Preparation of 2-oxazolidinones by enzymatic desymmetrisation

Article abstract of DOI:10.1016/S0957-4166(02)00547-5

Desymmetrisation of achiral N-Boc-serinol was achieved through enzymatic acetylation. Further transformation provided oxazolidinones with >98% enantiomeric excess.

Full text of DOI:10.1016/S0957-4166(02)00547-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2197–2199
Preparation of 2-oxazolidinones by enzymatic desymmetrisation
Claudia Neri and Jonathan M. J. Williams*
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 28 August 2002; accepted 11 September 2002
Abstract—Desymmetrisation of achiral N-Boc-serinol was achieved through enzymatic acetylation. Further transformation
provided oxazolidinones with >98% enantiomeric excess. © 2002 Elsevier Science Ltd. All rights reserved.
Previous work within this research group has investi-
gated enzymatic routes for the resolution of chiral
auxiliaries.1 In addition, we have also developed an
unusual approach to the use of racemic chiral auxil-
iaries in Evans’-type aldol reactions with subsequent
enzymatic resolution leading to enantiomerically
enriched recovered auxiliaries and aldol adducts.2
been reported previously and a 1,3-silyl shift was sug-
gested in this case as a likely cause of racemisation.7
Our overall desymmetrisation strategy involves the use
of N-Boc-protected serinol 1 to give a monoacetate 2,
followed by appropriate chemical transformation to
afford enantiomerically enriched oxazolidinones (e.g.
compound 3) (Scheme 1).
Herein, we wish to report an enzymatic desymmetrisa-
tion strategy, which has been successfully applied to the
preparation of enantiomerically enriched oxazolidi-
nones.
Boc-protection of achiral serinol (1,3-dihydroxy-2-
aminopropane) was achieved in 90% yield by treatment
of serinol with Boc anhydride in ethanol at 20°C for 1
h.8 The desymmetrisation of N-Boc-serinol was
achieved by selective monoacetylation using PPL
(Porcine pancreatic lipase) and vinyl acetate as
acylating agent, in organic solvent at 25°C (Scheme 2).9
A small amount of diacetylated material was also
observed, providing a self-correcting process10 for the
removal of the unwanted enantiomer of monoacetyl-
Desymmetrisation of achiral diols using enzymes is a
well known process for the formation of enantiomeri-
cally enriched mono-esters.3 The advantage of desym-
metrisation over conventional kinetic resolution
reactions being the potential ability to achieve high
enantiomeric excess even at 100% conversion.4 Serinol
derivatives have received only limited attention in
desymmetrisation reactions.5 A derivative of serinol
possessing an enantiomerically pure a-methyl benzyl
group on the nitrogen has been used in a chemical/aux-
iliary based diastereoselective synthesis of oxazolidi-
nones on treatment with chloroformate with up to 92%
d.e. (62% yield).6 Racemisation, during oxazolidinone
formation of a mono-silyl ether of N-Boc-serinol, has
Scheme 2. Desymmetrisation of N-Boc-serinol by PPL.
Scheme 1. General approach to preparation of oxazolidinones by enzymatic desymmetrisation.
* Corresponding author. E-mail: j.m.j.williams@bath.ac.uk
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00547-5

2198
C. Neri, J. M. J. Williams / Tetrahedron: Asymmetry 13 (2002) 2197–2199
Table 1. Influence of solvent on conversion, e.e. and mono-/diacetylated product ratioa,b
Entry
Solvent
Time (h)
Conversion (%)
E.e. (%)
Mono-/diacetylated
1
2
3
THF/hexane 1:1
iPr2O
Vinyl acetate
2
22
2
96
87
\99
\99
\99
\99
87
93
\99
a 140 mgenzyme/mmolsubstrate in solvent (5 mL) using N-Boc-serinol (1 mmol) and vinyl acetate (3 mmol); PPL was Porcine pancreas lipase (EC
3.1.1.3.) Type II, from Sigma®; CAL B was Chirazyme® L-2, carrier-fixed, Carrier 3, lyophilizate from Boehringer Mannheim.
b Conversion, enantiomeric excess and mono-/diacetylated ratio were determined by HPLC analysis (see text).
the oxazolidinone 3 although this product was obtained
as a racemic mixture.11 We assume that intramolecular
acetyl transfer occurs prior to the cyclisation, thereby
affording the racemic product. Nevertheless, oxazolidi-
none 312 was obtained with >98% e.e. on cyclisation
with thionyl chloride (Scheme 3).13
The absolute stereochemistry of oxazolidinone 3 was
confirmed by enzymatic hydrolysis of the acetate group
and comparison of the specific rotation with the litera-
Scheme 3. Synthesis of enantiomerically enriched 4-ace-
toxymethyl-2-oxazolidinone.
ture value.14 The 4-hydroxymethyl-2-oxazolidonone 4
has previously been converted into a range of 4-substi-
tuted oxazolidinones including the 4-benzyl and 4-ethyl
derivatives (Scheme 4).14
6 alternative approach, the enantiomerically enriched
mono-acetate
2
was benzylated using benzyl
trichloroacetimidate in reasonable yield,15 followed by
cyclisation to provide the oxazolidinone 6 (Scheme 5).16
Scheme 4. Hydrolysis of 4-acetoxymethyl-2-oxazolidinone.
In summary, we have developed an efficient enzymatic
desymmetrisation of N-Boc-serinol and exploited this
to prepare enantiomerically enriched 4-substituted 2-
oxazolidinones.
ated product. Only one enantiomer of the monoacetyl-
ated product was detected by chiral HPLC (Chiralcel®
OD column, hexane/iso-propanol 95:5, 1 mL min−1,
u=210 nm).
Acknowledgements
The choice of solvent was found to influence the enzy-
matic reaction, and solvent effects are illustrated in
Table 1.
We wish to thank the University of Bath and the
EPSRC for the funding of this project.
The reaction rate of the lipase-catalysed transesterifica-
tion was faster when vinyl acetate or a mixture THF/
hexane was used as solvent, whilst the reaction took 22
h to reach completion in iPr2O.
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Scheme 5. Synthesis of enantiomerically enriched 4-benzyloxymethyl-2-oxazolidinone.

C. Neri, J. M. J. Williams / Tetrahedron: Asymmetry 13 (2002) 2197–2199
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(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,
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colourless oil; Rf=0.31 (SiO2, EtOAc/hexane 1:1); HPLC
10.8 min (Chiralcel OD® column, hexane/isopropanol
95:5, 1 mL min−1, u=210 nm; [h]3D0=+3.5 (c 0.56,
CHCl3); wmax (neat)/cm−1 3370, 2975, 2965, 1710, 1690,
1525, 1370, 1240, 1170; 1H NMR (300 MHz; CDCl3) l
5.10 (1H, br d, J=8.4, NH), 4.19 (2H, d, J=5.7,
CH2OAc), 3.98–3.88 (1H, m, CHN), 3.65 (2H, dq, J=4.7
and 11.4, CH2OH), 3.02 (1H, s br, OH), 2.09 (3H, s,
COCH3) 1.45 (9H, s, 3×CCH3); 13C NMR (75.5 MHz,
CDCl3) l 171.8 (OCO), 155.2 (NCO), 80.3 (C(CH3)3),
63.4 (CH2OAc), 62.2 (CH2OH), 51.4 (CHN), 28.7 (3×
CCH3), 21.2 (COCH3); MS (70 eV): m/z (%): 234 Da
14. Sibi, M. P.; Rutherford, D.; Sharma, R. J. Chem. Soc.,
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16. (R)-(+)-4-Benzyloxymethyl-2-oxazolidinone: cream solid,
mp 49–51°C; Rf=0.34 (SiO2, EtOAc/hexane 2:1); HPLC
22.0 min (Chiralcel OD® column, hexane/isopropanol
75:25, 1 mL min−1, u=254 nm); [h]3D0=+25.0 (c 0.08,
CHCl3); wmax (CH2Cl2)/cm−1 3450, 2865, 1760, 1400,
1
+
’
1225, 1098; H NMR (300 MHz; CDCl3) l 5.28 (1H, br
(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.
s, NH), 4.54 (2H, s, CH2OCH2C6H5) 4.47 (1H, dd with
the appearance of a t, J=8.4, CHHOCO), 4.13–4.02 (2H,
m,
CHHOCO,
CHN),
3.50–3.46
(2H,
m,
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CH2OCH2C6H5); 13C NMR (100 MHz, CDCl3) l 160.0
(NCO), 137.3, 128.8 (2C), 128.3, 128.0 (2C) (aromatic C),
73.9 (CH2OCH2C6H5), 72.1 (CH2OCH2C6H5), 67.3
(CH2OCO), 52.2 (CHN); MS (70eV): m/z (%): 208 Da
(M +1, 100%), 174 (21), 91 (36). Anal. calcd for
C11H13NO3: C, 63.76; H, 6.32; N 6.76. Found: C, 64.1;
H, 6.3; N, 6.4%.
12. (S)-(−)-4-Acetoxymethyl-2-oxazolidinone: white solid, mp
77–79°C; Rf=0.31 (SiO2, EtOAc/hexane 9:1); HPLC 18.8
min (Chiralcel AD® column, hexane/isopropanol 90:10, 1
mL min−1, u=210 nm); [h]D30=−40.7 (c 1.35, CHCl3); wmax
+
’