Rearrangements and racemisation during the synthesis of L-serine derived oxazolidin-2-ones

Tetrahedron 58 (2002) 9387–9401

Rearrangements and racemisation during the synthesis of L-serine

derived oxazolidin-2-ones

a

b

Sean P. Bew,^aSteven D. Bull,^aStephen G. Davies,^aEdward D. Savory and David J. Watkin

,

*

^aDyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK

^bDepartment of Chemical Crystallography, University of Oxford, Parks Road, Oxford OX1 3PD, UK

Received 12 July 2002; revised 6 September 2002; accepted 26 September 2002

Abstract—The propensity for N-Boc-4-hydroxymethyl-oxazolidin-2-ones to undergo rapid O–O and N–O carbonyl transfer makes these

1. Introduction

There has recently been a concerted research effort to

immobilise many of the frequently used chiral auxiliaries

and reagents employed in modern synthetic organic

chemistry onto polymer support.¹Over the last 15 years,

the oxazolidin-2-one auxiliaries ﬁrst introduced by Evans

et al. have been widely employed as chiral auxiliaries within

asymmetric synthesis for utilisation in a wide range of

chemistries, which have included enolate alkylations,²aldol

reactions,³[4þ2]-cycloadditions,⁴and conjugate addition

reactions.⁵Unsurprisingly therefore, a number of groups

have reported on the development and use of a range of

polymer bound chiral auxiliaries derived via covalently

attaching the phenolate anion of a ^L-tyrosine derived

oxazolidin-2-one to different polymer supports. Thus,

L-tyrosine derived polymer supported oxazolidin-2-ones

have been employed by a number of different research

groups for stereoselective enolate alkylation reactions,⁶

aldol reactions,⁷[3þ2]-dipolar cycloadditions,⁸and [4þ2]

cycloadditions.⁹In an alternative approach, Allin and

Shuttleworth reported on the synthesis and use of a polymer

bound ^L-serine derived Evans chiral auxiliary for asym-

metric synthesis.¹⁰They reported that the L-serine derived

Evans N-Boc protected oxazolidin-2-one 1 had been grafted

onto polymer via a substitution reaction between the

Scheme 1. Reagents and conditions: (i) KH (1.5 equiv.), DMF, 08C; (ii)

Merriﬁeld resin, cat 18-crown-6, 808C, 5 days; (iii) dil HCl, DCM, D, 6 h;

(iv) (CH₃CH₂CO)₂O, DMAP (10%), Et₃N, THF, D, 4 days; (v) LDA

(2 equiv.), THF, 08C; BnBr (2 equiv.); NH₄Cl (aqueous); (vi) LiOH, THF,

H₂O.

potassium alkoxide 2 and Merriﬁeld resin 3. The polymer

bound chiral auxiliary 4 was then manipulated for the

asymmetric synthesis of (S)-a-methylhydrocinnamic acid 5

in a 42% yield and 96% ee according to the protocol

described in Scheme 1.

polymer supported Evans auxiliaries for asymmetric

synthesis, they do not address the key issue of polymer

recyclability. Evans oxazolidin-2-ones are not ideally suited

as a class of auxiliary for the immobilisation onto polymer

support. This is because of the widely recognised endo/exo-

cyclic cleavage problem, whereby nucleophiles are known

While these examples clearly demonstrate the potential of

Keywords: racemisation; L-serine; oxazolidin-2-one.

*

Corresponding author. Tel.: þ44-1865-275646; fax: þ44-1865-275633;

e-mail: steve.davies@chem.ox.ac.uk

PII: S0040-4020(02)01223-1

9388

S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

to competitively attack both endo and exo-carbonyl groups

of sterically hindered N-acyl-oxazolidin-2-ones, to afford

N-acyl-amino-alcohols as competing cleavage products. For

example, Evans et al. have shown that cleavage of 6 with

lithium benzyloxide results in predominantly (54%) the

endo-cyclic cleavage product 7 (Scheme 2).¹¹Clearly while

destruction of the oxazolidin-2-one functionality may be

tolerated in ‘solution phase’ this competing reaction path-

way will rapidly destroy any polymer bound oxazolidin-2-

one, preventing recycling of the polymer and its subsequent

use in asymmetric synthesis.

(4 equiv., 2788C to room temperature), yielding 9. Treat-

ment of 9 with potassium tert-butoxide afforded SuperQuat

10, which was subsequently N-Boc protected to yield 11.

Treatment of N-Boc-O-TBDMS SuperQuat 11 with a 1 M

solution of TBAF in THF, did not afford the desired N-Boc-

oxazolidin-2-one 14 but gave instead (S)-O-Boc-oxazolidin-

2-one 15 ([a]²_D³¼253.2 (c 0.66, CHCl₃); ¹H NMR, d

5.62 ppm, NH; ¹³C NMR, 153.0 (CvO) and 157.8 (CvO)

ppm; FT-IR, 1747 and 1720 cm²¹) as a clean product in

which the Boc protecting group had migrated from the

oxazolidin-2-one nitrogen to the oxygen of the 4-hydro-

xymethyl side-chain. Clearly TBAF mediated O-deprotec-

tion of the silyl protecting group on 11 afforded alkoxide

intermediate 12 which readily underwent intramolecular

attack at the N-Boc carbonyl group resulting in protecting

group migration (N–O) to afford O-Boc-oxazolidin-2-one

15 (Scheme 3). Attempts to O-benzylate (as a model

reaction for Merriﬁeld resin) the intermediate alkoxide

anion 12 before N–O-Boc protecting group migration could

occur were unsuccessful since TBAF deprotection of 11,

followed by immediate addition of a large excess of benzyl

bromide (Scheme 3) afforded (S)-N-benzyl-O-Boc-oxazoli-

din-2-one 16 ([a]_D²²¼þ11.2 (c 0.82, CHCl₃)).

The structure of O-Boc-oxazolidin-2-one 15 was readily

conﬁrmed by comparison with an authentic sample of the

corresponding N-Boc-oxazolidin-2-one 14, prepared via

Scheme 2. Reagents and conditions: (i) PhCH₂OLi, THF.

Our previous work directed towards solving this endo-cyclic

cleavage problem has resulted in the development of the

SuperQuat or 5,5-gem-dimethyloxazolidin-2-one chiral

auxiliary.¹²The SuperQuat chiral auxiliary efﬁciently

addresses the endo-cyclic cleavage problem by virtue of

the 5,5-gem-dimethyl group blocking the approach of any

nucleophiles towards the oxazolidin-2-one carbonyl.

Furthermore the conformational control of the 5,5-gem-

dimethyl group on the stereocontrolling 4-alkyl substituent

also serves to ensure that the stereoselectivities obtained for

reactions with this class of 5,5-gem-dimethyloxazolidin-2-

one are generally superior to those achieved with the

analogous Evans type oxazolidin-2-ones.¹³

As part of a general program directed towards the transfer of

SuperQuat 5,5-gem-dimethyloxazolidin-2-ones to polymer

support we wish to describe herein our attempts to

covalently attach the alkoxide anion of an ^L-serine-derived

SuperQuat 5,5-gem-dimethyloxazolidin-2-one to Merriﬁeld

resin. Part of this work has been previously communi-

cated.¹⁴

2. Results and discussion

2.1. Feasibility study into the attachment of ^L-serine

derived 5,5-gem-dimethyloxazolidin-2-ones

(SuperQuats) onto polymer support

Initial synthetic attempts were directed towards the

preparation of N-Boc-oxazolidin-2-one 14 as a monomer

for immobilisation on polymer support. Towards this aim,

readily available N-Boc-O-TBDMS-^L-serine methyl ester 8

was treated with excess methyl magnesium bromide

Scheme 3. Reagents and conditions: (i) MeMgBr (4 equiv.), THF, 2788C

to room temperature; (ii) KO^tBu, THF; (iii) (Boc)₂O, DMAP, Et₃N, DCM;

(iv) TBAF, THF; (v) NH₄Cl (aqueous); (vi) BnBr.

S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

9389

hydrogenolysis of N-Boc-O-benzyl-oxazolidin-2-one 20.

The instability of the corresponding potassium alkoxide

generated from 14 (Scheme 4) via treatment of 14 with KH

in DMF at 08C over a 2 h period, was conﬁrmed when

O-Boc-oxazolidin-2-one 15 (¹H NMR, d 5.59 ppm, NH; ¹³

C

NMR, 153.0 (CvO) and 157.8 (CvO) ppm; FT-IR, 1742

and 1720 cm²¹) was produced as a clean product in an

excellent yield (87%).

Scheme 6. Reagents and conditions: (i) Al(CH₃)₃, DCM, 2158C, 1.5 h.

epoxy-(1SR)-phenylpropan-1-ol 21, resulted in the for-

mation of N-benzoyl-oxazolidin-2-one anion 23, which

spontaneously underwent a 5-exo-trig N–O-benzoyl

migration to yield ester 24 (¹H NMR, d 6.88 ppm, NH;

FT-IR, 1760 and 1720 cm²¹) (Scheme 5).¹⁵

Yamamoto et al. have shown that this type of N–O-benzoyl

migration may also occur in the presence of Lewis acids

(Scheme 6) since treatment of (2S,3R)-epoxypropyl-

benzoylcarbamate 25 with trimethylaluminium gave N–O-

migrated O-benzoyl-oxazolidin-2-one 26 (¹H NMR, d

6.52 ppm, NH; ¹³C NMR, d 160.1 (CvO) and 165.7 ppm

(CvO); FT-IR, 1740 and 1720 cm²¹) in a 67% yield, with

no evidence of any of the corresponding N-benzoyl

oxazolidin-2-one 27.¹⁶

Deﬁnitive experiments by Katsumura et al. showed that

intramolecular cyclisation of the anion derived from (S)-N-

benzoyl-2,3-epoxypropylcarbamate 28 did not afford the

expected (S)-N-benzoyl-oxazolidin-2-one 32 but gave

instead the (S)-N–O-benzoyl rearrangement product 29

(Scheme 7). Furthermore, these workers demonstrated

the propensity of this class of oxazolidin-2-one to

racemisation. When hydrolysis of enantiomerically

Scheme 4. Reagents and conditions: (i) MeMgBr, (4 equiv.) 2788C to rt,

THF; (ii) KO^tBu, THF, room temperature; (iii) (Boc)₂O, DMAP, Et₃N,

DCM, room temperature; (iv) MeOH, H₂, 10% Pd on C; (v) KH, DMF, 08C,

2 h.

There is clear literature precedent for this type of N–O

carbonyl exo-cyclic rearrangement for N-carbonyl oxazoli-

din-2-ones. For example, Knapp et al. have reported that

deprotonation of (rac)-(2RS)-3-epoxy-(1SR)-phenylpropyl

benzoylcarbamate 22, synthesised from (rac)-(2RS)-3-

Scheme 7. Reagents and conditions:(i) PhCONCO, CH₂Cl₂, room tempera-

ture; (ii) K₂CO₃, PhCH₂N(CH₂CH₃)₃Cl, DCM/H₂O, 1:1, room temperature,

2 h;(iii)NaH, BnBr, (CH₃CH₂)₄NI, THF/DMF, room temperature; (iv) LiOH,

H₂O, THF; Cs₂CO₃, MeOH; or K₂CO₃, MeOH.

Scheme 5. Reagents and conditions: (i) PhCONCO, CCl₄, room

temperature; (ii) NaH (0.25 equiv.), THF, reﬂux.

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S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

enriched (S)-N-benzyl-O-benzoyl-oxazolidin-2-one 30 was

undertaken with a selection of inorganic bases (LiOH in

H₂O/THF; or Cs₂CO₃in MeOH; or K₂CO₃in MeOH) the

reaction afforded (rac)-N-benzyl-oxazolidin-2-one 31 pre-

sumably via an O–O-carbonyl migration pathway involving

attack of the alkoxide anion of the pendant 4-hydroxymethyl

group on the oxazolidin-2-one carbonyl.¹⁷

This O–O-carbonyl migration pathway is a common feature

for this class of 4-hydroxymethyl-oxazolidin-2-one. For

example, Shinozaki have shown in their studies directed

towards the total synthesis of ^D-erythro-Sphingosine that

treatment of trans-(2S,3R)-allylic chloride 33 with potas-

sium carbonate in methanol at ambient temperatures

afforded the O–O-carbonyl rearranged chloroallylic alcohol

34 in 92% yield (Scheme 8).¹⁸The driving force behind this

rearrangement is presumably release of the 1,2-cis-strain of

the substituents within oxazolidin-2-one ring 33. A similar

rearrangement was reported by McCombie et al. who

demonstrated that treatment of (2S,3R)-2,3-epoxy carba-

mate 35 with potassium carbonate afforded O-benzoate

ester 36 in 79% yield.¹⁹

The O–O-carbonyl rearrangement pathways described in

Schemes 7 and 8 cast doubt on the structural assignment of

O-Boc-oxazolidin-2-one 16, since alkoxide 12 (Scheme 3)

had the capacity to undergo this type of O–O-carbonyl

rearrangement to afford a N-benzyl-oxazolidin-2-one

species 40. We decided therefore to prepare an authentic

sample of oxazolidin-2-one 16, according to the protocol

described in Scheme 9, which would enable direct spectro-

scopic comparisons to be carried out. Thus, epoxidation of

3-methyl-but-2-ene-1-ol 37 with mCPBA gave (rac)-

Scheme 9. Reagents and conditions: (i) mCPBA; Na₂CO₃(aqueous), room

temperature; (ii) PhCONCO, cat [(n-Bu)₂SnCl]₂O, DCM; (iii) n-BuLi

(1 equiv.), THF, 2208C; (iv) NaH, THF, room temperature; (v) (Boc)₂O,

DMAP, Et₃N, DCM.

epoxide 38,²⁰which reacted with benzyl isocyanate in the

presence of a catalytic amount of bis-(dibutylchlorotin)-

oxide to afford (rac)-benzyl-carbamic acid-3,3-dimethyl-

oxiranyl methyl ester 39 (53%). Cyclisation of 39 via

deprotonation with n-BuLi afforded, after chromatographic

puriﬁcation, the oxazolidin-2-one tertiary alcohol 40 as a

colourless oil (61%). Deprotonation of 40 with sodium

hydride in THF resulted in rearrangement of oxazolidin-2-

one tertiary alcohol 40 to the corresponding primary alcohol

41.²¹A comparison of the 400 MHz ¹H NMR spectra of 40

and 41 clearly shows a signiﬁcant change in the environ-

ment of the constituent protons, for example the gem-

dimethyl groups have moved downﬁeld from d 1.17/1.23 to

d 1.36/1.44 ppm for 40 and 41, respectively. Furthermore,

the complexity of the HOCH₂CHN ¹H–¹H coupling

constants for 41 were signiﬁcantly simpler than those of

40 presumably due to the freely rotating exo-cyclic CH₂OH

group. The previously assigned structure of 16 (Scheme 3)

was conﬁrmed unambiguously by conversion of the primary

alcohol 41 into the corresponding (rac)-N-benzyl-O-Boc-

oxazolidin-2-one 16.

We concluded therefore that the endo and exo-cyclic

migrations described above render ^L-serine derived Super-

Quat 5,5-gem-dimethyloxazolidin-2-ones unsuitable for

attachment to polymer support via the 4-hydroxymethyl

side-chain.

2.2. Investigations into N–O carbonyl migration within

L-serine derived Evans’ oxazolidin-2-ones

In light of the results described above, the report by Allin

and Shuttleworth (Scheme 1) on the generation of an

alkoxide from 1 (KH, DMF, 08C) and clean attachment to

Merriﬁeld resin (DMF, catalytic 18-crown-6, 808C, 5 days)

without apparent racemisation (endo-cyclic O-O carbonyl

Scheme 8. Reagents and conditions: (i) K₂CO₃, MeOH, room temperature,

2 h; (ii) K₂CO₃, 5 mol% CH₃N(C₈H₁₇)₃Cl.

S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

9391

rearrangement), or N–O-Boc migration (exo-cyclic

rearrangement), seemed remarkable and merited investi-

gation. Synthesis of the key ^L-serine derived homochiral

N-Boc-oxazolidin-2-one 1 was undertaken via two different

protocols. Firstly, commercially available O-benzyl-^L-

serine 42 was reduced to yield the corresponding O-benzyl

amino alcohol 43,²²which was subsequently transformed

into O-benzyl-oxazolidin-2-one 44 via the phosgene

equivalent, carbonyl diimidazole.²³Subsequent N-Boc

protection of oxazolidin-2-one 44 yielded 45 which was

subjected to hydrogenolysis of the O-benzyl group, yielding

(S)-N-Boc-oxazolidin-2-one 46 ([a]²_D²¼þ42.8 (c 0.5,

CHCl₃)) in good yield (82%, ¹³C NMR, 149.9 (CvO)

Alternatively, N-Boc-oxazolidin-2-one 1 was prepared via a

modiﬁcation of the protocol originally employed by Allin

and Shuttleworth for their polymer bound oxazolidin-2-one

4 (Scheme 1).¹⁰Thus, treatment of L-serine methyl ester

hydrochloride salt with triphosgene and triethylamine

yielded 47, followed by N-Boc-protection to afford

N-Boc-oxazolidin-2-one methyl ester 48. Reduction of 48

under the original conditions of Sibi et al. ((i) NaBH₄, 08C;

(ii) sat. aqueous NH₄Cl) was problematic, affording only

low yields of the desired (R)-4-hydroxymethyl-N-Boc-

oxazolidin-2-one 46.²⁴Carrying out the reduction via

inverse addition of ester 48 to an ice-cold solution of

sodium borohydride (4 equiv.), followed by phosphate

buffer work-up (pH 4), gave the desired (R)-N-Boc-

oxazolidin-2-one 46 in a 64% yield ([a]²_D²¼245.6 (c 0.83,

CHCl₃)), ¹³C NMR, 151.0 (CvO) and 152.3 (CvO) ppm;

FT-IR, 1803 and 1706 cm²¹) (Scheme 11). The enantio-

meric purity of (R)-46 was determined to be .95% ee by

and 152.4 (CvO) ppm; FT-IR, 1798 and 1722 cm²¹

)

(Scheme 10).

1

comparison of the H NMR (250 MHz) spectra of (R)-46

with an authentic racemic sample of 46 in the presence of

40 mol% of (þ)-Europium(tfc)₃.

Scheme 10. Reagents and conditions: (i) BH₃·SMe₂/THF, 08C-reﬂux, 12 h;

H₂O₂; (ii) CDI, DCM, 12 h; (iii) (Boc)₂O, DMAP, Et₃N, DCM, room

temperature; (iv) MeOH, H₂, 10% Pd on C.

Scheme 11. Reagents and conditions: (i) triphosgene, DCM, Et₃N, 08C;

(ii) (Boc)₂O, DMAP, Et₃N; (iii) NaBH₄(4 equiv.), EtOH, 08C; phosphate

buffer pH 4.

It was considered important to conﬁrm unequivocally the

exact location of the Boc group, and as a consequence an

X-ray crystal structure of (S)-N-Boc-oxazolidin-2-one 46

was obtained which clearly revealed the presence of the Boc

protecting group on the nitrogen atom of the oxazolidin-2-

one (Fig. 1).

An authentic sample of 45 and (rac)-N-benzyl-O-Boc-

oxazolidin-2-one 50 were then prepared for comparative

purposes according to the protocol described in Scheme 12.

Thus, (rac)-glycidol was treated with benzyl isocyanate in

Figure 1. X-Ray crystal structure of (S)-4-hydroxymethyl-2-oxo-oxazoli-

din-3-carboxylic acid tert-butyl ester 46.

Scheme 12. Reagents and conditions:(i) PhCONCO, cat [(n-Bu)₂SnCl]₂O,

DCM; (ii) n-BuLi (1 equiv.), THF, 2208C; (iii) (Boc)₂O, DMAP, DCM.

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S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

oxazolidin-2-one 46 prepared via the synthetic route shown

in Scheme 11 was treated with KH in DMF at 08C, the

resulting anion was quenched with para-nitrobenzyl

bromide, this afforded the crystalline O-Boc-N-para-

nitrobenzyl oxazolidin-2-one (S)-51 (Scheme 14, ¹³C

NMR, 155.4 (CvO) and 160.9 (CvO) ppm; FT-IR, 1744

and 1733 cm²¹) which was subjected to X-ray crystal-

lographic analysis, this clearly revealed the presence of the

para-nitrobenzyl group on the nitrogen atom (Fig. 2).

Scheme 13. Reagents and conditions: (i) KH, DMF, 08C, 2 h; (ii) BnCl, cat

18-crown-6, 08C to rt, 12 h.

the presence of catalytic amounts of bis(di-n-butylchlorotin)

oxide, and the resulting carbamate 49 deprotonated with

n-BuLi to afford (rac)-N-benzyl-4-hydroxymethyl-oxazoli-

din-2-one 32, which was Boc protected on oxygen to afford

(rac)-N-benzyl-O-Boc-oxazolidin-2-one 50 (Scheme 12).

With quantities of (R)-N-Boc-oxazolidin-2-one 46 in hand

the reaction conditions employed by Allin and Shuttleworth

could be repeated. Treatment of a solution of (R)-46 in DMF

at 08C with KH presumably afforded potassium alkoxide

anion 2 (Scheme 13), was followed by addition of benzyl

chloride (as a mimic for Merriﬁeld resin) and a catalytic

amount of 18-crown-6. The resulting solution was heated at

808C for 4 days to afford a complex mixture of unidenti-

ﬁable reaction products. However, modiﬁcation of the

original reaction conditions involving generation of the

corresponding potassium alkoxide of (R)-46 using potas-

sium hydride in DMF at 08C and subsequent addition of

benzyl chloride and a catalytic amount of 18-crown-6

(warming to room temperature only) afforded a crude

reaction product which was shown, after ﬂash column

chromatography to be (S)-N-benzyl-O-Boc-oxazolidin-2-

one 50 (Scheme 13, [a]²_D³¼þ10.5 (c 1.54, CHCl₃)); ¹³C

NMR, 153.0 (CvO) and 158.2 (CvO) ppm; FT-IR, 1742

and 1724 cm²¹) via spectroscopic comparison with the

authentic sample of (rac)-50 (¹³C NMR, 152.9 (CvO) and

158.2 (CvO) ppm; FT-IR, 1744 and 1722 cm²¹) pre-

viously prepared according to the protocol outlined in

Scheme 12.

Figure 2. Crystal structure of (S)-carbonic acid tert-butyl ester-3-(4-

nitrobenzyl)-2-oxo-oxazolidin-4-yl methyl ester.

With these results in hand we next investigated the

possibility that N-benzyl-O-propionyl-oxazolidin-2-one 52

might prove inherently useful as a chiral auxiliary for the

asymmetric synthesis of a-substituted carboxylic acids such

as 5 (Scheme 1). Thus, O-Boc deprotection of (S)-N-benzyl-

O-Boc-oxazolidin-2-one 50 via treatment with aqueous 1 M

hydrochloric acid in reﬂuxing THF yielded N-benzyl-4-

hydroxymethyl-oxazolidin-2-one

(R)-32

(FT-IR,

1723 cm²¹) in a 76% yield, which was subsequently

O-propionylated via the method of Ager et al to afford

N-benzyl-O-propionyl-oxazolidin-2-one 52 in a 91% yield

([a]²_D³¼þ10.0 (c 1.35, CHCl₃)); ¹³C NMR, 158.2 (CvO)

and 173.9 (CvO) ppm.²⁵Treatment of N-benzyl-O-

propionyl-oxazolidin-2-one 52 with 2 equiv. of LDA at

2788C followed by addition of 2 equiv. of benzyl bromide

afforded a complex mixture of reaction products that

contained the ketones 53/54, with no spectroscopic evidence

of any of the expected a-benzylated-propionyl-oxazolidin-

2-ones 55/56 having been formed. Repeating this deproto-

nation reaction at 2788C, gave a cleaner reaction mixture

containing the ketones 53/54 and a small amount of starting

material 52 (37%), once again the 400 MHz ¹H NMR

provided no evidence of the diastereoisomers 55/56, as

would have been expected from a-benzylation of the

enolate derived from O-propionyl-N-benzyl-oxazolidin-2-

one 52. The absence of any resonances corresponding to the

a-benzylated-N-propionyl-oxazolidin-2-ones 55/56 within

the 400 MHz ¹H NMR spectra of these crude reaction

mixtures was conﬁrmed via spectroscopic comparison with

an authentic sample of 55/56 (0% de) which was prepared

Further evidence for the benzyl group being located on

nitrogen was sought. A sample of the crystalline (R)-N-Boc-

Scheme 14. Reagents and conditions: (i) KH, DMF, 08C, 2 h; para-

nitrobenzyl bromide, room temperature, 12 h.

S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

9393

via O-acylation of the hydroxyl functionality of (R)-32 with

(rac)-a-methylhydrocinnamoyl chloride (Scheme 15).²⁶

Figure 3. Selected ¹H–¹H-COSY and ¹H–¹³C-COSY correlations for 53.

solved in DMF, cooled to 08C under argon and potassium

hydride (oil free) added. The resulting solution was stirred

for 2 h at 08C and Merriﬁeld resin (loading 1.7 mmol/g) was

added. The resulting suspension was heated at 808C for 5

days with a catalytic amount of 18-crown-6, after which the

polymer was ﬁltered and washed sequentially with the

following solvents (in order), DMF, THF, DCM, MeOH and

Et₂O to ensure removal of excess reagents from the

polymer. A small portion of the polymer was subjected to

FT-IR analysis (KBr), which revealed a strong broad

absorbance (1785–1700 cm²¹) centred at 1742 cm²¹

which is consistent with the absorption’s expected for

both the carbonyls of a N-polymer-linked-O-Boc-oxazoli-

din-2-one (compare with 50 ,1742 and ,1724 cm²¹), but

not with the absorption’s expected for a O-polymer-linked-

N-Boc-oxazolidin-2-one 4 (compare with 45 ,1809 and

,1788 cm²¹). Removal of the Boc group from the auxiliary

was achieved via treatment with 1 M aqueous hydrochloric

acid in DCM at reﬂux. The polymer was again washed

sequentially with the solvent series outlined above, i.e.

DMF, THF, DCM, MeOH and Et₂O. This afforded a

polymer which displayed a broad FT-IR (KBr; 1795–

1705 cm²¹) centred at 1750 cm²¹. Subsequent acylation of

the polymer bound serine derived oxazolidin-2-one was

achieved using a mixture of propionic anhydride/triethyl-

amine/10% DMAP in reﬂuxing THF for 4 days. The

resulting polymer possessed a broad FT-IR (KBr) absorp-

tion spanning 1780–1724 cm²¹, with a weak stretch at

1650 cm²¹. It is also noted that the corresponding FT-IR

(thin ﬁlm) of N-benzyl-O-propionyl-oxazolidin-2-one 52

possesses similar absorbances within the CvO region i.e.

1759–1721 cm²¹, centred at 1738 cm²¹and a weak stretch

at 1643 cm²¹. Interestingly Allin and Shuttleworth¹⁰

themselves reported that ‘a new carbonyl band correspond-

ing to the N-propionyl side chain at 1652 cm²¹’ was

observed. The polymer was washed (solvents as above),

dried and suspended in THF. The suspension was cooled to

2788C and subsequently treated with LDA (2 equiv., 0.5 M

in THF), after 2 h at 2788C, freshly distilled benzyl

bromide was added and the resulting suspension allowed

to warm to room temperature over 12 h. Attempted cleavage

Scheme 15. Reagents and conditions: (i) 1 M HCl, THF; (ii) (CH₃CH_2-

CO)₂O, DMAP, Et₃N, DCM; (iii) LDA (2 equiv.), THF, 2788C; BnBr.

Puriﬁcation of the ketones 53/54 to homogeneity was

problematical, however after many attempts chromato-

graphic separation of the crude reaction mixture was

achieved using ether as the initial eluent to remove

unreacted starting material 52, followed by elution with

chloroform, which resulted in partial separation of the

mixture affording pure 53 in a 7.4% yield, and a mixture of

53/54 in which the minor ketone 54 was enriched. Salient

spectroscopic details for the major ketone 53 include a

characteristic singlet at d 5.92 ppm (minor epimer at d

1

5.48 ppm) in the H NMR spectrum corresponding to the

benzylic hydrogen; the presence of two peaks in the ¹³C

NMR spectrum corresponding to both a ketone and an

oxazolidin-2-one carbonyl functionality at d 211.8 and

158.9 ppm, respectively, and two absorbances at 1742

(oxazolidin-2-one CvO) and 1712 cm²¹(ketone CvO) in

the FT-IR. Further conﬁrmation of the proposed structure

for the major epimer 53 was obtained from correlated

¹H–¹H and ¹H–¹³C NMR (400 MHz) spectroscopic

studies, the salient features of which are described in Fig.

3. Importantly, the epimeric relationship between the major

and minor diastereoisomers was conﬁrmed by undertaking a

simple experiment. Dissolving pure major epimer 53 in a

small amount of DCM and subsequently passing the

solution through a pipette that had been charged with

basic alumina allowed the emerging DCM solution to be

collected, the solvent removed and a ¹H NMR recorded. The

H NMR clearly showed the product to be a 1:1 mixture of

53/54. With the characteristic benzylic singlets clearly

identiﬁable at d 5.92 and 5.48 ppm for 53/54 respectively.

We next attempted to repeat the synthesis of polymer 4

(Scheme 1) according to the protocol of Allin and

Shuttleworth.¹⁰Thus, N-Boc-oxazolidin-2-one 1 was dis-

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S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

of any N-acylated product from the polymer support was

then undertaken using aqueous THF/lithium hydroxide

solution over 12 h. Acidiﬁcation (2 M HCl) of the aqueous

cleavage solution followed by extraction (DCM) afforded

an organic soluble product, that the corresponding ¹H NMR

(200 MHz) revealed contained a large number of resonances

none of which corresponded to a-methylhydrocinnamic

acid 5. Repetition of the above experiment at 08C led to the

same result.

AC-400 or a Varian Gemini 200 and unless otherwise stated

deuterated chloroform was used as solvent. The ¹H-spectra

were recorded in ppm and referenced to residual CHCl₃

signal located at d 7.26. ¹³C NMR spectra were recorded in

ppm and referenced to residual CHCl₃signal found at d

77.00. Atmospheric Pressure Chemical Ionisation (APCI)

mass spectra were recorded on a Platform instrument. Major

peaks are listed with the intensities quoted as percentages of

the base peak. HRMS were obtained on a VG Autospec

instrument, and were recorded by Mr. R. Proctor of the

Dyson Perrins Laboratory. NH₃was used as the carrier gas

for CI. Melting points were obtained on either a Gallenkamp

capilliary apparatus or a Leica Galen III heated stage

apparatus and are uncorrected. Thin layer chromatography

was performed on Merck aluminium plates coated with

0.2 mm silica gel 60 F₂₅₄. Flash column chromatography

was performed on silica gel (Kieselgel 60).

In light of these observations we must conclude that the

material described by Allin and Shuttleworth and described

as the O-bound homochiral polymer supported N-Boc-

oxazolidin-2-one 4 was in fact N-bound polymer supported

O-Boc-oxazolidin-2-one 57 (Fig. 4). In light of these results

we are unable to explain their success in employing polymer

supported oxazolidin-2-ones for the generation of (S)-a-

methylhydrocinnamic acid 5 in 96% ee.¹⁰

4.1.1. {1-[(tert-Butyldimethylsilanoxymethyl)-2-hydroxy-

2-methyl]-propyl}-(S)-carbamic acid tert-butyl ester 9.

N-Boc-^L-serine methyl ester²⁷8 (21.6 g, 71.7 mmol) was

dissolved in tetrahydrofuran (300 mL) and subsequently

cooled to 2788C in a CO₂/acetone bath. A solution of

methyl magnesium bromide in ether (34.0 g, 95 mL,

285 mmol, 4 equiv., 3 M) was added dropwise to ester 8

over a 15 min period (care: methane evolved). The resulting

solution was stirred at 2788C for a further 4 h and then

allowed to warm to room temperature. After 12 h the

reaction mixture was cooled to 08C and carefully quenched

with aqueous saturated ammonium chloride (200 mL). The

quenched reaction was allowed to warm to room tempera-

ture over a 20 min period. The solvent was removed in

vacuo and replaced with dichloromethane (200 mL). To the

dichloromethane solution containing the crude reaction

mixture enough aqueous saturated ammonium chloride was

added so that all the magnesium salts dissolved. The

aqueous layer was partitioned and the dichloromethane

solution was washed with aqueous saturated ammonium

chloride (2£100 mL), saturated brine (2£100 mL), aqueous

saturated sodium bicarbonate (2£100 mL) and subsequently

dried (MgSO₄). Filtration and removal of the solvent in

vacuo yielded (S)-9 as a pale yellow oil. The title compound

was puriﬁed via ﬂash column chromatography using

n-pentane/ether (65:35) as the eluent, returning (S)-9 as a

clear oil (93%, 22.1 g); [a]²_D²¼þ38.4 (c 0.75, CHCl₃); n_max

(ﬁlm) (cm²¹) 3448, 2977, 2931, 1699 (s, CvO), 149.7,

1366, 1331, 125.6, 1173, 1099, 837; d_H(400 MHz, CDCl₃)

0.077 [6H, s, (CH₃)₂Si], 0.89 [9H, s, (CH₃)₃CSi], 1.19 [3H,

s, (CH₃)₂COH], 1.33 [3H, s, (CH₃)₂COH], 1.44 [9H, s,

(CH₃)₃CO], 3.38 (1H, m, CH(NH)), 3.58 (1H, s, OH), 3.85

(1H, dd, J¼10.7, 2.2 Hz, CH_ACH_BOTBDMS), 4.05 (1H, dd,

J¼10.7, 2.2 Hz, CH_ACH_BOTBDMS), 5.35 (1H, d, J¼

8.7 Hz, N–H); d_C(100.6 MHz, CDCl₃) 25.7 [(CH₃)₂Csi],

18.0, 25.8 [(CH₃)₃CSi)], 26.8 [(CH₃)₂COH], 27.8

[CH₃)₂COH], 28.4 [CH₃)₃CO)], 56.8, 64.4, 73.0, 79.2,

155.9 (CvO); m/z (APCIþ) 356.1 (5, MþNa^þ), 289.1 (5),

234.1 (100%), 216.1 (5).

Figure 4.

3. Conclusion

The propensity of N-Boc-4-hydroxymethyl-oxazolidin-2-

ones to undergo rapid O–O and N–O carbonyl transfer

reactions makes these ^L-serine derived chiral auxiliaries

unsuitable for attachment to polymer support. The success-

ful attachment of the SuperQuat 5,5-dimethyl-oxazolidin-2-

one chiral auxiliary derived from ^L-tyrosine to a polymer

support via its phenolic hydroxyl will be reported

elsewhere.

4. Experimental

4.1. General methods

All reactions were performed (under a positive pressure of

argon or nitrogen) in ﬂame dried ﬂasks, equipped with

stirrer beads unless otherwise stated. Ether and tetrahydro-

furan was freshly distilled from sodium benzophenone

ketyl. Dichloromethane was distilled from calcium hydride.

Toluene was distilled from sodium. N,N-Dimethylforma-

mide was stored over ﬂame dried 4 A molecular sieves

which were allowed to cool in vacuo. Ethanol was stored

˚

over activated 4 A molecular sieves. Water refers to

˚

distilled water. All other reagents were obtained and used

‘as is’ from commercial suppliers unless otherwise stated.

Optical rotations were performed on a Perkin–Elmer 241

polarimeter and are quoted for spectroscopic grade chloro-

4.1.2. (S)-(tert-Butyldimethylsilanyloxymethyl)-5,5-

dimethyloxazolidin-2-one 10. Tertiary alcohol (S)-9

(19.5 g, 58.6 mmol) was dissolved in tetrahydrofuran

(400 mL) whilst being stirred and cooled to 2788C. In

one portion potassium tert-butoxide (8.0 g, 71.3 mmol) was

form (Aldrich), [a]²_D²values are given in 10²¹deg cm²g²¹

.

FT-IR spectra were recorded on a Perkin–Elmer Paragon

1000FT infrared spectrometer. H and ¹³C NMR spectra

were recorded on either a Bruker AM-500, AMZ-500,

1

S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

9395

added, the solution quickly turning yellow. After 10 min at

2788C the reaction mixture was allowed to warm to room

temperature. After 16 h at this temperature the reaction was

quenched with aqueous saturated ammonium chloride

(100 mL). The crude product was extracted into dichloro-

methane (3£75 mL). The dichloromethane solution was

washed with aqueous hydrochloric acid (0.1 M, 2£100 mL),

saturated brine (2£50 mL), water (2£50 mL) and sub-

sequently dried (MgSO₄). Filtering the solution and removal

of the solvent in vacuo yielded the title compound as a solid.

Puriﬁcation of (S)-10 was achieved by crystallising from

n-pentane. SuperQuat (S)-10 (11.3 g, 67%) was a yellow

crystalline solid with the following physical characteristics;

mp 60–648C; [a]_D²²¼232 (c 0.52, CHCl₃); n_max(KBr)

(cm²¹) 3245 (N–H), 2957, 2857, 1756 (s, CvO), 1472,

1351, 1295, 1258, 1199, 1083, 840; d_H(500 MHz, CDCl₃)

0.02 [6H, s, (CH₃)₂Si], 0.83 [9H, s, (CH₃)₃CSi], 1.31 (3H, s,

5-C–CH₃), 1.42 (3H, s, 5-C–CH₃⁰), 3.46–3.60 (3H, m,

CH_ACH_BOTBDMS and 4-CH), 5.4 (1H, br s, N–H); d_C

(100.6 MHz, CDCl₃) 25.0 [(CH₃)₂Si], 18.5 [(CH₃)₃CSi],

21.8 (5-C–CH₃), 26.2 [(CH₃)₃CSi], 28.8 (5-C–CH₃⁰), 62.7,

62.8, 82.7, 158.9 (CvO); m/z (APCIþ) 282.2 (20,

MþNa^þ), 260.2 (100%), 216.2 (90), 120.0 (10), 102.1

(40); HRMS (CI^þ) (Found: MH^þ, 260.1690. C₁₂H₂₅NO₃Si

requires 260.1682).

151 mg, 0.58 mmol, 1 M solution in THF, Aldrich). The

resulting yellow/orange reaction mixture was stirred for a

further 12 h at room temperature. After 12 h, analysis of the

reaction mixture by tlc (n-pentane/ether, 75/25) indicated

that all of the starting material had been consumed. The

solvent was removed in vacuo and replaced with dichloro-

methane (2 mL). The dichloromethane solution was ﬁltered

through a short column of silica. The silica was further

eluted with three more aliquots of dichloromethane (2 mL).

The dichloromethane fractions were combined and the

solvent removed in vacuo yielding impure 15. Puriﬁcation

of the title compound was readily achieved via ﬂash column

chromatography using ether as the eluent. (S)-O-Boc-

SuperQuat 15 was isolated as a white solid which displayed

the following physical characteristics (58 mg, 86%); mp

112–1158C; [a]_D²³¼253.2 (c 0.66, CHCl₃); n_max(KBr)

(cm²¹) 3436 (N–H), 2980, 2934, 1774, 1747 (s, CvO),

1720 (s, CvO), 1455, 1393, 1370, 1276, 1256, 1157, 1090,

1002; d_H(400 MHz) 1.39 (3H, s, 5-C–CH₃), 1.49 [9H, s,

C(CH₃)₃], 1.51 (3H, s, 5-C–CH₃⁰), 3.72 (1H, m, 4-CH), 4.03

(1H, dd, J¼11.0, 8.1 Hz, CH_ACH_BO), 4.18 (1H, dd, J¼11.0,

4.6 Hz, CH_ACH_BO), 5.62 (1H, br s, N–H); d_C(100.6 MHz,

CDCl₃) 21.6 (5-C–CH₃), 27.6 [(CH₃)₃C], 28.0 (5-C–CH₃⁰),

59.6, 65.6, 81.8, 83.2, 153.0 (CvO), 157.8 (CvO); m/z

(APCIþ) 286.1 (25, MþNa^þ), 236 (5), 218 (5), 212 (5),

190.1 (100%), 167.9 (5), 146 (20), 128.1 (80), 116.1 (25),

102 (10); HRMS (CI^þ) (Found: MH^þ, 246.1338.

C₁₁H₂₀NO₅requires 246.1341.

4.1.3. (S)-[(tert-Butyldimethylsilanoxymethyl]-5,5-

dimethyl-2-oxo-oxazolidine-3-carboxylic acid tert-butyl

ester 11. A ﬂask was charged with SuperQuat (S)-10

(4.94 g, 19.1 mmol) and the solid dissolved in tetrahydro-

furan (100 mL). To the stirred solution was added

4-dimethylaminopyridine (1.16 g, 9.49 mmol), di-tert-

butyl dicarbonate (8.3 g, 38.0 mmol) and triethylamine

(3.84 g, 38.0 mmol). The reaction was stirred for 12 h at

room temperature and the solvent removed in vacuo.

Replacing the tetrahydrofuran with ether (100 mL) allowed

the crude reaction mixture to be washed with aqueous

hydrochloric acid (0.1 M, 3£25 mL), saturated aqueous

brine (3£50 mL) and subsequently dried (MgSO₄). After

ﬁltration the impure product was puriﬁed via ﬂash column

chromatography using a mixture of n-pentane and ether

(75:25) as the eluent. The puriﬁed title compound (S)-11

was a white solid (5.7 g, 83%) which had the following

physical characteristics; mp 110–1128C; [a]²_D²¼þ30.35 (c

1.12, CHCl₃), n_max(ﬁlm) (cm²¹) 2930, 2857, 1808 (s,

CvO), 1718 (s, CvO), 1473, 1363, 1331, 1290, 1256,

1157, 1078; d_H(400 MHz, CDCl₃) 0.025 [3H, s, (CH₃)₂Si)],

0.04 [3H, s, (CH₃)₂Si)], 0.86 [9H, s, (CH₃)₃CSi)], 1.42 (3H,

s, 5-C–CH₃), 1.53 (12H, s, [5-C–CH₃⁰and (CH₃)₃CO)],

3.78 (2H, m, CH_ACH_BOTBDMS), 3.96 (1H, dd, J¼11.25,

4.8 Hz, 4-CH); d_C(100.6 MHz, CDCl₃) 25.7 [(CH₃)₂Si],

17.9, 21.25 (5-C2CH₃⁰), 25.6 [(CH₃)₃CSi], 28.0

[(CH₃)₃CO], 28.7 (5-C2CH₃), 59.4, 64.0, 79.9, 83.5,

149.9 (CvO), 151.5 (CvO); m/z (APCIþ) 382.3 (30,

MþNa^þ), 374.3 (20), 304 (20), 260 (100%), 216 (25);

HRMS (CI^þ) (Found: M, 360.2206. C₁₇H₃₃NO₅Si requires

360.2220).

4.1.5. (S)-Carbonic acid 3-benzyl-5,5-dimethyl-2-oxo-

oxazolidin-4-yl methyl ester tert-butyl ester 16 (from

11). (S)-N-Boc-O-silyl SuperQuat 11 (100 mg, 0.28 mmol)

was dissolved in tetrahydrofuran (1 mL). The solution was

stirred at room temperature and TBAF (0.58 mL, 151 mg,

0.58 mmol, 1 M solution in THF, Aldrich) was added

dropwise. Immediately after the TBAF was added excess

benzyl bromide was added to the ﬂask (660 mg,

3.86 mmol). The resulting yellow/orange reaction mixture

was stirred for a further 12 h at room temperature. After

12 h a tlc (eluent; n-pentane/ether, 75:25) indicated that all

of the starting material had been consumed. The solvent was

removed in vacuo and the crude reaction mixture diluted

with dichloromethane (3 mL). The dichloromethane

solution was ﬁltered through a short column of silica. The

silica was further eluted with three more portions of

dichloromethane (3 mL). The dichloromethane fractions

were combined and the solvent removed in vacuo yielding

impure 16. Puriﬁcation of 16 was readily achieved via ﬂash

column chromatography using a mixture of n-pentane/ether

(1:1) as the eluent. (S)-O-Boc-N-benzyl-SuperQuat 16 was

isolated as a colourless oil (59 mg, 63%) which displayed

the following physical characteristics; [a]²_D²¼þ11.2 (c 0.82,

CHCl₃); n_max(ﬁlm) (cm²¹) 2980, 1813 (CvO), 1744 (s,

CvO), 1416, 1370, 1275, 1159; d_H(400 MHz, CDCl₃) 1.35

(3H, s, 5-C–CH₃), 1.39 (3H, s, 5-C–CH₃⁰), 1.48 [9H, s,

(CH₃)₃C], 3.38 (1H, t, J¼5.5 Hz, 4-C–H), 4.07 (1H, dd,

J¼11.7, 5.5 Hz, CH_ACH_BO), 4.20 (2H, m, CH_ACH_BO and

CH_AH_BPh), 4.84 (1H, d, J¼15.1 Hz, CH_AH_BPh), 7.30–7.35

(5H, m, Ar-H); d_C(100.6 MHz, CDCl₃) 21.7 (5-C–CH₃),

27.9 [(CH₃)₃CO], 28.5 (5-C–CH₃⁰), 46.7, 61.3, 63.8, 79.4,

82.9, 127.9 (Ar-H), 128.3 (Ar-H), 128.7 (Ar-H), 136.0

(Ar-H), 152.9 (CvO), 157.3 (CvO); m/z (APCIþ) 336.2

(35), 280.2 (85), 236.1 (100%), 192.0 (50), 162.0 (30);

4.1.4. (S)-Carbonic acid tert-butyl ester 5,5-dimethyl-2-

oxo-oxazolidin-4-yl methyl ester 15. N-Boc-O-TBDMS

SuperQuat (S)-11 (100 mg, 0.28 mmol) was dissolved in

tetrahydrofuran (1 mL). The solution was stirred at room

temperature and TBAF was added dropwise (0.58 mL,

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S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

HRMS (CI^þ) (Found: MNa^þ, 358.1630. C₁₈H₂₅NO₅Na

requires 358.1643).

as the eluent, the title compound (S)-19 was a white solid

(1.06 g, 82%) which displayed the following physical

characteristics; mp 35–378C; [a]²_D²¼239.64 (c 2.5,

CHCl₃); n_max(ﬁlm) (cm²¹) 3284 (N–H), 2973, 2875,

1744 (s, CvO), 1455, 1371, 1287, 1118, 1091, 1007; d_H

(400 MHz, CDCl₃) 1.35 (3H, s, 5-C–CH₃), 1.48 (3H, s,

5-C–CH₃⁰), 3.49 (2H, m, 4-C–CH₂CH_B), 3.67 (1H, m, 4-C-

H), 4.52 (2H, m, CH₂Ph), 6.10 (1H, br s, N–H), 7.29–7.38

(5H, m, Ar-H); d_C(100.6 MHz, CDCl₃) 21.5, 28.2, 60.5,

69.3, 73.6, 82.2, 127.7, 127.9, 128.5, 137.4, 158.7 (CvO);

m/z (APCIþ) 258.1 (100%, MþNa^þ), 236.1 (95), 210 (10),

192 (60); HRMS (CI^þ) (Found: MH^þ, 236.1287.

C₁₃H₁₈NO₃requires 236.1287).

4.1.6. (S)-(1-Benzyloxymethyl-2-hydroxy-2-methyl-pro-

pyl)carbamic acid tert-butyl ester 18. (S)-O-Benzyl-N-

Boc-^L-serine methyl ester 17 (4 g, 12.9 mmol) was

dissolved in tetrahydrofuran (60 mL) and the resulting

solution cooled to 2788C in a CO₂/acetone bath. A solution

of methyl magnesium bromide in ether (6 g, 17 mL,

50.3 mmol, 3.9 equiv., 3 M solution in ether) was added

dropwise to ester 17 over a 15 min period (care: methane

evolved). The resulting solution was stirred at 2788C for 4 h

and then allowed to warm to room temperature. After 12 h

at room temperature the reaction mixture was cooled to 08C

and carefully quenched with aqueous saturated ammonium

chloride (100 mL), the reaction mixture was subsequently

allowed to warm to room temperature over a 20 min period.

The solvent was removed in vacuo and replaced with

dichloromethane (200 mL). Transferring the solution con-

taining the crude reaction mixture to a separating funnel,

enough aqueous saturated ammonium chloride solution was

added so that all the magnesium salts dissolved in the

aqueous layer. The aqueous layer was partitioned from the

dichloromethane. The dichloromethane was washed with

aqueous saturated ammonium chloride (2£100 mL),

aqueous brine (2£100 mL), saturated aqueous sodium

bicarbonate (2£100 mL) and subsequently dried (MgSO₄).

Filtering the solution and removal of the solvent in vacuo

revealed the title product (S)-18 as a pale yellow crystalline

solid (2.7 g, 68%). Puriﬁcation of product (S)-18 was

achieved via ﬂash column chromatography incorporating

n-pentane/ether (1:1) as the eluent. Pure (S)-18 was

returned as a white solid with the following physical

characteristics; mp 52–548C; [a]²_D²¼þ27.3 (c 1.98, CHCl₃);

4.1.8. (S)-4-Benzyloxymethyl-5,5-dimethyl-2-oxo-oxa-

zolidine-3-carboxylic acid tert-butyl ester 20. Starting

material (S)-19 (200 mg, 0.85 mmol) was dissolved in ether

(2 mL) at room temperature. To the ethereal solution was

added 4-dimethylaminopyridine (104 mg, 0.85 mmol),

di-tert-butyl dicarbonate (370 mg, 1.69 mmol) and triethyl-

amine (86 mg, 0.85 mmol). The reaction mixture was stirred

for 12 h at room temperature and worked-up as outlined

previously for (S)-11. The title compound was puriﬁed via

ﬂash column chromatography using ether as the eluent.

Puriﬁed (S)-20 was a colourless oil that solidiﬁed on

standing to a white solid (157 mg, 55%). (S)-20 displayed

the following characteristics; mp 66–688C; [a]²_D²¼þ53.8 (c

0.55, CHCl₃); n_max(ﬁlm) (cm²¹) 2972, 1800 (s, CvO),

1718 (CvO), 1366, 1301, 1289, 1159, 1076; d_H(400 MHz,

CDCl₃) 1.45 (3H, s, 5-C–CH₃), 1.49 [9H, s, (CH₃)₃CO],

1.51 (3H, s, 5-C–CH₃⁰), 3.63 (1H, dd, J¼10.0, 2.4 Hz), 3.71

(1H, m), 3.94 (1H, dd, J¼6.1, 2.3 Hz), 4.52 (2H, s, CH₂Ph),

7.29–7.36 (5H, m, Ar-H); d_C(100.6 MHz, CDCl₃) 21.5,

27.9, 28.6, 62.7, 66.4, 73.4, 80.0, 83.7, 127.65 (Ar-H), 127.9

(Ar-H), 128.5 (Ar-H), 137.3 (Ar-H), 150.0, (CvO), 151.4

(CvO); m/z (APCIþ) 358.18 (50, MNa^þ), 280.16 (20),

258.15 (65), 236.15 (100%), 192.16 (100), 145.11 (55);

HRMS (CI^þ) (Found: MNH^þ₄, 353.2076. C₁₈H₂₉N₂O₅

requires 353.2083).

n

_max(ﬁlm) (cm²¹) 3432, 3346, 2982, 2934, 1709 (s, CvO),

1494, 1364, 1163; d_H(400 MHz, CDCl₃) 1.19 (3H, s, 2-C–

CH₃), 1.28 (3H, s, 2-C–CH₃⁰), 1.45 [9H, s, (CH₃)₃C], 3.27

(1H, s, OH), 3.55 [1H, m, CH(NH)], 3.66 (1H, dd, J¼9.8,

2.7 Hz, CH_ACH_BO), 3.89 (1H, dd, J¼9.8, 2.7 Hz, CH_A-

CH_BO), 4.47 (1H, AB, J¼11.8 Hz), 4.56 (1H, AB,

J¼11.8 Hz), 5.40 (1H, br d, J¼9.1 Hz, N–H); d_C

(100.6 MHz, CDCl₃) 26.8, 27.6, 28.4, 56.4, 71.4, 72.9,

73.8, 79.3, 127.8, 128.0, 128.5, 137.2 (CvO), 156.1

(CvO); m/z (APCIþ) 332.1 (MþNa^þ20), 265.2

(M2CO₂, 10), 210.1 (M2Boc, 100%), 192 (25); HRMS

(CI^þ) (Found: MH^þ, 310.2025. C₁₇H₂₈NO₄requires

310.2018).

4.1.9. (S)-4-Hydroxy-5,5-dimethyl-2-oxo-oxazolidine-3-

carboxylic acid-tert-butyl ester 14. A solution of (S)-N-

Boc-O-benzyl-SuperQuat 20 (100 mg, 0.30 mmol) was

dissolved in anhydrous methanol (2 mL). To this was

added a catalytic amount of 10% palladium on carbon

(,10 mg). The resulting solution was vigorously stirred

under an atmosphere of hydrogen contained within two

balloons inside each other. After stirring for 12 h the

solution was ﬁltered through Celite^w. The Celite^wwas

eluted with methanol (2£5 mL), the methanol fractions

were combined and the solvent evaporated in vacuo. The

title compound (S)-14 was returned as a white solid (64 mg,

88%) which displayed the following physical character-

istics; mp 133–1358C; [a]²_D²¼þ10.2 (c 0.5, CHCl₃); n_max

(KBr) (cm²¹) 2979, 1787 (s, CvO), 1700 (CvO), 1395,

1372, 1319; d_H(400 MHz, CDCl₃) 1.49 (3H, s, 5-C–CH₃),

1.51 (3H, s, 5-C–CH₃⁰), 1.56 [9H, s, (CH₃)₃CO], 2.80 (1H,

br s, OH), 3.83–3.93 (3H, m, 4-C(H)CH_ACH_BOH); d_C

(100.6 MHz, CDCl₃) 21.4, 27.9, 28.3, 60.4, 65.0, 80.1, 84.5,

150.8 (CvO), 151.4 (CvO); m/z (APCIþ) 268.1 (10,

MþNa^þ), 246.1 (5), 208.1 (5), 190.1 (60), 167.9 (10), 146.1

(100%), 128.1 (20), 116.1 (50); HRMS (CI^þ) (Found:

MNa^þ, 268.1161. C₁₁H₁₉NO₅Na requires 268.1165).

4.1.7. (S)-Benzyloxymethyl-5,5-dimethyloxazolidin-2-

one 19. To a solution of tetrahydrofuran (50 mL) containing

alcohol (S)-18 (1.7 g, 5.5 mmol) was added potassium tert-

butoxide in one portion (1.2 g, 10.7 mmol). The reaction

was stirred at room temperature for 12 h after which time it

was quenched with aqueous saturated ammonium chloride

(25 mL). The tetrahydrofuran was removed in vacuo and

replaced with dichloromethane (25 mL). The dichloro-

methane solution was transferred to a separating funnel

and washed with aqueous saturated ammonium chloride

(3£25 mL), saturated brine (2£25 mL), aqueous saturated

sodium bicarbonate (2£25 mL) and subsequently dried

(MgSO₄). Filtering the solution and removal of the

dichloromethane in vacuo yielded a yellow oil. The oil

was puriﬁed via ﬂash column chromatography using ether

S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

9397

4.1.10. (S)-Carbonic acid tert-butyl ester-5,5-dimethyl-2-

oxo-oxazolidin-4-yl methyl ester 15. A ﬂask was charged

with DMF (2 mL). To the ﬂask was added (S)-N-Boc-

oxazolidin-2-one 14 (23 mg, 0.094 mmol), the resulting

solution was stirred and cooled to 08C in an ice bath. To the

cold DMF solution was added oil free potassium hydride

(washed with n-pentane, 3£5 mL; 5.5 mg, 0.14 mmol). The

resulting solution was stirred at 08C for 2 h, and then

quenched at 08C with a saturated aqueous ammonium

chloride solution (2 mL). The aqueous DMF was removed

in vacuo, water was added (5 mL) and the organic material

extracted with dichloromethane (3£10 mL). The dichloro-

methane extracts were combined, dried (MgSO₄) and

ﬁltered. The resulting product was puriﬁed via ﬂash column

chromatography using ether as the eluent. (S)-O-Boc-

SuperQuat 15 was a white solid (20 mg, 87%) which had

essentially the same physical characteristics as the identical

compound synthesised previously from (S)-11; n_max(KBr)

(cm²¹) 3341 (br), 2917, 1742 (br s, CvO), 1370, 1257; d_H

(400 MHz, CDCl₃) 1.43 [3H, s, 5-C–CH₃), 1.49 (9H, s,

(CH₃)₃CO), 1.51 (3H, s, (5-C–CH₃⁰), 3.72 (1H, dd, J¼8.0,

4.5 Hz, 4-C(H)N), 4.03 (1H, dd, J¼11.0, 8.2 Hz,

4-C(H)CH_ACH_BO), 4.19 (1H, dd, J¼11.0, 4.5 Hz,

4-C(H)CH_ACH_BO), 5.59 (1H, br s, N–H); d_C

(100.6 MHz, CDCl₃) 21.6 (5-C–CH₃), 27.6 [(CH₃)₃CO],

28.0 (5-C–C⁰H₃), 59.6, 65.7, 81.8, 83.2, 153.0 (CvO),

157.8 (CvO); HRMS (CI^þ) (Found: MH^þ, 246.1349.

C₁₁H₂₀NO₅requires 246.1341).

quenched at 2208C with aqueous saturated ammonium

chloride (3 mL) and allowed to warm to room temperature

over 15 min. The quenched reaction was transferred to a

separating funnel and the organic products extracted into

ether (3£15 mL). The organic fractions were combined,

dried (MgSO₄) and ﬁltered. Removal of the solvent in vacuo

revealed an oil, the puriﬁcation of which was undertaken via

ﬂash column chromatography using ether as the eluent. The

title compound 40 was obtained as a colourless oil (70 mg,

61%) with the following physical characteristics; n_max(ﬁlm)

(cm²¹) 3424 (s), 2976, 2933, 1732 (s, CvO), 1428, 1368,

1235, 1149; d_H(400 MHz, CDCl₃) 1.17 (3H, s, CH₃), 1.23

(3H, s, CH₃⁰), 2.07 (1H, s, OH), 3.55 (1H, dd, J¼9.3, 5.2 Hz,

5-CH_ACH_B), 4.03 (1H, dd, J¼9.3, 5.2 Hz, 5-CH_ACH_B),

4.20 (1H, t, J¼9.3 Hz, 4-CH), 4.48 (1H, d, J¼15.0 Hz,

PhCH_ACH_B), 4.92 (1H, d, J¼15.0 Hz, PhCH_ACH_B); 7.25–

7.36 (5H, m, Ar-H); d_C(100.6 MHz, CDCl₃) 23.6

[(CH₃)₂C], 26.5 [(CH₃)₂C], 48.2, 62.0, 64.6, 73.2, 127.8

(Ar-H), 128.4 (Ar-H), 128.7 (Ar-H), 136.4 (Ar-H), 159.6

(CvO); m/z (APCIþ) 258.1. (10, MþNa^þ), 236.1 (100%),

192 (5); HRMS (CI^þ) (Found: MH^þ, 236.1287. C₁₃H₁₈NO₃

requires 236.1294).

4.1.13. (6)-3-Benzyl-4-hydroxymethyl-5,5-dimethyl-

oxazolidin-2-one 41. A ﬂask was charged with alcohol 40

(47 mg, 0.2 mmol) and the oil dissolved in tetrahydrofuran

(2 mL). To the cooled (08C) solution was added oil free

sodium hydride (washed with n-pentane 3£5 mL, 5.3 mg,

0.22 mmol). The reaction was allowed to warm to room

temperature over a 24 h period and then quenched with

aqueous saturated ammonium chloride (2 mL). The aqueous

tetrahydrofuran was removed in vacuo and replaced with

dichloromethane (5 mL), the dichloromethane was washed

with aqueous hydrochloric acid (3£5 mL, 1 M), brine

(10 mL), water (10 mL) and subsequently dried (MgSO₄).

Removing the solvent in vacuo allowed the resulting oil to

be puriﬁed via ﬂash column chromatography using ether as

the eluent. The title compound 41 was a colourless oil

(33 mg, 71%) with the following physical characteristics;

4.1.11. (6)-Benzyl-carbamic acid-3,3-dimethyl-oxiranyl

methyl ester 39. (rac)-Epoxide²⁰38 (573 mg, 5.41 mmol)

synthesised from 3-methyl-2-butene-1-ol 37 was dissolved

in anhydrous dichloromethane (5 mL), to the dichloro-

methane solution was added benzyl isocyanate (1.0 g,

7.51 mmol) and a catalytic amount (31 mg, 0.056 mmol,

1 mol%) of bis(dibutylchlorotin) oxide. The reaction was

stirred at room temperature. After 48 h removal of the

solvent was undertaken in vacuo and the impure carbamate

39 puriﬁed via ﬂash column chromatography using a

mixture of n-pentane/ether as eluent (25:75). The title

compound 39 was isolated as a colourless oil (694 mg,

53%); n_max(ﬁlm) (cm²¹) 3336 (br, N–H), 2970, 2932, 1797

(CvO), 1719 (CvO), 1528, 1244, 1148; d_H(400 MHz,

CHCl₃) 1.33 (3H, s, 3-C–CH₃), 1.35 (3H, s, 3-C–CH₃⁰),

3.01 (1H, dd, J¼7.0, 4.1 Hz, 2-CHO), 4.03 (1H, dd, J¼12.0,

7.0 Hz, 1-OCH_AH_B), 4.43 (3H, m, 1-OCH_AH_Band CH_A-

CH_BPh), 5.12 (1H, br, s, N–H), 7.27–7.37 (5H, m, Ar-H);

d_C(100.6 MHz, CDCl₃) 18.9 (3-C–CH₃), 24.6 (3-C–CH₃⁰),

45.1 (CH₂Ph), 58.2 (3-C–CH₃), 60.9 (1-CH₂O), 64.0

(2-CHO), 127.6 (Ar-H), 128.6 (Ar-H), 128.7 (Ar-H),

138.3 (Ar-H), 156.25 (CvO); m/z (APCIþ) 236.1

(M^þþH^þ, 100%), 218.1 (65), 152 (30) 103.1 (95); HRMS

(CI^þ) (Found: MH^þ, 236.1287. C₁₃H₁₈NO₃requires

236.1291).

n

_max(ﬁlm) (cm²¹) 3410, 2971, 2920, 1720 (s, CvO), 1425;

d_H(400 MHz, CDCl₃) 1.36 (3H, s, 5-C–CH₃), 1.44 (3H, s,

5-C–CH₃⁰), 2.28 (1H, br s, OH), 3.25 (1H, t, J¼4.7 Hz,

4-CH), 3.72 (2H, br s, CH_ACH_BOH), 4.31 (1H, d,

J¼15.2 Hz, PhCH_ACH_B), 4.74 (1H, d, J¼15.2 Hz, PhCH_A-

CH_B), 7.27–7.4 (5H, Ar-H); d_C(100.6 MHz, CDCl₃) 21.65,

28.6, 46.7, 59.6, 64.0, 79.7, 128.0 (Ar-H), 128.0 (Ar-H),

128.7 (Ar-H), 136.5 (Ar-H), 158.0 (CvO); m/z (APCIþ)

236.1 (100%), 218.1 (5), 206.1 (10), 192.1 (30), 162.1 (10);

HRMS (CI^þ) (Found: MH^þ236.1287. C₁₃H₁₈NO₃requires

236.1293).

4.1.14. (6)-Carbonic acid-3-benzyl-5,5-dimethyl-2-oxo-

oxazolidin-4-yl methyl ester tert-butyl ester 16 (from 41).

A stirred solution of (rac)-N-benzyl SuperQuat 41 (38 mg,

0.16 mmol) was dissolved in dichloromethane (3 mL). The

solution was stirred and 4-dimethylaminopyridine (9.8 mg,

0.08 mmol), di-tert-butyl dicarbonate (71 mg, 0.325 mmol)

and triethylamine (0.045 mL, 33 mg, 0.33 mmol) were

added. The reaction was stirred at room temperature for

12 h and worked-up as for 11. The title product (rac)-16 was

puriﬁed via ﬂash column chromatography using n-pentane/

ether (1:1), 16 was returned as a colourless oil (42 mg,

79%) and possessed essentially the same spectroscopic

4.1.12. (6)-3-Benzyl-4-(1-hydroxy-1-methylethyl)-oxa-

zolidin-2-one 40. A ﬂask was charged with racemic 39

(115 mg, 0.87 mmol) and the carbamate dissolved in

tetrahydrofuran (2 mL). The resulting solution was stirred

and cooled until the solution reached 2208C. Whilst at

2208C, n-BuLi was added dropwise (0.195 mL, 31 mg,

0.48 mmol, 2.5 M solution in hexanes). The reaction

mixture was stirred at 2208C for 2 h, after which it was

9398

S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

˚

21

characteristics as (S)-16, the identical compound syn-

thesised previously.

a¼9.6450(4) A, b¼11.2679(5) A, c¼11.2357(5) A,

3

˚

b¼114.111(4)8, U¼1114.59(9) A , Z¼2, m¼0.106 cm

,

colourless block, crystal dimensions¼0.4£0.4£0.4 mm³. A

total of 2384 unique reﬂections were measured for

1.99,u,26.33 and 2272 reﬂections were used in the

reﬁnement. The ﬁnal parameters were wR₂¼0.0402 and

R₁¼0.0335 [I.3s(I)].

4.1.15. (S)-4-Benzyloxymethyl-2-oxo-oxazolidine-3-car-

boxylic acid tert-butyl ester 45. To dichloromethane

(20 mL) was added (S)-44 (1.17 g, 5.65 mmol). The

resulting solution was stirred whilst 4-dimethylamino-

pyridine (345 mg, 2.82 mmol), di-tert-butyl dicarbonate

(2.54 g, 11.64 mmol) and triethylamine (571 mg,

5.64 mmol) were added. The reaction mixture was stirred

at room temperature. After 4 h the reaction was diluted with

dichloromethane (20 mL) and subsequently washed with

aqueous hydrochloric acid (0.1 M, 3£25 mL), aqueous

saturated sodium bicarbonate (2£25 mL), water (25 mL)

and dried (MgSO₄). The solution was ﬁltered and the

solvent removed in vacuo. The title compound (S)-45 (1.5 g,

87%) possessed the following physical characteristics; mp

Crystallographic data (excluding structure factors) has been

deposited with the Cambridge Crystallographic Data Centre

as supplementary publication number CCDC189191.

Copies of the data can be obtained, free of charge, on

application to CCDC, 12 Union Road, Cambridge CB2 1EZ,

UK [fax: þ44(0)-1223-336033 or e-mail: deposit@ccdc.

cam.ac.uk].

4.2.1. (S)-2-Oxo-oxazolidine-3,4-dicarboxylic acid-3-tert-

butyl ester-4-methyl ester 48. A solution of (S)-47^24b

(3.00 g, 20.7 mmol) was dissolved in dichloromethane

(50 mL) and the stirred solution subsequently cooled to

08C. To this solution was added 4-dimethylaminopyridine

(2.3 g, 18.8 mmol), di-tert-butyl dicarbonate (9.00 g,

41.4 mmol) and triethylamine (4.1 g, 41 mmol). The reac-

tion was stirred for 12 h and allowed to warm to room

temperature where upon it was worked-up as outlined for

(S)-11. The title product (S)-48 was crystallised from ether

(2.0 g, 40%) and possessed the following physical charac-

teristics; mp 100–1028C (ether), [a]²_D²¼265.5 (c 0.7,

CHCl₃); n_max(KBr) (cm²¹) 3011, 2978, 2950, 1806 (s,

CvO), 1748 (s, CvO), 1724 (s, CvO), 1486, 1442, 1400,

1351, 1295, 1260, 1212, 1189, 1078, 771; d_H(400 MHz,

CDCl₃) 1.51 [9H, s, (CH₃)₃CO], 3.83 (3H, s, CO₂CH₃), 4.27

(1H, dd, J¼9.3, 3.8 Hz, 5-CH_ACH_B), 4.51 (1H, t, J¼9.3 Hz,

4-C(H)N), 4.79 (1H, dd, J¼9.3, 3.8 Hz, 5-CH_ACH_B); d_C

(100.6 MHz, CDCl₃) 27.8 [(CH₃)₃C], 53.1, 56.1, 63.6, 84.7,

148.5 (CvO), 151.1 (CvO), 169.3 (CvO); m/z (APCIþ)

268.0 (20, MþNa^þ), 245.9 (10), 235.9 (10), 189.9 (80),

145.8 (100%); HRMS (CI^þ) (Found: MNH₄263.1243.

C₁₀H₁₉N₂O₆requires 263.1243).

93–968C; [a]_D²²¼þ56.3 (c 0.4, CHCl₃); n_max(ﬁlm) (cm²¹

)

2971, 2929, 2869, 1809 (s, CvO), 1788 (s, CvO), 1713,

1365 (s), 1331, 1285, 1259, 1158 (s), 1082; d_H(400 MHz,

CDCl₃) 1.50 [9H, s, (CH₃)₃CO], 3.65 [2H, m, 4-C(H)CH_A-

CH_BO], 4.35 (3H, m, 4-CH and 5-CH_ACH_B), 4.56 (2H, m,

PhCH_ACH_B), 7.29–7.38 (5H, m, Ar-H); d_C(100.6 MHz,

CDCl₃) 27.9 [(CH₃)₃C], 54.2 [(CH₃)₃C], 64.7, 68.4, 73.45,

83.9, 127.7 (Ar-H), 128.0 (Ar-H), 128.6 (Ar-H), 137.3

(Ar-H), 149.2 (CvO), 152.2 (CvO); m/z (APCIþ) 330.1

(5, MþNa^þ), 252.1 (12). 236.1 (10), 208.1 (45), 182

(100%), 149.9 (15); HRMS (CI^þ) (Found: MNH₄325.1763.

C₁₆H₂₅N₂O₅requires 325.1759).

4.1.16. (S)-4-Hydroxymethyl-2-oxo-oxazolidine-3-car-

boxylic acid tert-butyl ester 46. (S)-N-Boc-O-benzyl-

oxazolidin-2-one 45 (78 mg, 0.25 mmol) was treated with

a catalytic amount of 10% palladium on carbon (,10 mg) in

anhydrous methanol (5 mL) and placed under hydrogen

(balloon). After the reaction was complete the methanol

solution was ﬁltered through Celite. The Celite was

subsequently washed with methanol (3£5 mL), the com-

bined organic fractions had the solvent removed in vacuo

yielding (S)-N-Boc-4-hydroxymethyl-oxazolidin-2-one 46

as a white solid (64 mg, 82%). (S)-46 had the following

characteristics; mp 101–1048C; [a]²_D²¼þ42.8 (c 0.54,

CHCl₃); n_max(ﬁlm) (cm²¹) 3489, 2980, 2934, 2361, 1798

(s, CvO), 1722 (s, CvO), 1478, 1371, 1299, 1257, 1158;

d_H(400 MHz, CDCl₃) 1.55 [9H, s, (CH₃)₃CO], 3.78

(1H, m), 3.88 (1H, m), 4.28–4.41 (3H, m); d_C

(100.6 MHz, CDCl₃) 27.9 [(CH₃)₃C], 53.2, 62.3, 64.2,

84.5, 149.9 (CvO), 152.4 (CvO); m/z (APCIþ) 236.1 (5,

M^þþNa), 218.0 (12). 182.0 (20), 176.0 (100%), 160 (20),

135.8 (20).

4.2.2. (R)-4-Hydroxymethyl-2-oxo-oxazolidine-3-car-

boxylic acid tert-butyl ester 46. A ﬂask was charged with

anhydrous ethanol (3 mL) and subsequently cooled to 08C in

an ice bath. To the cold ethanol was added sodium

borohydride (62 mg, 1.64 mmol). A separate ﬂask was

charged with ester (S)-48 (100 mg, 0.41 mmol) and ethanol

(2 mL) this solution was stirred and cooled to 08C in an ice

bath. The cold ester (S)-48 solution was added dropwise to

the ethanolic sodium borohydride solution at 08C, the

resulting mixture was stirred at 08C until tlc analysis (eluent:

ether) indicated all the starting material had been consumed.

Whilst at 08C the reaction mixture was quenched by adding

the resulting ethanolic solution to an excess of pH 4

phosphate buffer, ensuring that the pH of the resulting

solution did not go above pH 6, by adding, if necessary more

pH 4 buffer. Allow the quenched reaction mixture to stir for

a further 2 h at room temperature and then remove the

ethanol in vacuo. Extract the organic components into ethyl

acetate (4£10 mL). Dry the combined ethyl acetate

fractions (MgSO₄), ﬁlter the solution and remove the ethyl

acetate in vacuo. (R)-46 was puriﬁed via ﬂash column

chromatography using ether as the eluent. The title

compound was a colourless oil (56 mg, 64%), which

4.2. X-Ray crystal structure determination for (S)-46

Data were collected using an Enraf-Nonius CAD4 diffract-

ometer with graphite monochromated Mo Ka radiation

using standard procedures at room temperature. The

structure was solved by direct methods (Sir92), all non-

hydrogen atoms were reﬁned with anisotropic thermal

parameters. Hydrogen atoms were added at idealised

positions. The structure was reﬁned using CRYSTALS.²⁸

X-Ray crystal structure data for (S)-46: [C₁₈H₃₀N₂O₁₀];

M¼434.44,

monoclinic,

space

group

P1211,

S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

9399

solidiﬁed on standing. The product could be further puriﬁed

by crystallisation from ether; mp 106–1088C (ether);

[a]²_D²¼245.6 (c 0.83, CHCl₃); n_max(KBr) (cm²¹) 3523,

2985, 2935, 1803 (s, CvO), 1706 (CvO), 1407, 1370,

1307, 1261, 1163, 1084, 1047; d_H(400 MHz, d₆-benzene)

1.41 [9H, s, (CH₃)₃CO], 2.19 (1H, br t, OH, J¼5.5 Hz), 3.13

(1H, m), 3.29 (1H, m), 3.41 (1H, m), 3.56 (2H, m); d_C

(100.6 MHz, d₆-benzene) 28.1 [(CH₃)₃CO], 56.3, 62.2,

63.9, 83.7, 151.0 (CvO), 152.3 (CvO); m/z (APCIþ)

240.03. (80, MþNa^þ), 183.9 (25), 161.8 (40), 139.8

(100%), 117.8 (70).

4.2.5. (6)-Carbamic acid 3-benzyl-2-oxo-oxazolidin-4-yl

methyl ester tert-butyl ester 50 (from 32). To a stirred

solution of dichloromethane (5 mL) was added (rac)-32

(87 mg, 0.42 mmol). To the resulting solution was added

4-dimethylaminopyridine (25 mg, 0.2 mmol), di-tert-butyl

dicarbonate (183 mg, 0.84 mmol) and triethylamine (85 mg,

0.84 mmol). The reaction mixture was stirred at room

temperature for 5 h. After which the reaction was diluted

with dichloromethane (5 mL) and subsequently washed

with aqueous hydrochloric acid (0.1 M, 3£10 mL), aqueous

saturated sodium bicarbonate (2£10 mL), water (10 mL)

and dried (MgSO₄). The solution was ﬁltered and the

solvent removed in vacuo. The title compound (rac)-50

(108 mg, 84%) possessed the following physical character-

istics; n_max(ﬁlm) (cm²¹) 2982, 2911, 1740 (br s, CvO),

1724 (CvO), 1455, 1278, 1251; d_H(400 MHz, CDCl₃) 1.48

[9H, s, (CH₃)₃CO], 3.81 (1H, m), 4.03 (1H, dd, J¼11.7,

4.3 Hz), 4.12–4.21 (3H, m), 4.33 (1H, t, J¼9.0 Hz), 4.83

(1H, d, J¼15.2 Hz, PhCH_ACH_B), 7.29–7.375 (5H, m,

Ar-H); d_C(100.6 MHz, CDCl₃) 27.6 [(CH₃)₃CO], 46.5,

53.1, 64.3, 64.7, 83.1, 128.0 (Ar-H), 128.2 (Ar-H), 128.8

(Ar-H), 135.6 (Ar-H), 152.9 (CvO), 158.2 (CvO); m/z

(APCIþ) 330.3 (5, MþNa^þ), 308.3 (5, MþH^þ), 252.2

(100%), 208.25 (45). HRMS (CI^þ) (Found: MNa^þ

330.1318. C₁₆H₂₁NO₅Na requires 330.1317).

4.2.3. (6)-Benzylcarbamic acid oxiranylmethyl ester 49.

(rac)-Glycidol (573 mg, 7.73 mmol) was dissolved in

dichloromethane (5 mL) to this solution was added benzyl

isocyanate (1.0 g, 7.51 mmol) and a catalytic amount of

bis(dibutylchlorotin) oxide (43 mg, 1 mol%). The resulting

solution was stirred for 48 h at room temperature. The

reaction mixture was subsequently washed with aqueous

hydrochloric acid (0.5 M, 3£25 mL), water (3£25 mL) and

dried (MgSO₄). Removal of the solvent in vacuo yielded a

pale yellow oil which was puriﬁed via ﬂash column

chromatography using a mixture of n-pentane and ether as

the eluent (25:75). The title compound was isolated as a

colourless oil (992 mg, 62%) with the following physical

characteristics; n_max(ﬁlm) (cm²¹) 3328 (br, N–H), 2945,

1707 (s, CvO), 1528, 1248, 1148; d_H(400 MHz, CDCl₃)

2.64 (1H, m), 2.83 (1H, t, J¼4.5 Hz), 3.21 (1H, m), 3.90

(1H, dd, J¼12.2, 6.4 Hz), 4.37 (2H, d, J¼6.0 Hz), 4.46 (1H,

dd, J¼12.2, 2.9 Hz), 5.40 (1H, br s, N–H), 7.26–7.36 (5H,

m, Ar-H); d_C(100.6 MHz, CDCl₃) 44.6, 45.0, 49.8, 65.5,

127.5 (Ar-H), 128.4 (Ar-H), 128.6 (Ar-H), 138.3 (Ar-H),

156.1 (CvO); m/z (APCIþ) 208.1 (M^þþH^þ, 100%), 152

(5), 108.9 (5).

4.2.6. (S)-Carbonic acid-3-benzyl-2-oxo-oxazolidin-4-

ylmethyl ester tert-butyl ester 50 (from 46). A ﬂask was

charged with DMF (2 mL). To this was added (R)-N-Boc-

oxazolidin-2-one 46 (57 mg, 0.26 mmol), the resulting

solution was stirred and cooled to 08C in an ice bath. To

the cold DMF solution was added oil free potassium hydride

(washed with n-pentane, 3£5 mL; 16 mg, 0.40 mmol). The

resulting solution was stirred at 08C for 2 h, then benzyl

chloride (freshly distilled) was added (35 mg, 0.27 mmol)

and a catalytic amount (50 mg) of 18-crown-6. The solution

was stirred for a further 12 h warming from 08C to room

temperature. The reaction was quenched with aqueous

saturated ammonium chloride (1 mL). The aqueous DMF

was removed in vacuo, water was added (5 mL) and the

organic products extracted with dichloromethane

(3£10 mL). The dichloromethane was dried (MgSO₄),

ﬁltered and the crude product puriﬁed via ﬂash column

chromatography using ether/n-pentane (1:1) to give the title

compound (S)-50 (68 mg, 85%); mp 110–1138C;

[a]²_D²¼þ10.5 (c 1.54, CHCl₃).

4.2.4. (6)-3-Benzyl-4-hydroxymethyl-oxazolidine-2-one

32. (rac)-N-Benzyl carbamate 49 (210 mg, 1.0 mmol) was

added to a ﬂask and the solid dissolved in tetrahydrofuran

(2 mL), the resulting solution was cooled to 08C in an ice

bath. To the carbamate solution was added n-BuLi (65 mg,

1.01 mmol, 2.5 M solution in hexanes, Aldrich). The

resulting mixture was stirred for 2 h at 08C. Whilst at 08C

the reaction mixture was quenched by adding saturated

aqueous ammonium chloride (2 mL). The majority of the

solvent was removed in vacuo, and the remaining aqueous

phase extracted with dichloromethane (3£10 mL). The

combined organic layers were washed with aqueous

hydrochloric acid (1 M, 3£25 mL), saturated brine

(2£25 mL), water (2£25 mL) and dried (MgSO₄). Filtering

the solution and removal of the solvent in vacuo, yielded a

yellow oil. Puriﬁcation of oxazolidin-2-one 32 was achieved

via ﬂash column chromatography using ether as the eluent.

(rac)-N-Benzyl-oxazolidin-2-one 32 (155 mg, 74%) had the

following physical characteristics; n_max(ﬁlm) (cm²¹) 3415

(br s, OH), 2922, 1726 (s, CvO), 1479, 1444, 1252, 1093,

1035; d_H(400 MHz, CDCl₃) 3.20 (1H, br s, OH), 3.52 (1H,

br d, J¼10.4 Hz), 3.71 (2H, m), 4.28 (3H, m), 4.72 (1H, d,

J¼15.3 Hz, PhCH_ACH_B), 7.27–7.36 (5H, m, Ar-H);

d_C(100.6 MHz, CDCl₃) 46.2, 55.7, 60.3, 64.6, 128.0 (£2,

Ar-H), 128.9 (Ar-H), 136.0 (Ar-H), 159.1 (CvO); m/z

(APCIþ) 208 (M^þH^þ, 100%), 164 (5), 130 (5); HRMS

(CI^þ) (Found: MH^þ208.0974. C₁₁H₁₄NO₃requires

208.0973).

4.2.7. (S)-Carbonic acid tert-butyl ester-3-(4-nitro-

benzyl)-2-oxo-oxazolidin-4-yl methyl ester 51. A ﬂask

was charged with DMF (1 mL). To the ﬂask was added

(R)-N-Boc-oxazolidin-2-one 46 (25 mg, 0.12 mmol), the

resulting solution was stirred whilst being cooled to 08C. To

the cold DMF solution was added oil free potassium hydride

(washed with n-pentane, 5 mg, 0.13 mmol). The resulting

solution was stirred at 08C for 2 h and 4-nitrobenzyl

bromide was added in one portion (50 mg, 0.23 mmol).

The reaction was allowed to warm to room temperature over

12 h under argon and then quenched with aqueous saturated

ammonium chloride (1 mL). The aqueous DMF was

removed in vacuo, water was added (5 mL) and the crude

product extracted with dichloromethane (3£10 mL). The

dichloromethane fractions were combined, dried (MgSO₄),

ﬁltered and the crude product puriﬁed via ﬂash column

9400

S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

chromatography using a mixture of ether and n-pentane

(75:25) as the eluent. The title compound (S)-51 was a white

solid (23 mg, 56%) which displayed the following physical

characteristics; n_max(KBr) (cm²¹) 2980, 2921, 1744 (s,

CvO), 1733 (s, CvO), 1606, 1518, 1409, 1347, 1258,

1158; d_H(400 MHz, CDCl₃) 1.46 [9H, s, (CH₃)₂CO], 3.87

(1H, m), 4.01 (1H, dd, J¼11.8, 5.0 Hz), 4.17 (2H, m), 4.43

(2H, m), 4.78 (1H, d, J¼15.8 Hz, PhCH_ACH_B), 7.52 (2H, d,

J¼8.7 Hz, Ar-H), 8.23 (2H, d, J¼8.7 Hz, Ar-H ortho to

nitro); d_C(100.6 MHz, CDCl₃) 30.3 [(CH₃)₃CO], 48.9, 56.5,

67.0, 67.75, 81.8, 86.1, 126.7, 131.6, 146.1, 150.4, 155.4

(CvO), 160.9 (CvO); m/z (APCIþ) 297.0 (10), 253.0 (10),

221.0 (25), 195.0 (10), 161.9 (30), 121.9 (65), 118.1

(100%), 106.1 (90).

4.67 (1H, d, J¼15.3 Hz, PhCH_ACH_B), 7.00–7.15 (5H, Ar-

H); d_CNMR (100 MHz, d₆-benzene) 46.5, 55.9, 60.5, 64.3,

137.3 (Ar-H), rest of the Ar-H peaks obscured by C₆D₆

solvent peaks, 159.4 (CvO); m/z (APCIþ) 208.2 (100%,

MþH^þ), 164.1 (5), 130.1 (25), 122.0 (5); HRMS (CI^þ)

(Found: MH^þ208.0972. C₁₁H₁₄NO₃requires 208.0973).

4.3.2. (R)-Propionic acid 3-benzyl-2-oxo-oxazolidin-4-yl

methyl ester 52. (R)-N-Benzyl-oxazolidin-2-one 32

(130 mg, 0.63 mmol) was dissolved in dichloromethane

(5 mL). To this solution was added propionic anhydride

(164 mg, 1.26 mmol), 4-dimethylaminopyridine (77 mg,

0.63 mmol) and triethylamine (0.26 mL, 190 mg,

1.88 mmol). The solution was stirred for 12 h at room

temperature and then worked-up as outlined for (S)-11. The

crude product was puriﬁed via ﬂash column chromato-

graphy using n-pentane/ether (1:1) as the eluent. The title

compound (R)-52 was a colourless oil (150 mg, 91%) with

the following physical characteristics; [a]²_D³¼þ10.0 (c 1.35,

CHCl₃); n_max(ﬁlm) (cm²¹) 2983, 2940, 1759–1721 (br s,

CvO), 1643, 1419, 1234, 1178; d_H(400 MHz, CDCl₃) 1.14

[3H, t, J¼7.6 Hz, CH₃CH₂CO], 2.35 (2H, q, J¼7.6 Hz,

CH₃CH₂CO), 3.83 (1H, m), 4.05 (1H, dd, J¼12.0, 3.6 Hz),

4.14–4.21 (2H, m), 4.25 (1H, dd, J¼12, 4 Hz), 4.35 (1H, t,

J¼9.0 Hz), 4.82 (1H, d, J¼15.3 Hz, PhCH_ACH_B), 7.27–

7.39 (5H, m, Ar-H); d_C(100 MHz, CHCl₃) 8.9 (CH₃CH₂),

27.3 (CH₃CH₂), 46.4, 53.2, 61.8, 64.5, 128.0 (Ar-H), 128.9

(£2, Ar-H), 135.6 (Ar-H), 158.2 (CvO), 173.9 (CvO); m/z

(APCIþ) 264.2 (100%), 208.0 (30), 164 (10).

4.3. X-Ray crystal structure determination for (S)-51

Data were collected using an Enraf-Nonius CAD4 diffract-

ometer with graphite monochromated Cu Ka radiation

using standard procedures at room temperature. The

structure was solved by direct methods (Sir92), all non-

hydrogen atoms were reﬁned with anisotropic thermal

parameters. The carbonate residue was modelled as

disordered equally over two sites. Hydrogen atoms were

added at idealised positions. The structure was reﬁned using

CRYSTALS.²⁸

X-Ray crystal structure data for (S)-51: [C₁₆H₁₆N₂O₇];

M¼348.31, orthorhombic, space group P212121, a¼

˚

6.0043(5) A, b¼10.846(1) A, c¼26.727(3) A, U¼

1740.61(3) A , Z¼4, b¼0.902 cm²¹, colourless block,

4.3.3. 4-Hydroxymethyl-3-(2-oxo-1-phenylbutyl)-oxa-

zolidin-2-one 53/54. A ﬂask was charged with oxazolidin-

2-one 52 (108 mg, 0.21 mmol) and the solid dissolved in

tetrahydrofuran (1 mL). The tetrahydrofuran solution was

cooled to 2788C (acetone/CO₂) and a solution of LDA in

tetrahydrofuran (0.84 mL, 44 mg, 0.42 mmol, 2 equiv.,

0.5 M solution) was added dropwise. The reaction mixture

changes from a clear to yellow solution within 15 min. After

30 min benzyl bromide (70 mg, 0.41 mmol) was added and

the reaction was left stirring at 2788C for a further 2.5 h

whereupon it was quenched with an aqueous saturated

ammonium chloride solution (3 mL). The quenched reac-

tion mixture was allowed to warm to room temperature over

15 min. The organic components of the reaction mixture

were extracted with dichloromethane (3£10 mL), the

combined dichloromethane fractions were dried (MgSO₄),

ﬁltered and the solvent removed in vacuo. The resulting

mixture of products (tlc analysis, eluent; ether) were

separated via ﬂash column chromatography using, in the

ﬁrst instance, ether as the eluent to remove unreacted

starting material 52 (37%). After which changing the

solvent from ether to chloroform allowed the partial

separation of the ketones 53/54 (38 mg, 35%). Of this

mixture the major component 53 was separated and isolated

as a white solid (8 mg, 7.4%). The impure minor fraction 54

(contaminated with the major fraction 53) was isolated as an

oily liquid. The major component (53) had the following

3

˚

crystal dimensions¼0.2£0.4£0.8 mm. A total of 2081

unique reﬂections were measured for 3.31,u,74.23 and

1907 reﬂections were used in the reﬁnement. The ﬁnal

parameters were wR₂¼0.0748 and R₁¼0.0599 [I.1s(I)].

Crystallographic data (excluding structure factors) has been

deposited with the Cambridge Crystallographic Data Centre

as supplementary publication number CCDC189192.

Copies of the data can be obtained, free of charge, on

application to CCDC, 12 Union Road, Cambridge CB2 1EZ,

UK [fax: þ44(0)-1223-336033 or e-mail: deposit@ccdc.

cam.ac.uk].

4.3.1. (R)-3-Benzyl-4-hydroxymethyloxazolidin-2-one

32. A ﬂask was charged with (S)-N-benzyl-O-Boc-oxa-

zolidin-2-one 50 (46 mg, 0.15 mmol) dissolved in tetra-

hydrofuran (5 mL). To the tetrahydrofuran solution was

added aqueous hydrochloric acid (2 mL, 1 M). The resulting

solution was heated at reﬂux for 30 min. Removing the

solvent in vacuo and extracting the solution with dichloro-

methane (3£10 mL) allowed the N-benzyl oxazolidin-2-one

to be washed with water (10 mL) and dried (MgSO₄).

Filtering and removal of the solvent in vacuo yielded an oil

which was puriﬁed via ﬂash column chromatography using

ether as the eluent. The puriﬁed title product (R)-32 (24 mg,

76%) was isolated as an oil and possessed the following

physical characteristics; [a]²_D³¼þ29.0 (c 0.17, CHCl₃).

Lit^17bþ29.8, (c 1.0, CHCl₃); n_max(KBr) (cm²¹) 3376 (s),

2931, 2880, 1723 (s, CvO), 1448, 1252, 1087; d_H

(400 MHz, d₆-benzene) 2.58 (1H, m, OH), 2.84–2.94 (2H,

m), 3.18–3.23 (1H, m), 3.52 (1H, t, J¼8.7 Hz), 3.82 (1H,

dd, J¼8.5, 5.8 Hz), 4.02 (1H, d, J¼15.3 Hz, PhCH_ACH_B),

physical characteristics; mp 110–1138C; n_max(KBr) (cm²¹

)

3468, 2942, 2881, 1742 (s, CvO), 1712 (s, CvO), 1418,

1246, 1117; d_H(400 MHz, CDCl₃) 1.14 [3H, t, J¼7.3 Hz,

CH₃CH₂CO], 2.60 (2H, m, CH₃CH₂CO), 3.21 (2H, m), 3.58

(1H, br d, J¼12.3 Hz), 4.24 (1H, t, J¼8.4 Hz), 4.44 (2H, m),

5.92 (1H, s, NCHCO), 7.18–7.49 (5H, m, Ar-H); d_C

S. P. Bew et al. / Tetrahedron 58 (2002) 9387–9401

9401

3. Evans, D. A.; Bartroli, J. A.; Shih, T. L. J. Am. Chem. Soc.

1981, 103, 2127.

(100 MHz, CDCl₃) 8.0 (CH₃CH₂), 34.3, 55.8, 61.6, 65.3,

67.5, 129.8, 129.9, 129.9, 131.6, 159.1 (CvO), 211.8

(CvO); m/z (APCIþ) 264.2 (50%), 246.2 (15), 220.1 (5),

147.1 (100%); HRMS (CI^þ) (Found: MNa^þ286.1055).

C₁₄H₁₇NO₄Na requires 286.1068). Key H NMR data for

ketone 54 that is signiﬁcantly different to 53 d_H(400 MHz,

CDCl₃) 3.01 (1H, br m), 5.48 (1H, s).

4. Clive, D. L. J.; Murthy, K. S. K.; Wee, A. G. H.; Prasad, J. S.;

Da Silva, G. V. J.; Majewski, M.; Anderson, P. C.; Evans,

C. F.; Haugen, R. D.; Heerze, L. D.; Barrie, J. R. J. Am. Chem.

Soc. 1990, 112, 3018.

1

5. Phoon, C.; Abell, C. W. Tetrahedron Lett. 1998, 39, 2655.

6. Burgess, K.; Lim, D. J. Chem. Soc., Chem. Commun. 1997,

785.

4.3.4. 2-Methyl-3-phenylpropionic acid-3-benzyl-2-oxo-

oxazolidin-4-yl methyl ester 55/56. A ﬂask was charged

(R)-N-benzyl-oxazolidin-2-one 32 (5.5 mg, 0.026 mmol)

the solid was dissolved in dichloromethane (0.5 mL) and

the ﬂask cooled to 08C in an ice bath. To the dichloro-

methane was added a-methylhydrocinnamoyl chloride²⁶

(0.008 mL, 5.4 mg, 0.03 mmol) followed by dropwise

addition of triethylamine (5.4 mg, 0.05 mmol). The result-

ing solution was stirred for 12 h, and allowed to warm to

room temperature. After 12 h the reaction was quenched by

the addition of aqueous saturated ammonium chloride

(2 mL) and diluted with dichloromethane (5 mL). The

dichloromethane layer was separated and the aqueous layer

further extracted with dichloromethane (2£3 mL). The

combined organic layers were washed with aqueous

hydrochloric acid (0.1 M, 3£10 mL), saturated brine

(3£10 mL), saturated aqueous sodium bicarbonate and

dried (MgSO₄). Filtering the solution and removing the

solvent in vacuo yielded ester 55/56. The product was

puriﬁed via ﬂash column chromatography using a mixture

of ether and n-pentane (75:25) as the eluent. A mixture of

epimers 55/56 were isolated as a pale yellow oil (5.8 mg,

64%) with the following physical characteristics; n_max(ﬁlm)

(cm²¹) 2971, 2924, 1744 (s, CvO), 1728 (s, CvO), 1492,

1452, 1417, 1255, 1149, 1082; d_H(400 MHz, CDCl₃) 1.12

(3H, m), 2.58–2.71 (3H, m), 2.85 [1H, dd, J¼13.8, 7.8 Hz),

3.56 (1H, m), 3.80–3.98 (3H, m), 4.02–4.16 (1H, m), 4.67

(1H, t, J¼15.4 Hz), 7.05–7.29 (10H, m, Ar-H); d_C

(100.6 MHz, CDCl₃) 17.4 (CH₃), 40.4, 41.8, 46.7, 53.5,

62.2, 65.0, 126.9 (Ar-H), 127.0 (Ar-H), 128.5 (Ar-H), 128.9

(Ar-H), 129.4 (Ar-H), 136.0 (Ar-H), 139.4 (Ar-H), 139.5

(Ar-H), 158.6 [OC(O)N], 176.1 [OC(O)CH]; m/z (APCIþ)

354.3 (M^þþH^þ, 100%), 237.2 (10), 208.2 (70), 190.1 (5);

HRMS (CI^þ) (Found: MH^þ354.1705. C₂₁H₂₄NO₄requires

354.1713).

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Article Doi

Rearrangements and racemisation during the synthesis of L-serine derived oxazolidin-2-ones

DOI: 10.1016/S0040-4020(02)01223-1

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