)H_AH_B, C(3)H_AH_B), 1.42 (9H, s, C(CH₃)₃), 1.59

(2H, app d, J 8.1, C(3)H_AH_B, C(5)H_AH_B), 1.72–1.76 (1H, app

d, J 5.1, C(4)H_AH_B), 2.09 (1H, br s, NH), 2.28 (2H, app d, J 7.1,

C(2^ꢀ)H₂), 2.64 (1H, dt., J 6.3, 2.6, C(6)H_AH_B), 2.70–2.89 (1H,

m, C(2)H), 3.04 (1H, d, J 6.3, C(6)H_AH_B).

methylbenzylamino)-7-hydroxyheptanoate (59)

Following the general procedure 1, n-BuLi (1.6 M, 1.10 mL,

2.6 mmol), (S)-N-benzyl-N-a-methylbenzylamine (0.4 mL,

2.5 mmol) in THF (5 mL) and alcohol 57 (100 mg, 0.8 mmol)

in THF (5 mL) gave the crude reaction product. Puriﬁcation via

column chromatography (1 : 5, Et₂O : pentane) on silica gave 59

(221 mg, 82%) as a colourless oil; [a]²_D⁴−12.8 (c 1.00, CHCl₃);

v_max(ﬁlm) 1602, 1723, 2876, 2912, 3341; d_H(400 MHz, CDCl₃)

1.31 (3H, d, J 6.9, C(a)CH₃), 1.33–1.42 (2H, m, C(5)H₂), 1.38

(2H, app d, J_4,3;4,55.5, C(4)H₂), 1.39 (9H, s, C(CH₃)₃), 1.44–1.46

(2H, m, C(6)H₂), 1.88 (1H, dd, J_2,214.7, J_2,39.5, C(2)H_AH_B),

1.96 (1H, dd, J_2,214.7, J_2,33.4, C(2)H_AH_B), 3.31–3.33 (1H, m,

C(3)H), 3.51 (1H, AB d, J 15.0, CH_AH_BPh), 3.60–3.68 (3H, m,

C(7)H₂OH), 3.81 (1H, AB d, J 15.0, CH_AH_BPh), 3.84 (1H, q,

J 6.9, C(a)H), 7.35–7.52 (10H, m, 2x o/m/p-Ph); d_C(100 MHz,

CDCl₃) 20.6 (C(a)CH₃), 22.9 (C(4)H₂), 28.1 (C(CH₃)₃), 32.6

(C(5)H₂), 33.2 (C(6)H₂), 37.6 (C(2)H₂), 50.1 (CH₂Ph), 53.8

(C(3)H), 58.5 (C(a)H), 63.0 (C(7)H₂), 80.0 (C(CH₃)₃), 126.6,

126.8 2x(p-Ph), 127.9, 128.0, 128.1, 128.3, 128.5 2x(o/m-Ph),

142.0, 143.1 2x(i-Ph), 172.2 (CO₂); m/z (CI⁺) 412.2849 (MH⁺,

Preparation of tert-butyl-(1R,2S,5S)-2-hydroxy-5-amino-

cyclopentanoate (62)

Following the general procedure 4, Pd(OH)₂/C (75 mg, 50%

w/w), b-amino ester 47 (150 mg, 0.35 mmol) and MeOH (5 mL)

gave the amino alcohol 62 (79 mg, 98%) as a clear oil without

further puriﬁcation; [a]²_D⁴+2.9 (c 0.55, CHCl₃); v_max(ﬁlm)

1718, 2872, 3003, 3364; d_H(400 MHz, MeOD) 1.44–1.49

(1H, m, C(4)H_AH_B), 1.49 (9H, s, C(CH₃)₃), 1.63–1.72 (1H, m,

C(3)H_AH_B), 2.06–2.13 (1H, m, C(3)H_AH_B), 2.18–2.28 (1H, m,

C(4)H_AH_B), 2.61 (1H, dd, J_1,28.6, J_1,53.6, C(1)H), 3.81 (1H, app

q, J 8.6, C(2)H), 4.46–4.49 (1H, m, C(5)H), 7.31 (1H, app d, J

4.4, O-H); d_C(100 MHz, MeOD) 27.5 (C(CH₃)₃), 29.8 (C(4)H₂),

32.9 (C(3)H₂), 52.1 (C(5)H), 58.8 (C(1)H), 73.6 (C(2)H), 81.2

+

C₂₆H₃₈NO₃requires 412.2852); (EI⁺) 413 (49%), 412 ((MH)⁺,

100).

Preparation of tert-butyl-(3S,aS)-3-(N-benzyl-N-(a-

methylbenzylamino)-6-oxohexanoate (46)

Anhydrous DMSO (0.36 mL, 5.04 mmol) was added to a

solution of oxalyl chloride (0.2 mL, 2.5 mmol) in DCM (5 mL)

at −78 ^◦C and stirred for 20 min followed by the addition of

+

(C(CH₃)₃), 171.2 (CO₂); m/z (CI⁺) 202.1451 (MH⁺, C₁₀H₂₀NO₃

requires 202.1443); (EI⁺) 243 (100%), 202 ((MH)⁺, 78).

1 2 9 8

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

View Article Online

+

Alternatively, acetate 63 (81 mg, 0.37 mmol) was stirred in

2.5 M LiOH dissolved in 1 : 3, H₂O : MeOH for 24 h, after

which it was neutralised with 1 M HCl, passed through a silica

frit (EtOAc as eluent) and concentrated in vacuo to furnish the

amino alcohol 62 (71 mg, 88%) as a clear oil with spectroscopic

properties consistent as these quoted above.

172.6 (CO₂); m/z (CI⁺) 216.1608 (MH⁺, C₁₁H₂₂NO₃requires

216.1600); (EI⁺) 279 (100%), 216 ((MH)⁺, 40).

Preparation of tert-butyl-(1R,2S,6S)-2-acetoxy-6-

aminocyclohexanoate (67)

Following the general procedure 4, Pd(OH)₂/C (50 mg, 17%

w/w), protected acetate 44 (300 mg, 0.64 mmol) and MeOH

(5 mL) gave the 67 as a brown oil without further puriﬁcation

(155 mg, 96%); [a]_D²⁴+97.1 (c 0.85, MeOH); v_max(ﬁlm) 1737,

3243; d_H(400 MHz, CD₃OD) 1.23–1.25 (1H, m, C(5)H_AH_B),

1.31–1.36 (1H, m, C(4)H_AH_B), 1.41 (9H, s, C(CH₃)₃), 1.49–1.51

(1H, m, C(3)H_AH_B), 1.60–1.68 (1H, m, C(4)H_AH_B), 1.90–1.94

(1H, m, C(3)H_AH_B), 2.03 (3H, s, CH₃CO₂), 2.03–2.08 (1H, m,

C(5)H_AH_B), 2.41 (1H, dd, J_1ax,6ax7.8, J_1ax,2eq3.0, C(1)H), 3.31–

3.38 (1H, m, C(6)H), 5.50 (1H, br s, C(2)H); d_C(125 MHz,

CD₃OD) 18.8 (C(4)H₂), 21.2 (CH₃CO₂), 27.2 (C(CH₃)₃), 29.0

(C(3)H₂), 30.4 (C(5)H₂), 47.1 (C(6)H), 52.1 (C(1)H), 71.1

(C(2)H), 81.2 (C(CH₃)₃), 170.3 (CH₃CO₂), 171.0 (CO₂tBu); m/z

(CI⁺) 258.1715 (MH⁺, C₁₃H₂₄NO₄⁺requires 258.1705); (EI⁺) 258

((MH)⁺, 100%), 202 (95).

Preparation of tert-butyl-(1R,2S,5S)-2-acetoxy-5-amino-

cyclopentanoate (63)

Following the general procedure 4, Pd(OH)₂/C (75 mg, 50%

w/w), b-amino ester 48 (150 mg, 0.33 mmol) and MeOH (5 mL)

gave the cyclic acetate 63 (77 mg, 93%) as a clear oil without

further puriﬁcation; [a]²_D⁴+4.1 (c 0.90, MeOH); v_max(ﬁlm) 1604,

1739, 2987, 3310; d_H(400 MHz, MeOD) 1.46 (9H, s, C(CH₃)₃),

1.46 (1H, obst dt, J 11.0, 7.9, C(4)H_AH_B), 1.68–1.74 (1H, m,

C(4)H_AH_B), 2.01 (3H, s, CH₃CO₂), 2.10–2.24 (2H, m, C(3)H₂),

2.72 (1H, dd, J 8.5, 5.0, C(1)H), 3.75 (1H, app dd, J 8.5, 7.9,

C(5)H), 5.39–5.50 (1H, m, C(2)H); d_C(100 MHz, MeOD) 20.8

(CH₃CO₂), 27.3 (C(CH₃)₃), 29.6 (C(4)H₂), 30.6 (C(3)H₂), 56.3

(C(1)H), 56.9 (C(5)H), 76.4 (C(2)H), 81.4 (C(CH₃)₃), 176.4,

181.2 2x(CO₂); m/z (CI⁺) 244.1553 (MH⁺, C₁₂H₂₂NO₄⁺requires

244.1549); (EI⁺) 267 (30%), 245 (34), 244 ((MH)⁺, 100).

Preparation of (1R,2S,6S)-2-hydroxy-6-aminocyclohexanoic

acid (68)

Preparation of (1R,2S,5S)-2-hydroxy-5-amino-cyclopentanoic

acid (64)

Following the general procedure 5, amino-ester 66 (50 mg,

0.23 mmol) and TFA–DCM (5 mL) gave the title compound

68 (27 mg, 73%) as a yellow solid after ion-exchange chro-

matography (Dowex 50WX8-200, 1 M NH₄OH_(aq)eluent); mp

Following the general procedure 5, amino-ester 62 (25 mg,

0.12 mmol) and TFA–DCM (5 mL) gave the b-amino acid

64 (12.3 mg, 86%) as a green solid after ion-exchange chro-

matogr_◦aphy (Dowex 50WX8-200, 1 M NH₄OH_(aq)eluent); mp

84–86 C (1 M NH₃); [a]²_D⁴+64.4 (c 0.41, H₂O); v_max(ﬁlm)

1731, 3209, 3318; d_H(400 MHz, D₂O) 1.48–1.52 (1H, m,

C(4)H_AH_B), 1.73–1.75 (1H, m, C(4)H_AH_B), 2.11–2.18 (2H, m,

C(3)H₂), 2.89 (1H, dd, J_1,27.1, J_1,56.4, C(1)H), 3.11–3.21 (1H,

m, C(5)H), 5.01–5.11 (1H, m, C(2)H); d_C(125 MHz, D₂O)

29.5 (C(4)H₂), 32.6 (C(3)H₂), 52.9 (C(5)H), 58.6 (C(1)H), 73.2

◦

139–141 C (1 M NH₃); [a]²_D⁴+17.1 (c 0.55, H₂O); v_max(ﬁlm)

1579, 2984, 3317, 3321; d_H(400 MHz, D₂O) 1.31–1.42 (3H,

m, C(4)H₂, C(5)H_AH_B), 1.51–1.69 (2H, m, C(3)H₂), 2.01–

2.09 (1H, m, C(5)H_AH_B), 2.31 (1H, dd, J_1ax,6ax10.8, J_1ax,2eq

2.8, C(1)H), 3.33 (1H, dt, J_6ax,1ax10.8, J_{6ax,6eq;6ax,5}7.8, C(6)H),

4.44 (1H, br s, C(2)H); d_C(100 MHz, D₂O) 18.2 (C(4)H₂),

30.6 (C(5)H₂), 32.8 (C(3)H₂), 46.8 (C(6)H), 55.8 (C(1)H), 68.2

(C(2)H), 174.1 (CO₂); m/z (CI⁻) 158.0811 ((M–H)⁻. C₇H₁₃NO₃

−

requires 158.0817); (EI⁻) 158 ((M–H)⁻, 100%).

(C(2)H), 173.2 (CO₂); m/z (CI⁺) 146.0811 (MH⁺, C₆H₁₂NO₃

+

requires 146.0817); (EI⁺) 169 (70%), 146 ((MH)⁺, 100).

Preparation of (1R,2S,6S)-2-acetoxy-6-aminocyclohexanoic

acid (69)

Preparation of (1R,2S,5S)-2-acetoxy-5-amino-cyclopentanoic

acid (65)

Following the general procedure 5, amino-ester 67 (75 mg,

0.29 mmol) and TFA–DCM (5 mL) gave the title compound

69 (49 mg, 84%) as an off-white solid after ion-exchange

chromatography (Dowex 50WX8-200, 1 M NH₄OH_(aq)eluent);

Following the general procedure 5, amino-ester 63 (20 mg, 0.08

mmol) and TFA–DCM (5 mL) gave the title compound 65

(14.1 mg, 92%) as a brown solid after ion-exchange chromatogra-

phy (Dowex 50WX8-200, 1 M NH₄OH_(aq)eluent); mp 92–94 ^◦C

(1 M NH₃); [a]²_D⁴+112.9 (c 0.55, H₂O); v_max(ﬁlm) 1736, 3211,

3318; d_H(400 MHz, D₂O) 1.50–1.54 (1H, m, C(4)H_AH_B), 1.71–

1.77 (1H, m, C(4)H_AH_B), 1.91 (3H, s, CH₃CO₂), 2.08–2.22 (2H,

m, C(3)H₂), 2.79 (1H, dd, J_1,26.7, J_1,55.1, C(1)H), 3.80–3.88

(1H, m, C(5)H), 5.27–5.29 (1H, m, C(2)H); d_C(125 MHz, D₂O)

21.4 (CH₃CO₂), 25.4 (C(4)H₂), 30.6 (C(3)H₂), 56.1 (C(5)H),

68.7 (C(1)H), 77.3 (C(2)H), 174.0, 180.9 2x(CO₂); m/z (CI⁺)

◦

mp 131–133 C (1 M NH₃); [a]²⁴+24.1 (c 1.05, H₂O); v_max

(KBr) 1646, 3020, 3431, 3444; d_H^D(400 MHz, D₂O) 1.24–1.52

(3H, m, C(3)H_AH_B, C(4)H_AH_B, C(5)H_AH_B), 1.52–1.57 (1H,

m, C(4)H_AH_B), 1.57–1.68 (1H, br s, C(5)H_AH_B), 2.04 (3H, s,

CH₃CO₂), 2.03–2.06 (1H, m, C(3)H_AH_B), 2.32 (1H, app t, J_1,6;1,2

8.9, C(1)H), 3.48 (1H, dt, J_6,18.9, J_6.6;6,57.6, C(6)H), 4.52 (1H,

br s, C(2)H); d_C(100 MHz, D₂O) 18.8 (C(4)H₂), 21.3 (CH₃CO₂),

29.2 (C(3)H₂), 30.7 (C(5)H₂), 47.2 (C(6)H), 52.2 (C(1)H), 71.3

(C(2)H), 170.4, 177.0 2x(CO₂); m/z (CI⁻) 201.0925 ((M–H)⁻.

+

188.0927 (MH⁺, C₈H₁₄NO₄requires 188.0923); (EI⁺) 211

C₉H₁₅NO₄requires 201.0923); (EI⁻) 201 ((M–H)⁻, 100).

−

(41%), 188 ((MH)⁺, 100).

Acknowledgements

Preparation of tert-butyl-(1R,2S,6S)-2-hydroxy-6-

aminocyclohexanoate (66)

The authors wish to thank the CICYT, Junta de Castilla y Leon

and F. S. E. for ﬁnancial support (SA 036/01), the Spanish

Ministerio de Educacion y Cultura for a doctoral fellowship

(S. H. D.), and New College, Oxford for a Junior Research

Fellowship (A. D. S.).

Following the general procedure 4, Pd(OH)₂/C (50 mg, 20%

w/w), protected cyclohexane 43 (250 mg, 0.59 mmol) and

MeOH (5 mL) gave the 66 as an orange oil without further

puriﬁcation (121.5 mg, 94%); [a]²_D⁴+42.6 (c 0.80, MeOH); v_max

(ﬁlm) 1719, 3214; d_H(400 MHz, CD₃OD) 1.26 (1H, app d, J 5.9,

C(5)H_AH_B), 1.49 (9H, s, C(CH₃)₃), 1.46–1.61 (2H, m, C(4)H₂),

1.78 (2H, br t, J 10.2, C(3)H₂), 1.92 (1H, br d, J 6.1, C(5)H_AH_B),

2.28 (1H, dd, J_1ax,6ax9.5, J_1ax,2eq3.0, C(1)H), 3.32 (1H, dt, J 3.0,

1.6, C(6)H), 4.39 (1H, br s, C(2)H); d_C(125 MHz, CD₃OD)

18.4 (C(4)H₂), 27.5 (C(CH₃)₃), 31.6 (C(5)H₂), 32.6 (C(3)H₂),

46.7 (C(6)H), 55.4 (C(1)H), 68.0 (C(2)H), 81.5 (C(CH₃)₃),

References

1 See: (a) L. F. Tietze and U. Beifuss, Angew. Chem., Int. Ed. Engl.,

1993, 32, 131; (b) T. L. Ho, Tandem Reactions in Organic Synthesis,

Wiley, New York, 1992; L. F. Tietze, Chem. Ind., 1995, 453; (c) L. F.

Tietze, Chem. Rev., 1996, 96, 115; (d) S. E. Denmark and A.

Thorarensen, Chem. Rev., 1996, 96, 137; (e) P. J. Parsons, C. S. Penkett

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

1 2 9 9

View Article Online

and A. J. Shell, Chem. Rev., 1996, 96, 195; (f) M. Malacria, Chem.

Rev., 1996, 96, 289.

Chem. Soc., 1998, 120, 10555; 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.

2 (a) R. D. Little and J. R. Dawson, Tetrahedron Lett., 1980, 21, 2609;

(b) S. Saito, Y. Horohara, O. Narahara and T. Moriwake, J. Am.

Chem. Soc., 1989, 111, 4533; (c) L.-C. Wang, A. L. Luis, K. Agapiou,

H.-Y. Jang and M. J. Krische, J. Am. Chem. Soc., 2002, 124, 2402;

(d) K. Takeda, N. Ohkawa, K. Hori, T. Koizumi and E. Yoshii,

Heterocycles, 1998, 47, 277; (e) M. Ono, K. Nishimura, Y. Nagaoka

and K. Tomioka, Tetrahedron Lett., 1999, 40, 6979.

3 For a review see: (a) C. Thebtaranonth and Y. Thebtaranonth,

Tetrahedron, 1990, 46, 1385; for other selected examples, see:;

(b) H. Yoshizaki, T. Tanaka, E. Yoshii, T. Koizumi and K. Takeda,

Tetrahedron Lett., 1998, 39, 47; (c) Y. Nagaoka, H. Inoue, N. El-

Koussi and K. Tomioka, Chem. Commun., 2002, 122; (d) H. Inoue,

Y. Nagaoka and K. Tomioka, J. Org. Chem., 2002, 67, 5864; (e) M.

Ono, K. Nishimura, H. Tsubouchi, Y. Nagaoka and K. Tomioka,

J. Org. Chem., 2001, 66, 8199.

10 J. G. Urones, N. M. Garrido, D. D´ıez, S. H. Dominguez and S. G.

Davies, Tetrahedron: Asymmetry, 1999, 10, 1637.

11 J. F. Costello, S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry,

1994, 5, 3919.

12 (a) S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1,

1994, 1129; (b) S. G. Davies, O. Ichihara and I. A. S. Walters, J. Chem.

Soc., Perkin Trans. 1, 1994, 1141; (c) S. G. Davies, A. D. Smith and

A. R. Cowley, SYNLETT, 2004, 1957.

13 A. Barco, S. Benetti, G. Spalluto, A. Casolari, G. P. Pollini and V.

Zanirato, J. Org. Chem., 1992, 57, 6279.

14 It has been shown that the introduction of a heteroatom, such as

nitrogen, in place of a carbon in a six membered ring does not change

the fundamental preference for the chair conformation that is seen

in cyclohexane. However, the N-protecting group may invert readily

between equatorial and axial positions by ‘umbrella inversion’ of the

N atom. The conformational preferences of piperidine and its N-alkyl

derivatives have been the subject of many structural investigations

and much controversy, with low temperature NMR measurements

and IR studies of NH overtones indicating that in the parent (NH)

piperidine, the predominant conformation at 25 ^◦C is that with N–

H_eq, in a ratio of 65 : 35 (N–H_eq: N–H_ax). N-alkyl piperidines have

been much less studied, but it seems that there is a tendency for N–R

to adopt an equatorial position. For instance, the currently accepted

value for the conformational free energy of the N–Me group in N-

methylpiperidine is 11.3 kJ mol⁻¹, a value larger than that accepted

for methylcyclohexane of 7.1 kJ mol⁻¹. For references that contain

this information see: (a) J. B. Lambert and Y. Takeuchi, Cyclic

Organonitrogen Stereodynamics, VCH, 1992; (b) T. A. Crabb and

A. R. Katritzky, Adv. Heterocycl. Chem., 1984, 36, 1; (c) F. A. L. Anet

and I. Yavari, J. Am. Chem. Soc., 1977, 99, 2794; (d) R. W. Baldock

and A. R. Katritzky, Tetrahedron Lett., 1968, 9, 1159; (e) R. W.

Baldock and A. R. Katritzky, J. Chem. Soc. B, 1968, 1470; (f) P. J.

Crowley, M. J. T. Robinson and M. G. Ward, Tetrahedron, 1977, 33,

915; (g) D. C. Appleton, J. McKenna, J. M. McKenna, L. B. Sims

and A. R. Walley, J. Am. Chem. Soc., 1976, 98, 292.

4 (a) T. Uyehara, N. Shida and Y. Yamamoto, Chem. Commun., 1989,

113; (b) T. Uyehara, N. Shida and Y. Yamamoto, J. Org. Chem., 1992,

57, 3139.

5 N. Shida, T. Uyehara and Y. Yamamoto, J. Org. Chem., 1992, 57,

5049.

6 For selected examples see: (a) S. G. Davies and O. Ichihara,

Tetrahedron: Asymmetry, 1991, 2, 183; (b) S. D. Bull, S. G. Davies,

S. Delgado-Ballester, M. Gianotti, P. M. Kelly, L. J. Kotchie, M.

Laderas and A. D. Smith, J. Chem. Soc., Perkin Trans. 1, 2001, 3112;

(c) S. D. Bull, S. G. Davies and A. D. Smith, J. Chem. Soc., Perkin

Trans. 1, 2001, 2931; (d) S. D. Bull, S. G. Davies, M. Gianotti, P. M.

Kelly, E. D. Savory and A. D. Smith, J. Chem. Soc., Perkin Trans. 1,

2002, 1858; (e) S. G. Davies, C. J. R. Hedgecock and J. M. McKenna,

Tetrahedron: Asymmetry, 1995, 6, 827; (f) M. E. Bunnage, A. J. Burke,

S. G. Davies, N. L. Millican, R. L. Nicholson, P. M. Roberts and

A. D. Smith, Org. Biomol. Chem., 2003, 3708; (g) S. Bailey, S. G.

Davies, A. D. Smith and J. M. Withey, Chem. Commun., 2002, 2910;

(h) M. E. Bunnage, A. M. Chippendale, S. G. Davies, R. M. Parkin,

A. D. Smith and J. M. Withey, Org. Biomol. Chem., 2003, 3698;

(i) S. G. Davies, D. D´ıez, 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.

7 J. G. Urones, N. M. Garrido, D. D´ıez, M. M. El Hammouni, S. H.

Dominguez, J. A. Casaseca, S. G. Davies and A. D. Smith, Org.

Biomol. Chem., 2004, 364.

15 Puriﬁcation gave the minor N-Me and N-tert-butyl diastereoisomers

33 and 37 contaminated with a small amount (<10%) of the

corresponding starting diester.

8 The lithium amide initiated tandem conjugate addition–cyclisation

reactions of functionalized a,b-unsaturated acceptors with cyclisa-

tion via displacement of an sp³leaving group (Cl, OTs etc) has been

previously reported, see: (a) D. A. Price, SYNLETT, 1999, 1919;

(b) M. Baenziger, L. Gobbi, B. P. Riss, F. Schaefer and A. Vaupel,

Tetrahedron: Asymmetry, 2000, 11, 2231; for related approaches, see:;

(c) P. O’Brien, D. W. Porter and N. M. Smith, SYNLETT, 2000,

1336; (d) J.-P. R. Hernet, M. J. McGrath, P. O’Brien, D. W. Porter

and J. Gilday, Chem. Commun., 2004, 1830; for examples of conjugate

addition–aldol reactions, see:; (e) M. Ono, K. Nishimura, Y. Nagaoka

and K. Tomioka, Tetrahedron Lett., 1999, 40, 6979; (f) M. Ono, K.

Nishimura, H. Tsubouchi, Y. Nagaoka and K. Tomioka, J. Org.

Chem., 2001, 66, 8199; (g) E. Richards, P. J. Murphy, F. Dinon,

S. Fratucello, P. M. Brown, T. Gelbrich and M. B. Hursthouse,

Tetrahedron, 2001, 57, 7771.

16 S. Masamune, W. Choy, J. S. Petersen and L. R. Sita, Angew. Chem.,

Int. Ed. Engl., 1985, 24, 1.

17 Conjugate addition of lithium amides to a,b-unsaturated esters

proceeds only when the ester can achieve the syn-s-cis conformation,

giving the corresponding (Z)-lithium enolate, see: N. Asao, T.

Uyehara and Y. Yamamoto, Tetrahedron, 1990, 46, 4563; S. G. Davies,

G. Hermann, A. D. Smith and M. J. Sweet, Chem. Commun., 2004,

46, 1128.

18 This model is consistent with that proposed by Yamamoto for a

similar lithium amide initiated dienedioate cyclisation; see ref. 9b.

19 Oshima et al. have demonstrated that raising the temperature in

related tandem conjugate–addition aldol reactions has a beneﬁcial

effect upon cyclisation, see: K. Yagi, T. Turitani, H. Shinokubo and

K. Oshima, Org. Lett., 2002, 3, 3111.

20 F. Garro-Helion, A. Merzouk and F. Guibe´, J. Org. Chem., 1993, 58,

9449.

9 For leading selected references that delineate the propensity of

oligomers of b-amino acids (b-peptides) to show deﬁned secondary

structural characteristics, see: (a) contributions from Seebach et al.;

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, 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; (b) contributions from

Gellman et al.: 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.

21 As shown by derivatisation with Moshers acid chloride and compar-

ison of the ¹H and ¹⁹F NMR of the derived amides and comparison

with an authentic standard.

22 E. Stahl, Thin Layer Chromatography, Springer-Verlag, Berlin, 1969,

p. 873.

23 J. R. Scheffer and R. A. Wostradowski, J. Org. Chem., 1972, 37, 4317.

24 J. D. Anderson, M. B. Baizer and J. P. Petrovich, J. Org. Chem., 1966,

31, 3890.

25 B. T. O’Neill, P. F. Thadeio, M. N. Bundesmann, A. M. Elder, S.

McLean and D. K. Bryce, Tetrahedron, 1997, 53, 11121.

26 F. Heaney, C. Burke, D. Cunningham and P. McArdle, J. Chem. Soc.,

Perkin Trans. 1, 2001, 622.

27 B. Cardillo, R. Galeazzi, G. Mobbili, M. Orena and M. Rossetti,

Heterocycles, 1994, 38, 2663.

28 R. M. Rodebaugh and N. H. Cromwell, J. Heterocycl. Chem., 1971,

8, 19.

29 C. M. Main, R. P. C. Cousins, G. Coumbarides and N. S. Simpkins,

Tetrahedron, 1990, 46, 523.

30 Although we report here the speciﬁc rotation of (S)-60 as {[a]²_D³−1.5

(c 1.00, CHCl₃)} we have previously reported the speciﬁc rotation

of (S)-60 as {[a]²_D³+1.0 (c 1.55, CHCl₃)},³¹which is of the same

magnitude and sign as that previously reported by Enders et al. {[a]_D²⁷

+1.5 (c 0.99, CHCl₃)}.³²Upon ester hydrolysis and ion exchange

1 3 0 0

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

View Article Online

chromatography, samples of (S)-60 prepared by the route described

in this paper, and in our previous report,³¹gave (S)-homoproline with

the same magnitude and sign of speciﬁc rotation {[a]²_D³+3.4 (c 1.00,

H₂O) and [a]²_D³+3.7 (c 0.83, H₂O), respectively} as reported in the

literature {[a]²_D⁵+4.0 (c 1.00, H₂O)}.³³The reasons for the discrepancy

in the data for (S)-60 is bewildering.

31 A. M. Chippindale, S. G. Davies, K. Iwamoto, R. M. Parkin, C. A. P.

Smethurst, A. D. Smith and H. Rodriguez-Solla, Tetrahedron, 2003,

59, 3253.

32 D. Enders and J. Wiedemann, Liebigs Ann. Chem., 1997, 699.

33 R. Busson and H. Vanderhaeghe, J. Org. Chem., 1978, 43,

4438.

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 2 8 4 – 1 3 0 1

1 3 0 1

Article Doi

Cyclic β-amino acid derivatives: Synthesis via lithium amide promoted tandem asymmetric conjugate addition-cyclisation reactions

DOI: 10.1039/b500223k

Source and publish data:

Authors:

Article abstract of DOI:10.1039/b500223k

Full text of DOI:10.1039/b500223k

Products guided by the article

R&D Labs maybe for 852052-27-8

Relevant to this article

Hot Product