New Routes to Chiral Evans Auxiliaries by Enzymatic Desymmetrisation and Resolution Strategies

Article abstract of DOI:10.1002/adsc.200303006

This paper describes how enantiomerically enriched Evans auxiliaries can be successfully prepared by either an enzymatic desymmetrisation strategy or an asymmetric synthesis using racemic auxiliaries and an enzymatic resolution. Desymmetrisation of N-Boc-protected serinol has been achieved in good yield and high enantiomeric excess using porcine pancreas lipase. This has been exploited in different ways to prepare enantiomerically enriched (4R)- and (4S)-substituted 2-oxazolidinones. In another approach to asymmetric synthesis, starting from a racemic Evans auxiliary, by means of a diastereoselective aldol reaction coupled with a lipase-catalysed resolution, we achieved the preparation of enantiomerically enriched β-hydroxy acids and enantiomerically enriched 2-oxazolidinones.

Full text of DOI:10.1002/adsc.200303006

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New Routes to Chiral Evans Auxiliaries by Enzymatic
Desymmetrisation and Resolution Strategies
Claudia Neri, Jonathan M. J. Williams*
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
Fax: ‡ 44-(0)1225 386231, e-mail: j.m.j.williams@bath.ac.uk
Received: January 10, 2003; Accepted: April 4, 2003
Abstract: This paper describes how enantiomerically other approach to asymmetric synthesis, starting from
enriched Evans auxiliaries can be successfully pre- a racemic Evans auxiliary, by means of a diastereo-
pared by either an enzymatic desymmetrisation selective aldol reaction coupled with a lipase-cata-
strategy or an asymmetric synthesis using racemic lysed resolution, we achieved the preparation of
auxiliaries and an enzymatic resolution. Desymmetr- enantiomerically enriched b-hydroxy acids and enan-
isation of N-Boc-protected serinol has been achieved tiomerically enriched 2-oxazolidinones.
in good yield and high enantiomeric excess using
porcine pancreas lipase. This has been exploited in Keywords: acylation; aldol reaction; diastereoselec-
different ways to prepare enantiomerically enriched tivity; enzymatic desymmetrisation; enzymatic reso-
(4R)- and (4S)-substituted 2-oxazolidinones. In an- lution; racemic auxiliaries
Introduction
desymmetrisation over conventional kinetic resolution
reactions is the potential ability to achieve high enan-
The introduction of enantiomerically pure 2-oxazolidi- tiomeric excess even at 100% conversion.[9] Desym-
nones (Evans chiral auxiliaries) can be considered a metrisation of achiral diols using enzymes is a well
milestone in the history of asymmetric synthesis using known process for the formation of enantiomerically
covalently bound auxiliaries.[1] The ability to induce high enriched mono-esters.[10 13] Our overall desymmetrisa-
stereocontrol in asymmetric synthesis is in practice the tion strategy involved the use of N-Boc-protected
main reason why a specified chiral auxiliary is chosen to serinol 1 to give a mono-acetate 2, followed by
achieve asymmetric synthesis. Evans auxiliaries fulfil all appropriate chemical transformation to afford enantio-
the criteria required from a good chiral auxiliary. merically enriched oxazolidinones (e.g., compound 3)
Nevertheless, the choice of Evans auxiliary can be (Scheme 1).[14]
limited by the availability of an appropriate enantio-
In another approach to auxiliary-based asymmetric
merically pure amino acid or alcohol. Aside from the synthesis, we decided to attempt an unusual strategy
(S)-substituted 2-oxazolidinones readily available from using a racemic aldol adduct from a diastereoselective
naturally occurring a-amino acids such as l-valine and aldol reaction and an enzymatic resolution. In order to
l-phenylalanine,[2] their configurational antipodes are achieve this goal, the auxiliary has to relay its stereo-
less accessible. The sterically constrained, designed chemistry to the substrate, which can then be resolved by
chiral 2-oxazolidinones, such as 4,5-disubstituted-2- the enzyme (Scheme 2).[15]
oxazolidinones conformationally fixed by bicyclo[2.2.1]
We envisaged that through the application of this
and bicyclo[2.2.2] systems,[3] are also less easily avail- methodology we could obtain both enantiomerically
able. That explains why since 1981 much work has been
published about the use of novel Evans-type chiral
auxiliaries, chemically designed and from sources other
than natural a-amino acids.[4 8]
We disclose herein that enantiomerically enriched
Evans auxiliaries can be obtained from sources other
than natural a-amino acid by two simple approaches to
asymmetric synthesis, which involve the use of enzymes
in desymmetrisation and resolution processes.
Desymmetrisation of meso-configured or otherwise
prochiral substrates to yield enantiomerically enriched
products is a powerful synthetic tool. The advantage of nones by enzymatic desymmetrisation.
Scheme 1. General approach to preparation of oxazolidi-
Adv. Synth. Catal. 2003, 345, 835 848
DOI: 10.1002/adsc.200303006
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Claudia Neri, Jonathan M. J. Williams
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Scheme 2. General approach to asymmetric synthesis with a racemic auxiliary.
enriched auxiliary and enantiomerically enriched prod-
uct.
Only one enantiomer of the mono-acetylated product
was detected by chiral HPLC.
The effects of solvent and temperature variations on
the conversion and selectivity of the acylation reaction
were investigated. We first examined the effect of
solvent on the acylation of protected serinol 1 at 308C
(Table 1).
As can be seen (entries 1 and 3), striking differences in
reactivity were found, with vinyl acetate and a mixture
of THF/n-hexane being the best reaction solvents. The
Results and Discussion
Preparation of Enantiomerically Enriched 2-
Oxazolidinones by Enzymatic Desymmetrisation
Serinol derivatives have only received limited attention increase in conversion was particularly evident when
in desymmetrisation reactions. A literature search compared with solvents such as cyclohexane, toluene
reveals few examples in which serinol has been used as and acetonitrile (entries 4, 5, 7).
starting material in desymmetrisation-based synthe-
The reaction in vinyl acetate was examined at differ-
ses.[16 18] We decided to focus our attention upon the ent reaction temperatures. In Table 2 the relative results
enzymatic desymmetrisation of serinol as a potential after 2 h are displayed.
precursor of enantiomerically enriched oxazolidinones.
Increasing the temperature (entries 2 and 3) had a
Desymmetrisation of serinol (1,3-dihydroxy-2-amino- noticeable effect upon the amount of di-acetylated
propane) required previous protection of the amino product, which appears after only 2 h.
group to avoid N-acylation.[19] Boc-protection of achiral
Although PPL is widely used for the resolution of
serinol 4 was achieved in 90% yield by treatment of prochiral diols,[23] we also examined other enzymes in
serinol with Boc anhydride (Scheme 3).[20]
our desymmetrisation strategy. Lipase from Candida
The desymmetrisation of N-Boc-serinol was achieved antarctica type B (CAL B), lipase from Candida
by the selective mono-acetylation using PPL (porcine cylindracea (CCL), lipase from Pseudomonas cepacia
pancreas lipase) and vinyl acetate as the acylating agent, (PCL) and from Pseudomonas fluorescens (PFL) im-
in organic solvent (Scheme 4). A small amount of di- mobilized on Sol-Gel-AK, lipase from Aspergillus niger
acetylated material was also observed, presumably (ANL) were tested for their activity and selectivity in
formed from the unwanted enantiomer of mono-acety- the acylation reaction illustrated in Scheme 5. Again
lated product, thereby providing a self-correcting proc- vinyl acetate was used as both the acylating agent and
ess.[21]
solvent at 308C (Table 3).
The conversion after 2 h was greater than 96% when
PPL, CAL B, PCL and PFL (entries 1, 2, 4, 6) were used
as catalysts. The best selectivity was observed with PPL.
No selectivity was observed with CAL B. The di-
acetylated product only was formed in reactions in both
vinyl acetate and THF/n-hexane media (Table 3, entry
2).
Scheme 3. Boc-protection of achiral serinol 4.
In summary, the maximum conversion ( > 99%, after
2 hours) and selectivity ( > 99% ee and>99% mono-/di-
acetylated product) were obtained when the reaction
was performed in vinyl acetate at 308C, using PPL as
catalyst. The isolated yield of product was 69%, with
some material lost on work-up.
Scheme 4. Desymmetrisation of N-Boc-serinol by PPL.
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New Routes to Chiral Evans Auxiliaries
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Table 1. Influence of solvent on conversion, ee and mono-/di-acetylated product ratio.[a, b]
Entry
Solvent
Conversion [%]
ee [%]
Mono-/
di-acetylated ratio[c]
1
2
3
4
5
6
THF/n-hexane 1: 1
i-Pr2O
Vinyl acetate
Cyclohexane
Toluene
96
42
> 99
28
29
> 99
> 99
> 99
> 99
> 99
> 99
> 99
87
> 99
> 99
> 99
> 99
98
Acetone
72
7Acetonitrile
28
> 99
[a]
140 mgenzyme/mmolsubstrate in 5 mL solvent using 1 mmol of N-Boc-serinol and 3 mmol vinyl acetate.
[b]
[c]
Conversion, enantiomeric excess and mono-/di-acetylated ratio were determined by HPLC analysis.[22]
(mono/mono- ‡ di-acetylated)  100.
Table 2. Influence of temperature on conversion, ee and mono-/di-acetylated product ratio.[a, b]
Entry
Temperature [ 8C]
Conversion [%]
ee [%]
Mono-/
di-acetylated ratio[c]
1
2
3
30
40
50
> 99
> 99
> 99
> 99
> 99
> 99
> 99
85
84
[a]140 mgenzyme/mmolsubstrate in 5 mL vinyl acetate using 1 mmol of N-Boc-serinol.
[b]
[22]
Conversion, enantiomeric excess and mono-/di-acetylated ratio were determined by HPLC analysis.
[c]
(mono-/mono- ‡ di-acetylated)  100.
Table 3. Influence of catalyst on conversion, ee and mono-/di-acetylated product ratio.[a]
Entry
Lipase
Conversion [%]
ee [%]
Mono-/
di-acetylated[c]
1
2
3
4
5
6
PPL
> 99
> 99
49
96
16
> 99
1
> 99
> 99
> 99
> 99
> 99
< 1
94
91
> 99
92
CAL B[b]
CCL
PCL
ANL
PFL
96
[a]
For reaction conditions see Table 1.
Reaction with CAL B was performed in both vinyl acetate and THF/n-hexane solution.
{(mono-)/(mono- ‡ di-acetylated)}  100.
[b]
[c]
Scheme 5. Lipase-catalysed kinetic resolution of rac-3.
The next step in our study was to establish the oxazolidinone 3. Unfortunately, this product was ob-
cyclisation of acetate 2. tained as a racemic mixture. We assume that intra-
The intramolecular reaction was first attempted under molecular acetyl transfer occurs prior to the cyclisation,
basic conditions. Treatment of enantiomerically en- thereby affording the racemic product. Nevertheless,
riched acetate 2 with potassium carbonate at 1308C kinetic resolution of rac-3 was achieved by enzymatic
under vacuum[24] (Scheme 6) afforded the racemic hydrolysis in phosphate buffer (Scheme 5).
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Table 4. Kinetic resolution of rac-3 with different lipases.[a]
In an alternative approach, we envisaged that protec-
tion of the oxygen would be an advantage. The
enantiomerically enriched mono-acetate 2 was benzy-
lated using benzyl trichloroacetimidate, in the presence
of a catalytic amount of triflic acid,[27] to afford the N-
benzyloxycarbonyl-O-benzyl acylated serinol 7 in rea-
sonable yield. Cyclisation with potassium carbonate
then provided the (R)-oxazolidinone 8 in>99% ee
(Scheme 7).
Entry
Lipase
Yield
[%]
Optical purity
[%][b]
1
2
3
CAL B
PCL
PPL
33
36
42
93
90
84
[a]
140 mgenzyme/mmolsubstrate in 1.5 mL phosphate buffer solu-
tion (0.1 M, pH 7) using 0.6 mmol of racemic 4-acetox-
Protection of the hydroxylic group avoided any
racemisation during the base-catalysed cyclisation re-
action. Catalytic water was found to be essential for the
activation of the acylated hydroxy group as nucleophile.
ymethyl-2-oxazolidinone 3.
[b]
30
Optical purity (%) ˆ {[a]D of obtained (R)-4}/{[a]D of
30
enantiopure (R)-4} Â 100.
Porcine pancreas lipase, lipase from Pseudomonas
cepacia and from Candida antarctica type B were Racemic Auxiliaries: Applications to Asymmetric
examined for their activity and selectivity towards the Synthesis
reaction studied. The reactions were stopped after 8
hours by removal of the enzymes by filtration. The yields The main objective ofour resolution strategy was to find a
of the reactions catalysed by the different lipases were good stereoselective aldol reaction, which could afford
determined after chromatographic purification of the only two enantiomers, separable by an enzyme-catalysed
products. The optical purity of hydroxymethyl-oxazoli- resolution. The actual number of isomers formed depends
dinone (R)-6 was determined by comparing the specific upon the stereoselectivity of the aldol reaction used.
rotation of the obtained alcohol with that reported in the
literature for the corresponding enantiopure form.[25] aldol reactions with TiCl4 and ClTi(O-i-Pr)3,[29] we
The results are illustrated in Table 4. decided to investigate the use of Ti-enolates, particularly
Given the high diastereomeric excess obtained in
[28]
The (R)-enantiomer of oxazolidinone 3 reacted faster a tetrachlorotitanium-enolate generated by diisopropy-
than the (S)-enantiomer. After 8 hours, optical purities lethylamine. Instead of using the racemic auxiliary
greater than 84% were detected.
We decided to try another approach to the cyclisation outcome of the aldol reaction was determined by
reaction and to avoid basic conditions. Enantiomerically reacting (R)-3-propionyl-4-benzyl-2-oxazolidinone
directly, we simplified the matter. The stereochemical
enriched (S)-oxazolidinone (S)-3 was obtained in a one- (R)-9 and (S)-3-propionyl-4-benzyl-2-oxazolidinone
step reaction by cyclisation with thionyl chloride (S)-9 separately. Considering the effect of lipase specif-
(Scheme 6).[26] The reaction proceeded with>98% icity towards the steric bulk of the substituents,[30]
enantiomeric excess and 72% yield. The absolute acetaldehyde was selected instead of benzaldehyde.
stereochemistry of oxazolidinone (S)-3 was confirmed
First, we examined the aldol reaction between oxazo-
by enzymatic hydrolysis of the acetate group (Scheme 6) lidinone (R)-9 and acetaldehyde in the presence of
and comparison of the specific rotation of hydroxy- titanium tetrachloride and diisopropylethylamine
oxazolidinone (S)-6 with literature data.[25]
(Scheme 8).
Scheme 6. Synthesis of (S)-4-acetoxymethyl-2-oxazolidinone 3 and its enzymatic hydrolysis.
Scheme 7. Synthesis of enantiomerically enriched 4-benzyloxymethyl-2-oxazolidinone.
838
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Table 5. Time course and diastereoselectivity of the enzy-
matic reaction in hexane.[a]
[b]
t [h]
% conv.
% dep
% des[c]
0
3
6
24
48
0
30
46
50
56
0
42
84
> 99
> 99
> 99
> 99
> 99
88
Scheme 8. The synthesis of the (4R)-aldol adducts via TiCl4/
i-Pr2NEt-enolates.
[a]
50 mgenzyme/mmolsubstrate in 5 mL solvent using 1 mmol of
diastereomeric aldol and 2 mmol vinyl acetate.
Diastereomeric excess of the product.
[b]
[c]
Diastereomeric excess of the remaining substrate.
Each pair of aldol adducts was tested in the enzymatic
resolution. The enzymatic resolution of aldols
(4R,2'S,3'R)-10 and (4R,2'S,3'S)-10 from oxazolidinone
(R)-9 was carried out using vinyl acetate in hexane at
408C, catalysed by lipase from Candida antarctica type
B (Scheme 10).
The enzymatic resolution was successful. The (3'R)
diastereomer reacted faster than the (3'S) one. The
progress and the diastereomeric excess of the reaction
Scheme 9. The synthesis of the (4S)-aldol adducts via TiCl4 /
i-Pr2NEt-enolates.
Of the four possible isomers that could be obtained, were monitored by chiral HPLC analysis after removal
we got only the ™non-Evans∫ syn and the anti aldol of the enzyme by filtration. In Table 5, the transester-
adducts, in a 1:1 ratio. ification rate and diastereoselectivity of the enzymatic
The ™non-Evans∫ syn and the anti relative configu- reaction in hexane are illustrated.
rations for aldol adducts 10 were established from the
Our next step was to find out if the same diastereo-
1
observed H NMR coupling constants for the vicinal selectivity could be observed when the aldol adducts
protons at the newly created stereogenic centres,[31] by from oxazolidinone (S)-9 were reacted with vinyl
comparison with analogous compounds synthesised by acetate in the presence of CAL B.
us in subsequent studies and by enzymatic resolution of
the diastereomeric product (see below).
The enzymatic resolution of aldols (4S,2'R,3'S)-10 and
(4S,2'R,3'R)-10 from oxazolidinone (S)-9 was carried
Given that the reaction with the (R)-enantiomer out as described above for aldols from (R)-9
proceeded diastereoselectively, we wanted then to (Scheme 11).
ensure that the same diastereoselectivity could be
As we expected, the (3'R) diastereomer reacted faster
observed when the other enantiomer was used. Oxazo- than the (3'S) diastereomer. Conversion and enantio-
lidinone (S)-9 was reacted in the same reaction con- meric excess were similar to those obtained when the
ditions, as shown in Scheme 9.
aldol adducts from (R)-9 were enzymatically resolved.
Again, only the ™non-Evans∫ syn and the anti aldol In Table 6 the time course and diastereoselectivity of the
adducts were formed in 1:1 ratio.
In summary, each enantiomer of the acylated oxazo-
enzymatic reaction in hexane are reported.
We had found a diastereoselective aldol reaction,
lidinone 9 gave as the major products two of the four which employed TiCl4/i-Pr2NEt-enolate. Only two of
possible diastereomers of aldol adduct 10, according to the four possible diastereomers were formed from each
chiral HPLC and NMR analysis. The given yield is the enantiomer of the acylated oxazolidinone 9 in a 1:1
total yield of the aldol mixture, calculated after chro- mixture. The use of CAL B as catalyst was found to be a
matographic purification.
valid method for the resolution of diastereomers of aldol
Scheme 10. The enzymatic resolution of aldol adducts.
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Scheme 11. The enzymatic resolution of the adducts from TiCl4 /i-Pr2NEt aldol reaction.
Table 6. Time course and diastereoselectivity of the enzy-
Racemic 4-benzyl-2-oxazolidinone 12 was prepared
matic reaction in hexane.[a]
from the corresponding racemic amino acid phenyl-
alanine, following the procedure reported by Wu and
Shen.[24] The racemic oxazolidinone was then acylated to
obtain the racemic 3-propionyl-4-benzyl-2-oxazolidi-
none 9.[33] The subsequent diastereoselective aldol
reaction with acetaldehyde in the presence of TiCl4,
(À)-sparteine and N-methyl-2-pyrrolidinone[32] provid-
ed racemic syn-10 in 99% diastereomeric excess
(Scheme 12).
Sparteine was used as a convenient base and did not,
as expected, exert any observable stereocontrol upon
the aldol reaction.
Enzymatic resolution of the enantiomers of aldol
adduct rac-syn-10 via transesterification catalysed by
[b]
t [h]
% conv.
% dep
% des[c]
0
1
4
8
24
48
0
3
18
39
51
60
0
3
22
63
> 99
> 99
> 99
> 99
> 99
89
80
[a]
50 mgenzyme/mmolsubstrate in 5 mL hexane using 1 mmol of
diastereomeric aldol and 2 mmol vinyl acetate.
Diastereomeric excess of the product.
[b]
[c]
Diastereomeric excess of the remaining substrate.
adducts from acetaldehyde. Moreover, the (3'R) dia- Candida antarctica lipase type B, afforded the (3'R)-
stereomers were preferentially acylated by the enzyme. acylated aldol adduct 11 and the (3'S)-non-acylated
We would expect that by means of an aldol reaction aldol adduct 10 (Scheme 13). The choice of solvent was
with better stereoselectivity, we might be able to obtain crucial to this process, and the solvent effects are
only one diastereomer from each enantiomer of N- illustrated in Table 7.
propionyloxazolidinone 9, i.e., two enantiomers, sepa-
rable upon the chiral preference of the lipase towards ification was faster in non-polar solvents such as n-
(3×R) stereocentres. hexane and toluene (Entries 1 and 3), whilst it was
The reaction rate of the lipase-catalysed transester-
The desired stereoselectivity for the aldol reaction slower in polar solvents such as dichloromethane (Entry
was obtained when we used the same reaction con- 5).[34 36] The selectivity of Candida antarctica lipase type
ditions reported by Crimmins and co-workers for an B towards the aldol adduct enantiomers was in accord-
analogous asymmetric aldol reaction.[32]
ance with the reported stereoselectivity of this enzyme
towards racemic secondary alcohols.[37]
Finally, hydrolysis[33] of the enzymatically resolved
aldol 10 and ester 11 afforded the enantiomerically
enriched 3-hydroxy-2-methylbutanoic acids (2R,3S)-13
and (2S,3R)-13 and the enantiomerically enriched 2-
oxazolidinones (R)-12 and (S)-12 (Scheme 14).
For comparison, the enantiomer of the lipase-acylated
oxazolidinone 11 was synthesised by chemical esterifi-
cation of (4R,2'R,3'S)-10 with acetic acid in the presence
of DCC and dimethylaminopyridine.[38] Ester
(4R,2'R,3'S)-11 was prepared in 65% isolated yield.
Scheme 12. Acylation and aldol reaction of rac-4-benzyl-2-
oxazolidinone 12. Reaction conditions: (i) n-BuLi, EtCOCl/
THF, À 788C (88%); (ii) TiCl4, (À)-sparteine, N-methyl-2-
pyrrolidinone, CH3CHO/DCM, 0 ! À 788C (54%).
Scheme 13. Lipase-catalysed aldol adduct resolution.
840
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New Routes to Chiral Evans Auxiliaries
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Table 7. Influence of solvent on conversion and enantiomeric excess.[a]
Entry
Solvent
Conversion [%]
(4R,2'R,3'S)-10 ee %
(4S,2'S,3'R)-11 ee %
1
2
3
4
5
n-hexane
i-Pr2O
toluene
Vinyl acetate
DCM
50
45
42
34
6
> 99
81
72
51
6
> 99
> 99
> 99
> 99
> 99
[a]
30 mgenzyme/mmolsubstrate in 5 mL solvent using 1 mmol of racemic aldol and 2 mmol vinyl acetate.
Scheme 17. The synthesis of the racemic rac-syn-21 4-ethyl-
oxazolidinone. Reaction conditions: (i) Na2CO3/EtO2CCl,
H2O; (ii) K2CO3, 125 1308C, vacuum (90%); (iii) n-BuLi,
EtCOCl/THF, À 788C (64%); (iv) TiCl4, (À)-sparteine, N-
methyl-2-pyrrolidinone, CH3CHO/DCM, 0 ! À 788C (54%).
Scheme 14. Hydrolysis of enzymatic resolution products.
12 was acylated using butyryl chloride to obtain the N-
butanoyloxazolidinone 14. This underwent the diaster-
eoselective aldol reaction with acetaldehyde in the
presence of TiCl4/(À)-sparteine/NMP to afford the rac-
syn-15 in 59% yield and 95% de, according to
1H NMR[39] and chiral HPLC analysis (Scheme 15).
Enzymatic resolution of the enantiomers of aldol
adduct 15 via transesterification catalysed by Candida
antarctica lipase type B in n-hexane, afforded the
Scheme 15. Acylation of ( Æ )-4-benzyl-2-oxazolidinone 12
with n-PrCOCl and subsequent aldol reaction. Reaction
conditions: (i) n-BuLi, n-PrCOCl/THF, À 788C (88%); (ii)
TiCl4, (À)-sparteine, N-methyl-2-pyrrolidinone, CH3CHO/
DCM, 0 ! À 788C (59%).
The chemical esterification gave, as expected, the acylated aldol adduct 16 and the non-acylated aldol
ester with opposite specific rotation with respect to the adduct 15 with 50% conversion and>99% enantiomeric
ester obtained by the enzymatic reaction.
To prove the general application of our methodology
excess of the product after 20 hours (Scheme 16).
We were pleased to discover that the aldol reaction
to obtain enantiomerically enriched auxiliary and was still highly selective even when the acyl moiety was
enantiomerically enriched product, we decided to changed. The enzymatic resolution was effective even
change the acyl moiety of our oxazolidinone. We when the 2'-methyl substituent was exchanged with an
intended to see if this structural change could affect ethyl group.
the aldol reaction diastereoselectivity or/and the enzy-
Our aim was now to prove that our approach could be
matic resolution. This time, the racemic oxazolidinone generally exploited to obtain the indirect resolution of
Scheme 16. Lipase-catalysed aldol adduct resolution.
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Scheme 18. Enzymatic resolution of aldols 21 and subsequent hydrolysis.
chemically designed racemic auxiliaries. For example, acids and the indirect resolution of different 4-substi-
racemic 2-amino-1-butanol is readily available at low tuted racemic Evans auxiliaries.
cost. We envisaged that using this inexpensive starting
material we could obtain enantiomerically enriched 4-
ethyl-2-oxazolidinones.
Racemic 2-amino-1-butanol 17 was used to synthesise
Experimental Section
racemic (2',3')-syn-21, following the procedure above
described for the synthesis of rac-syn-10 and 15
(Scheme 17).
The application of our methodology produced re-
solved alcohol (4R,2'R,3'S)-21 and acetate (4S,2'S,3'R)-
General Remarks
1H NMR spectra were run in CDCl3, unless otherwise stated,
using either a Bruker AM-300 (300 MHz) or a Jeol GX400
(400 MHz) instrument. Chemical shifts are reported relative to
22 (Scheme 18). Hydrolysis of the resolved alcohol and Me4Si (d ˆ 0.00 ppm) as internal standard. Coupling constants
(J) are given in Hertz and multiplicities denoted as singlet (s),
doublet (d), triplet (t), doublet of doublets (dd), doublet of
quartets (dq) or multiplet (m). 13C NMR spectra were run in
CDCl3, unless otherwise stated, using either a Bruker AM-300
(75.5 MHz) or a Jeol GX400 (100 MHz) instrument. Mass
spectra, including high-resolution spectra, were recorded on a
Fisons NG-Micromass Autospec Spectrometer using electron
impact (EI ‡ ) ionisation, chemical impact (CI ‡ ) ionisation
and/or fast atom bombardment (FAB ‡ ) ionisation. Elemen-
tal analyses were performed using a Carlo Erba 1106 Ele-
acetate afforded enantiomerically enriched (2R,3S)-13
and (2S,3R)-13 and the enantiomerically enriched 4-
ethyl-2-oxazolidinones (R)-19 and (S)-19. Again the
strategy proved to be successful affording products
with>99% ee.
Conclusion
We have developed different strategies to obtain mental Analyser at the University of Bath. HPLC was
performed using a tsp liquid chromatograph (Spectra Series
P200 Pump, Spectra Series UV100 Lamp, ChromJet SP4400
Integrator). All HPLC separations were carried out using
Chiralcel OD and AD columns obtained from Fisher
Scientific Supplies. Flash chromatography was carried out
using Merck Kiesegel 60H and Fisher Matrex Silica 60 silica.
TLC using commercially available Merck Kiesegel G/UV254
neutral silica coated aluminium and glass plates monitored all
reactions. TLC plates were visualised by 254 nm light or with
KMnO4 dip followed by heating. Melting points were meas-
enantiomerically enriched Evans auxiliaries, by enzy-
matic desymmetrisation of N-Boc-serinol and by enzy-
matic resolution of diastereomeric and enantiomeric
aldol adducts.
Different lipases have been shown to catalyse selec-
tively the mono-acetylation of N-Boc-serinol with vinyl
acetate in organic solvent. Aspects of the reaction such
as effect of solvent, temperature and lipase origin were
discussed and we can conclude that the desymmetrisa-
¾
¾
tion of N-Boc-protected serinol can be successfully ured on a B¸chii 535 Series instrument and are uncorrected.
Optical rotations were measured with a Optical Activity LTD
AA-10 automatic polarimeter. IR spectra were recorded as
thin films, solutions (CH2Cl2, CHCl3 or CDCl3) or KBr discs,
using a Perkin-Elmer 1600 Series FT-IR spectrophotometer in
the range of 4000 600 cmÀ1, with internal background scan.
achieved in good yield and high ee in 2 hours, by using
the inexpensive crude commercial PPL in vinyl acetate
at 308C. The desymmetrisation of N-Boc-serinol has
been exploited in different ways to prepare enantio-
merically enriched (4S)- and (4R)-substituted 2-oxazo-
lidinones.
Starting from a racemic Evans auxiliary, by means of a
diastereoselective aldol reaction coupled with a lipase-
catalysed resolution, we proved that we could achieve
¾
Candida antarctica lipase type B (CAL B, Chirazyme L-2,
carrier-fixed C3, lyophilisate) was a gift from Boeringer
Mannheim. Porcine pancreas lipase (PPL, EC 3.1.1.3. type
II) was from Sigma. Pseudomonas cepacia lipase (PCL) and
Pseudomonas fluorescens lipase (PFL) immobilised in Sol-
the preparation of enantiomerically enriched b-hydroxy Gel-AK, Candida cylindracea lipase (CCL), and Aspergillus
842
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2003, 345, 835 848

New Routes to Chiral Evans Auxiliaries
FULL PAPERS
niger lipase (ANL) were from Fluka. All enzymes were used as
supplied.
Preparation of (R/S)-( ‡ / )-4-Acetoxymethyl-2-
oxazolidinone rac-3[24]
Powdered K2CO3 (10 mg, 0.06 mmol) was added to desym-
metrised serinol (R)-2 (685.8 mg, 2.94 mmol) and the mixture
was heated to 1308C with magnetic stirring under vacuum,
until the gas evolution stopped (approximately 2 hours). After
cooling down to room temperature, the mixture was purified
by flash chromatography (SiO2, n-hexane/EtOAc 10:90), to
give rac-3 as a colourless oil. Recrystallisation from n-hexane/
isopropanol afforded rac-3 as a white solid (266.7mg, 57%);
Preparation of N-(tert-Butoxycarbonyl)-1,3-
propanediol (N-Boc-Serinol) 1[20]
Di-tert-butyl dicarbonate (1.3 g, 6 mmol) was gently added to a
stirred solution of serinol (2-amino-1,3-propanediol)
4
(455 mg, 5 mmol) in EtOH (15 mL). After 1 hour at room
temperature, the solvent was removed under reduced pressure.
The residue was extracted with EtOAc (2 Â 15 mL), and the
organic phase was dried (Na2SO4) and concentrated under
vacuum. The obtained white solid was recrystallised from
hexane/EtOAc to give 1 as white needles; yield: 1.1 g (95%);
mp 77 798C; Rf (n-hexane/EtOAc, 10:90) ˆ 0.41; HPLC
¾
(Chiralcel
AD column, n-hexane/2-propanol, 90:10,
1 mL minÀ1, l ˆ 210 nm): tR ˆ 16.3 and 18.8 min; IR (film):
n ˆ 3435, 2950, 1720, 1660, 1450, 1370, 995 cmÀ1; 1H NMR
(300 MHz, CDCl3): d ˆ 5.71 (1H, br s, NH), 4.51 (1H, dd app. t,
J ˆ 8.5 Hz, CHHO), 4.24 4.01 (4H, m, CH2OCOCH3, CHHO,
CHN), 2.11 (3H, s, COCH3); 13C NMR (75.5 MHz, CDCl3):
d ˆ 170.8 (OCO), 159.8 (NCO), 66.9 (CH2OCOCH3), 64.9
(CH2OCON), 51.1 (CHN), 20.7(CO CH3); MS (CI ‡ , 7 0 eV):
mp 84 858C (Lit.[20] 87 88 8C); HPLC (Chiralcel OD
¾
column, n-hexane/2-propanol, 95:5, 1 mL minÀ1, l ˆ 210 nm):
tR ˆ 8.6 min; IR (CH2Cl2): n ˆ 3425, 2965, 2885, 1700, 1500,
1165, 1050 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 5.25 (1H, br
d, J ˆ 5.4 Hz, NH), 3.82 3.63 (5H, m, 2  CH2OH and CHN),
2.68 (4H, t, J ˆ 5.5 Hz, 2  CH2OH), 1.45 (9H, s, 3  CH3);
13C NMR (75.5 MHz, CDCl3): d ˆ 156.8 (CO), 80.3 (C(CH3)3),
63.2 (2 Â CH2OH), 53.5 (CHN), 28.7(3 Â CH3); anal. calcd. for
C8H17NO4: C 50.25%, H 8.96%, N 7.32%; found: C 50.2%, H
8.9%, N 7.2%.
‡
m/z 160 (M ‡ 1, 100%), 118 (23), 99 (20), 86 (30); anal. calcd.
for C6H9NO4: C 45.28%, H 5.70%, N 8.80%; found: C 45.3%, H
5.7%, N 8.6%.
General Procedure for the Enzymatic Hydrolysis of
(R/S)-( ‡ / )-4-Acetoxymethyl-2-oxazolidinone rac-3
In a typical experiment a solution of rac-3 (94.5 mg, 0.6 mmol)
in aqueous phosphate buffer (1.5 mL, 0.1 M, pH 7) was stirred
at 308C with the lipase (84 mg, 140 mgenzyme/mmolsubstrate). After
8 hours, the reaction was stopped by filtering off the enzyme.
The aqueous phase was extracted with ethyl acetate (3 Â 2 mL)
and the combined organic extracts were concentrated under
vacuum. The residue was purified by flash chromatography
(EtOAc/MeOH, 90:10) to give (R)-6 as a white solid. Enan-
tiomeric excesses were calculated comparing the obtained
specific rotations with that of the pure compound reported in
literature {Lit.[27] [a]D30: ‡ 32.2 (c 1.04, MeOH)}.
General Procedure for the Enzymatic
Desymmetrisation of N-Boc-Serinol 1
In a typical experiment a solution of N-Boc-serinol 1 (0.7g,
3.6 mmol) and vinyl acetate (2.6 mL, 28.8 mmol), in organic
solvent (20 mL) was stirred with the lipase (500 mg, 140 mgenzyme
/
mmolsub) at different temperatures for 2 hours. Aliquots were
taken from the different solutions and analysed by chiral
HPLC. The reaction performed in vinyl acetate at 308C, using
PPL as catalyst was followed until completion was reached (2
hours). The reaction was then stopped by filtering the solution.
The solution was concentrated under vacuum and the residue
purified by flash chromatography (SiO2, n-hexane/EtOAc,
50:50) to give (R)-2 as a colourless oil (587.6 mg, 69% isolated
yield) and traces of 5 (30.2 mg, 3%) as a yellow oil.
(R)-(‡)-4-Hydroxymethyl-2-oxazolidinone (R)-6[25]
Hydroxymethyloxazolidinone (R)-6 was obtained as a white
solid; mp 95 978C (Lit.[25] 96 998C); Rf (EtOAc/MeOH,
90:10) ˆ 0.38; 1H NMR (300 MHz, D2O): d ˆ 4.50 (1H, dd app.
t, J ˆ 9.0 Hz, CHHOCON), 4.23 (1H, dd, J ˆ 9.0, 5.2 Hz,
CHHOCON), 4.04 3.97(1H, m, C HN), 3.61 (1H, dd, J ˆ 12.0
and 3.7Hz, CH HOH), 3.52 (1H, dd, J ˆ 12.0 and 4.1 Hz,
CHHOH).
(R)-(‡)-3-O-Acetyl-2-N-(tert-butoxycarbonyl)serinol
(R)-2
Desymmetrised serinol (R)-2 was obtained as a colourless oil
(587.6 mg, 69% isolated yield); Rf (n-hexane/EtOAc 50:50):
¾
0.29; [a]D30: ‡ 3.5 (c 0.56, CHCl3); HPLC (Chiralcel OD
column, n-hexane/2-propanol, 95:5, 1 mL minÀ1, l ˆ 210 nm):
tR ˆ 10.8 min; IR (film): n ˆ 3370 (br), 2975, 1710, 1690, 1525,
1370, 1240, 1170, 1040 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ
5.10 (1H, br d, J ˆ 8.4 Hz, NH), 4.19 (2H, d, J ˆ 5.7Hz,
CH2OCO), 3.98 3.88 (1H, m, CHN), 3.65 (2H, dq, J ˆ 4.7and
11.4 Hz, CH2OH), 3.02 (1H, s br, OH), 2.09 (3H, s, COCH3)
1.45 (9H, s, 3  CCH3); 13C NMR (75.5 MHz, CDCl3): d ˆ 171.8
(OCO), 155.2 (NCO), 80.3 (C(CH3)3), 63.4 (CH2OCO), 62.2
(CH2OH), 51.4 (CHN), 28.7(3 Â CCH3), 21.2 (COCH3); MS
Preparation of (S)-(-)-4-Acetoxymethyl-2-
oxazolidinone (S)-3[26]
To astirred solution of (R)-2 (700 mg, 3 mmol) inTHF(90 mL)
was added thionyl chloride (1.9 mL, 24 mmol) at room
temperature under a nitrogen atmosphere. After the solution
was heated at reflux for 5 hours, the reaction mixture was
concentrated under vacuum and the residue was purified by
flash chromatography (EtOAc/hexane, 90:10). Recrystallisa-
tion from n-hexane/isopropanol afforded (S)-3 as a white solid
(343 mg, 2.16 mmol, 72%); mp 77 798C; Rf (n-hexane/EtOAc,
‡
(CI ‡ , 7 0 eV):m/z ˆ 234 (M ‡ 1, 45%), 178 (100), 160 (53),
134 (62), 118 (60), 102 (72); anal. calcd. for C10H19NO5: C
51.49%, H 8.21%, N 6.00%; found: C 51.1%, H 8.2%, N 5.9%.
Adv. Synth. Catal. 2003, 345, 835 848
asc.wiley-vch.de
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
843

Claudia Neri, Jonathan M. J. Williams
FULL PAPERS
¾
10:90) ˆ 0.41; HPLC (Chiralcel AD column, n-hexane/iso-
propanol, 90:10, 1 mL minÀ1, l ˆ 210 nm): tR ˆ 18.8 min;
[a]D30: À 40.7( c 1.35, CHCl3); IR (CH2Cl2): n ˆ 3435, 2950,
1720, 1660, 1450, 1370, 995 cmÀ1; 1H NMR (300 MHz, CDCl3):
d ˆ 5.71 (1H, br s, NH), 4.51 (1H, dd app. t, J ˆ 8.5 Hz,
CHHOCON), 4.24 4.01 (4H, m, CH2OCOCH3, CHHOCON,
CHN), 2.11 (3H, s, COCH3); 13C NMR (75.5 MHz, CDCl3):
d ˆ 170.8 (OCO), 159.8 (NCO), 66.9 (CH2OCOCH3), 64.9
(CH2OCON), 51.1 (CHN), 20.7(CO CH3); MS (CI ‡ , 7 0 eV):
Preparation of (R)-(‡)-4-Benzyloxymethyl-2-
oxazolidinone 8
Powdered K2CO3 (10 mg, 0.06 mmol) and water (8 mL,
0.4 mmol, 20%) were added to 7 (725 mg, 2.02 mmol). The
mixture was heated to 1508C with magnetic stirring under
vacuum, until the gas evolution stopped. After cooling down to
room temperature, the mixture was purified by flash chroma-
tography (SiO2, EtOAc/n-hexane, 65:35), to afford
(264.2 mg, 1.27mmol, 63%) as a cream solid; mp 49 51 8C;
8
‡
m/z ˆ 160 (M ‡ 1, 100%), 118 (23), 99 (20), 86 (30); HRMS
Rf (SiO2, EtOAc/n-hexane, 65:35) ˆ 0.34; HPLC (Chiralcel
(FAB ‡ ): calcd. for C6H9NO4: 159.0532; found: 159.0535; anal.
calcd. for C6H9NO4: C 45.28%, H 5.70%, N 8.80%; found: C
45.3%, H 5.7%, N 8.6%.
¾
OD column, n-hexane/isopropanol, 75:25, 1 mL minÀ1, l ˆ
254 nm): tR ˆ 22.0 min; [a]D30: ‡ 25.0 (c 0.08, CHCl3); IR
(CH2Cl2): n ˆ 3450, 2865, 1760, 1400, 1225, 1098 cmÀ1; 1H
ˆ
NMR (300 MHz, CDCl3): d? 5.28 (1H, br s, NH), 4.54 (2H, s,
CH2OCH2Ph) 4.47(1H, dd app. t, J ˆ 8.4 Hz, CHHOCO),
4.13 4.02 (2H, m, CHHOCO, CHN), 3.50 3.46 (2H, m,
CH2OCH2Ph); 13C NMR (100 MHz, CDCl3): d ˆ 160.0
(NCO), 137.3, 128.8 (2C), 128.3, 128.0 (2C) (aromatic C),
73.9 (CH2OCH2Ph), 72.1 (CH2OCH2Ph), 67.3 (CH2OCO),
Preparation of (S)-(À)-4-Hydroxymethyl-2-
oxazolidinone (S)-6
A solution of (S)-3 (33 mg, 0.2 mmol) in aqueous phosphate
buffer (0.5 mL, 0.1 M, pH 7) was stirred at 308C with CAL B
(28 mg, 140 mgenzyme/mmolsub) for 24 hours. The aqueous layer
was extracted with EtOAc (3 Â 1 mL) and the combined
organic extracts were concentrated under vacuum. Flash
chromatography purification (SiO2, EtOAc/MeOH, 90:10)
afforded (S)-6 as a white solid (18 mg, 77%); [a]D30: À 30.0 (c 0.6,
MeOH); spectroscopic data were in accordance with those
above described for (R)-6.
‡
52.2 (CHN); MS (CI ‡ , 7 0 eV):m/z ˆ 208 (M ‡ 1, 100%), 174
(21), 91 (36); HRMS (FAB ‡ ): calcd. for C11H13NO3: 207.0895;
found: 207.0904; anal. calcd. for C11H13NO3: C 63.76%, H
6.32%, N 6.76%; found: C 64.1%, H 6.3%, N 6.4%.
General Procedure for the Preparation of
Diastereomeric Aldol Adducts[40]
Preparation of (R)-(À)-1-O-Benzyl-3-O-acetyl-2-N-
(benzyloxycarbonyl)serinol (R)-7[27]
A solution of TiCl4 in dichloromethane (1 M, 5.4 mL,
5.4 mmol) was added to a stirred solution of 4-benzyl-N-
propionyl-2-oxazolidinone (R)- or (S)-9 (606.5 mg, 2.6 mmol)
in dichloromethane (20 mL) at À 788C under an atmosphere
of nitrogen. After 10 minutes, diisopropylethylamine (0.9 mL,
5.4 mmol) was added, followed 1 hour later by freshly distilled
acetaldehyde (0.3 mL, 5.2 mmol). The reaction mixture was
maintained at À 788C for 5 hours and allowed to warm to room
temperature overnight. Saturated NH4Cl solution (10 mL) was
added and the mixture was extracted with DCM (3 Â 50 mL).
The dichloromethane extracts were washed with water
(30 mL), dried over MgSO4 and concentrated under vacuum.
Purification by flash chromatography (SiO2, n-hexane/EtOAc,
50:50) gave a mixture of the two diastereomers.
To a stirred solution of (R)-2 (1.4 g, 6 mmol) in cyclohexane/
DCM (60 mL, 50:50) under nitrogen, benzyl 2,2,2,-trichloro-
acetimidate (3 mL, 18 mmol) was added. The reaction mixture
was stirred with trifluoromethanesulphonic acid (54 mL,
0.6 mmol, 10%) at À 108C for 2 hours, warmed to 08C and
then left warming to room temperature overnight. The
reaction mixture was filtered, quenched with saturated NaH-
CO3 solution (20 mL), and the aqueous layer was extracted
with ethyl acetate (3 Â 50 mL). The combined organic layers
were washed with brine (100 mL), dried (MgSO4), filtered and
concentrated under vacuum. The residue was purified by flash
chromatography (SiO2, n-hexane/EtOAc/CHCl3, 70:20:10) to
give (R)-7 (1.2 g, 3.3 mmol, 55%) as a colourless solid, mp 119
1218C; Rf (SiO2, hexane/EtOAc/CHCl3, 70:20:10) ˆ 0.31;
¾
HPLC (Chiralcel OD column, n-hexane/isopropanol, 90:10,
1 mL minÀ1, l ˆ 254 nm): tR ˆ 8.7min; [ a]30: À 5.2 (c 3.25,
CHCl3); IR (CH2Cl2): n ˆ 3365 (br), 1711 (br), 1525, 1235 cmÀ1;
1H NMR (400 MHz, CDCl3): d ˆ 7.36 7.26 (10H, m, 2 Â
C6H5), 5.19 (1H, d, J ˆ 8.2 Hz, NH), 5.10 (2H, s, CO2CH2Ph),
4.50 (2H, s app. d, J ˆ 3.1 Hz, CH2OCH2Ph), 4.24 4.03 (3H, m,
CH2OCOCH3, CHN), 3.58 (1H, dd, J ˆ 3.3 and 9.3 Hz,
CHHOCH2Ph), 3.50 (1H, dd, J ˆ 4.7and 9.3 Hz,
CHHOCH2Ph), 1.99 (3H, s, COCH3); 13C NMR (100 MHz,
CDCl3): d ˆ 170.8 (OCO), 155.5 (NCO), 137.2, 135.9, 128.2
(2C), 128.1 (2C), 127.9, 127.8, 127.5 (2C), 127.4 (2C) (aromatic
C), 73.1 (CH2OCH2Ph), 68.4 (CH2OCH2Ph), 66.7
(CO2CH2Ph), 63.2 (CH2OCOCH3), 49.5 (CHN), 21.0
General Procedure for the Enzymatic Resolution of
Aldol Adducts 10
In a typical experiment the two diastereomers (55.5 mg,
0.20 mmol) and Candida antarctica lipase type B (10 mg,
50 mgenzyme/mmolsubstrate) in hexane were stirred with vinyl
acetate (40 mL, 0.40 mmol) at 408C. Periodically aliquots were
removed, filtered, diluted in a n-hexane/isopropanol 80:20
solution, and analysed by chiral HPLC. After 24 48 hours, the
reaction was stopped by filtering off the enzyme and the ester
was separated from unreacted alcohol by flash chromatogra-
phy (SiO2, n-hexane/EtOAc, 60:40).
‡
(COCH3); MS (CI ‡ , 7 0 eV):m/z ˆ 358 (M ‡ 1, 25%), 314
(31), 181 (42), 161 (73), 91 (100).
844
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2003, 345, 835 848

New Routes to Chiral Evans Auxiliaries
FULL PAPERS
72.1 (CHOCOCH3), 65.8 (CH2O), 55.2 (CHN), 42.7
(COCHCH3), 37.7 (CH2Ph), 21.1 (OCOCH3), 17.2
(AcOCHCH3), 13.7(COCH CH3); MS (EI ‡ , 7 0 eV):m/z ˆ
(4R,2'S,3'R)-N-(3-Acetoxy-2-methylbutanoyl)-4-
benzyl-2-oxazolidinone (4R,2'S,3'R)-11
‡
Ester (4R,2'S,3'R)-11 was obtained as a yellow oil (25.5 mg,
319 (M , 70%), 303 (40), 286 (26); 259 (34), 143 (32), 117 (25),
40% in n-hexane); Rf (n-hexane/EtOAc, 60:40) ˆ 0.64; HPLC
83 (100), 55 (30), 43 (60); anal. calcd. for C17H21NO5: C 63.93%,
H 6.62%, N 4.38%; found: C 63.8%, H 6.6%, N 4.4%.
¾
(Chiralcel
OD column, n-hexane/2-propanol, 80:20,
1 mL minÀ1, l ˆ 254 nm): tR ˆ 8.7min; [ a]D30: À 9.4 (c 1.0,
CHCl3); IR (film): n ˆ 1780, 1735, 1695 cmÀ1; 1H NMR
(300 MHz, CDCl3): d ˆ 7.36 7.22 (5H, m, C6H5), 5.40 (1H,
dq, J ˆ 4.2 and 6.4 Hz, CHOCOCH3), 4.71 4.63 (1H, m,
NCH), 4.20 4.08 (2H, m, CHCH2O), 3.91 (1H, dq, J ˆ 4.2 and
6.9 Hz, COCHCH3), 3.34 (1H, dd, J ˆ 3.3 and 13.4 Hz,
CHHPh), 2.67(1H, dd, J ˆ 10.3 and 13.4 Hz, CHHPh), 2.04
(4S,2∫R,3'S)-N-(3-Hydroxy-2-methylbutanoyl)-4-
benzyl-2-oxazolidinone (4S,2'R,3'S)-10
Unreacted alcohol (4S,2'R,3'S)-10 was obtained as a white
solid (16.6 mg, 30% in vinyl acetate); mp 112 1148C; Rf (n-
ˆ
(3H, s, OCOCH3), 1.33 (3H, d, J 6.4 Hz, COCHCH3), 1.22
¾
hexane/EtOAc, 50:50) ˆ 0.59; HPLC (Chiralcel OD column,
(3H, d, J ˆ 6.9 Hz, AcOCHCH3); 13C NMR (75.5 MHz,
CDCl3): d ˆ 174.3 (CCO), 170.7 (OCOCH3), 153.7(O CON),
135.9, 129.8 (2C), 129.3 (2C), 127.6 (aromatic C), 70.7
(CHOCOCH3), 66.6 (CH2O), 55.8 (CHN), 42.7(CO CHCH3),
CH2Ph), 21.5 (OCOCH3), 18.4 (AcOCHCH3), 11.2
n-hexane/2-propanol, 80:20, 1 mL minÀ1, l ˆ 254 nm): tR ˆ
12.8 min; [a]D30: ‡ 42.0 (c 0.50, CHCl3); IR (CH2Cl2): n ˆ 3575
(br), 1775, 1690 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.37
7.21 (5H, m, C6H5), 4.73 4.65 (1H, m, NCH), 4.24 4.15 (3H,
m, CHCH2O, CHOH), 3.84 (1H, dq, J ˆ 3.0 and 7.0 Hz,
COCHCH3), 3.31 (1H, dd, J ˆ 3.4 and 13.4 Hz, CHHPh), 2.86
(1H, d, J ˆ 2.5 Hz, OH), 2.77 (1H, dd, J ˆ 9.6 and 13.4 Hz,
CHHPh), 1.23 (3H, d, J ˆ 6.4 Hz, COCHCH3), 1.21 (3H, d, J ˆ
7.0 Hz, CHOHCH3); 13C NMR (75.5 MHz, CDCl3): d ˆ 176.7
(CCO), 153.4 (OCON), 135.1, 129.4 (2C), 128.9 (2C), 127.4
(aromatic C), 68.1 (CHOH), 66.1 (CH2O), 55.4 (CHN), 43.0
(COCHCH3), 38.0 (CH2Ph), 19.5 (CHOHCH3), 10.6
(COCHCH3).
‡
(COCHCH3); MS (EI ‡ , 7 0 eV):m/z ˆ 320 (M ‡ 1, 77%),
260 (100), 178 (15), 143 (14), 117.1 (10), 83 (69); anal. calcd. for
C17H21NO5: C 63.93%, H 6.62%, N 4.38%; found: C 63.8%, H
6.6%, N 4.3%.
(4R,2'S,3'S)-N-(3-Hydroxy-2-methylbutanoyl)-4-
benzyl-2-oxazolidinone (4R,2'S,3'S)-10
Unreacted alcohol (4R,2'S,3'S)-10 was obtained as a white
solid (19.4 mg, 35% in n-hexane); mp 74 768C; Rf (n-hexane/
¾
General Procedure for the Preparation of rac-syn-
EtOAc, 50:50) ˆ 0.63; HPLC (Chiralcel OD column, n-
hexane/2-propanol, 80:20, 1 mL minÀ1, l ˆ 254 nm): tR
12.2 min; [a]D30: À 19.8 (c 0.5, CHCl3); IR (CH2Cl2): n ˆ 3570
(br), 1780, 1690 cmÀ1; 1H NMR (300 MHz, CDCl3): dH ˆ 7.37
7.22 (5H, m, C6H5), 4.73 4.65 (1H, m, NCH), 4.24 4.16 (2H,
m, CHCH2O), 3.96 (1H, dq app. t, J ˆ 6.4 Hz, CHOH), 3.83
(1H, dq, J ˆ 7.0 and 7.0 Hz, COCHCH3), 3.33 (1H, dd, J ˆ 3.3
and 13.4 Hz, CHHPh), 2.79 (1H, dd, J ˆ 9.6 and 13.4 Hz,
CHHPh), 2.55 (1H, s br, OH), 1.31 (3H, d, J ˆ 6.3 Hz,
COCHCH3),1.20 (3H, d, J ˆ 6.9 Hz, CHOHCH3); 13C NMR
(75.5 MHz, CDCl3): d ˆ 176.6 (CCO), 153.2 (OCON), 135.2,
129.4 (2C), 128.9 (2C), 127.3 (aromatic C), 70.7 (CHOH), 66.1
(CH2O), 55.6 (CHN), 45.0 (COCHCH3), 37.8 (CH2Ph), 21.2
(CHOHCH3),14.6 (COCHCH3).
Aldol Adducts[32]
Synthesis of rac-syn-aldol adducts was carried out following
the procedure described in the literature.[32] N-Acyl-2-oxazo-
lidinone rac-9, rac-14 or rac-20 (2.46 mmol) was reacted with
acetaldehyde (0.240 mL, 6.9 mmol) in the presence of TiCl4
(1 M solution in DCM, 2.58 mg, 2.58 mmol), (À)-sparteine
(0.56 mL,
2.46 mmol)
and
N-methyl-2-pyrrolidinone
(0.24 mL, 2.46 mmol). Purification via flash chromatography
(SiO2, hexane/EtOAc) afforded rac-syn-aldol adducts.
General Procedure for the Enzymatic Resolution of
rac-syn-Aldol Adducts 10, 15 or 21
In a typical experiment racemic alcohol (0.18 mmol) and
(4S,2'R,3'R)-N-(3-Acetoxy-2-methylbutanoyl)-4-
benzyl-2-oxazolidinone (4S,2'R,3'R)-11
Candida antarctica lipase type B (6 mg, 30 mgenzyme/mmolsubstrate
)
in organic solvent (vinyl acetate, n-hexane, toluene, dichloro-
methane or diisopropyl ether, 0.8 mL) were stirred with vinyl
acetate (34 mL, 0.36 mmol) at 408C. After 24 hours, the
reaction was stopped by filtering off the enzyme. The ester
was separated from unreacted alcohol by flash chromatogra-
phy (SiO2, n-hexane/EtOAc).
Acylated oxazolidinone (4S,2'R,3'R)-11 was obtained as a
white solid (24.3 mg, 38% in vinyl acetate); mp89 918C; Rf (n-
¾
hexane/EtOAc, 60:40) ˆ 0.58; HPLC (Chiralcel OD column,
n-hexane/2-propanol, 80:20, 1 mL minÀ1, l ˆ 254 nm): tR
14.1 min; [a]D30: ‡ 40.0 (c 1.0, CHCl3); IR (CH2Cl2): n ˆ 1790,
1
1740, 1690 cmÀ1; H NMR (400 MHz, CDCl3): d ˆ 7.37 7.21
(5H, m, C6H5), 5.22 (1H, dq, J ˆ 6.3 and 8.8 Hz, CHOCOCH3),
4.74 4.66 (1H, m, NCH), 4.23 4.13 (2H, m, CH2O), 4.07(1H,
dq, J ˆ 7.0 and 8.8 Hz, COCHCH3), 3.24 (1H, dd, J ˆ 3.2 and
13.2 Hz, CHHPh), 2.74 (1H, dd, J ˆ 9.5 and 13.2 Hz, CHHPh),
2.00 (3H, s, OCOCH3), 1.31 (3H, d, J ˆ 6.3 Hz, COCHCH3),
1.20 (3H, d, J ˆ 7.0 Hz, AcOCHCH3); 13C NMR (100 MHz,
CDCl3): d ˆ 174.5 (CCO), 170.0 (OCOCH3), 153.0
(OCON),135.0, 129.4 (2C), 129.0 (2C), 127.4 (aromatic C),
(4S,2'S,3'R)-N-(3-Acetoxy-2-methylbutanoyl)-4-
benzyl-2-oxazolidinone (4S,2'S,3'R)-11
Yellow needles (43% in hexane); mp 79 808C; Rf (n-hexane/
¾
EtOAc, 60:40) ˆ 0.66; HPLC (Chiralcel OD column, n-
hexane/2-propanol, 80:20, 1 mL minÀ1, l ˆ 254 nm): tR ˆ
8.2 min; [a]D30: ‡ 77.7 (c 0.99, CHCl3); IR (CH2Cl2): n ˆ 2975,
Adv. Synth. Catal. 2003, 345, 835 848
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Claudia Neri, Jonathan M. J. Williams
FULL PAPERS
1780, 1735, 1695, 1450, 1370, 1225, 1110 cmÀ1; 1H NMR
(300 MHz, CDCl3): d ˆ 7.36 7.19 (5H, m, C6H5), 5.30 (1H,
dq, J ˆ 4.3 and 6.4 Hz, CHOCOCH3), 4.64 4.56 (1H, m,
(100), 69 (29), 43 (50); anal. calcd. for C18H23NO5: C 64.85%, H
6.95%, N 4.20%; found: C 64.7%, H 7.0%, N 4.0%.
ˆ
NCH), 4.28 4.08 (2H, m, CH2O), 3.95 (1H, dq, J 4.3 and
6.9 Hz, COCHCH3), 3.27(1H, dd, J ˆ 3.1 and 13.2 Hz,
CHHPh), 2.76 (1H, dd, J ˆ 9.7and 13.3 Hz, C HHPh), 2.05
(3H, s, OCOCH3), 1.28 (3H, d, J ˆ 6.5 Hz, COCHCH3),1.22
(3H, d, J ˆ 6.9 Hz, AcOCHCH3); 13C NMR (75.5 MHz,
CDCl3): dC ˆ 172.2 (CCO), 151.7(O CON), 168.8 (OCOCH3),
(2C), 127.1 (2C), 125.5 (aromatic C), 68.4 (CHOCOCH3), 64.5
(CH2O), 54.0 (NCH), 40.5 (COCHCH3), 36.1 (CH2Ph), 19.3
(OCOCH3), 16.2 (AcOCHCH3), 8.9 (COCHCH3); MS (EI ‡ ,
(4R,2'R,3'S)-N-(3-Hydroxy-2-ethylbutanoyl)-4-benzyl-
2-oxazolidinone (4R,2'R,3'S)-15
Alcohol (4R,2'R,3'S)-15 was isolated as a cream solid (30%);
mp 73 748C (Lit.[40] 74 768C); Rf (n-hexane/EtOAc,
¾
50:50) ˆ 0.55; HPLC (Chiralcel OD column, n-hexane/2-
propanol, 90:10, 1 mL minÀ1, l ˆ 254 nm): tR ˆ 14.6 min;
[a]D30: À 15.8 (c 1.2, CHCl3); IR (CH2Cl2): n ˆ 3590, 2980,
‡
1
1780, 1690, 1385, 1350, 1215, 1110 cmÀ1; H NMR (300 MHz,
7 0 eV):m/z ˆ 319 (M , 10%), 259 (57), 244 (46), 178 (30), 83
(95), 43 (100); HRMS (EI ‡ ): calcd. for C17H21NO5: 319.1420;
found: 319.1417; anal. calcd. for C17H21NO5: C 63.93%, H
6.62%, N 4.38%; found: C 63.5%, H 6.6%, N 4.2%.
CDCl3): d ˆ 7.37 7.22 (5H, m, C6H5), 4.78 4.70 (1H, m,
NCH), 4.22 4.07(3H, m, C H2O, CHOH), 4.03 3.97(1H, m,
CHCH2CH3), 3.36 (1H, dd, J ˆ 3.2 and 13.2 Hz, CHHPh), 2.70
(1H, dd, J ˆ 10.0 and 13.2 Hz, CHHPh), 2.54 (1H, s, OH),
1.91 1.83 (1H, m, CHHCH3), 1.74 1.66 (1H, m, CHHCH3),
1.24 (3H, d, J ˆ 7.0 Hz, CHCH3), 0.98 (3H, t, J ˆ 7.4 Hz,
CH2CH3); 13C NMR (75.5 MHz, CDCl3): d ˆ 175.5 (CCO),
153.9 (OCON), 135.2, 129.4 (2C), 129.0 (2C), 127.4 (aromatic
C), 68.6 (CHOH), 66.0 (CH2O), 55.6 (CHN), 50.1
(CHCH2CH3), 38.1 (CH2Ph), 20.7( CH2CH3), 19.5 (CHCH3),
11.9 (CH2CH3); MS (EI ‡ , 7 0 eV):m/z ˆ 291 (M¥‡, 11%), 158
(26), 128 (27), 99 (100), 86 (67), 71 (77), 53 (33), 43 (90); anal.
calcd. for C16H21NO4: C 65.96%, H 7.27%, N 4.81%; found: C
65.6%, H 7.2%, N 4.6%.
(4R,2'R,3'S)-N-(3-Hydroxy-2-methylbutanoyl)-4-
benzyl-2-oxazolidinone (4R,2'R,3'S)-10
Colourless crystals (39% in hexane); mp 114 1158C; Rf (n-
¾
hexane/EtOAc, 50:50) ˆ 0.37; HPLC (Chiralcel OD column,
n-hexane/2-propanol, 80:20, 1 mL minÀ1, l ˆ 254 nm): tR ˆ
1
10.0 min; [a]D30: À 54.5 (c 0.99, CHCl3); H NMR (400 MHz,
CDCl3): d ˆ 7.36 7.20 (5H, m, C6H5), 4.74 4.67 (1H, m,
NCH), 4.26 4.10 (3H, m, CHCH2O, CHOH), 3.74 (1H, dq,
J ˆ 2.7and .70 Hz, COC HCH3), 3.25 (1H, dd, J ˆ 3.5 and
13.2 Hz, CHHPh), 2.91 (1H, d, J ˆ 2.7Hz, O H), 2.79 (1H, dd,
J ˆ 9.7and 13.4 Hz, C HHPh), 1.27(3H, d,
J ˆ 7.0 Hz,
(4S,2'S,3'R)-N-(3-Acetoxy-2-methylbutanoyl)-4-ethyl-
2-oxazolidinone (4S,2'S,3'R)-22
COCHCH3), 1.21 (3H, d, J ˆ 6.2 Hz, CHOHCH3); 13C NMR
(75.5 MHz, CDCl3): d ˆ 178.0 (CCO), 153.7(O CON), 135.6,
130.0 (2C), 129.6 (2C), 128.0 (aromatic C), 68.2 (CHOH), 66.8
(CH2O), 55.7( CHN), 43.7(CO CHCH3), 38.4 (CH2Ph), 20.1
(CHOHCH3), 11.1 (COCHCH3); MS (FAB ‡ , 7 0 eV):m/z ˆ
Ester (4S,2'S,3'R)-22 was isolated as a yellow oil (33%); HPLC
¾
(Chiralcel
OD column, n-hexane/2-propanol 80:20,
1 mL minÀ1, l ˆ 254): tR ˆ 6.0; [a]D30: À 86.6 (c 0.30, CHCl3);
IR (film): n ˆ 2985, 2940, 1780, 1735, 1385, 1370, 1700, 1240,
1210 cmÀ1; 1H NMR (300 MHz, CDCl3): dH ˆ 5.27(1H, dq, J ˆ
3.2 and 6.4 Hz, CHOCOCH3), 4.44 4.35 (2H, m, CHN,
OCHH), 4.13 (1H, dd, J ˆ 1.8 and 8.0 Hz, OCHH), 3.96 (1H,
dq, J ˆ 3.4 and 6.9 Hz, COCHCH3), 2.02 (3H, s, OCOCH3),
ˆ
‡
278 (M ‡ 1, 100%), 261 (9), 178 (25), 117 (10), 101 (7); HRMS
(FAB ‡ ): calcd. for C15H19NO4: 277.1314; found: 277.1314;
anal. calcd. for C15H19NO4: C 64.97%, H 6.91%, N 5.05%;
found: C 64.3%, H 6.9%, N 5.1%.
1.82 1.72 (2H, m, CH2CH3), 1.26 (3H, d, J
6.4 Hz,
COCHCH3), 1.19 (3H, d, J ˆ 6.9 Hz, AcOCHCH3), 0.92 (3H,
t, J ˆ 7.5 Hz, CH2CH3); 13C NMR (75.5 MHz, CDCl3): d ˆ
174.0 (CCO), 170.6 (OCOCH3), 153.8 (OCON), 70.3 (CHOC-
OCH3), 66.8 (CH2O), 55.6 (CHN), 42.1 (COCHCH3), 25.1
(CH2CH3), 21.1 (OCOCH3), 18.1 (AcOCHCH3), 11.0
(COCHCH3), 8.2 (CH2CH3); MS (CI ‡ , 7 0 eV):m/z ˆ 258
(4S,2'S,3'R)-N-(3-Acetoxy-2-ethylbutanoyl)-4-benzyl-
2-oxazolidinone (4S,2'S,3'R)-16
Ester (4S,2'S,3'R)-16 was isolated as a cream solid (35%);
recrystallised from n-hexane/EtOAc; mp 61 638C; Rf (n-
¾
hexane/EtOAc, 50:50) ˆ 0.85; HPLC (Chiralcel OD column,
‡
n-hexane/2-propanol, 90:10, 1 mL minÀ1, l ˆ 254 nm): tR ˆ
11.5 min; [a]D30: ‡ 57.1 (c 1.05, CHCl3); IR (CH2Cl2): n ˆ 2965,
(M ‡ 1, 55%), 198 (100), 171 (12), 143 (21), 83 (40); anal. calcd.
for C12H19NO5 : C 56.02%, H 7.44%, N 5.44%; found C 55.6%,
H 7.5%, N 5.4%.
1
1780, 1730, 1695, 1380, 1235, 1110 cmÀ1; H NMR (300 MHz,
CDCl3): d ˆ 7.36 7.21 (5H, m, C6H5), 5.30 5.22 (1H, m,
CHCH3), 4.72 4.64 (1H, m, NCH), 4.24 4.10 (2H, m, CH2O),
4.04 3.98 (1H, m, CHCH2CH3), 3.32 (1H, dd, J ˆ 3.2 and
13.2 Hz, CHHPh), 2.73 (1H, dd, J ˆ 9.9 and 13.2 Hz, CHHPh),
2.01 (3H, s, OCOCH3), 1.91 1.83 (1H, m, CHHCH3), 1.74
1.66 (1H, m, CHHCH3), 1.27(3H, d, J ˆ 6.7Hz, CHC H3), 0.95
(3H, t, J ˆ 7.4 Hz, CH2CH3); 13C NMR (75.5 MHz, CDCl3):
d ˆ 173.3 (CCO), 170.4 OCOCH3), 153.4 (OCON), 135.3,
129.4 (2C), 128.9 (2C), 127.3 (aromatic C), 70.1 (CHCH3), 66.1
(CH2O), 55.7( CHN), 48.6 (CHCH2CH3), 38.1 (CH2Ph), 21.1
(4R,2'R,3'S)-N-(3-Hydroxy-2-methylbutanoyl)-4-
ethyl-2-oxazolidinone (4R,2'R,3'S)-21
Unreacted alcohol (4R,2'R,3'S)-21 was obtained as a colour-
less oil (36%); Rf (n-hexane/EtOAc, 40:60) ˆ 0.53; HPLC
¾
(Chiralcel
OD column, n-hexane/2-propanol 80:20,
1 mL minÀ1, l ˆ 254): tR ˆ 7.3 min; [a]D30: À 40.0 (c 0.35,
1
ˆ
CHCl3); H NMR (300 MHz, CDCl3): dH 4.50 4.45 (1H,
(OCOCH3), 20.0 (CH2CH3), 17.7 (CHCH3), 11.7(CH CH3);
m, CHN), 4.40 (1H, app. t, J ˆ 8.5 Hz, OCHH), 4.17 4.10 (2H,
2
‡
MS (EI ‡ , 7 0 eV):m/z ˆ 333 (M , 30%), 258 (20), 157(32), 97
m, OCHH, CHOH), 3.71 (1H, dq, J ˆ 3.5 and 7.1 Hz,
846
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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New Routes to Chiral Evans Auxiliaries
FULL PAPERS
COCHCH3), 2.98 (1H, s, OH), 1.82 1.72 (2H, m, CH2CH3),
1.24 (3H, d, J ˆ 7.0 Hz, COCHCH3), 1.19 (3H, d, J ˆ 6.4 Hz,
CHOHCH3), 0.93 (3H, t, J ˆ 7.5 Hz, CH2CH3); 13C NMR
(75.5 MHz, CDCl3): d ˆ 177.9 (CCO), 153.8 (OCON), 67.8
(CHOH), 67.1 (CH2O), 55.3 (CHN), 43.4 (COCHCH3), 25.3
(CH2CH3), 19.9 (CHOHCH3), 11.0 (COCHCH3), 8.4
Preparation of (4R,2'R,3'S)-N-(3-Acetoxy-2-
methylbutanoyl)-4-benzyl-2-oxazolidinone
(4R,2'R,3'S)-10[38]
Ester (4R,2'R,3'S)-10 was prepared following the procedure
reported in the literature.[40]
‡
Acetic acid (20.2 mL, 0.35 mmol), DMAP (4-dimethylami-
nopyridine) (34.5 mg, 0.28 mmol) and DCC (dicyclohexylcar-
bodiimide) (80.4 mg, 0.39 mmol) were reacted with alcohol
(4R,2'R,3'S)-10 (296 mg, 1.06 mmol) in anhydrous dichloro-
methane (5 mL). Purification via flash chromatography (n-
hexane/EtOAc, 60:40) afforded acylated aldol adduct
(4R,2'R,3'S)-11 as yellow needles (220 mg, 65%); mp 81
(CH2CH3); MS (CI ‡ , 7 0 eV):m/z ˆ 216 (M ‡ 1, 100%), 198
(81), 171 (16), 142 (11), 116 (23), 83 (11); anal. calcd. for
C10H17NO4: C 55.80%, H 7.96%, N 6.51% ; found C 55.6%, H
7.9%, N 6.6%.
¾
828C; Rf (n-hexane/EtOAc, 60:40) ˆ 0.65; HPLC (Chiralcel
General Procedure for the Hydrolysis of Unreacted
Alcohols (4R,2'R,3'S)-10 and 21 and
Esters(4S,2'S,3'R)-11 and 22[33]
OD column, n-hexane/2-propanol 80:20, 1 mL minÀ1, l ˆ
ˆ
254 nm): tR
7.6 min; [a]D30: À 75.5 (c 0.96, CHCl3); IR
(CHCl3): n ˆ 3520, 2980, 1780, 1735, 1700, 1450, 1380, 1235,
1110 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.36 7.19 (5H, m,
C6H5), 5.30 (1H, dq, J ˆ 4.3 and 6.4 Hz, CHOCOCH3), 4.64
4.56 (1H, m, NCH), 4.28 4.08 (2H, m, CH2O), 3.95 (1H, dq,
J ˆ 4.3 and 6.8 Hz, COCHCH3), 3.27(1H, dd, J ˆ 3.2 and
13.3 Hz, CHHPh), 2.76 (1H, dd, J ˆ 9.7and 13.3 Hz, C HHPh),
2.05 (3H, s, OCOCH3), 1.28 (3H, d, J ˆ 6.4 Hz, COCHCH3),
1.23 (3H, d, J ˆ 6.9 Hz, AcOCHCH3); 13C NMR (75.5 MHz,
CDCl3): d ˆ 172.2 (CCO), 168.8 (OCOCH3), 151.7(O CON),
135.8, 129.9 (2C), 129.4 (2C), 127.8 (aromatic C), 70.8
(CHOCOCH3), 66.8 (CH2O), 56.2 (NCH), 42.8 (COCHCH3),
CH2Ph), 21.6 (OCOCH3), 18.5 (AcOCHCH3), 11.3
Hydrolyses of the enzymatically resolved esters and alcohol
was carried out following the procedure reported in the
literature.[34] To a solution of alcohol or ester (0.37mmol) in
THF/H2O (2 mL, 80:20) at 08C, 30% aqueous hydrogen
peroxide (15 mL) was added slowly, followed by LiOH
(11.7mg, 0.5 mmol) in water (1 mL).
(2R,3S)-3-Hydroxy-2-methylbutanoic Acid (2R,3S)-13
‡
1
Yellow oil; [a]D30: ‡ 6.9 (c 1.02, CHCl3); H NMR (400 MHz,
(COCHCH3); MS (FAB, 70 eV): m/z ˆ 320 (M ‡ 1, 88%),
260 (100), 178 (14), 143 (12), 117 (9), 83 (65); anal. calcd. for C17
H21NO5: C 63.93%, H 6.62%, N 4.38%; found: C 64.4%, H
6.8%, N 4.0%.
CDCl3): d ˆ 5.8 (2H, br s, 2  OH), 4.15 3.94 (1H, dq app. m,
CHOH), 2.59 (1H, dq, J ˆ 3.7and 7.2 Hz, COC HCH3), 1.23
(3H, d, J ˆ 3.9 Hz, COCHCH3), 1.22 (3H, d, J ˆ 3.1 Hz,
CHOHCH3); 13C NMR (100 MHz, CDCl3): d ˆ 180.5
(COOH), 67.9 (COCHCH3), 45.2 (CHOH), 19.7
(CHOHCH3), 10.9 (COCHCH3). 1H and 13C NMR data were
in accordance with those reported in the literature.[39]
Acknowledgements
We wish to thank the University of Bath and EPSRC for funding
this project.
(2S,3R)-3-Hydroxy-2-methylbutanoic Acid (2S,3R)-13
Yellow oil; [a]D30: À 6.8 (c 1.02, CHCl3); 1H and 13C NMR data
References
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Yellow oil (82%); [a]D30: ‡ 5.5 (c 0.63, CHCl3), (Lit.[41] ‡ 5.8 (c
1.02, CHCl3); 1H NMR (300 MHz, CDCl3): d ˆ 6.52 (1H, s br,
NH), 4.48 (1H, app. t, J ˆ 8.5 Hz, CHHO), 4.03 (1H, dd, J ˆ 6.0
and 8.5 Hz, CHHO), 3.86 3.77 (1H, m, CHN), 1.66 1.55 (2H,
m, CH2CH3),0.92 (3H, t, J ˆ 7.5 Hz, CH2CH3); 13C NMR
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Yellow oil (87%); [a]D30: À 5.3 (c 0.60, CHCl3). 1H and 13C NMR
data were in accordance with those above reported for 4-ethyl-
2-oxazolidinone (R)-19.
Adv. Synth. Catal. 2003, 345, 835 848
asc.wiley-vch.de
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
847

Claudia Neri, Jonathan M. J. Williams
FULL PAPERS
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