SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of α-alkyl and β-alkyl aldehydes

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SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the

asymmetric synthesis of ꢀ-alkyl and ꢁ-alkyl aldehydes

Steven D. Bull, Stephen G. Davies,* Rebecca L. Nicholson, Hitesh J. Sanganee and

Andrew D. Smith

The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,

UK OX1 3QY. E-mail: steve.davies@chemistry.ox.ac.uk

Received 19th May 2003, Accepted 26th June 2003

First published as an Advance Article on the web 14th July 2003

The proclivity of α-branched N-2Ј-benzyl-3Ј-phenylpropionyl derivatives of (S)-4-benzyl-5,5-dimethyl-,

(S)-4-phenyl-5,5-dimethyl-, (S)-4-isopropyl-5,5-dimethyl-, (S)-4-benzyl- and (S)-4-benzyl-5,5-diphenyl-oxazolidin-

2-ones to generate directly 2-benzyl-3-phenylpropionaldehyde upon hydride reduction with DIBAL is investigated.

The (S)-4-benzyl-5,5-dimethyl-derivative proved optimal for inhibition of endocyclic nucleophilic attack, giving

2-benzyl-3-phenylpropionaldehyde in good yield upon reduction. Application of this methodology for the

asymmetric synthesis of chiral aldehydes via diastereoselective enolate alkylation of a range of (S)-N-acyl-4-benzyl-

5,5-dimethyloxazolidin-2-ones to aﬀord an array of α-substituted-N-acyl-5,5-dimethyloxazolidin-2-ones (85–94%

de) and subsequent reduction with DIBAL aﬀorded directly non-racemic α-substituted aldehydes without loss of

stereochemical integrity (87–94% ee). The extension of this protocol for the asymmetric synthesis of β-substituted

aldehydes is demonstrated, via the diastereoselective conjugate addition of a range of organocuprates to (S)-N-acyl-

4-phenyl-5,5-dimethyloxazolidin-2-ones which proceeds with high diastereoselectivity (generally >95% de).

Reduction of the conjugate addition products with DIBAL gives non-racemic β-substituted aldehydes in high

yields and in high ee (generally >95% ee). This methodology is exempliﬁed by the asymmetric synthesis of

(R)-3-isopropenylhept-6-enal, which has previously been used in the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-

3,9-decadien-1-yl acetate, a component of the sex pheromones of the California red scale.

Introduction

Homochiral aldehydes are used widely in organic synthesis,

with these versatile intermediates being utilised for a range of

complex transformations in total synthesis. Synthetically useful

homochiral aldehydes may be prepared directly from amino

acid or monosaccharide sources, but due to the inherent struc-

tural limitations of this approach, the majority of enantio-

merically enriched aldehydes are synthesised using chiral

auxiliary techniques. Although many versatile chiral auxiliaries

have been developed, only a small number allow direct access to

aldehydes upon reduction. For instance, Oppolzer et al. have

demonstrated that certain N-acylsultams 1 can be reduced

with DIBAL to aﬀord the corresponding aldehydes in excellent

yield and in high ee,¹and Myers’ pseudoephedrine auxiliary

has also been successfully used for the synthesis of some

non-racemic α-substituted aldehydes via reduction of N-acyl-

derivatives

2

with lithium triethoxyaluminium hydride.²

Similarly, an α-substituted N-acyl-2-phenylimino-2-oxazolidine

3 can be cleanly reduced with DIBAL to aﬀord the corre-

sponding homochiral aldehyde in good yield (Fig. 1).³

Fig. 1 Direct reduction of N-acyl auxiliaries to aldehydes.

Perhaps the most frequently used family of chiral auxil-

iaries in synthesis are the oxazolidin-2-ones, introduced initially

by Evans⁴and developed further within this group⁵and by

others.⁶Oxazolidin-2-ones exhibit high levels of stereocontrol

in a number of diastereoselective reactions including enol-

ate alkylations,⁷conjugate additions⁸and aldol reactions,⁹

although direct conversion of N-acyloxazolidin-2-ones to the

corresponding aldehydes is complicated by competing endo-

and exocyclic cleavage pathways. A variety of approaches have

been utilised to circumvent this problem, with the most

popular involving reduction to the homochiral alcohol fol-

lowed by chemoselective oxidation to the desired aldehyde.¹⁰

An alternative approach involves transamidation of the

N-acyloxazolidin-2-one to the corresponding Weinreb amide

with N,O-dimethylhydroxylamine and trimethylaluminium,¹¹

with subsequent DIBAL reduction giving the corresponding

aldehyde. Another less commonly used technique involves con-

version of the N-acyloxazolidin-2-one to the thioester, followed

by reduction with triethylsilane and palladium on carbon.¹²

Although N-acyl-derivatives of the related thiazolidine-2-

thione auxiliaries furnish the aldehyde directly upon DIBAL

reduction, the application of this methodology appears to be

limited (Fig. 2).¹³

There is therefore no current general methodology available

for the direct reduction of N-acyloxazolidinones to the corre-

sponding homochiral aldehydes.¹⁴Previous investigations from

this laboratory have shown that DIBAL reduction of achiral

N-acyl-5,5-dimethyloxazolidinones generate stable, tetrahedral

carbinol species which may be fragmented upon treatment with

base to the aldehyde, or in a tandem protocol with a lithiated

phosphonate reagent to the α,β-unsaturated ester.¹⁵This,

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 8 6 – 2 8 9 9

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 3

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With model compounds 10–12 in hand, their behaviour upon

reduction was probed via treatment with two equivalents of

DIBAL in DCM at Ϫ78 ЊC. Reduction of (S)-4-benzyl-N-acyl-

oxazolidinone 10 proceeded to complete conversion, and gave

selectively the desired aldehyde 13 in 86% isolated yield and

returned auxiliary 4 in 92% yield upon puriﬁcation. In con-

trast, reduction of the (S)-4-isopropyl- and (S)-4-phenyl-

N-acyloxazolidinones 11 and 12 furnished a mixture of

products, giving aldehyde 13 and the formate esters 14 and 15

(arising from endocyclic cleavage of the N-acyloxazolidinone)

respectively, plus the parent oxazolidinone auxiliary in each

case (Scheme 2). Reduction of the 4-isopropyl-derivative 11

gave, at 80% conversion, a 66 : 66 : 33 ratio of 13 : 5 : 14,¹⁹with

puriﬁcation by chromatography giving 13 in 54% yield, oxazol-

idinone 5 in 56% yield and formate ester 14 in 30% yield.

Reduction of the 4-phenyl-derivative 12 gave, at 100%

conversion, a 45 : 45 : 55 ratio of 13 : 6 : 15, furnishing 13 in

38% yield, oxazolidinone 6 in 26% yield and (S)-formate ester

14 in 14% isolated yield after puriﬁcation. The propensity of

the related N-acyl derivatives of (S)-4-benzyloxazolidinone 18

and (S)-4-benzyl-5,5-diphenyloxazolidinone 21 to yield alde-

hyde 13 upon reduction with DIBAL was next investigated.

Following standard procedures, (S)-4-benzyl-N-2Ј-benzyl-3Ј-

phenylpropionyloxazolidinone 16 and (S)-4-benzyl-N-2Ј-

benzyl-3Ј-phenylpropionyl-5,5-diphenyloxazolidinone 17 were

prepared in high yield, with DIBAL reduction (under identical

conditions to the SuperQuat derivative 10) giving a complex

mixture of products in each case. Reduction of the Evans’

(S)-4-benzyl-N-acyloxazolidinone 16 gave, at 87% conversion,

a 46 : 46 : 20 : 33 ratio of 13 : 18 : 19 : 20, which on puriﬁcation

aﬀorded aldehyde 13 in 27% yield, (S)-4-benzyloxazolidin-

2-one 18 in 27% yield, formate ester 19 in 13% yield and

Fig. 2 Methodology for the conversion of N-acyloxazolidinones to

aldehydes.

combined with the ability of homochiral SuperQuat auxiliaries

to control the stereoselectivity of alkylation reactions of

attached enolate fragments,¹⁶and conjugate addition reactions

to attached enones,¹⁷suggested a direct stereoselective synthesis

of homochiral α-substituted and β-substituted aldehydes. The

realisation of this strategy is described herein, part of which has

been communicated previously.¹⁸

Results and discussion

(S)-N-1Ј-hydroxyalkyloxazolidin-2-one 20 (as

a

single

Asymmetric synthesis of ꢀ-alkyl substituted aldehydes

diastereoisomer of unknown absolute conﬁguration at C-1Ј)

in 13% yield.²⁰Reduction of the (S)-4-benzyl-N-acyl-5,5-

diphenyloxazolidinone 17 gave, at 83% conversion, a 67 : 71 : 29

ratio of 13 : 21 : 22, which on puriﬁcation aﬀorded aldehyde

13,²¹5,5-diphenyloxazolidinone 21 in 66% yield and formate

ester 22 in 12% yield.

Initial investigations concentrated upon establishing conditions

for the direct reduction of homochiral N-acyl SuperQuat 5,5-

dimethyloxazolidinones to the corresponding α-substituted

aldehydes, employing a sterically demanding N-acyl side chain

as a model system to evaluate the eﬃciency of this method-

ology. (S)-4-Benzyl-, (S)-4-isopropyl- and (S)-4-phenyl-5,5-

dimethyloxazolidinones 4–6 respectively were therefore treated

with n-BuLi and hydrocinnamoyl chloride, to aﬀord N-hydro-

cinnamoyl oxazolidinones 7–9 in 94–98% yield. Subsequent de-

protonation with LHMDS and alkylation with BnBr gave the

desired N-2Ј-benzyl-3Ј-phenylpropionyl oxazolidinones 10–12

in 61–77% yields (Scheme 1).

Having demonstrated that (S)-4-benzyl-5,5-dimethyloxazol-

idin-2-one 4 was the auxiliary of choice for direct and eﬃcient

reduction of α-branched N-acyloxazolidinones to their corre-

sponding aldehydes for a model system, the generality of this

methodology for the asymmetric synthesis of α-alkyl substi-

tuted aldehydes was studied. SuperQuat auxiliary 4 was there-

fore N-acylated with 4-methylvaleryl chloride and butyryl

chloride, giving N-acyloxazolidinones 23 and 24 in 92% and

78% yield respectively. Subsequent deprotonation of N-acyl-

oxazolidinones 7, 23 and 24 with LHMDS, and alkylation of

the lithium enolate of 7 with methyl iodide, allyl bromide and

4-bromo-2-methyl-2-butene, and alkylation of the lithium

enolate of 23 and 24 with benzyl bromide gave N-acyl-2Ј-alkyl-

oxazolidin-2-ones 25–29 in 85–94% de.²²In each case the

conﬁguration of the major diastereoisomer was assigned in

accordance with the standard model for deprotonation/alkyl-

ation of N-acyloxazolidinones.²³Attempts to purify the mix-

ture of diastereoisomers 25–29 to homogeneity via repeated

chromatography were unsuccessful, with ¹H NMR spectro-

scopic analysis indicating no evidence of any enhancement in

diastereoisomeric purity (Scheme 3).

Treatment of the diastereoisomeric mixtures 25–29 (85–94%

de) with DIBAL in DCM at Ϫ78 ЊC aﬀorded, in each case, a

mixture of (S)-4-benzyl-5,5-dimethyloxazolidin-2-one 4 and

the enantiomerically enriched aldehydes 30–34 as the sole reac-

tion products. Puriﬁcation to homogeneity was readily achieved

via chromatography, giving oxazolidinone 4 in 81–98% yield

and the required aldehydes 30–34 in 74–95% isolated yield.

The ees of aldehydes 30–34 were determined by immediate

reduction of the puriﬁed aldehydes with LiAlH₄to the res-

pective alcohols,²⁴which were derivatised via treatment with

Scheme 1 Reagents and conditions: (i). n-BuLi, THF, Ϫ78 ЊC then

hydrocinnamoyl chloride, Ϫ78 ЊC to rt; (ii). LHMDS, THF, Ϫ78 ЊC

then BnBr, Ϫ78 ЊC to 0 ЊC; (iii) LHMDS, THF, 0 ЊC then BnBr, 0 ЊC.

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1

Scheme 2 Reagents and conditions: (i). DIBAL, DCM, Ϫ78 ЊC then NH₄Cl_(aq). Numbers in brackets refer to the product ratios derived from H

NMR spectroscopic analysis of the crude reaction mixture.

Scheme 4 Reagents and conditions: (i). DIBAL, DCM, Ϫ78 ЊC then

NH₄Cl_(aq)

.

Scheme 3 Reagents and conditions: (i). LHMDS, THF, Ϫ78 ЊC then

alkyl halide, Ϫ78 ЊC to 0 ЊC.

the lithium anions of (S)-4-benzyl-, (S)-4-isopropyl- and

(S)-4-phenyl-5,5-dimethyloxazolidinones 4–6 with cinnamoyl

chloride aﬀorded (S)-N-cinnamoyl-4-alkyl-5,5-dimethyloxazol-

idin-2-ones 35–37 in good yields, which were each subjected to

BF₃promoted conjugate addition of an organocuprate derived

from CuBrؒSMe₂complex and methylmagnesium bromide.

While conjugate addition to (S)-4-phenyl-N-cinnamoyloxazol-

idinone 37 gave the known (4S,3ЈS)-N-[(3-methyl)-dihydro-

cinnamoyl]-4-phenyl-5,5-dimethyloxazolidin-2-one 40 in >96%

de,¹⁷addition to the (S)-4-benzyl- and (S)-4-isopropyl-derived

substrates 35 and 36 proceeded with much lower levels of

diastereoselectivity, giving (4S,3ЈS)-N-[(3-methyl)dihydrocin-

namoyl]-4-benzyl-5,5-dimethyloxazolidin-2-one 38 in 29% de

and (4S,3ЈS)-N-[(3-methyl)dihydrocinnamoyl]-4-isopropyl-5,5-

dimethyloxazolidin-2-one 39 in 19% de. In the 4-phenyl case,

puriﬁcation by chromatography gave (4S,3ЈS)-40 in 99% yield

and in >96% de, while in the 4-isopropyl case [combined yield

of diastereoisomers 81%] repeated puriﬁcation yielded a homo-

genous sample of the major diastereoisomer (4S,3ЈS)-39 in

16% isolated yield. However, the diastereoisomers of the

4-benzyl-derivative (4S,3ЈS)-38 proved inseparable (29% de) by

repeated chromatography (88% isolated yield), and so were

taken on to the reduction stage as a mixture (Scheme 5).

Although there is no conclusive explanation for the remarkable

disparity in stereodirecting capability shown by the SuperQuat

oxazolidinones in organocuprate conjugate addition reactions,

(R)-Mosher’s acid chloride and the ¹⁹F NMR spectra of the

resulting Mosher’s esters compared with those prepared from

authentic racemic alcohols.²⁵Within experimental error, the ees

of the alcohols corresponds to the des of the starting N-acyl-

oxazolidinones 25–29, indicating that no racemisation had

occurred at the stereogenic centres of aldehydes 30–34 under

the reductive conditions of the reaction (Scheme 4).

Having demonstrated that diastereoselective alkylation of

SuperQuat oxazolidinone enolates followed by DIBAL reduc-

tion allows the direct synthesis of enantiomerically enriched

α-substituted aldehydes, the extension of this methodology

for the asymmetric synthesis of β-substituted aldehydes via

diastereoselective conjugate addition and DIBAL reduction

was investigated.²⁶

Asymmetric synthesis of ꢁ-substituted aldehydes

The diastereoselective conjugate addition of organocuprates

and other nucleophilic reagents to homochiral α,β-unsaturated

compounds has been widely used in asymmetric synthesis.²⁷

Initial studies on the application of organocuprate method-

ology for the asymmetric synthesis of β-substituted aldehydes

were directed towards determining which SuperQuat auxiliary

4–6 would be best suited to this approach. N-Acylation of

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Scheme 6 Reagents and conditions: (i). DIBAL, DCM, Ϫ78 ЊC then

NH₄Cl_(aq)

.

one 42 aﬀording the desired conjugate addition products 43–47

in >91% de. With the exception of N-acyloxazolidinone 47,

puriﬁcation of each of the major diastereoisomers to homo-

geneity via chromatography was possible, giving β-substituted

oxazolidinone derivatives 43–47 in >58% yield, with subsequent

treatment of 43–47 with DIBAL aﬀording the desired β-substi-

tuted aldehydes 48–52 in 72–90% yield. The ees of aldehydes 41

and 48–52 were determined as >91% ee,³¹consistent with no

loss of stereochemical integrity of the β-centre upon produc-

tion of the aldehyde (Scheme 7).

The utility of this methodology was further exempliﬁed by

the synthesis of (R)-3-isopropenylhept-6-enal 55, which has

previously been used in the synthesis of (3Z,6R)-3-methyl-6-

isopropenyl-3,9-decadien-1-yl acetate 56, a component of the

sex pheromones of the California red scale. Conjugate addition

of the isopropenyl-derived organocuprate to the readily pre-

pared N-acyloxazolidinone 53 gave β-isopropenyl substituted

oxazolidinone 54 in 63% yield and >95% de after puriﬁcation,

which on reduction with DIBAL gave the desired aldehyde

55 {[α]²_D⁵ϩ8.6 (c 1.2, CHCl₃), lit.³²[α]_Dϩ9.0 (c 1.4, CHCl₃)} in

84% yield and in >95% ee (Scheme 8).³¹

Scheme 5 Reagents and conditions: (i). n-BuLi, THF, Ϫ78 ЊC then

cinnamoyl chloride, THF, Ϫ78 ЊC to rt; (ii) MeMgBr, CuBrؒSMe₂, BF₃ؒ

Et₂O, THF–SMe₂(v : v 1 : 2), Ϫ40 ЊC.

this selectivity parallels related work by Hruby, who showed

that organometallic conjugate addition to Evans’ (S)-4-pheny-

loxazolidin-2-one derivatives proceeded with much higher levels

of diastereoselectivity than addition to the (S)-4-benzyloxazol-

idin-2-one derivatives.²⁸

Reduction of (4S,3ЈS)-4-phenyl-40 (>96% de) with DIBAL

in DCM at Ϫ78 ЊC aﬀorded (S)-3-phenylbutanal 41 in 88%

yield, whose speciﬁc rotation {[α]²_D⁵ϩ33.8 (c 0.5, Et₂O); lit.²⁹[α]²_D⁵

ϩ38.0 (c 0.2, Et₂O), lit.³⁰[α]²_D⁵ϩ37.1 (c 0.2, Et₂O)} conﬁrmed

the sense of asymmetric induction at C(3) in the conjugate

addition reaction. Similarly, treatment of the 4-Bn and 4-ⁱPr

derivatives 38 and 39 (>98% de and 29% de respectively) gave

aldehyde 41 (71% and 76% yield respectively) and the parent

oxazolidinone as the only reaction products upon treatment

with DIBAL (Scheme 6).

In conclusion, we have demonstrated that both α-substituted

and β-substituted aldehydes may be selectively prepared by

direct reduction of N-acyl-5,5-dimethyloxazolidin-2-ones

with DIBAL in DCM with no loss of stereochemical integrity.

The further application of this methodology for complex

natural product synthesis³³is currently under way within this

laboratory.

While reduction of each N-acyl-5,5-dimethyloxazolidinone

38–40 furnished selectively the aldehyde upon treatment with

DIBAL, (S)-4-phenyl-5,5-dimethyloxazolidin-2-one

4 was

Experimental

chosen as the auxiliary of choice for the asymmetric syn-

thesis of β-substituted aldehydes due to the high level of

diastereoselectivity noted upon conjugate addition to N-acyl

derivative 37. Further investigations were directed toward

establishing the generality of this protocol, with the BF₃

promoted conjugate addition of a range of organocuprates to

(S)-N-cinnamoyl-4-phenyl-5,5-dimethyloxazolidin-2-one 37 or

the known (S)-N-crotonyl-4-phenyl-5,5-dimethyloxazolidin-2-

General experimental

All reactions were carried out under nitrogen or argon using

standard vacuum line techniques, using glassware that was

ﬂame dried and cooled under nitrogen. THF and Et₂O were

distilled from sodium–benzophenone ketyl; DCM was distilled

from calcium hydride prior to use. n-Butyllithium was used as a

Scheme 7 Reagents and conditions: (i). RЈMgX, Me₂SؒCuBr, BF₃, Me₂S : THF (v : v 1 : 2), Ϫ40 ЊC; (ii). DIBAL, DCM Ϫ78 ЊC then NH₄Cl_(aq)

.

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Scheme 8 Reagents and conditions: (i). CH_2᎐᎐C(Me)MgBr, Me₂SؒCuBr, BF₃ؒEt₂O, Me₂S–THF, Ϫ40 ЊC; (ii). DIBAL, DCM, Ϫ78 ЊC then NH₄Cl_(aq)

.

solution in hexanes and was titrated against diphenylacetic acid

prior to use. LHMDS was used as supplied (Aldrich) as a 1 M

solution in THF. DIBAL was used as supplied (Aldrich) as a

1 M solution in hexanes. LiAlH₄was used as supplied (Aldrich)

as a 1 M solution in THF. CuBrؒSMe₂was recrystallised from

SMe₂and pentane immediately prior to use. Grignard reagents

were used as solutions in THF and titrated against menthol

and phenanthroline. All other reagents were used as supplied

without further puriﬁcation. Flash column chromatography

was performed on silica gel (Kieselgel 60). TLC was performed

on Merck aluminium sheets coated with 0.2 mm silica gel

60 F₂₅₄. Plates were visualised either by UV light (254 nm),

iodine, ammonium molybdate (7% solution in ethanol) or

potassium permanganate (1% in 2% aqueous acetic acid, con-

taining 7% potassium carbonate). Infra red spectra were

recorded as thin ﬁlms or KBr discs using a Perkin-Elmer

PARAGON 1000 FT-IR spectrometer. Selected peaks are

Representative Procedure 1

n-BuLi (1.1 eq) was added to a stirred solution of the oxazol-

idin-2-one (1.0 eq) in THF at Ϫ78 ЊC. After 15 minutes, the acid

chloride (1.3 eq) was added dropwise and stirred at Ϫ78 ЊC for

15 minutes before being warmed to rt. After 2 hours, the reac-

tion mixture was quenched with saturated aqueous NH₄Cl

solution and acetic acid, extracted with EtOAc, washed sequen-

tially with saturated aqueous NaHCO₃and brine and dried.

The organic extracts were concentrated in vacuo and puriﬁed

by either ﬂash column chromatography on silica gel or

recrystallisation.

Representative Procedure 2a and 2b

LHMDS (1.5 eq) was added to a stirred solution of N-acyl-

oxazolidin-2-one (1.0 eq) in THF (a) at 0 ЊC or (b) at Ϫ78 ЊC.

After 30 minutes, the alkyl halide (3.0 eq) was added via syringe

to the resultant enolate and the reaction mixture stirred at 0 ЊC

for 5 hours before the addition of saturated aqueous NH₄Cl

solution, and the solution extracted with EtOAc, washed with

brine and dried. The organic extracts were concentrated in

vacuo and puriﬁed by ﬂash column chromatography on silica

gel.

1

reported in cm^Ϫ1. H NMR spectra were recorded on Varian

Gemini 200 (200 MHz), Bruker DPX-200 (200 MHz),

Bruker DPX-400 (400 MHz), Bruker DQX-400 (400 MHz) or

Bruker AM-500 (500 MHz) spectrometers. Chemical shifts

(δ_H) are reported in parts per million (ppm) and are refer-

enced to the residual solvent peak. Coupling constants (J)

are measured in Hertz. Two dimensional COSY spectra were

recorded on the Bruker DPX-200 (200 MHz), the Bruker

DQX-400 (400 MHz) or the Bruker DPX-400 (400 MHz)

spectrometers. ¹³C spectra were recorded at 50.31 MHz on

the Varian Gemini 200 or the Bruker DPX-200 spectro-

meters, at 100.62 MHz on the Bruker DQX-400 or the Bruker

DPX-400 spectrometers and at 125.77 MHz on the Bruker

AM-500 spectrometer. Low resolution mass spectra (m/z)

were recorded on either a VG Masslab 20–250 instrument (CI,

NH₃) or Platform instrument (APCI). MALDI spectra were

recorded on a Micromass MALDI TOF SPEC 2E spectro-

meter. Major peaks are listed with intensities quoted as per-

centages of the base peak. Accurate mass measurements were

recorded on a VG Autospec and a Waters 2790-Micromass

LCT electrospray ionisation mass spectrometer operating at a

resolution of 5000 full width half height. Positive ion spectra

were calibrated relative to PEG with tetraoctylammonium

bromide as the internal lock mass. Negative ion spectra were

calibrated relative to poly--alanine with leucine enkephalin

as the internal lock mass. Optical rotations were recorded on a

Perkin-Elmer 241 polarimeter, using a path length of 10 cm, in

spectroscopic grade solvents (Aldrich), with concentrations

(c) given in g/100 cm³, solvent and temperature as recorded.

Elemental analyses were obtained by Mrs A. Douglas of

the Inorganic Chemistry Analytical Department using an

Elementar Vario EL combustion elemental analyser. Melting

points were recorded on a Gallenkamp Hot Stage apparatus

and are uncorrected.

Representative Procedure 3

DIBAL (2.0 eq) was added dropwise to a stirred solution of N-

acyloxazolidin-2-one (1.0 eq) in CH₂Cl₂at Ϫ78 ЊC. The reac-

tion was quenched at Ϫ78 ЊC after 20 minutes with saturated

aqueous NH₄Cl solution, warmed to rt and stirred for a further

20 minutes. The resultant mixture was ﬁltered through Celite^®

(eluent: CH₂Cl₂), dried, and concentrated in vacuo.

Representative Procedure 4

LiAlH₄(2.0 eq) was added to a stirred solution of aldehyde

(1.0 eq) in THF at 0 ЊC. After 10 minutes the reaction was

quenched with ice and EtOAc and stirred for a further 3 hours

at rt. The resultant mixture was ﬁltered through Celite^®, dried

and concentrated in vacuo. The crude reaction mixture was

puriﬁed by ﬂash column chromatography on silica gel to

furnish the desired alcohol.

Representative Procedure 5

RMgHal (3.0 eq) was added to a stirred solution of freshly

recrystallised CuBrؒSMe₂(1.5 eq) in SMe₂and THF (v : v 1 : 2)

at Ϫ40 ЊC. After 10 minutes, BF₃ؒEt₂O (1.5 eq) was added

dropwise via syringe. The resultant mixture was stirred for

10 minutes before addition of N-acyl-5,5-dimethyloxazolidin-2-

one (1.0 eq) via cannula as a solution in THF. After 20 hours,

saturated aqueous NH₄Cl was added and the solvents evapor-

ated. EtOAc and water (v : v 3 : 1) was added to the solid residue

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and the resultant suspension ﬁltered through glass wool before

the organic layer was washed sequentially with 10% NH₄OH

(x 2), water and brine. The resultant solution was dried, concen-

trated in vacuo and puriﬁed by ﬂash column chromatography

on silica gel to give the desired product.

(1.10 mL, 8.97 mmol) in THF (40 mL) furnished 10 (0.93 g,

73%) as a white solid by ﬂash column chromatography; R_f0.29

[7 : 1 hexane : Et₂O]; mp 84–86 ЊC [hexane–Et₂O]; [α]²_D²

ϩ38.9 (c = 1.0, CHCl₃); δ_H(400 MHz, CDCl₃) 0.84 [3H, s,

C(CH₃)_A(CH₃)_B], 1.18 [3H, s, C(CH₃)_A(CH₃)_B], 2.50 [1H, dd,

J 14.6, 9.9, CHCH_AH_BPh], 2.73 [1H, dd, J 14.6, 3.4, CHCH_A-

H_BPh], 2.83–3.11 [4H, m, CH(CH₂Ph)₂], 4.25 [1H, dd, J 9.9,

3.4, CHCH₂Ph], 4.74–4.82 [1H, m, CH(CH₂Ph)₂], 7.16–7.32

[15H, m, PhH ]; δ_C(100 MHz, CDCl₃) 22.0, 27.6 [C(CH₃)₂],

34.9 [CHCH₂Ph], 38.6, 39.0 [CH(CH₂Ph)₂], 45.8 [CHCH₂Ph],

63.3 [CH(CH₂Ph)₂], 81.7 [C(CH₃)₂], 126.4, 126.6 [p-Ph], 128.4,

128.6, 129.0, 129.1, 129.3 [m/o-Ph], 137.1, 138.7, 138.9 [i-Ph],

Preparationof(S )-3-(3Ј-phenylpropionyl)-4-benzyl-5,5-dimethyl-

oxazolidin-2-one 7

Following Representative Procedure 1, n-BuLi (1.3 M, 1.1 mL,

1.48 mmol), (S)-4 (300 mg, 1.46 mmol) and hydrocinnamoyl

chloride (0.24 mL, 1.60 mmol) in THF (40 mL) furnished 7

(481 mg, 98%) as a pale yellow oil after ﬂash column chromato-

graphy; R_f0.24 [5 : 1 hexane : Et₂O]; C₂₁H₂₃NO₃requires C,

74.75, H, 6.9, N, 4.15%; found C, 75.0, H, 6.6, N, 4.15%; [α]²_D²

Ϫ27.8 (c = 1.0, CHCl₃); δ_H(400 MHz, CDCl₃) 1.33 [3H, s,

C(CH₃)_A(CH₃)_B], 1.37 [3H, s, C(CH₃)_A(CH₃)_B], 2.86 [1H, dd,

J 14.4, 9.5, CHCH_AH_BPh], 2.93–2.99 [2H, m, CH₂CH₂Ph], 3.13

152.1 [C᎐O endocyclic], 175.5 [C᎐O exocyclic]; ν_max(KBr) 1781

᎐

[C᎐O exocyclic], 1696 [C᎐O endocyclic]; m/z APCIϩ 206 [90%,

᎐

SQH^ϩ], 428 [100%, MH^ϩ]; HRMS C₂₈H₃₀NO₃[MH^ϩ] requires

428.2221; found 428.2236.

Preparation of (S )-3-(2Ј-benzyl-3Ј-phenylpropionyl)-4-isopropyl-

5,5-dimethyloxazolidin-2-one 11

[1H,dd,

CH₂CH₂Ph], 4.51 [1H, dd, J 9.5, 3.9, CHCH₂Ph], 7.19–7.33

[10H, m, PhH ]; ν_max(CHCl ) 1774 [C᎐O exocyclic], 1698 [C᎐O

J 14.4, 3.9, CHCH_AH_BPh], 3.22–3.29 [2H, m,

Following Representative Procedure 2a, LHMDS (2.10 mL,

2.07 mmol), 8 (0.40 g, 1.38 mmol) and benzyl bromide (0.49

mL, 4.15 mmol) in THF (10 mL) furnished 11 (0.32 g, 61%) as a

white solid after ﬂash column chromatography; R_f0.3 [5 : 1

hexane : Et₂O]; mp 80–81 ЊC [hexane–Et₂O]; [α]²_D²ϩ37.5 (c = 1.0,

CHCl₃); δ_H(400 MHz, CDCl₃) 0.52 [3H, d, J 6.8, CH(CH₃)_A-

(CH₃)_B], 0.70 [3H, s, C(CH₃)_A(CH₃)_B], 0.71 [3H, d, J 6.8,

CH(CH₃)_A(CH₃)_B], 1.32 [3H, s, C(CH₃)_A(CH₃)_B], 1.84–2.18 [1H,

m, CH(CH₃)₂], 2.83–3.12 [4H, m, CH(CH₂Ph)₂], 3.87 [1H,

d, J 2.8, CHCH(CH₃)₂], 4.85–4.93 [1H, m, CH(CH₂Ph)₂],

7.11–7.35 [10H, m, PhH ]; δ_C(50 MHz, CDCl₃) 16.7, 21.6

[CH(CH₃)₂], 21.6 [CH(CH₃)₂], 28.1, 29.8 [C(CH₃)₂], 39.3, 40.0

[CH(CH₂Ph)₂], 45.8 [CHCH(CH₃)₂], 66.7 [CH(CH₂Ph)₂], 82.7

[C(CH₃)₂], 126.8, 126.9 [p-Ph], 128.9, 129.6, 129.8 [m/o-Ph],

᎐

3

endocyclic]; δ_C(125 MHz, CDCl₃) 22.2, 28.4 [C(CH₃)₂], 30.4,

35.2 [C(4)CH₂Ph and CH₂CH₂Ph], 37.2 [CH₂CH₂Ph], 63.5

[C(4)H], 82.3 [C(CH₃)₂], 126.5, 127.0, 128.5, 128.7, 128.9, 129.3

[p/m/o-Ph], 137.2, 140.7 [i-Ph], 152.9 [C᎐O endocyclic], 173.0

᎐

[C᎐O exocyclic]; m/z (CI^ϩ, NH ), 338 (100%, MH^ϩ).

᎐

3

Preparation of (S )-3-(3Ј-phenylpropionyl)-4-isopropyl-5,5-di-

methyloxazolidin-2-one 8

Following Representative Procedure 1, n-BuLi (10.50 mL, 21.0

mmol), (S)-5 (3.00 g, 19.1 mmol) and hydrocinnamoyl chloride

(3.69 mL, 24.84 mmol) in THF (75 mL) furnished 8 (5.19 g,

94%) as a pale yellow oil after ﬂash column chromatography; R_f

0.16 [5 : 1 40–60 ЊC petrol : Et₂O]; C₁₇H₂₃NO₃requires C, 70.6,

H, 8.0, N, 4.8%; found C, 70.5, H, 8.3, N, 4.65%; [α]²_D⁵ϩ33.6

(c = 1.3, CHCl₃); δ_H(400 MHz, CDCl₃) 0.91 [3H, d, J 6.9,

CH(CH₃)_A(CH₃)_B], 0.99 [3H, d, J 7.0, CH(CH₃)_A(CH₃)_B], 1.32

[3H, s, C(CH₃)_A(CH₃)_B], 1.49 [3H, s, C(CH₃)_A(CH₃)_B], 2.05–2.16

[1H, m, CH(CH₃)₂] 2.95–3.08 [2H, m, CH₂CH₂Ph], 3.22–3.39

[2H, m, CH₂CH₂Ph], 4.14 [1H, d, J 6.5, CHCH(CH₃)₂], 7.17–

139.1, 139.4 [i-Ph], 153.6 [C᎐O endocyclic], 176.1 [C᎐O exo-

᎐

cyclic]; ν_max(KBr) 1771 [C᎐O exocyclic], 1695 [C᎐O endocyclic];

᎐

m/z APCIϩ 336 [60%, MH^ϩϪ CO₂], 380 [50%, MH^ϩ], 402

[100%, MNa^ϩ]; HRMS C₂₄H₃₀NO₃[MH^ϩ] requires 380.2221;

found 380.2238.

Preparation of (S )-3-(2Ј-benzyl-3-phenyl-propionyl)-4-phenyl-

5,5-dimethyloxazolidin-2-one 12

7.31 [5H, m, PhH ]; ν_max(CHCl ) 1774 [C᎐O exocyclic], 1699

᎐

3

[C᎐O endocyclic]; δ (125 MHz, CDCl ) 17.0, 21.4 [CH(CH ) ],

᎐

C

3

3 2

Following Representative Procedure 2a, LHMDS (0.93 mL,

0.93 mmol), 9 (200 mg, 0.62 mmol) and benzyl bromide

(0.24 mL, 1.86 mmol) in THF (10 mL) furnished 12 (200 mg,

77%) as a white solid after ﬂash column chromatography;

R_f0.23 [5 : 1 hexane : Et₂O]; mp 148–150 ЊC [hexane–Et₂O];

[α]²_D²ϩ43.2 (c = 0.5, CHCl₃); δ_H(400 MHz, CDCl₃) 0.79 [3H,

s, C(CH₃)_A(CH₃)_B], 1.06 [3H, s, C(CH₃)_A(CH₃)_B], 2.79–3.05

[4H, m, CH(CH₂Ph)₂], 4.74 [1H, s, CHPh], 4.86–4.93 [1H, m,

CH(CH₂Ph)₂], 7.16–7.30 [15H, m, PhH ]; δ_C(100 MHz, CDCl₃)

23.9, 28.6 [C(CH₃)₂], 39.2, 39.8 [CH(CH₂Ph)₂], 46.4 [CHPh],

67.3 [CH(CH₂Ph)₂], 82.3 [C(CH₃)₂], 126.5, 126.7, 126.9 [p-Ph],

128.6, 128.9, 129.2, 129.6, 129.7 [m/o-Ph], 136.5, 139.1, 139.4

28.7 [C(CH₃)₂], 29.5 [C(4)CH], 30.7 [CH₂CH₂Ph], 36.9

[CH₂CH₂Ph], 66.3 [C(4)H], 82.8 [C(CH₃)₂], 126.2, 128.4, 128.5

[p/m/o-Ph], 140.5 [i-Ph], 153.5 [C᎐O endocyclic], 173.0 [C᎐O

᎐

exocyclic]; m/z (CI^ϩ, NH₃), 290 (100%, MH^ϩ).

Preparation of (S )-3-(3Ј-phenylpropionyl)-4-phenyl-5,5-di-

methyloxazolidin-2-one 9

Following Representative Procedure 1, n-BuLi (1.15 mL, 2.9

mmol), (S)-5 (500 mg, 2.6 mmol) and hydrocinnamoyl chloride

(0.5 mL, 3.41 mmol) in THF (20 mL) furnished 9 (793 mg,

94%) as a white solid after recrystallisation; mp 148–150 ЊC

[hexane–Et₂O] [α]²_D⁵ϩ35.9 (c = 1.0, CHCl₃); δ_H(400 MHz,

CDCl₃) 0.99 [3H, s, C(CH₃)_A(CH₃)_B], 1.58 [3H, s, C(CH₃)_A-

(CH₃)_B], 2.88–3.01 [2H, m, CH₂CH₂Ph], 3.31–3.35 [2H, m,

CH₂CH₂Ph], 5.06 [1H, s, C(4)H ], 7.01–7.53 [10H, m, PhH ];

[i-Ph], 153.1 [C᎐O endocyclic], 175.6 [C᎐O exocyclic]; ν_max(KBr)

᎐

1777 [C᎐O endocyclic], 1703 [C᎐O exocyclic]; m/z APCIϩ 414

᎐

[95%, MH^ϩ], 436 [100%, MNa^ϩ]; HRMS C₂₇H₃₀NO₃[MH^ϩ]

requires 416.2221; found 416.2234.

ν_max(CHCl ) 1780 [C᎐O exocyclic], 1703 [C᎐O endocyclic];

᎐

3

Preparation of 2-benzyl-3-phenylpropionaldehyde 13³⁴from

(S )-10

δ_C(125 MHz, CDCl₃) 23.7, 28.9 [C(CH₃)₂], 30.3 [CH₂CH₂Ph],

37.3 [CH₂CH₂Ph], 66.9 [C(4)H], 81.5 [C(CH₃)₂], 126.2, 128.4,

128.5, 128.9 [p/m/o-Ph], 136.3, 140.7 [i-Ph], 153.2 [C᎐O endo-

᎐

cyclic], 172.2 [C᎐O exocyclic]; HRMS C H NO [MH^ϩ]

Following Representative Procedure 3, DIBAL (0.70 mL,

0.70 mmol) and (S)-10 (150 mg, 0.35 mmol) in CH₂Cl₂(5 mL)

furnished 13 (68 mg, 86%) as a clear, colourless oil and (S)-4 as

a white solid (66 mg, 92%) after ﬂash column chromatography.

Data for 13; R_f0.33 [7 : 1 hexane : Et₂O]; δ_H(400 MHz, CDCl₃)

2.74–2.82 [2H, m, CH(CH₂Ph)_A(CH₂Ph)_B], 2.99–3.06 [3H, m,

CH(CH₂Ph)_A(CH₂Ph)_Band CH(CH₂Ph)₂], 7.17–7.34 [10H, m,

PhH ], 9.75 [1H, s, CHO].

᎐

20 22

3

requires 324.1595; found 324.1604.

Preparation of (S )-3-(2Ј-benzyl-3Ј-phenylpropionyl)-4-benzyl-

5,5-dimethyloxazolidin-2-one 10

Following Representative Procedure 2b, LHMDS (4.49 mL,

4.49 mmol), 7 (1.00 g, 2.99 mmol) and benzyl bromide

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 8 6 – 2 8 9 9

2891

View Article Online

Preparation of 2-benzyl-3-phenylpropionaldehyde 13 and

(S )-2-(2Ј-benzyl-3Ј-phenylpropionylamino)-1,1-dimethyl-2-

isopropylethyl formate 14 from (S )-11

Preparation of (S )-3-(2Ј-benzyl-3Ј-phenylpropionyl)-4-benzyl-

5,5-diphenyloxazolidin-2-one 17

n-BuLi (0.4 mL, 0.64 mmol) was added to a stirred solution

of (S)-4-benzyl-5,5-diphenyloxazolidin-2-one (200 mg, 0.61

mmol) in anhydrous THF (20 mL) at 0 ЊC. After stirring

for 5 minutes, hydrocinnamoyl chloride (0.11 mL, 0.73 mmol)

was added dropwise via syringe and the reaction mixture

allowed to warm to ambient temperature. After 20 hours the

reaction mixture was quenched with saturated aqueous

ammonium chloride solution, extracted with diethyl ether,

washed sequentially with 1 M hydrochloric acid, 1 M sodium

hydroxide and brine, dried over MgSO₄and concentrated in

vacuo. Puriﬁcation by ﬂash column chromatography on silica

Following Representative Procedure 3, DIBAL (1.10 mL,

0.80 mmol) and (S)-11 (150 mg, 0.40 mmol) in CH₂Cl₂(5 mL)

furnished 13 (48 mg, 54%) as a clear oil, (S)-14 (46 mg, 30%) as

a white solid and (S)-5³⁵(35 mg, 56%) as a white solid after

ﬂash column chromatography. Data for (S)-14; R_f0.3 [1 : 1

hexane : Et₂O]; m.p 86–87 ЊC [hexane–Et₂O]; [α]²_D²Ϫ4.3 (c = 1.0,

CHCl₃); δ_H(400 MHz, CDCl₃) 0.42 [3H, d, J 6.8, CH(CH₃)_A-

(CH₃)_B], 0.53 [3H, d, J 6.9, CH(CH₃)_A(CH₃)_B], 0.86 [3H, s,

C(CH₃)_A(CH₃)_B], 1.39 [3H, s, C(CH₃)_A(CH₃)_B], 1.89–1.95 [1H,

m, CH(CH₃)₂], 2.75–2.82 [1H, m, CH(CH₂Ph)₂], 2.85–2.92 [2H,

m, CH(CH₂Ph)_A(CH₂Ph)_B], 2.98–3.04 [2H, m, CH(CH₂Ph)_A-

(CH₂Ph)_B], 3.63 [1H, dd, J 10.3, 2.3, CHCH(CH₃)₂], 5.48 [1H,

d, J 10.3, NH ], 7.13–7.30 [10H, m, PhH ], 7.81 [1H, s, OCHO];

δ_C(100 MHz, CDCl₃) 16.2, 22.0 [CH(CH₃)₂], 23.9, 24.8

[C(CH₃)₂], 27.4 [CH(CH₃)₂], 39.1, 39.4 [CH(CH₂Ph)₂], 52.8

[CH(CH₂Ph)₂], 59.7 [CHCH(CH₃)₂], 85.5 [C(CH₃)₂], 126.4

[p-Ph], 128.4, 128.5, 128.6, 129.0, 129.1 [m/o-Ph], 139.4, 139.5

aﬀorded

(S)-3-(3Ј-phenylpropionyl)-4-benzyl-5,5-diphenyl-

oxazolidin-2-one (267 mg, 0.58 mmol, 95%) as a pale yellow oil;

R_f0.38 [3 : 1 30–40 ЊC petroleum ether : Et₂O]; [α]²_D⁴Ϫ214.17

(c 1.2, CHCl₃); δ_H(400 MHz, CDCl₃) 2.556 [4H, m, CHCH₂Ph

& CH(CH_AH_BPh)(CH_CH_DPh)], 2.867 [1H, dd, J 13.9, 8.6, CH-

(CH_AH_BPh)(CH_CH_DPh)],3.090[1H,dd,J14.5,6.9,CH(CH_AH_B-

Ph)(CH_CH_DPh)], 4.427–4.500 [1H, m, CH(CH₂Ph)₂], 5.520

[1H, dd, J 4.7, 7.7, CHCH₂Ph], 6.586–6.606 [2H, m, PhH ],

6.927–6.969 [2H, m, PhH ], 6.987–7.129 [8H, m, PhH ], 7.174–

7.435 [13H, m, PhH ]; δ_C(100 MHz, CDCl₃) 30.2, 37.0

[CH₂CH₂Ph], 36.6 [CHCH₂Ph], 61.9 [CHCH₂Ph], 88.5 [CPh₂],

125.9, 126.2, 126.4, 126.5 [p-Ph], 128.2, 128.3, 128.4, 128.4,

128.8, 128.9, 129.0 [m/o-Ph], 136.2, 137.5, 140.3, 141.4 [i-Ph],

[i-Ph], 160.2 [OCHO], 173.5 [C᎐O]; ν

(KBr) 1726 [C᎐O

᎐

max

formate ester], 1666 [C᎐O amide]; m/z APCIϩ 336 [100%,

᎐

MH^ϩϪ HCO₂H], 404 [10%, MNa^ϩ]; HRMS C₂₄H₃₂NO₃

[MH^ϩ] requires 382.2377; found 382.2370.

Preparation of 2-benzyl-3-phenylpropionaldehyde 13,

(S )-2-(2Ј-benzyl-3Ј-phenylpropionylamino)-1,1-dimethyl-

2-phenylethyl formate 15 from (S )-12

152.0 [C᎐O endocyclic], 171.6 [C᎐O exocyclic]; ν_max(ﬁlm) 1783,

᎐

1699 [C᎐O]; HRMS C H NO [MH^ϩ] requires 462.2064,

31 28

3

found 462.2090; m/z ES ϩ 484 [95%, MNa^ϩ].

Following Representative Procedure 3, DIBAL (0.96 mL,

0.68 mmol) and (S)-12 (140 mg, 0.34 mmol) in CH₂Cl₂(5 mL)

furnished 13 (30 mg, 38%) as a clear oil, (S)-15 (19 mg, 14%) as

a white solid and (S)-6 (38 mg, 26%) as a cream solid after ﬂash

column chromatography. Data for (S)-15; R_f0.39 [1 : 1 hexane :

Et₂O]; mp 78–81 ЊC [hexane–Et₂O]; [α]²_D²Ϫ25.0 (c = 0.5, CHCl₃);

δ_H(400 MHz, CDCl₃) 1.01 [3H, s, C(CH₃)_A(CH₃)_B], 1.17 [3H, s,

C(CH₃)_A(CH₃)_B], 2.60–2.78 [1H, m, CH(CH₂Ph)₂], 2.83–3.06

[4H, m, CH(CH₂Ph)₂], 4.72 [1H, d, J 9.2, CHPh], 6.12 [1H, d,

J 9.2, NH ], 6.91–7.28 [15H, m, PhH ], 7.80 [1H, s, OCHO];

δ_C(100 MHz, CDCl₃) 23.6, 24.8 [C(CH₃)₂], 39.2, 39.4 [CH-

(CH₂Ph)₂], 53.0 [CH(CH₂Ph)₂], 60.6 [CHPh], 84.5 [C(CH₃)₂],

126.2, 126.4, 127.4 [p-Ph], 128.1, 128.3, 128.5, 128.6, 129.1

[m/o-Ph], 137.8, 139.1, 139.5 [i-Ph], 160.2 [OCHO], 172.8

LHMDS (0.65 mL, 0.65 mmol) was added dropwise to a

stirred solution of (S)-3-(3Ј-phenylpropionyl)-4-benzyl-5,5-di-

phenyloxazolidin-2-one (200 mg, 0.43 mmol) in anhydrous

THF (10 mL) at Ϫ78 ЊC. After stirring for 30 minutes, benzyl

bromide (0.15 mL, 1.30 mmol) was added dropwise via syringe

and the resultant mixture was warmed to 0 ЊC. After stirring for

5 hours the reaction mixture was quenched with saturated

aqueous ammonium chloride solution, extracted with ethyl

acetate, washed with brine, dried and concentrated in vacuo.

Puriﬁcation by ﬂash column chromatography aﬀorded 17 (124

mg, 52%) as a pale yellow oil and returned (S)-3-(3Ј-phenyl-

propionyl)-4-benzyl-5,5-diphenyloxazolidin-2-one (59 mg,

30%); R_f0.40 [5 : 1 30–40 ЊC petroleum ether : Et₂O]; [α]²_D⁴

Ϫ119.9 (c 1.95, CHCl₃); δ_H(400 MHz, CDCl₃) 2.56 [4H, m,

[C᎐O]; ν (ﬁlm) 1723 [C᎐O formate ester], 1670 [C᎐O amide];

᎐

max

m/z APCIϩ 370 [100%, MH^ϩϪ HCO₂H], 416 [75%, MH^ϩ], 439

[80%, MNa^ϩ]; HRMS C₂₇H₃₀NO₃[MH^ϩ] requires 416.2221;

found 416.2234.

CHCH₂Ph

& CH(CH_AH_BPh)(CH_CH_DPh)], 2.87 [1H, dd,

J 13.9, 8.6, CH(CH_AH_BPh)(CH_CH_DPh)], 3.090 [1H, dd, J 14.5,

6.9, CH(CH_AH_BPh)(CH_CH_DPh)], 4.43–4.50 [1H, m, CH(CH₂-

Ph)₂], 5.52 [1H, dd, J 4.7, 7.7, CHCH₂Ph], 6.59–6.61 [2H, m,

PhH ], 6.93–6.97 [2H, m, PhH ], 6.99–7.13 [8H, m, PhH ], 7.17–

7.44 [13H, m, PhH ]; δ_C(100 MHz, CDCl₃) 36.1 [CHCH₂Ph],

37.2, 38.0 [CH(CH₂Ph)₂], 46.1 [CH(CH₂Ph)₂], 62.1 [CHCH₂-

Ph], 88.1 [CPh₂], 125.7, 126.2, 126.3, 126.4, 126.5 [p-Ph],

128.0, 128.1, 128.2, 128.4, 128.6, 128.8, 128.9, 129.3 [m/o-Ph],

Preparation of (S )-3-(2Ј-benzyl-3Ј-phenylpropionyl)-4-

benzyloxazolidin-2-one 16

Following Representative Procedure 2b, LHMDS (2.43 mL,

2.43 mmol), (S)-3-(3-phenylpropionyl)-4-benzyloxazolidin-2-

one (500 mg, 1.62 mmol) and benzyl bromide (0.58 mL, 4.86

mmol) in THF (25 mL) furnished (S)-16 (520 mg, 80%) as a

white solid after ﬂash column chromatography; R_f0.1 [5 : 1 40–

60 ЊC petrol : Et₂O]; mp 98–99 ЊC [hexane–Et₂O]; [α]²_D²ϩ94.2

(c = 1.0, CHCl₃); δ_H(400 MHz, CDCl₃) 2.43–2.49 [1H, m,

CH₂CHCH_AH_BPh], 2.84–2.97 [4H, m, CH(CH₂Ph)_A(CH_AH_B-

Ph)_Band CH₂CHCH_AH_BPh], 3.00–3.19 [1H, m, CH(CH₂Ph)_A-

(CH_AH_BPh)_B], 3.77–3.81 [1H, m, CH_AH_BCHCH₂Ph], 3.93–3.95

[1H, m, CH_AH_BCHCH₂Ph], 4.40–4.46 [1H, m, CH₂CHCH₂Ph],

4.46–4.71 [1H, m, CH(CH₂Ph)₂], 6.97–7.34 [15H, m, PhH ];

δ_C(50 MHz, CDCl₃) 38.0, 38.6, 39.2 [CH(CH₂Ph)₂and

CH₂CHCH₂Ph], 46.7 [CH(CH₂Ph)₂], 55.5 [CH₂CHCH₂Ph],

66.1 [CH₂CHCH₂Ph], 126.9, 127.7 [p-Ph], 128.8, 128.9, 129.3,

136.1, 137.4, 138.5, 128.9, 141.2 [i-Ph], 151.7 [C᎐O endocyclic],

᎐

174.4 [C᎐O exocyclic]; ν

(KBr) 1783, 1700 [C᎐O]; HRMS

᎐

max

C₃₈H₃₄NO₃[MH^ϩ] requires 552.2534, found 552.2534; m/z

CIϩ 460 [40%, MH^ϩϪ CH₂Ph], 508 [100%, MH^ϩϪ CO₂], 552

[85%, MH^ϩ].

Preparation of 2-benzyl-3-phenylpropionaldehyde 13,

(S )-2-(2Ј-benzyl-3Ј-phenylpropionylamino)-2-benzylethyl form-

ate 19, (S )-3-(2Ј-benzyl-1Ј-hydroxy-3Ј-phenylpropyl)-4-benzyl-

oxazolidin-2-one 20 from (S )-16

Following Representative Procedure 3, DIBAL (1.00 mL, 1.00

mmol) and (S)-16 (200 mg, 0.50 mmol) in CH₂Cl₂(8 mL)

furnished 13 (32 mg, 27%) as a clear colourless oil, 20 (26 mg,

13%) as a white solid, (S)-19 (26 mg, 13%) as a white solid

and 18 (25 mg, 27%) as a white solid and returned unreacted

(S)-16 (40 mg, 20%) after ﬂash column chromatography.

129.6, 129.8 [m/o-Ph], 135.6, 139.3, 139.4 [i-Ph], 153.3 [C᎐O

᎐

endocyclic], 175.8 [C᎐O exocyclic]; ν (KBr) 1770 [C᎐O endo-

᎐

max

cyclic], 1689 [C᎐O exocyclic]; m/z APCIϩ 356 [30%, MH^ϩ

Ϫ

᎐

CO₂], 374 [100%, MH^ϩϪ CO], 400 [100%, MH^ϩ]; HRMS

C₂₆H₂₆NO₃[MH^ϩ] requires 400.1908; found 400.1921.

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 8 6 – 2 8 9 9

2892

View Article Online

Data for 20: R_f0.1 [1 : 1 hexane : Et₂O]; mp 87–90 ЊC [hexa-

ne–Et₂O]; [α]²_D⁵ϩ32.4 (c = 0.25, CHCl₃); δ_H(400 MHz, CDCl₃)

2.53 [1H, dd, J 14.0, 6.5, CH(CH_AH_BPh)(CH₂Ph)], 2.613 [1H,

dd, J 13.8, 10.8, CH(CH₂Ph)(CH_CH_DPh)], 2.66–2.78 [3H, m,

CH(CH_AH_BPh)(CH_CH_DPh) and OH ], 3.15–3.21 [1H, m,

CH(CH₂Ph)₂], 3.36 [1H, app. t, J 8.3, CH_AH_BCHCH₂Ph], 3.40–

3.50 [2H, m, CHCH₂Ph], 3.57–3.64 [1H, m, CH₂CHCH₂Ph],

3.77 [1H, dd, J 8.7, 4.1, CH_AH_BCHCH₂Ph], 5.27 [1H, dd, J 8.8,

5.3, CH(OH)], 6.99–7.36 [15H, m, PhH ]; δ_C(100 MHz, CDCl₃)

36.2, 36.5, 40.1 [CH(CH₂Ph)₂and CH₂CHCH₂Ph], 44.64

[CH(CH₂Ph)₂], 55.3 [CH₂CHCH₂Ph], 66.7 [CH₂CHCH₂Ph],

81.8 [CH(OH)], 126.2, 127 [i-Ph], 128.5, 128.7, 128.9, 128.9,

1.48–1.64 [3H, m, CH₂CH(CH₃)₂], 2.85–2.94 [3H, m,

CHCH_AH_BPh and CH₂CH₂CH(CH₃)₂], 3.14 [1H, dd, J 14.3,

3.9, CHCH_AH_BPh], 4.51 [1H, dd, J 9.5, 3.9, CHCH₂Ph], 7.22–

7.33 [5H, m, PhH ]; δ_C(50 MHz, CDCl₃) 22.7 [CH(CH₃)₂],

22.8 [CH(CH₃)₂], 28.1, 29.0 [C(CH₃)₂], 33.6 [CH₂CH(CH₃)₂],

34.2 [CH₂CH₂CH(CH₃)₂], 35.8 [CHCH₂Ph], 63.9 [CHCH₂Ph],

82.5 [C(CH₃)₂], 127.2 [p-Ph], 129.1, 129.5 [m/o-Ph], 137.5

[i-Ph], 153.1 [C᎐O endocyclic], 174.2 [C᎐O exocyclic]; ν_max(ﬁlm)

᎐

1778 [C᎐O endocyclic], 1699 [C᎐O exocyclic]; m/z APCIϩ

᎐

260 [10%, MH^ϩϪ CO₂], 304 [35%, MH^ϩ], 326 [15%,

MNa^ϩ]; HRMS C₁₈H₂₆N0₃[MH^ϩ] requires 304.1908; found

304.1903.

129.6 [m/o-Ph], 136.2, 139.5, 140.2 [p-Ph], 157.9 [C᎐O]; ν

᎐

max

(KBr) 1730 [C᎐O]; m/z CIϩ 178 [100%, auxH^ϩ], 384 [10%,

᎐

Preparation of (S )-3-butyryl-4-benzyl-5,5-dimethyloxazolidin-2-

MH^ϩϪ H₂O].

one 24

Data for 19: R_f0.23 [1 : 1 hexane : Et₂O]; mp 92–97 ЊC [hexa-

ne–Et₂O]; [α]²_D²Ϫ3.1 (c = 1.0, CHCl₃); δ_H(400 MHz, CDCl₃)

2.40 [1H, dd, J 13.7, 8.3, CH₂CHCH_AH_BPh], 2.46–2.52 [1H, m,

CH(CH₂Ph)₂], 2.57 [1H, dd, J 13.7, 5.4, CH₂CHCH_AH_BPh],

2.78–2.84 [2H, m, CH(CH_AH_BPh)(CH_CH_DPh)], 2.96–3.04 [2H,

m, CH(CH_AH_BPh)(CH_CH_DPh)], 3.62 [1H, dd, J 11.4, 4.3,

CH_AH_BCHCH₂Ph], 3.81 [1H, dd, J 11.4, 5.4, CH_AH_BCH-

CH₂Ph], 4.25–4.33 [1H, m, CH₂CHCH₂Ph], 5.04 [1H, d, J 8.6,

NH ], 6.85–7.36 [15H, m, PhH ], 7.73 [1H, s, CHO]; δ_C(100

MHz, CDCl₃) 37.1, 37.4 [CH(CH₂Ph)₂and CH₂CHCH₂Ph],

48.3 [CH(CH₂Ph)₂], 53.1 [CH₂CHCH₂Ph], 63.5 [CH₂CH-

CH₂Ph], 126.3, 126.5, 126.7 [p-Ph], 128.2, 128.4, 128.5, 128.,

Following Representative Procedure 1, n-BuLi (5.37 mL, 10.73

mmol), (S)-4 (2.00 g, 9.76 mmol) and butyryl chloride (1.32

mL, 12.69 mmol) in THF (50 mL) furnished 24 (2.06 g, 77%) as

a white solid after ﬂash column chromatography; R_f0.18 [5 : 1

40–60 ЊC petrol : Et₂O]; mp 109–110 ЊC [hexane–Et₂O]; [α]²_D²

Ϫ44.6 (c = 1.0, CHCl₃); δ_H(400 MHz, CDCl₃) 0.96 [3H, t, J 7.4,

CH₂CH₂CH₃], 1.35 [3H, s, C(CH₃)_A(CH₃)_B], 1.368 [3H, s,

C(CH₃)_A(CH₃)_B], 1.65–1.71 [2H, m, CH₂CH₂CH₃], 2.85–2.93

[3H, m, CH₂CH₂CH₃and CHCH_AH_BPh], 3.13 [1H, dd, J 14.3,

4.0, CHCH_AH_BPh], 4.51 [1H, dd, J 9.5, 4.0, CHCH₂Ph], 7.20–

7.32 [5H, m, PhH ]; δ_C(50 MHz, CDCl₃) 14.1 [CH₂CH₂CH₃],

18.2 [CH₂CH₂CH₃], 22.7, 29.0 [C(CH₃)₂], 35.8 [CHCH₂Ph],

38.0 [CH₂CH₂CH₃], 63.9 [CHCH₂Ph], 82.6 [C(CH₃)₂], 127.2 [p-

128.9, 129.1 [m/o-Ph], 136.4, 139.5, 139.5 [i-Ph], 160.6 [C᎐O

᎐

formate ester], 173.3 [C᎐O amide]; ν (KBr) 1725 [C᎐O form-

᎐

max

ate ester], 1637 [C᎐O amide]; m/z APCIϩ 402 [100%, MH^ϩ],

Ph], 129.1, 129.5 [m/o-Ph], 137.5 [i-Ph], 153.1 [C᎐O endocyclic],

᎐

424 [20%, MNa^ϩ]; HRMS C₂₆H₂₈NO₃[MH^ϩ] requires

402.2064; found 402.2064.

173.9 [C᎐O exocyclic]; ν (KBr) 1771 [C᎐O endocyclic], 1699

᎐

max

[C᎐O exocyclic]; m/z APCIϩ 276 [10%, MH^ϩ], 298 [5%,

᎐

MNa^ϩ]; HRMS C₁₆H₂₂NO₃[MH^ϩ] requires 276.1595; found

276.1594.

Preparation of (S )-2-(2Ј-benzyl-3Ј-phenylpropionylamino)-2-

benzyl-1,1-diphenylethyl formate 22

Preparation of (2ЈS,4S )-3-(2Ј-methyl-3Ј-phenylpropionyl)-4-

Following Representative Procedure 3, DIBAL (0.44 mL, 0.44

mmol) and (S)-17 (120 mg, 0.22 mmol) in CH₂Cl₂(5 mL) fur-

nished 13 contaminated with unidentiﬁed products (52 mg),

(S)-22 (15 mg, 14%) and 21 (48 mg, 66%) as a white solid after

ﬂash column chromatography. Data for 22: R_f0.09 [5 : 1 30–40

ЊC petroleum ether : Et₂O; double eluted]; [α]²_D⁴Ϫ59.2 (c 0.60,

CHCl₃); δ_H(400 MHz, CDCl₃) 2.14 [1H, dd, J 14.3, 10.1,

CHCH_AH_BPh], 2.20–2.26 [1H, m, CH(CH₂Ph)₂], 2.32 [1H, dd,

J 13.8, 5.4, CH(CH_AH_BPh)(CH₂Ph)], 2.42 [1H, dd, J 13.8, 8.8,

CH(CH_AH_BPh)(CH₂Ph)], 2.52 [1H, dd, J 13.6, 4.8, CH(CH₂-

Ph)(CH_CH_DPh)], 2.67 [1H, dd, J 13.6, 9.5, CH(CH₂Ph)(CH_C-

H_DPh)], 3.02 [1H, dd, J 14.3, 3.5, CHCH_AH_BPh], 5.28 [1H, s,

NH ], 5.80–5.86 [1H, m, CHCH₂Ph], 6.88 [2H, d, J 6.8, PhH ],

6.99–7.41 [23H, m, PhH ], 7.88 [1H, s, CHO]; δ_C(100 MHz,

CDCl₃) 37.1, 37.4, 38.0 [CHCH₂Ph, CH(CH₂Ph)₂and

CH(CH₂Ph)₂], 52.5 [CHCH₂Ph], 90.0 [CPh₂], 126.0, 126.2,

126.6, 126.6, 128.0 [i-Ph], 127.7, 128.0, 128.2, 128.3, 128.4,

128.9, 129.0, 129.3 [m/o-Ph], 137.1, 139.4, 139.5, 139.7 [p-Ph],

benzyl-5,5-dimethyloxazolidin-2-one 25

Following Representative Procedure 2b, LHMDS (4.45 mL,

4.45 mmol), (S)-7 (1.00 g, 2.97 mmol) and methyl iodide (0.55

mL, 8.91 mmol) in THF (50 mL) furnished 25 (782 mg, 75%,

85% de) as pale yellow solid after ﬂash column chromato-

graphy; R_f0.2 [5 : 1 hexane : Et₂O]; mp 90–91 ЊC [hexane–Et₂O];

C₂₂H₂₅NO₃requires C, 75.2, H, 7.2, N, 4.0%; found C, 75.0, H,

7.1, N, 3.9%; [α]²_D⁵ϩ34.8 (c = 0.5, CHCl₃); δ_H(400 MHz, CDCl₃)

1.03 [3H, s, C(CH₃)_A(CH₃)_B], 1.17 [3H, d, J 6.8, CHCH₃], 1.33

[3H, s, C(CH₃)_A(CH₃)_B], 2.68 [1H, dd, J 13.4, 6.9, CHCH_AH_BPh

(exocyclic)], 2.88 [1H, dd, J 14.3, 9.0, CHCH_AH_BPh (auxiliary)],

3.03 [1H, dd, J 14.3, 4.6, CHCH_AH_BPh (auxiliary)], 2.98 [1H,

dd, J 13.4, 8.5, CHCH_AH_BPh (exocyclic)], 4.15–4.21 [1H, m,

CHCH₃], 4.37 [1H, dd, J 9.0, 4.6, CHCH₂Ph], 7.15–7.32 [10H,

m, PhH ]; δ_C(125 MHz, CDCl₃) 17.3 [CHCH₃], 22.0, 27.7

[C(CH₃)₂], 35.1 [CHCH₂Ph], 39.2 [CH(CH₃)], 39.9

[CHCH₂Ph], 63.4 (CH₂Ph)], 82.1 [C(CH₃)₂], 126.5, 127.0,

128.6, 128.8, 129.3 [p/m/o-Ph], 137.7, 138.7, 139.6 [i-Ph], 152.6

173.8 [CHO], 175.0 [C᎐O amide]; ν (ﬁlm) 1724, 1683 [C᎐O];

᎐

max

HRMS C₃₈H₃₅NO₃Na [MNa^ϩ] requires 576.2510, found

576.2516; m/z ESϩ 508 [70%, MH^ϩϪ CO₂], 576 [100%,

MNa^ϩ].

max

3

[C᎐O endocyclic], 176.9 [C᎐O exocyclic]; ν (CHCl ) 1771 [C᎐

᎐

O exocyclic], 1697 [C᎐O endocyclic]; m/z (CI^ϩ, NH ) 352 [100%,

᎐

3

MH^ϩ].

Preparation of (S )-3-(4Ј-methylpentanoyl)-4-benzyl-5,5-di-

methyloxazolidin-2-one 23

Preparation of (2ЈS,4S )-3-(2Ј-allyl-3Ј-phenylpropionyl)-4-ben-

zyl-5,5-dimethyloxazolidin-2-one 26

Following Representative Procedure 1, n-BuLi (1.10 mL, 2.68

mmol), (S)-4 (500 mg, 2.46 mmol) and 4-methylvaleryl chloride

(prepared by treatment of 4-methylvaleric acid (1.59 g, 9.76

mmol) with oxalyl chloride (4.26 mL, 48.8 mmol) and DMF

(cat.) in hexane (10 mL)) in THF (20 mL) furnished 23 (580 mg,

78%) as a clear colourless oil after ﬂash column chromato-

graphy; R_f0.28 [5 : 1 30–40 ЊC petrol : Et₂O]; [α]²_D²Ϫ37.7 (c = 1.0,

CHCl₃); δ_H(400 MHz, CDCl₃) 0.93 [6H, d, J 6.4, CH(CH₃)₂],

1.36 [3H, s, C(CH₃)_A(CH₃)_B], 1.38 [3H, s, C(CH₃)_A(CH₃)_B],

Following Representative Procedure 2b, LHMDS (1.35 mL,

1.35 mmol), (S)-7 (300 mg, 0.90 mmol) and allyl bromide (0.24

mL, 2.70 mmol) in THF (20 mL) furnished 161 (250 mg, 71%,

86% de) as a yellow oil after ﬂash column chromatography; R_f

0.18 [7 : 1 hexane : Et₂O]; [α]²_D²ϩ53.4 (c = 0.5, CHCl₃); δ_H(400

MHz, CDCl₃) 0.89 [3H, s, C(CH₃)_A(CH₃)_B], 1.26 [3H, s,

C(CH ) (CH ) ], 2.30–2.37 [1H, m, CH H CH᎐CH ], 2.46–

᎐

3

A

3

B

A

B

2

2.53 [1H, m, CH H CH᎐CH ], 2.77–3.06 [4H, m, CHCH Ph

᎐

A

B

2

(auxiliary and exocyclic)], 4.32 [1H, dd, J 9.8, 3.5, CHCH₂Ph

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 8 6 – 2 8 9 9

2893

View Article Online

(auxiliary)], 4.40–4.48 [1H, m, CHCH CH᎐CH ], 5.02–5.12

94%, 94% de) as a clear colourless oil by ﬂash column chrom-

atography; R_f0.24 [5 : 1 hexane : Et₂O]; C₂₃H₂₇NO₃requires C,

75.6, H, 7.45, N, 3.8%; found C, 75.4, H, 7.5, N, 3.5%; [α]²_D²

Ϫ69.6 (c = 0.5, CHCl₃); δ_H(400 MHz, CDCl₃) 0.94 [3H, t,

J 7.4, CHCH₂CH₃] 1.28 [3H, s, C(CH₃)_A(CH₃)_B], 1.31 [3H, s,

C(CH₃)_A(CH₃)_B], 1.53–1.63 [1H, m, CHCH_AH_BCH₃], 1.71–1.82

[1H, m, CHCH_AH_BCH₃], 2.55 [1H, dd, J 14.6, 10.0, CHCH_A-

H_BPh (auxiliary)], 2.76 [1H, dd, J 13.4, 7.1, CHCH_AH_BPh (exo-

cyclic)], 2.84 [1H, dd, J 14.6, 3.2, CHCH_AH_BPh (auxiliary)],

3.00 [1H, dd, J 13.4, 8.2, CHCH_AH_BPh (exocyclic)], 4.20–4.27

[1H, m, CHCH₂CH₃], 4.48 [1H, dd, J 10.0, 3.2, CHCH₂Ph

(auxiliary)], 7.16–7.31 [10H, m, PhH ]; δ_C(100 MHz, CDCl₃)

11.7 [CHCH₂CH₃], 22.2, 28.5 [C(CH₃)₂], 25.1 [CHCH₂CH₃],

34.8, 38.6 [CHCH₂Ph (auxiliary and exocyclic)], 45.8 [CHCH₂-

CH₃], 63.6 [CHCH₂Ph (auxiliary)], 81.7 [C(CH₃)₂], 126.3, 126.7

[p-Ph], 128.3, 128.6, 129.0, 129.3 [m/o-Ph], 137.1, 139.1 [i-Ph],

᎐

2

[2H, m, CH CH᎐CH ], 5.77–5.87 [1H, m, CH CH᎐CH ], 7.14–

᎐

2

7.32 [10H, m, PhH ]; δ_C(100 MHz, CDCl₃) 22.1, 27.6

[C(CH ) ], 35.4, 37.0 [2 × CH Ph], 38.3 [CH CH᎐CH ], 43.7

᎐

3

2

[CHCH CH᎐CH ], 63.6 [CHCH Ph], 81.9 [C(CH ) ], 117.3

᎐

2

3 2

[CH CH᎐CH ], 126.3, 126.7 [p-Ph], 128.4, 128.6, 128.9, 129.0

᎐

2

[m/o-Ph], 135.0 [CH CH᎐CH ], 137.0, 139.0 [i-Ph], 152.3 [C᎐O

᎐

2

endocyclic], 175.5 [C᎐O exocyclic]; ν (ﬁlm) 1773 [C᎐O endo-

᎐

max

cyclic], 1696 [C᎐O exocyclic]; m/z APCIϩ 334 [40%, MH^ϩ

Ϫ

᎐

CO₂], 378 [80%, MH^ϩ]; HRMS C₂₄H₂₈NO₃[MH^ϩ] requires

378.2064; found 378.2065.

Preparation of (2ЈS,4S )-3-(2Ј-benzyl-5Ј-methylhex-4Ј-enoyl)-4-

benzyl-5,5-dimethyloxazolidin-2-one 27

Following Representative Procedure 2b, LHMDS (1.12 mL,

1.12 mmol), (S)-7 (250 mg, 0.75 mmol) and 1-bromo-3-methyl-

but-2-ene (0.26 mL, 2.25 mmol) in THF (15 mL) furnished 27

(241 mg, 80%, 94% de) as pale yellow oil by ﬂash column

chromatography; R_f0.25 [5 : 1 hexane : Et₂O]; [α]²_D²ϩ26.4

152.3 [C᎐O endocyclic], 176.5 [C᎐O exocyclic]; ν_max(ﬁlm) 1777

᎐

[C᎐O endocyclic], 1695 [C᎐O exocyclic]; m/z APCIϩ 366

᎐

[100%, MH^ϩ], 388 [10%, MNa^ϩ].

(c = 1.0, CHCl₃); δ_H(400 MHz, CDCl ) 0.89 [3H, s, CH᎐

᎐

Preparation of (S )-2-methyl-3-phenylpropionaldehyde 30³⁶

3

C(CH ) (CH ) ], 1.26 [3H, s, CH᎐C(CH ) (CH ) ], 1.61 [3H, s,

᎐

3

A

3

B

3

A

3 B

C(CH₃)_A(CH₃)_B], 1.69 [3H, s, C(CH₃)_A(CH₃)_B], 2.21–2.28 [1H,

m, CH H CH᎐C(CH ) ], 2.43–2.51 [1H, m, CH H CH᎐

C(CH₃)₂], 2.76–3.02 [4H, m, 2 × CHCH₂Ph], 4.31 [1H, dd,

J 9.7, 3.5, CHCH₂Ph (auxiliary)], 4.35–4.43 [1H, dd, J 9.7, 3.5,

Following Representative Procedure 3, DIBAL (1.15 mL, 1.15

mmol) and 25 (200 mg, 0.56 mmol) in CH₂Cl₂(5 mL) furnished

30 (74 mg, 87%, 87% ee) as a clear, colourless oil and (S)-4 (115

mg, 98%) as a white solid after ﬂash column chromatography.

Data for 30; R_f0.27 [10 : 1 40–60 ЊC petrol : Et₂O]; δ_H(400

MHz, CDCl₃) 1.10 [3H, d, J 6.9, CHCH₃], 2.59–2.74 [2H, m,

CHCH_AH_BPh], 3.11 [1H, dd, J 13.3, 5.6, CHCH_AH_BPh], 7.15–

7.33 [5H, m, PhH ], 9.74 [1H, d, J 1.5, CHO]; [α]²_D²Ϫ1.1 (c = 1.0,

CHCl₃), {lit.³⁶[α]²_D³Ϫ4.42 (c = 0.4, MeOH)}.

Following Representative Procedure 4, LiAlH₄(0.07 mL,

0.07 mmol) and 30 (20 mg, 0.14 mmol) in THF (2 mL) fur-

nished (S)-2-methyl-3-phenylpropan-1-ol³⁷(17 mg, 79%) as a

clear colourless oil after ﬂash column chromatography; R_f0.22

[2 : 1 30–40 ЊC petrol : Et₂O]; δ_H(200 MHz, CDCl₃) 0.93 [3H,

d, J 6.7, CHCH₃], 1.45 [1H, s, OH ], 1.91–2.04 [1H, m,

CHCH₂Ph], 2.44 [1H, dd, J 13.4, 7.9, CHCH_AH_BPh], 2.77 [1H,

dd, J 13.4, 6.3, CHCH_AH_BPh], 3.44–3.60 [2H, m, CH₂OH],

7.17–7.34 [5H, m, PhH ]; [α]¹_D⁸Ϫ14.0 (c = 0.25, CHCl₃), {lit.^37a

[α]²_D⁰Ϫ11.1 (c = 0.83, CHCl₃); lit.^37b[α]²_D⁰Ϫ10.1 (c = 0.8,

CHCl₃)}.

᎐

A

B

3

2

A

B

CHCH Ph (exocyclic)], 5.18–5.22 [1H, m, CH᎐C(CH ) ], 7.12–

᎐

2

3 2

7.33 [10H, m, PhH ]; δ_C(50 MHz, CDCl ) 18.3, 26.3 [CH᎐

᎐

3

C(CH₃)₂], 22.6, 28.1 [C(CH₃)₂], 32.0, 35.7 [CHCH₂Ph (aux-

iliary and exocyclic)], 38.7 [CH CH᎐C(CH ) ], 44.9 [CHCH Ph

᎐

2

3

2

(exocyclic)], 64.0 [CHCH₂Ph (auxiliary)], 82.2 [C(CH₃)₂],

121.2 [CH᎐C(CH ) ], 126.7, 127.2 [p-Ph], 128.8, 129.1, 129.5

᎐

3

2

[m/o-Ph], 134.6 [CH᎐C(CH ) ], 137.6, 139.8 [i-Ph], 152.7

᎐

3

2

[C᎐O endocyclic], 176.5 [C᎐O exocyclic]; ν

(ﬁlm) 1776

᎐

max

[C᎐O exocyclic], 1695 [C᎐O endocyclic]; m/z APCIϩ 362 [30%,

᎐

MH^ϩϪ CO₂], 406 [100%, MH^ϩ]; HRMS C₂₆H₃₂NO₃[MH^ϩ]

requires 406.2377; found 406.2377.

Preparation of (2ЈR,4S )-3-(2Ј-phenyl-4Ј-methylpentanoyl)-4-

benzyl-5,5-dimethyloxazolidin-2-one 28

Following Representative Procedure 2b, LHMDS (1.50 mL,

1.50 mmol), (S)-23 (300 mg, 0.99 mmol) and benzyl bromide

(0.35 mL, 2.97 mmol) in THF (15 mL) furnished 28 (390 mg,

98%, 91% de) as a white solid after ﬂash column chromato-

graphy; R_f0.29 [5 : 1 hexane : Et₂O]; [α]²_D²Ϫ62.7 (c = 1.0,

CHCl₃); mp 94–96 ЊC [hexane–Et₂O]; δ_H(400 MHz, CDCl₃)

0.89 [3H, d, J 6.6, CH(CH₃)_A(CH₃)_B], 0.93 [3H, d, J 6.6,

CH(CH₃)_A(CH₃)_B], 1.27 [3H, s, C(CH₃)_A(CH₃)_B], 1.32 [3H, s,

C(CH₃)_A(CH₃)_B], 1.27–1.36 [1H, m, CH_AH_BCH(CH₃)₂], 1.53–

1.63 [1H, m, CH₂CH(CH₃)₂], 1.75–1.82 [1H, m, CH_AH_BCH-

(CH₃)₂], 2.52 [1H, dd, J 14.5, 10.1, C(4)HCH_AH_BPh], 2.75 [1H,

dd, J 13.3, 7.3, C(2Ј)HCH_AH_BPh], 2.83 [1H, dd, J 14.5, 2.9,

C(4)HCH_AH_BPh], 2.97 [1H, dd, J 13.3, 8.0, C(2Ј)HCH_AH_BPh],

4.38–4.51 [2H, m, C(4)HCH₂Ph and CHCH₂(CH₃)₂], 7.19–7.42

[10H, m, PhH ]; δ_C(100 MHz, CDCl₃) 22.2, 22.3 [CH(CH₃)₂],

23.1 [CH(CH₃)₂], 26.3, 28.4 [C(CH₃)₂], 34.7 [CH₂CH(CH₃)₂],

39.5, 40.9 [C(4)HCH₂Ph and C(2Ј)HCH₂Ph], 42.2 [C(2Ј)H],

63.6 [C(4)H], 81.7 [C(CH₃)₂], 126.3, 126.7 [p-Ph], 128.3, 128.6,

Preparation of (S )-2-allyl-3-phenylpropionaldehyde 31³⁸

Following Representative Procedure 3, DIBAL (1.07 mL, 1.07

mmol) and 26 (200 mg, 0.53 mmol) in CH₂Cl₂(5 mL) furnished

31 (70 mg, 76%, 87% ee) as a clear, colourless oil and (S)-4

(88 mg, 0.43 mmol, 81%) as a white solid after ﬂash column

chromatography; R_f0.26 [10 : 1 hexane : Et₂O]; δ_H(400 MHz,

CDCl ) 2.26–2.33 [1H, m, CH H CH᎐CH ], 2.37–2.44 [1H, m,

᎐

3

A

B

2

CH H CH᎐CH ], 2.72–3.04 [2H, m, CHCH H Ph], 3.47–3.52

᎐

A

B

2

A

B

[1H, m, CHCH H Ph], 5.06–5.13 [2H, m, CH CH᎐CH ], 5.72–

᎐

A

B

2

5.83 [1H, m, CH CH᎐CH ], 7.17–7.36 [5H, m, PhH ], 9.72 [1H,

᎐

2

d, J 1.8, CHO]; [α]²_D²Ϫ28.4 (c = 1, CHCl₃).

Following Representative Procedure 4, LiAlH₄(0.03 mL,

0.03 mmol) and 31 (10 mg, 0.05 mmol) in THF (2 mL)

furnished (S)-2-allyl-3-phenylpropan-1-ol³⁹(10 mg, 100%)

as a clear colourless oil after ﬂash column chromatography;

R_f0.26 [2 : 1 30–40 ЊC petrol : Et₂O]; δ_H(200 MHz, CDCl₃)

1.44 [1H, s, OH ], 1.87–2.01 [1H, m, CHCH₂Ph], 2.16 [2H, t,

128.8, 129.0, 129.3 [m/o-Ph], 137.1, 138.9 [i-Ph], 152.2 [C᎐O

᎐

exocyclic], 176.8 [C᎐O endocyclic]; ν (KBr) 1770 [C᎐O endo-

᎐

max

cyclic], 1691 [C᎐O exocyclic]; m/z APCIϩ 350 [20%, MH^ϩ

Ϫ

J 7.0, CH CH᎐CH ], 2.64–2.68 [2H, m, CH Ph], 3.50–3.61 [2H,

᎐

2

CO₂], 394 [100%, MH^ϩ], 416 [10%, MNa^ϩ]; HRMS C₂₅H₃₂NO₃

[MH^ϩ] requires 394.2377; found 394.2390.

m, CH OH], 5.05–5.14 [2H, m, CH᎐CH ], 5.76–5.97 [1H, m,

᎐

2 2

CH᎐CH ], 7.19–7.35 [5H, m, PhH ]; [α]²_D⁰Ϫ13.3 (c = 0.55,

᎐

2

CHCl₃).

Preparation of (2ЈR,4S )-3-(2Ј-benzylbutyryl)-4-benzyl-5,5-

dimethyloxazolidin-2-one 29

Preparation of (S )-2-benzyl-5-methyl-hex-4-enal 32

Following Representative Procedure 2b, LHMDS (1.64 mL,

1.64 mmol), (S)-24 (0.30 g, 1.09 mmol) and benzyl bromide

(0.39 mL, 3.27 mmol) in THF (15 mL) furnished 29 (370 mg,

Following Representative Procedure 3, DIBAL (1.00 mL, 1.00

mmol) and 27 (200 mg, 0.50 mmol) in CH₂Cl₂(5 mL) furnished

32 (75 mg, 74%, 94% ee) as a clear, colourless oil and (S)-4

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 8 6 – 2 8 9 9

2894

View Article Online

(87 mg, 85%) as a white solid after ﬂash column chromato-

graphy; Data for 32; R_f0.26 [12 : 1 hexane : Et₂O]; [α]²_D³Ϫ54.8

Following Representative Procedure 4, LiAlH₄(0.06 mL,

0.06 mmol) and 34 (20 mg, 0.12 mmol) in THF (5 mL) fur-

nished (R)-2-benzylbutan-1-ol⁴²(18 mg, 91%) as a clear colour-

less oil; R_f0.18 [2 : 1 hexane : Et₂O]; δ_H(400 MHz, CDCl₃) 0.95

[3H, t, J 3.4, CHCH₂CH₃], 1.29–1.50 [3H, m, CHCH₂CH₃and

OH ], 1.71–1.77 [1H, m, CHCH₂CH₃], 2.65 [2H, app. d, J 7.0,

CHCH₂Ph], 3.55 [2H, d, J 5.2, CH₂OH], 7.19–7.31 [5H, m,

PhH ]; [α]¹_D⁸Ϫ8.0 (c = 0.55, CHCl₃), {lit.⁴²[α]²_D³Ϫ5.0 (c = 1.0,

CH₂Cl₂)}.

(c = 1.0, CHCl₃); ν_max(ﬁlm) 1732 [C᎐O]; δ_H(400 MHz, CDCl₃)

᎐

1.58 [3H, s, CH᎐C(CH ) (CH ) ], 1.71 [3H, s, CH᎐C(CH ) -

᎐

3

A

3

B

3 A

(CH ) ], 2.18–2.35 [2H, m, CH CH᎐C(CH ) ], 2.64–2.78 [2H,

᎐

3

B

2

3 2

m, CHCH_AH_BPh], 2.97–3.03 [1H, m, CHCH_AH_BPh], 5.08–5.13

[1H, m, CH᎐C(CH ) ], 7.16–7.41 [5H, m, PhH ], 9.70 [1H, d,

᎐

3

2

J 2.0, CHO]; δ_C(100 MHz, CDCl ) 17.8, 25.8 [CH᎐C(CH ) ],

᎐

3

3 2

27.2 [CH CH᎐C(CH ) ], 34.4 [CHCH Ph], 53.8 [CHCH Ph],

᎐

2

3

2

120.1 [CH᎐C(CH ) ], 126.3 [p-Ph], 129.0, 129.3 [m/o-Ph], 134.4

᎐

3

2

[i-Ph], 139.0 [CH᎐C(CH ) ], 204.6 [CHO]; m/z CIϩ (NH ) 203

Preparation of (4S,2ЈE )-3-(3Ј-phenylacryloyl)-4-benzyl-5,5-

dimethyloxazolidin-2-one 35

᎐

3

2

3

[10%, MH^ϩ], 220 [100%, MNH₃^ϩ]; HRMS C₁₄H₁₈O [MH^ϩ]

requires 202.1353; found 202.1356.

Following Representative Procedure 1, n-BuLi (2.20 mL, 5.37

mmol), (S)-4 (1.00 g, 4.89 mmol) and cinnamoyl chloride (1.06

g, 6.36 mmol) in THF (60 mL) furnished 35 (1.11 g, 68%) as an

orange oil after ﬂash column chromatography; R_f0.24 [3 : 1

hexane : Et₂O]; [α]²_D³Ϫ64.9 (c = 1.0, CHCl₃); δ_H(400 MHz,

CDCl₃) 1.40 [3H, s, C(CH₃)_A(CH₃)_B], 1.42 [3H, s, C(CH₃)_A-

(CH₃)_B], 2.94 [1H, dd, J 14.4, 9.7, CHCH_AH_BPh], 3.28 [1H, dd,

J 14.4, 3.6, CHCH_AH_BPh], 4.64 [1H, dd, J 9.7, 3.6, CHCH₂Ph],

7.19–7.43 [8H, m, PhH ], 7.59–7.66 [2H, m, PhH ], 7.82–7.96

Following Representative Procedure 4, LiAlH₄(0.03 mL,

0.03 mmol) and 32 (10 mg, 0.05 mmol) in THF (2 mL) fur-

nished (S)-2-benzyl-5-methylhex-4-en-1-ol⁴⁰(9 mg, 0.04 mmol,

80%) as a clear colourless oil; R_f0.21 [2 : 1 hexane : Et₂O];

δ_H(400 MHz, CDCl ) 1.61 [3H, s, CH᎐C(CH ) (CH ) ], 1.72

᎐

3

A

3 B

[3H, s, CH᎐C(CH ) (CH ) ], 1.83–1.93 [1H, m, CHCH Ph],

᎐

3

A

3

B

2

2.02–2.19 [2H, m, CHCH Ph], 2.59–2.69 [2H, m, CH CH᎐

᎐

2

C(CH ) ], 3.48–3.58 [2H, m, CH OH], 5.17–5.21 [1H, m, CH᎐

᎐

3

2

C(CH₃)₂], 7.18–7.31 [5H, m, PhH ]; [α]²_D³Ϫ30.2 (c = 0.5, CHCl₃),

{lit.⁴⁰ent- [α]²_D⁴ϩ27.0 (c = 1, CHCl₃)}.

[2H, m, CH᎐CH ]; δ_C(50 MHz, CDCl₃) 22.3, 8.6 [C(CH₃)₂],

᎐

35.3 [CH Ph], 63.9 [CHCH Ph], 82.3 [C(CH ) ], 117.3 [CH᎐

᎐

2

3 2

CHPh], 126.8, 130.6 [p-Ph], 128.0, 128.6, 128.9, 129.1 [m/o-Ph],

134.6, 137.1 [i-Ph], 146.1 [CH᎐CHPh], 152.7 [C᎐O endocyclic],

Preparation of (R)-2-benzyl-4-methylpentanal 33

᎐

Following Representative Procedure 3, DIBAL (1.02 mL, 1.02

mmol) and 28 (200 mg, 0.51 mmol) in CH₂Cl₂(5 mL) furnished

33 (93 mg, 95%, 91% ee) as a clear colourless and (S)-4 (94 mg,

90%) as a white solid after ﬂash column chromatography; Data

for 33; R_f0.28 [12 : 1 hexane : Et₂O]; [α]²_D⁵ϩ1.1 (c = 1.0, CHCl₃);

δ_H(400 MHz, CDCl₃) 0.88 [3H, d, J 6.5, CH(CH₃)_A(CH₃)_B],

0.90 [3H, d, J 6.4, CH(CH₃)_A(CH₃)_B], 1.24–1.31 [1H, m, CH_AH_B-

CH(CH₃)₂], 1.58–1.70 [2H, m, CH_AH_BCH(CH₃)₂and CH₂CH-

(CH₃)₂], 2.68–2.93 [1H, m CHCH_AH_BPh], 2.94–2.99 [1H, m,

CHCH_AH_BPh], 7.14–7.32 [5H, m, PhH ], 9.65 [1H, d, J 2.8,

CHO]; δ_C(100 MHz, CDCl₃) 22.9, 22.2 [CH(CH₃)₂], 25.7

[CH(CH₃)₂], 35.6 [CH₂CH(CH₃)₂], 37.9 [CHCH₂Ph], 51.5

[CHCH₂Ph], 126.4 [p-Ph], 128.6, 128.9 [m/o-Ph], 138.7 [i-Ph],

165.5 [C᎐O exocyclic]; ν (ﬁlm) 1770 [C᎐O endocyclic], 1682

᎐ ᎐

max

[C᎐O exocyclic]; m/z APCIϩ 336 [100%, MH^ϩ]; HRMS

᎐

C₂₁H₂₁NO₃[MH^ϩ] requires 336.1595, found 336.1610.

Preparation of (4S,2ЈE )-3-(3Ј-phenylacryloyl)-4-isopropyl-5,5-

dimethyloxazolidin-2-one 36

Following Representative Procedure 1, n-BuLi (2.90 mL, 7.01

mmol), (S)-5 (1.00 g, 6.37 mmol) and cinnamoyl chloride (1.38

g, 8.28 mmol) in THF (40 mL) furnished 36 (1.81 g, 99%) as a

white solid after ﬂash column chromatography; R_f0.18 [5 : 1

40–60 ЊC petrol : Et₂O]; mp 71–73 ЊC [hexane–Et₂O]; C₁₇H₂₁-

NO₃requires C. 71.0, H. 7.4, N, 4.9%, found C, 71.05, H, 7.5,

N, 4.8%; [α]²_D³Ϫ108.7 (c = 1.0, CHCl₃); δ_H(400 MHz, CDCl₃)

1.00 [3H, d, J 6.8, CH(CH₃)_A(CH₃)_B], 1.08 [3H, d, J 7.0,

CH(CH₃)_A(CH₃)_B], 1.43 [3H, s, C(CH₃)_A(CH₃)_B], 1.55 [3H, s,

C(CH₃)_A(CH₃)_B], 2.17–2.25 [1H, m, CH(CH₃)₂], 4.31 [1H, d,

J 3.4, CHCH(CH₃)₂], 7.39–7.45 [3H, m, PhH ], 7.61–7.66 [2H,

204.9 [CHO]; ν_max(ﬁlm) 1707 [C᎐O]; m/z EIϩ 91 [100%,

᎐

CH₂Ph^ϩ], 190 [15%, M^ϩ]; HRMS C₁₃H₁₈O [M^ϩ] requires

190.1353; found 190.1354.

Following Representative Procedure 4, LiAlH₄(0.13 mL,

0.13 mmol) and 33 (50 mg, 0.26 mmol) in THF (5 mL) fur-

nished (R)-2-benzyl-4-methylpentan-1-ol (44 mg, 89%) as a

clear colourless oil; R_f0.19 [2 : 1 hexane : Et₂O]; [α]¹_D⁸ϩ2.2

(c = 1.75, CHCl₃); δ_H(400 MHz, CDCl₃) 0.86 [3H, d, J 9.9,

CH(CH₃)_A(CH₃)_B], 0.89 [3H, d, J 9.8, CH(CH₃)_A(CH₃)_B], 0.91–

1.20 [2H, m, CH_AH_BCH(CH₃)₂and OH ], 1.24–1.33 [1H, m,

CH_AH_BCH(CH₃)₂], 1.64–1.76 [1H, m, CH(CH₃)₂], 1.84–1.94

[1H, m, CHCH₂Ph], 2.64 [2H, app. d, J 7.2, CHCH₂Ph], 3.51

[2H, app. d, J 5.0, CH₂OH], 7.19–7.22 [3H, m, PhH ], 7.27–7.31

[2H, m, PhH ]; δ_C(50 MHz, CDCl₃) 22.6, 22.7 [CH(CH₃)₂], 25.1

[CH(CH₃)₂], 37.7 [CHCH₂Ph], 40.0, 40.3 [CHCH₂Ph and

CH₂CH(CH₃)₂], 64.9 [CH₂OH], 126.0 [p-Ph], 128.4, 129.4

[m/o-Ph], 141.0 [i-Ph]; ν_max(ﬁlm) 3349.9 [O–H]; m/z CIϩ (NH₃)

210 [100%, MNH₄^ϩ]; HRMS C₁₃H₂₄NO [MNH₄^ϩ] requires

210.1851, found 210.1856.

m, PhH ], 7.84–8.02 [2H, m, CH᎐CH ]; δ (50 MHz, CDCl₃)

᎐

C

17.1, 21.4 [CH(CH₃)₂], 21.5, 29.7 [C(CH₃)₂], 28.8 [CH(CH₃)₂],

66.5 [CHCH(CH₃)₂], 82.8 [C(CH₃)₂], 117.2 [p-Ph], 128.6, 128.8

[m/o-Ph], 130.5 [CH᎐CHPh], 134.6 [i-Ph], 146.2 [CH᎐CHPh],

᎐

153.6 [C᎐O endocyclic], 165.9 [C᎐O exocyclic]; ν_max(KBr) 1774

᎐

[C᎐O endocyclic], 1680 [C᎐O exocyclic]; m/z APCIϩ 288

᎐

[100%, MH^ϩ].

Preparation of (4S,2ЈE )-3-(3Ј-phenylacryloyl)-4-phenyl-5,5-

dimethyloxazolidin-2-one 37¹⁷

Following Representative Procedure 1, n-BuLi (11.5 mL, 28.79

mmol), (S)-6 (5.00 g, 26.18 mmol) and cinnamoyl chloride

(5.70 g, 34.03 mmol) in THF (250 mL) furnished 37 (8.38 g,

99%) as a white solid after ﬂash column chromatography;

R_f0.14 [3 : 1 hexane : Et₂O]; mp 147–150 ЊC [hexane–EtOAc]

{lit.⁵149 ЊC [40–60 ЊC petrol–EtOAc]}; δ_H(400 MHz, CDCl₃)

1.04 [3H, s, C(CH₃)_A(CH₃)_B], 1.66 [3H, s, C(CH₃)_ACH₃)_B], 5.23

[1H, s, CHPh], 7.21–7.43 [8H, m, PhH ], 7.55–7.64 [2H, m,

Preparation of (R)-2-benzylbutanal 34⁴¹

Following Representative Procedure 3, DIBAL (1.09 mL, 1.09

mmol) and 29 (200 mg, 0.55 mmol) in CH₂Cl₂(5 mL) furnished

34 (85 mg, 95%, 94% ee) as a clear colourless oil and (S)-4 (92

mg, 0.45 mmol, 82%) as a white solid after ﬂash column chro-

matography; R_f0.27 [12 : 1 hexane : Et₂O]; [α]²_D²ϩ4.5 (c = 1.0,

CHCl₃); δ_H(400 MHz, CDCl₃) 0.95 [3H, t, J 7.5, CHCH₂CH₃],

1.52–1.74 [2H, m, CHCH₂CH₃], 2.54–2.61 [1H, m, CHCH₂-

CH₃], 2.73 [1H, dd, J 14.1, 7.1, CHCH_AH_BPh], 3.00 [1H, dd,

J 14.1, 7.4, CHCH_AH_BPh], 7.17–7.37 [5H, m, PhH ], 9.68 [1H,

d, J 2.4, CHO];

PhH ], 7.80 [1H, d, J 15.7, CH᎐CHPh], 8.05 [1H, d, J 15.7, CH᎐

᎐

CHPh]; [α]²_D³Ϫ27.0 (c = 1.0, CHCl₃) {lit.¹⁷ent-[α]²_D⁶ϩ26.0

(c = 1.0, CHCl₃)}.

Preparation of (3ЈS,4S )- and (3ЈR,4S )-4-benzyl-3-(3Ј-phenyl-

butyryl)-5,5-dimethyloxazolidin-2-one 38

Following Representative Procedure 5, CuBrؒSMe₂(185 mg,

0.90 mmol), MeMgBr (0.60 mL, 1.80 mmol), BF₃ؒEt₂O

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 8 6 – 2 8 9 9

2895

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(0.11 mL, 0.90 mmol) and 35 (200 mg, 0.60 mmol) in SMe₂

(4 mL) and THF (8 mL, 4 mL) furnished an inseparable mix-

ture of (3ЈS,4S)- and (3ЈR,4S)-38 (186 mg, 88%, 29% de) as a

white solid after ﬂash column chromatography; R_f0.21 [5 : 1

hexane : Et₂O, double eluted]; mp 85–88 ЊC [hexane–Et₂O];

δ_H(400 MHz, CDCl₃) 1.13 [3H, s, C(CH₃)_A(CH₃)_B(minor)],

1.30–1.33 [15H, m, C(CH₃)_A(CH₃)_B(minor), C(CH₃)₂(major)

and CHCH₃(major and minor)], 2.68 [1H, dd, J 14.5, 9.8,

CHCH_AH_BPh (major)], 2.82 [1H, dd, J 14.4, 9.6, CHCH_AH_BPh

(minor)], 2.98 [1H, dd, J 14.5, 3.5, CHCH_AH_BPh (major)],

3.04–3.17 [3H, m, CHCH_AH_BPh (minor), CHCH₃(minor) and

CH_AH_BCHCH₃(major)], 3.33–3.51 [4H, m, CHCH₃(major),

CH₂CHCH₃(minor) and CH_AH_BCHCH₃(major)], 4.40 [1H,

dd, J 9.5, 4.0, CHCH₂Ph (minor)], 4.47 [1H, dd, J 9.8, 3.5,

CHCH₂Ph (major)], 7.17–7.33 [20H, m, PhH (major and

minor)]; δ_C(100 MHz, CDCl₃) 22.0, 22.2, 22.3 [C(CH₃)₂(major

and minor)], 28.1 [CHCH₃(minor)], 28.5 [CHCH₃(major)],

34.9 [CHCH₃(major)], 35.3 [CHCH₃(minor)], 36.2 [CHCH₂-

Ph (major)], 36.4 [CHCH₂Ph (minor)], 42.9 [CH₂CHCH₃

(minor)], 43.3 [CH₂CHCH₃(major)], 63.4, 63.3 [CHCH₂Ph

(major and minor)], 82.0, 82.1 [C(CH₃)₂(major and minor)],

126.3, 126.4 [p-Ph (major and minor)], 126.7, 127.0, 128.4,

128.5, 128.6, 128.9, 129.0 [m/o-Ph (major and minor)], 136.9

cyclic], 172.4 [C᎐O exocyclic]; ν

(KBr) 1771 [C᎐O endo-

᎐

max

᎐

cyclic], 1698 [C᎐O exocyclic]; m/z APCIϩ 260 [15%,

᎐

MH^ϩϪCO₂], 304 [10%, MH^ϩ]; HRMS C₁₈H₂₆NO₃[MH^ϩ]

requires 304.1908, found 304.1914.

Preparation of (3ЈS,4S )-4-phenyl-3-(3Ј-phenylbutyryl)-5,5-

dimethyloxazolidin-2-one 40¹⁷

Following Representative Procedure 5, CuBrؒSMe₂(481 mg,

2.34 mmol), MeMgBr (1.56 mL, 4.67 mmol), BF₃ؒEt₂O (0.30

mL, 2.34 mmol) and 37 (500 mg, 1.56 mmol) in SMe₂(10 mL)

and THF (30 mL) furnished 40 (518 mg, 1.54 mmol, 99%) as a

white solid after ﬂash column chromatography; R_f0.18 [5 : 1

hexane : Et₂O]; mp 111–113 ЊC [hexane–Et₂O], {lit.¹⁷mp 112 ЊC

[hexane–Et₂O]}; δ_H(400 MHz, CDCl₃) 1.00 [3H, s, C(CH₃)_A-

(CH₃)_B], 1.33 [3H, d, J 7.0, CHCH₃], 1.46 [3H, s, C(CH₃)_A-

(CH₃)_B], 3.18 [1H, dd, J 16.2, 6.5, CH_AH_BCHCH₃], 3.40–3.43

[1H, m, CHCH₃], 3.59 [1H, dd, J 16.2, 8.3, CH_AH_BCHCH₃],

4.99 [1H, s, CHPh], 7.14–7.45 [10H, m, PhH ]; [α]²_D³ϩ66.5

(c = 1.0, CHCl₃).

Preparation of (S )-3-phenylbutanal 41³⁰from 40

Following Representative Procedure 3, DIBAL (0.89 mL, 0.89

mmol) and (3ЈS,4S)-40 (150 mg, 0.45 mmol) in CH₂Cl₂(5 mL)

furnished (S)-41 (58 mg, 88%, >95% ee) as a clear, colourless

oil and (S)-6 (64 mg, 0.33 mmol, 75%) as a white solid after

ﬂash column chromatography; R_f0.31 [6 : 1 pentane : Et₂O];

δ_H(400 MHz, CDCl₃) 1.33 [3H, d, J 7.0, CHCH₃], 2.67 [1H,

ddd, J 16.7, 7.7, 2.0, CH_AH_BCHCH₃], 2.77 [1H, ddd, J 16.7, 6.8,

2.0, CH_AH_BCHCH₃], 3.33–3.42 [1H, m, CHCH₃], 7.20–7.34

[5H, m, PhH ], 9.72 [1H, t, J 2.0, CHO]; [α]²_D⁵ϩ33.8 (c = 0.5,

Et₂O), lit.²⁹[α]²_D⁵ϩ38.0 (c 0.2, Et₂O), lit.³⁰[α]²_D⁵ϩ37.1 (c = 0.2,

Et₂O)}.

Following Representative Procedure 4, LiAlH₄(0.03 mL,

0.03 mmol) and (S)-41 (10 mg, 0.06 mmol) in THF (2 mL)

furnished (S)-3-phenylbutan-1-ol⁴³(9 mg, 0.06 mmol, 99%) as

a clear colourless oil; R_f0.25 [1 : 1 pentane : Et₂O]; δ_H(200

MHz, CDCl₃) 1.36 [3H, d, J 7.0, CHCH₃], 1.88–1.98 [2H, m,

CH₂CHCH₃], 2.91–3.02 [1H, m, CHCH₃], 3.59–3.67 [2H, m,

CH₂OH], 7.23–7.43 [5H, m, PhH ]; [α]²_D⁵ϩ28.9 (c = 0.45,

CHCl₃), {lit.^43a[α]²_D⁵ϩ29.0 (c = 1.4, CHCl₃), lit.^43b[α]²_D⁵ϩ25.5

(c = 1.52, CHCl₃)}.

[i-Ph (major and minor)], 145.5, 145.6 [C᎐O endocyclic (major

᎐

and minor)], 172.3, 172.1 [C᎐O exocyclic (major and minor)];

᎐

ν_max(KBr) 1784 [C᎐O endocyclic], 1698 [C᎐O exocyclic]; m/z

᎐

APCIϩ 352 [50%, MH^ϩ]; HRMS C₂₂H₂₆NO₃[MH^ϩ] requires

352.1908, found 352.1906.

Preparation of (3ЈS,4S )- and (3ЈR,4S )-4-isopropyl-

3-(3Ј-phenylbutyryl)-5,5-dimethyloxazolidin-2-one 39

Following Representative Procedure 5, CuBrؒSMe₂(321 mg,

1.56 mmol), MeMgBr (1.04 mL, 3.12 mmol), BF₃ؒEt₂O (0.19

mL, 1.56 mmol) and 36 (300 mg, 1.04 mmol) in SMe₂(3 mL)

and THF (6 mL) furnished (3ЈS,4S)-39 (50 mg, >98% de, 16%)

as a white solid. Further elution gave fractions consisting of a

5 : 4 mixture of (3ЈS,4S)- and (3ЈR,4S)-39 (190 mg, 60%) as a

clear colourless oil and a 3 : 14 mixture of (3ЈS,4S)- and

(3ЈR,4S)- (17 mg, 0.06 mmol, 5%) as a clear colourless oil after

repeated ﬂash column chromatography.

Data for major diastereoisomer (3ЈS,4S)-39: R_f0.3 [5 : 1 hex-

ane : Et₂O; double eluted]; mp 52Њ–53 ЊC [hexane/–₂O]; [α]²_D⁵

ϩ58.0 (c = 0.5, CHCl₃); δ_H(400 MHz, CDCl₃) 0.93 [3H, d, J 6.8,

CH(CH₃)_A(CH₃)_B], 0.96 [3H, d, J 7.0, CH(CH₃)_A(CH₃)_B], 1.10

[3H, s, C(CH₃)_A(CH₃)_B], 1.34 [3H, d, J 6.9, CHCH₃], 1.45 [3H, s,

C(CH₃)_A(CH₃)_B], 2.05–2.12 [1H, m, CH(CH₃)₂], 3.12 [1H, dd,

J 15.5, 6.3, CH_AH_BCHCH₃], 3.36–3.45 [1H, m, CHCH₃], 3.50

[1H, dd, J 15.5, 8.3, CH_AH_BCHCH₃], 4.02 [1H, d, J 3.3,

CHCH(CH₃)₂], 7.15–7.19 [1H, m, PhH ], 7.24–7.30 [4H, m,

PhH ]; δ_C(100 MHz, CDCl₃) 17.0, 21.3 [CH(CH₃)₂], 21.3

[CHCH₃], 22.5, 29.5 [C(CH₃)₂], 28.3 [CH(CH₃)₂], 36.5

[CHCH₃], 42.5 [CH₂CHCH₃], 66.2 [CHCH(CH₃)₂], 82.7

[C(CH₃)₂], 125.2 [p-Ph], 127.0, 128.5 [m/o-Ph], 145.6 [i-Ph],

Preparation of 3-phenylbutanal 41 from 38

Following Representative Procedure 3, DIBAL (0.28 mL,

0.28 mmol) and (3ЈS,4S):(3ЈS,4S)-38 (50 mg, 29% de, 0.14

mmol) in CH₂Cl₂(5 mL) furnished 41 (15 mg, 76%) as a clear,

colourless oil and (S)-4 (23 mg, 80%) as a white solid after ﬂash

column chromatography.

Preparation of (S )-3-phenylbutanal 41 from 39

Following Representative Procedure 3, DIBAL (0.92 mL,

0.92 mmol) and 39 (70 mg, >98% de, 0.23 mmol) in CH₂Cl₂

(5 mL) furnished (S)-41 (24 mg, 71%) as a clear, colourless oil

and (S)-5 (27 mg, 75%) as a white solid after ﬂash column

chromatography; R_f0.31 [6 : 1 pentane : Et₂O]; [α]²_D⁵ϩ34.2

(c = 1.0, Et₂O).

153.6 [C᎐O endocyclic], 172.3 [C᎐O exocyclic]; ν_max(KBr) 1772

᎐

[C᎐O endocyclic], 1700 [C᎐O exocyclic]; m/z APCIϩ 304 [5%,

᎐

MH^ϩ]; HRMS C₁₈H₂₆NO₃[MH^ϩ] requires 304.1908, found

304.1908.

Data for minor diastereoisomer (3ЈR,4S)-39: R_f0.25 [5 : 1

hexane : Et₂O; double eluted]; δ_H(400 MHz, CDCl₃) 0.75 [3H,

d, J 6.7, CH(CH₃)_A(CH₃)_B], 0.82 [3H, d, J 7.0, CH(CH₃)_A-

(CH₃)_B], 1.34 [3H, d, J 7.0, CHCH₃], 1.36 [3H, s, C(CH₃)_A-

(CH₃)_B], 1.48 [3H, s, C(CH₃)_A(CH₃)_B], 1.99–2.07 [1H, m,

CH(CH₃)₂], 3.05 [1H, dd, J 15.7, 7.2, CH_AH_BCHCH₃], 3.37–

3.46 [1H, m, CHCH₃], 3.55 [1H, dd, J 15.7, 7.6, CH_AH_B-

CHCH₃], 4.12 [1H, d, J 3.1, CHCH(CH₃)₂], 7.15–7.41 [5H, m,

PhH ]; δ_C(100 MHz, CDCl₃) 16.7, 22.2 [CH(CH₃)₂], 21.3, 29.5

[C(CH₃)₂], 28.3 [CH(CH₃)₂], 28.8 [CHCH₃], 36.4 [CHCH₃],

42.9 [CH₂CHCH₃], 66.1 [CHCH(CH₃)₂], 82.6 [C(CH₃)₂], 125.3

Preparation of (S )-3-(3Ј-methylacryloyl)-4-phenyl-5,5-di-

methyloxazolidin-2-one 42¹⁷

Following Representative Procedure 1, n-BuLi (3.5 mL, 8.64

mmol), (S)-6 (1.5 g, 7.85 mmol) and crotonyl chloride (0.98

mL, 10.21 mmol) in THF (30 mL) furnished 42 (1.83 g, 91%) as

a white solid after ﬂash column chromatography; R_f0.22 [2 : 1

hexane : Et₂O]; mp 96–99 ЊC [hexane–Et₂O] {lit.¹⁷104 ЊC [40–

60 ЊC petrol–EtOAc]}; δ_H(400 MHz, CDCl₃) 1.00 [3H, s,

C(CH₃)_A(CH₃)_B], 1.62 [3H, s, C(CH₃)_A(CH₃)_B], 1.95 [3H, dd,

[p-Ph], 127.0, 128.4 [m/o-Ph], 145.6 [i-Ph], 153.5 [C᎐O endo-

J 6.9, 1.6, CH᎐CHCH ], 5.13 [1H, s, CHPh], 7.05–7.17 [3H, m,

᎐

3

᎐

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 8 6 – 2 8 9 9

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432PhH and CH᎐CH ], 7.30–7.39 [4H, m, PhH ]; [α]²_D³ϩ79.1

[C᎐O endocyclic], 1710 [C᎐O exocyclic]; m/z APCIϩ 414 [10%,

᎐

(c = 1.0, CHCl₃) {lit.¹⁷ent-[α]²_D⁴Ϫ82.6 (c = 1.0, CHCl₃).

MH^ϩ].

Preparation of (3ЈR,4S )-3-(3Ј-phenylbutyryl)-4-phenyl-5,5-

Preparation of (3ЈS,4S )-3-(3Ј-phenylhex-5-enyl)-4-phenyl-5,5-

dimethyloxazolidin-2-one 43

dimethyloxazolidin-2-one 46¹⁷

Following Representative Procedure 5, CuBrؒSMe₂(596 mg,

2.90 mmol), PhMgBr (8.8 mL, 5.79 mmol), BF₃ؒEt₂O (0.37 mL,

2.90 mmol) and 42 (500 mg, 1.93 mmol) in SMe₂(10 mL) and

THF (30 mL) furnished (3ЈR,4S)-46 (453 mg, 70%, 97% de) as

a white solid after ﬂash column chromatography; R_f0.15 [5 : 1

hexane : Et₂O, double eluted]; mp 117–118 ЊC [hexane–Et₂O],

{lit.¹⁷mp 114 ЊC [pentane–EtOAc]}; δ_H(400 MHz, CDCl₃) 0.95

[3H, s, C(CH₃)_A(CH₃)_B], 1.28 [3H, s, CHCH₃], 1.59 [3H, s,

C(CH₃)_A(CH₃)_B], 3.20 [1H, dd, J 15.7, 7.8, CH_AH_BCHCH₃],

3.32–3.38 [1H, m, CHCH₃], 3.51 [1H, dd, J 15.7, 6.8, CH_AH_B-

CHCH₃], 5.04 [1H, s, CHPh], 7.19–7.30 [10H, m, PhH ]; [α]²_D³

ϩ25.0 (c = 1.0, CHCl₃) {lit.¹⁷ent-[α]²_D⁸Ϫ28.8 (c = 1.0, CHCl₃)}.

Following Representative Procedure 5, CuBrؒSMe₂(481 mg,

2.34 mmol), CH ᎐CHCH MgBr (2.34 mL, 4.67 mmol), BF ؒ

᎐

2

3

Et₂O (0.30 mL, 2.34 mmol) and 37 (500 mg, 1.56 mmol) in

SMe₂(10 mL) and THF (30 mL) furnished 43 (551 mg, 97%,

>95% de) as a white solid after ﬂash column chromatography;

R_f0.16 [5 : 1 hexane : Et₂O]; mp 85–89 ЊC [hexane/Et₂O]; [α]²_D³

ϩ91.6 (c = 1.0, CHCl₃); δ_H(400 MHz, CDCl₃) 0.94 [3H, s,

C(CH₃)_A(CH₃)_B], 1.35 [3H, s, C(CH₃)_A(CH₃)_B], 2.33–2.46 [2H,

m, CH CH᎐CH ], 3.16 [1H, dd, J 16.4, 5.3, CH H CHPh],

᎐

2

A

B

3.25–3.32 [1H, m, CH₂CHPh], 3.62 [1H, dd, J 16.4, 9.4, CH_AH_B-

CHPh], 4.89 [1H, s, C(4)HPh], 4.93–5.00 [2H, m, CH CH᎐

᎐

2

CH ], 5.58–5.69 [1H, m, CH CH᎐CH ], 7.07–7.37 [10H, m,

᎐

2

PhH ]; δ_C(100 MHz, CDCl₃) 23.5, 28.6 [C(CH₃)₂], 40.7 [CH₂-

CH᎐CH ], 41.0 [CH CHPh], 41.6 [CH CHPh], 66.9 [CHPh

Preparation of (3ЈS,4S )-4-phenyl-3-(3Ј-methyl-4-phenyl-

butyryl)-5,5-dimethyloxazolidin-2-one 47

᎐

2

(auxiliary)], 82.3 [C(CH ) ], 116.9 [CH CH᎐CH ], 126.6, 127.7

᎐

3

2

[p-Ph], 128.4, 128.5, 128.6, 129.51 [m/o-Ph], 136.2, 136.0 [i-Ph],

143.6 [CH CH᎐CH ], 153.2 [C᎐O endocyclic], 171.7 [C᎐O exo-

Following Representative Procedure 5, CuBrؒSMe₂(596 mg,

2.90 mmol), PhCH₂MgBr (3.15 mL, 5.79 mmol), BF₃ؒEt₂O

(0.37 mL, 2.90 mmol) and 42 (500 mg, 1.93 mmol) in SMe₂

(10 mL) and THF (30 mL) furnished 47 (561 mg, 83%, 91% de)

as a white solid after ﬂash column chromatography; R_f0.2 [5 : 1

hexane : Et₂O, double eluted]; mp 130–131 ЊC [hexane–Et₂O];

[α]²_D⁵ϩ41.0 (c = 0.5, CHCl₃); δ_H(400 MHz, CDCl₃) 0.88 [3H, d,

J 6.6, CHCH₃], 0.99 [3H, s, C(CH₃)_A(CH₃)_B], 1.58 [3H, s,

C(CH₃)_A(CH₃)_B], 2.33–2.39 [1H, m, CHCH₃], 2.46 [1H, dd,

J 13.2, 8.2, CHCH_AH_BPh], 2.68 [1H, dd, J 13.2, 5.9, CHCH_A-

H_BPh], 2.87 [1H, dd, J 16.2, 8.1, CH_AH_BCHCH₃], 3.01 [1H, dd,

J 16.2, 5.5, CH_AH_BCHCH₃], 5.08 [1H, s, CHPh], 7.12–7.39

[10H, m, PhH ]; δ_C(100 MHz, CDCl₃) 19.2 [CHCH₃], 23.7, 29.0

[C(CH₃)₂], 31.6 [CHCH₃], 43.0, 42.1 [CHCH₂Ph and CH₂-

CHCH₃], 67.0 [CHPh], 82.3 [C(CH₃)₂], 125.9, 128.6 [p-Ph],

᎐

2

cyclic]; ν_max(KBr) 1770 [C᎐O endocyclic], 1702 [C᎐O exocyclic];

᎐

m/z APCIϩ 364 [50%, MH^ϩ]; HRMS C₂₃H₂₆NO₃[MH^ϩ]

requires 364.1908, found 364.1905.

Preparation of (3ЈR,4S )-3-(4Ј-methyl-3Ј-phenylpentanoyl)-4-

phenyl-5,5-dimethyloxazolidin-2-one 44

Following Representative Procedure 5, CuBrؒSMe₂(480 mg,

2.34 mmol), Me₂CHMgBr (2.34 mL, 4.67 mmol), BF₃ؒEt₂O

(0.30 mL, 2.34 mmol) and 37 (500 mg, 1.56 mmol) in SMe₂

(10 mL) and THF (30 mL) furnished 44 (340 mg, 60%, >95%

de) as a white solid after ﬂash column chromatography; R_f0.2

[5 : 1 hexane : Et₂O; double eluted]; mp 122–124 ЊC [hexane/

Et₂O]; [α]²_D³ϩ108.7 (c = 1.0, CHCl₃); δ_H(400 MHz, CDCl₃) 0.74

[3H, d, J 6.7, CH(CH₃)_A(CH₃)_B], 0.92 [3H, s, C(CH₃)_A(CH₃)_B],

0.96 [3H, d, J 6.7, CH(CH₃)_A(CH₃)_B], 1.26 [3H, s, C(CH₃)_A-

(CH₃)_B], 1.83–1.92 [1H, m, CH(CH₃)₂], 2.92–2.97 [1H, m,

CHCH(CH₃)₂], 3.12 [1H, dd, J 16.0, 4.5, CH_AH_BCHPh], 3.79

[1H, dd, J 16.0, 10.9, CH_AH_BCHPh], 4.80 [1H, s, CHPh (aux-

iliary)], 7.03–7.35 [10H, m, PhH ]; δ_C(100 MHz, CDCl₃) 20.5,

20.7 [CH(CH₃)₂], 23.5, 28.4 [C(CH₃)₂], 33.4 [CH(CH₃)₂], 38.5

[CH₂CHPh], 49.1 [CHCH(CH₃)₂], 66.9 [CHPh (auxiliary)],

82.2 [C(CH₃)₂], 126.3 [p-Ph], 128.1, 128.4, 128.5, 128.7 [m/o-

128.2, 128.9, 129.3 [m/o-Ph], 136.4, 140.3 [i-Ph], 153.2 [C᎐O

᎐

endocyclic], 172.4 [C᎐O exocyclic]; ν (KBr) 1774 [C᎐O endo-

᎐

max

cyclic], 1701 [C᎐O exocyclic]; m/z APCIϩ 352 [5%, MH^ϩ];

᎐

HRMS C₂₂H₂₆NO₃[MH^ϩ] requires 352.1908, found 352.1921.

Preparation of (S )-3-phenylhex-5-enal 48⁴⁴

Following Representative Procedure 3, DIBAL (0.83 mL, 0.83

mmol) and 43 (150 mg, 0.41 mmol) in CH₂Cl₂(5 mL) furnished

48 (63 mg, >95% ee, 88%) as a clear, colourless oil and (S)-6

(77 mg, 98%) as a white solid after ﬂash column chromato-

graphy; R_f0.18 [12 : 1 pentane : Et₂O]; δ_H(400 MHz, CDCl₃)

Ph], 136.2, 142.9 [i-Ph], 153.3 [C᎐O endocyclic], 172.3 [C᎐O

᎐

exocyclic]; ν_max(KBr) 1771 [C᎐O endocyclic], 1698 [C᎐O exo-

᎐

cyclic]; m/z APCIϩ 366 [5%, MH^ϩ]; HRMS C₂₃H₂₈NO₃[MH^ϩ]

2.31–2.47 [2H, m, CH CH᎐CH ], 2.70–2.83 [2H, m, CH -

᎐

2

requires 366.2064, found 366.2060.

CHPh], 3.31 [1H, app. quin., J 7.3, CHPh], 4.97–5.05 [2H, m,

CH᎐CH ], 5.62–5.72 [1H, m, CH᎐CH ], 7.10–7.34 [5H, m,

᎐

2

PhH ], 9.69 [1H, t, J 1.9, CHO]; [α]²_D⁵ϩ14.4 (c = 0.5, CHCl₃),

{lit.^44bent-[α]²_D⁰Ϫ13.4 (c = 0.98, C₆H₆; 82% ee).

Preparation of (3ЈS,4S )-3-(3Ј,4Ј-diphenylbutyryl)-4-phenyl-5,5-

dimethyloxazolidin-2-one 45

Following Representative Procedure 5, CuBrؒSMe₂(480 mg,

2.34 mmol), PhCH₂MgCl (3.34 mL, 4.67 mmol), BF₃ؒEt₂O

(0.30 mL, 2.34 mmol) and 37 (500 mg, 1.56 mmol) in SMe₂

(10 mL) and THF (30 mL) 45 (374 mg, 58%, >95% de) as a

white solid after ﬂash column chromatography; R_f0.13 [5 : 1

hexane : Et₂O]; mp 94–96 ЊC [hexane–Et₂O]; C₂₇H₂₇NO₃

requires C, 78.4, H, 6.6, N, 3.4%, found C, 78.3, H, 6.6, N,

3.3%; [α]²_D³ϩ47.0 (c = 1.0, CHCl₃); δ_H(400 MHz, CDCl₃) 0.93

[3H, s, C(CH₃)_A(CH₃)_B], 1.32 [3H, s, C(CH₃)_A(CH₃)_B], 2.88–2.98

[2H, m, CHCH₂Ph], 3.07 [1H, dd, J 16.3, 5.1, CH_AH_BCHPh],

3.46–3.53 [1H, m, CHCH₂Ph], 3.77 [1H, dd, J 16.3, 9.9, CH_AH_B-

CHPh], 4.86 [1H, s, CHPh (auxiliary)], 7.03–7.38 [15H, m,

PhH ]; δ_C(100 MHz, CDCl₃) 23.4, 28.5 [C(CH₃)₂], 40.3

[CHCH₂Ph], 43.2 [CH₂CHPh], 43.9 [CHCH₂Ph], 66.9 [CHPh

(auxiliary)], 82.3 [C(CH₃)₂], 126.1, 126.5 [p-Ph], 127.7, 128.1,

128.5, 128.8, 129.2, 129.5 [m/o-Ph], 136.2, 139.5, 143.3 [i-Ph],

Preparation of (R)-4-methyl-3-phenylpentanal 49⁴⁵

Following Representative Procedure 3, DIBAL (0.82 mL, 0.82

mmol) and 44 (150 mg, 0.41 mmol) in CH₂Cl₂(5 mL) furnished

49 (52 mg, >95% ee, 72%) as a pale yellow oil and (S)-6 (52 mg,

66%) as a white solid after ﬂash column chromatography; R_f

0.24 [12 : 1 pentane : Et₂O]; δ_H(400 MHz, CDCl₃) 0.78 [3H, d,

J 6.7, CH(CH₃)_A(CH₃)_B], 0.96 [3H, d, J 6.7, CH(CH₃)_A(CH₃)_B],

1.84–1.92 [1H, m, CH(CH₃)₂], 2.72–2.85 [2H, m, CH₂CHPh],

2.94–2.99 [1H, m, CHPh], 7.15–7.32 [5H, m, PhH ], 9.61 [1H, t,

J 2.2, CHO]; [α]²_D³Ϫ8.4 (c = 0.5, CHCl₃).

Preparation of (S )-3,4-diphenylbutanal 50⁴⁶

Following Representative Procedure 3, DIBAL (0.48 mL, 0.48

mmol) and 45 (100 mg, 0.24 mmol) in CH₂Cl₂(5 mL) furnished

50 (52 mg, >95% ee, 96%) as a clear, colourless oil and (S)-6

153.2 [C᎐O endocyclic], 171.7 [C᎐O exocyclic]; ν_max(KBr) 1773

᎐

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 8 6 – 2 8 9 9

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(39 mg, 84%) as a white solid after ﬂash column chromato-

graphy; R_f0.15 [12 : 1 pentane : Et₂O]; δ_H(400 MHz, CDCl₃)

2.71–2.84 [2H, m, CH₂Ph], 2.89 [1H, dd, J 13.5, 7.9, CH_AH_B-

CHPh], 2.97 [1H, dd, J 13.5, 7.1, CH_AH_BCHPh], 3.46–3.54 [1H,

m, CHPh], 7.00–7.08 [2H, m, PhH ], 7.16–7.49 [8H, m, PhH ],

9.60 [1H, s, CHO]; [α]²_D³Ϫ6.6 (c = 0.5, CHCl₃), {lit.⁴⁶[α]²_D³Ϫ8.4

(c = 0.5, CHCl₃)}.

[CH CH CH᎐CH ], 40.0 [CH CH(C(CH )᎐CH ], 42.8

᎐ ᎐

2 2 2 2 3 2

[CH(C(CH )᎐CH ], 67.0 [CHPh], 82.3 [C(CH ) ], 112.4, 114.6

᎐

3

2

3 2

[CH CH CH᎐CH and CH(C(CH )᎐CH )], 128.7, 128.8

᎐

2

3

2

[m/o-Ph], 136.3 [i-Ph], 138.4 [p-Ph], 146.0 [CH(C(CH )᎐CH )],

᎐

3

2

153.1 [C᎐O endocyclic], 171.8 [C᎐O exocyclic]; ν_max(ﬁlm) 1778

᎐

[C᎐O endocyclic], 1715 [C᎐O exocyclic]; m/z APCIϩ 342

᎐

[100%, MH^ϩ]; HRMS C₂₁H₂₈NO₃[MH^ϩ] requires 342.2064,

found 342.2067.

Preparation of (R)-3-phenylbutanal 51

Preparation of (R)-3-isopropenylhept-6-enal 55³²

Following Representative Procedure 3, DIBAL (0.89 mL, 0.89

mmol) and 46 (150 mg, 0.45 mmol) in CH₂Cl₂(5 mL) furnished

51 (55 mg, >95% ee, 84%) as a clear, colourless oil and (S)-6 (83

mg, 98%) as a white solid after ﬂash column chromatography;

(R)-51: R_f0.15 [12 : 1 pentane : Et₂O]; [α]²_D⁵Ϫ34.6 (c = 0.5,

Et₂O), {lit.²⁹[α]²_D⁵Ϫ38.0 (c = 0.2, Et₂O), lit.³⁰[α]²_D⁵Ϫ38.5 (c = 0.2,

Et₂O)}.

Following Representative Procedure 3, DIBAL (1.26 mL, 1.26

mmol), 54 (215 mg, 0.63 mmol) in CH₂Cl₂(10 mL) furnished 55

(80 mg, >95% ee, 84%) as a pale, yellow oil and (S)-6 (93 mg,

77%) as a white solid after ﬂash column chromatography; R_f

0.38 [6 : 1 30–40 ЊC petrol : Et₂O]; δ_H(400 MHz, CDCl₃) 1.46–

1.62 [2H, m, CH CH CH᎐CH ], 1.67 [3H, s, CH(C(CH )᎐

᎐

3

2

CH )], 1.93–2.09 [2H, m, CH CH CH᎐CH ], 2.39–2.50 [2H, m,

᎐

2

Preparation of (S )-3-methyl-4-phenylbutanal 52⁴⁷

CH CHO], 2.51–2.75 [1H, m, CH(C(CH )᎐CH )], 4.80–4.84

᎐

2

3

2

[2H, m, CH(C(CH )᎐CH )], 4.94–5.05 [2H, m, CH CH CH᎐

᎐

3

2

Following Representative Procedure 3, DIBAL (0.86 mL, 0.86

mmol) and 47 (150 mg, 0.43 mmol) in CH₂Cl₂(5 mL) furnished

52 (62 mg, 90%, 91% ee) as a clear, colourless oil and (S)-6

(75 mg, 92%) as a white solid after ﬂash column chromato-

graphy; R_f0.21 [12 : 1 pentane : Et₂O]; δ_H(400 MHz, CDCl₃)

0.99 [3H, d, J 6.6, CHCH₃], 2.25 [1H, ddd, J 15.6, 7.4, 2.4,

CH_AH_BCHCH₃], 2.34–2.47 [2H, m, CHCH₃and CH_AH_B-

CHCH₃], 2.54–2.64 [2H, m, CH₂Ph], 7.16–7.32 [5H, m, PhH ],

9.72 [1H, t, J 2.0, CHO]; [α]²_D³Ϫ8.4 (c = 0.5, CHCl₃; 91% ee).

CH ], 5.75–5.85 [1H, m, CH CH CH᎐CH ], 9.68 [1H, t, J 2.5,

᎐

2

CHO]; [α]²_D⁵ϩ8.6 (c = 1.15, CHCl₃), {lit.³²[α]_Dϩ9.0 (c = 1.4,

CHCl₃)}.

Following Representative Procedure 4, LiAlH₄(0.05 mL,

0.05 mmol), 55(10 mg, 0.05 mmol) in THF (2 mL) furnished

(R)-3-isopropenylhept-6-en-1-ol (6 mg, 60%) as a pale, yellow

oil; δ_H(400 MHz, CDCl ) 1.36–1.50 [2H, m, CH CH CH᎐

᎐

3

2

CH₂], 1.57 [1H, br s, OH ], 1.59–1.64 [2H, m, CH₂CH₂OH], 1.63

[3H, s, CH(C(CH )᎐CH )], 1.89–2.05 [2H, m, CH CH CH᎐

᎐

3

2

CH ], 2.21–2.28 [1H, m, CH(C(CH )᎐CH )], 3.55–3.65 [2H, m,

᎐

2

3

2

Preparation of (S )-3-(hepta-2Ј,6Ј-dienoyl)-4-phenyl-5,5-

dimethyloxazolidin-2-one 53

CH CH OH], 4.76–4.79 [2H, m, CH(C(CH )᎐CH )], 4.92–5.02

᎐

2

3

2

[2H, m, CH CH CH᎐CH ], 5.75–5.85 [1H, m, CH CH CH᎐

᎐

2

CH₂]; [α]²_D⁵Ϫ5.6 (c = 0.25, CHCl₃), {lit.³²[α]_DϪ5.0 (c = 1.5,

Following Representative Procedure 1, n-BuLi (1.15 mL, 2.88

mmol), (S)-6 (500 mg, 2.62 mmol) and hepta-2,6-dienoyl chlor-

ide (3.4 mmol; prepared from hepta-2,6-dienoic acid (429 mg,

3.40 mmol), oxalyl chloride (1.49 mL, 17.02 mmol) and DMF

(cat.) in hexane) furnished 53 (571 mg, 77%) as a pale yellow oil

after ﬂash column chromatography; R_f0.32 [1 : 1 pentane :

Et₂O]; [α]²_D⁴ϩ64.8 (c = 0.4, CHCl₃); δ_H(400 MHz, CDCl₃) 1.00

[3H, s, C(CH₃)_A(CH₃)_B], 1.62 [3H, s, C(CH₃)_A(CH₃)_B], 2.21–2.26

CHCl₃)}.

Acknowledgements

The authors wish to thank Astra-Zeneca International plc for

the award of a DPhil studentship (R. L. N) and to New College,

Oxford for a Junior Research Fellowship (A. D. S).

[2H, m, CH CH CH᎐CH ], 2.35–2.40 [2H, m, CH CH CH᎐

᎐

2

CH ], 4.98–5.08 [2H, m, CH CH CH᎐CH ], 5.13 [1H, s,

᎐

2

CHPh], 5.76–5.86 [1H, m, CH CH CH᎐CH ], 7.05–7.39 [7H,

᎐

2

References and notes

m, PhH and CO.CH᎐CH ]; δ (100 MHz, CDCl₃) 23.7, 29.0

᎐

C

1 W. Oppolzer, C. Darcel, P. Rochet, S. Rosset and J. De Brabander,

Helv. Chim. Acta, 1997, 80, 1319.

2 A. G. Myers, B. H. Yang, H. Chen and J. L. Gleason, J. Am. Chem.

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3 G-J. Lee, T. H. Kim, J. N. Kim and U. Lee, Tetrahedron: Asymmetry,

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4 D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981, 103,

2127; D. A. Evans, Aldrichimica Acta, 1982, 15, 2.

[C(CH ) ], 31.9, 32.0 [CH CH CH᎐CH ], 67.2 [CHPh], 82.3

᎐

3

2

[C(CH ) ], 115.6 [CH CH CH᎐CH ], 120.8 [CH CH CH᎐

᎐

3

2

CH ], 128.5 [p-Ph], 128.8 [m/o-Ph], 136.4 [i-Ph], 137.0 [CH᎐

᎐

2

CHCH CH CH᎐CH ], 150.8 [CH᎐CHCH CH CH᎐CH ],

᎐

2

153.2 [C᎐O endocyclic], 164.8 [C᎐O exocyclic]; ν_max(ﬁlm) 1771

᎐

[C᎐O endocyclic], 1694 [C᎐O exocyclic]; m/z APCIϩ 256 [30%,

᎐

MH^ϩϪCO₂], 300 [50%, MH^ϩ]; HRMS C₁₈H₂₂NO₃[MH^ϩ]

5 S. G. Davies and H. J. Sanganee, Tetrahedron: Asymmetry, 1995, 6,

671.

requires 300.1594, found 300.1605.

6 C. L. Gibson, K. Gillan and S. Cook, Tetrahedron Lett., 1998, 39,

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7 D. A. Evans, M. D. Ennis and D. J. Mathre, J. Am. Chem. Soc., 1982,

104, 1737.

Preparation of (3ЈR,4S )-3-(3-isopropenylhept-6-enoyl)-4-

phenyl-5,5-dimethyloxazolidin-2-one 54

Following Representative Procedure 5, CuBrؒSMe₂(436 mg,

2.12 mmol), (C(CH )᎐CH )MgCl (8.98 mL, 4.49 mmol), BF ؒ

᎐

3

2

3

Et₂O (0.27 mL, 2.12 mmol) and 53 (400 mg, 1.41 mmol) in

SMe₂(10 mL) and THF (30 mL) furnished 54 (287 mg, 63%) as

a pale yellow oil after ﬂash column chromatography; R_f0.3

[5 : 1 pentane : Et₂O, double eluted]; [α]²_D⁴ϩ74.2 (c = 1.0,

CHCl₃); δ_H(400 MHz, CDCl₃) 0.99 [3H, s, C(CH₃)_A(CH₃)_B],

8 For example see M. P. Sibi, M. D. Johnson and T. Punniyamurthy,

Can. J. Chem., 2001, 1546; P. Pollock, J. Dambacher, R. Anness and

M. Bergdahl, Tetrahedron Lett., 2002, 43, 3693.

9 For example see D. A. Evans and J. Bartroli, Tetrahedron Lett., 1982,

23, 807; Y. Ito and S. Terashima, Tetrahedron Lett., 1987, 28, 6629;

H. Danda, M. M. Hansen and C. H. Heathcock, J. Org. Chem.,

1990, 55, 173; D. A. Evans, S. J. Clark, R. Metternich, V. J. Novack

and G. S. Shepphard, J. Am. Chem. Soc., 1990, 112, 866; J. R. Gage

and D. A. Evans, Org. Synth., 1990, 68, 83; D. A. Evans, J. S. Tedrow,

J. T. Shaw and C. W. Downey, J. Am. Chem. Soc., 2002, 124, 392.

10 The Swern oxidation is typically employed in this transformation,

although alternative oxidants have also been used. For leading

examples see D. A. Evans and A. E. Weber, J. Am. Chem. Soc., 1986,

108, 6757; D. A. Evans, R. P. Polniaszek, K. M. DeVries, D. E.

Guinn and D. J. Mathre, J. Am. Chem. Soc., 1991, 113, 7613;

1.42–1.51 [2H, m, CH CH CH᎐CH ], 1.60 [3H, s, C(CH ) -

᎐

2

3 A

(CH ) ], 1.66 [3H, s, CH(C(CH )᎐CH )], 1.89–2.06 [2H, m,

᎐

3

B

3

2

CH CH CH᎐CH ], 2.65–2.72 [1H, m, CH(C(CH )᎐CH )],

᎐

2

3

2

3.01–3.12 [2H, m, CH CH(C(CH )᎐CH )], 4.72–4.75 [2H, m,

᎐

2

3

2

CH(C(CH )᎐CH )], 4.92–5.01 [2H, m, CH CH CH᎐CH ], 5.05

᎐

3

2

[1H, s, CHPh], 5.72–5.82 [1H, m, CH CH CH᎐CH ], 7.11–7.15

᎐

2

[2H, m, PhH ], 7.30–7.39 [3H, m, PhH ]; δ_C(100 MHz, CDCl₃)

18.6, 23.6 [C(CH ) ], 29.0 [CH(C(CH )᎐CH )], 31.3, 32.0

᎐

3

2

3

2

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 8 6 – 2 8 9 9

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an Evans’ N-acyloxazolidinone generates

a

stable tetrahedral

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section.

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 8 6 – 2 8 9 9

2899

Article Doi

SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of α-alkyl and β-alkyl aldehydes

DOI: 10.1039/b305623f

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