Lipase-mediated resolution of 3-hydroxy-4-trityloxybutanenitrile: synthesis of 2-amino alcohols, oxazolidinones and GABOB

Article abstract of DOI:10.1016/j.tetasy.2006.04.019

Lipase-mediated kinetic resolution of 3-hydroxy-4-trityloxybutanenitrile gave the (S)-alcohol and (R)-acetate in good yields and high enantioselectivities. The resolution using Pseudomonas cepacia lipase (Burkholderia cepacia) immobilized on modified cera

Full text of DOI:10.1016/j.tetasy.2006.04.019

Tetrahedron: Asymmetry 17 (2006) 1281–1289
Lipase-mediated resolution of
3-hydroxy-4-trityloxybutanenitrile: synthesis
of 2-amino alcohols, oxazolidinones and GABOB
Ahmed Kamal,* G. B. Ramesh Khanna, T. Krishnaji and R. Ramu
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 24 March 2006; accepted 21 April 2006
Abstract—Lipase-mediated kinetic resolution of 3-hydroxy-4-trityloxybutanenitrile gave the (S)-alcohol and (R)-acetate in good yields
and high enantioselectivities. The resolution using Pseudomonas cepacia lipase (Burkholderia cepacia) immobilized on modified ceramic
particles (PS-C) in diisopropyl ether gave the best results. The use of base additives in this transesterification drastically reduces the reac-
tion time without effecting the yields or enantioselectivities. Resolved 3-hydroxy-4-trityloxybutanenitrile has been utilized for the synthe-
sis of enantiomerically pure 5-tosyloxymethyl-1,3-oxazolidine-2-one, which is an important intermediate for the preparation of b-
adrenergic blocking agents and oxazolidinone based antimicrobial agents. Enantiomerically pure (R)-3-hydroxy-4-trityloxybutanenitrile
and (S)-5-tosyloxymethyl-1,3-oxazolidine-2-one have been utilized in the enantioconvergent synthesis of (R)-GABOB.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
Enantiomerically pure 5-tosyloxymethyl-1,3-oxazolidine-2-
one is an important intermediate for the synthesis of a wide
variety of biologically important compounds, such as oxa-
zolidinone based antimicrobials, b-adrenergic blocking
agents and c-amino-b-hydroxybutyric acid (GABOB). In
view of the need for the development of practically efficient
procedures for the preparation of these compounds in
enantiomerically pure forms, we considered enantiomeri-
cally pure 5-hydroxymethyl-1,3-oxazolidine-2-one, as an
important intermediate for the synthesis of these com-
pounds. This oxazolidinone intermediate can be prepared
from enantiomerically pure 3-hydroxy-4-trityloxybutane-
nitrile (Fig. 1). In conjunction with our previous studies
towards the synthesis of biologically important compounds
employing lipases,12 we herein report an enzymatic resolu-
tion of 3-hydroxy-4-trityloxybutanenitrile and its applica-
tion in the synthesis of optically active b-adrenergic
blocking agents, oxazolidinone based antimicrobial agents
The importance of b-hydroxy nitriles is well known in
organic chemistry and they have been extensively studied
and employed1 in the preparation of various intermediates,
particularly for the synthesis of naturally occurring as well
as synthetic biologically important compounds,2 while chi-
ral b-hydroxy nitriles have enormous synthetic potential
for the preparation of optically active b-hydroxy amides,3
b-hydroxy acids,4 b-hydroxy esters,4c,5 diols4c,6 and amino
alcohols7 as the cyano group can be readily transformed
into different functional groups by simple procedures.
These compounds derived from optically active b-hydroxy
nitriles are synthetically interesting, highly functionalized
chiral synthons and versatile intermediates in both asym-
metric synthesis and medicinal chemistry. Moreover, the
stereogenicity at the hydroxyl group in these derived com-
pounds has been used to control the generation of new ste-
reocentres, thus offering a potential diastereoselective route
to 1,3-diols8 and 1,3-amino alcohols,9 intermediates in a
large number of natural products, antibiotics10 and chiral
auxiliaries.11
O
OH
O
N
TrO
NH
HO
*
*
S and R
S and R
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189;
e-mail addresses: ahmedkamal@iict.res.in; ahmedkamal@iictnet.org
Figure 1.
0957-4166/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.04.019

1282
A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 1281–1289
and (R)-GABOB via optically active 5-tosyloxymethyl-1,3-
oxazolidine-2-one.
and chromatographic properties with those of the com-
pounds of known configuration. In this process, enantio-
merically pure 3-hydroxy-4-trityloxybutanenitrile was
converted to enantiomerically pure 3-hydroxy-4-tos-
yloxybutanenitrile. Comparison of the specific rotation of
the derived 3-hydroxy-4-tosyloxybutanenitrile with that
of the reported15 hydroxynitrile established the S configu-
ration of the alcohol (S)-3 and the (R)-configuration of
the acetate (R)-4.
2. Results and discussion
2.1. Preparation of 3-hydroxy-4-trityloxybutanenitrile
(b-hydroxy nitrile)
Herein, ( )-3-hydroxy-4-trityloxybutanenitrile 3 has been
prepared. Glycidol was protected with trityl group by
employing trityl chloride and pyridine. Trityl protected
glycidol 2 was then subjected to nucleophilic ring opening
with NaCN in aqueous alcohol to afford ( )-3-hydroxy-
4-trityloxybutanenitrile 3 (see Scheme 1).
In the first instance, a number of lipases were examined for
the transesterification of ( )-3-hydroxy-4-trityloxybutane-
nitrile 3 in diisopropylether. This process gave poor con-
versions at room temperature. Therefore, this process was
carried out at higher temperature and optimized between
45 and 47 ꢁC. The results are illustrated in Table 1.
2.2. Lipase-mediated kinetic resolution of 3-hydroxy-4-
trityloxybutanenitrile
Table 1. Transesterification of 3-hydroxy-4-trityloxybutanenitrile with
various lipasesa in diisopropyl ether between 45 and 47 ꢁC
The preparation of enantiomerically pure b-hydroxynitriles
has been generally carried out by employing enzymatic
approaches such as, the reduction of a carbonyl group of a
ketonitrile by microbes13 or by lipase-mediated enantiose-
lective hydrolysis of their corresponding acetates.14 How-
ever, in the present investigation and in continuation of
the earlier efforts towards the preparation of enantiomeri-
cally pure b-hydroxynitriles,12 lipase-mediated transesterifi-
cation process has been applied and studied in detail
(Scheme 2).
Entry Lipasesa
Time
(h)
Alcohol
Acetate
E
Yieldb eec
Yieldb eec
(%)
(%)
(%)
(%)
1
2
3
4
5
6
7
8
PS-C
PS-D
AK
60
232
238
232
45
49
71
74
74
82
86
90
90
90
>99
88
34
26
27
15
10
6
45
42
21
18
17
10
8
6
5
<5
>99 1057
>99
>99
>99
>99
>99
>99
>99
>99
>99
581
280
257
257
230
219
212
210
203
PS
Lipozyme 232
CRL
CCL
AYS
P
240
242
250
232
240
In the first series of experiments, the efficiency of different
commercially available lipases to catalyze the transesterifi-
cation of ( )-3-hydroxy-4-trityloxybutanenitrile 3 was
investigated. As the solvent variation in many cases of
lipase-catalyzed kinetic resolution can influence the enantio-
meric or enantiotopic selectivity, as well as the reaction
rates, the effect of the solvents on this substrate was also
studied.
9
10
5
2
CAL-B
a Pseudomonas cepacia lipase immobilized on modified ceramic particles
(PS-C), P. cepacia lipase immobilized on diatomite (PS-D), Pseudomonas
fluorescens lipase (AK), P. cepacia (PS), Candida rugosa lipase (AYS)
were obtained from Amano Pharmaceutical company, Japan; Mucor
meihei (Lipozyme), Candida Pseudomonas fluorescens lipase immobilized
in Sol–Gel-AK on sintered glass (P) from Fluka; Candida antartica lipase
immobilized in Sol–Gel-AK on sintered glass (CAL B) (Fluka), Candida
rugosa lipase (CRL) and cyclindracea lipase (CCL) from Sigma.
b Isolated yields.
Enantiomeric excesses have been calculated from the enan-
tiomeric ratios obtained by HPLC employing a Chiralcel
OD column. Initially, the absolute configuration of the
alcohol and acetate obtained after enzymatic resolution
was arbitrarily assigned as (S)-alcohol and (R)-acetate
and then later confirmed by comparison of their chiroptical
c Determined by chiral HPLC (chiral column OD; Diacel) employing
hexane–isopropanol (90:10) as mobile phase at 0.5 mL/min and moni-
tored by UV (254 nm).
OH
O
O
N
i
ii
HO
TrO
TrO
(82%)
(71%)
1
2
3
Scheme 1. Reagents and conditions: (i) TrCl, pyridine, CH2Cl2; (ii) NaCN, EtOH–H2O, rt.
O
OH
OH
O
i
N
N
N
+
TrO
TrO
TrO
3
(S)-3
(R)-4
Scheme 2. Reagents and conditions: (i) PS-C, vinyl acetate, diisopropyl ether, 45–47 ꢁC.

A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 1281–1289
1283
Table 3. Effect of base additives on the transesterification of 3-hydroxy-4-
trityloxybutanenitrile by lipase PS-C between 45 and 47 ꢁC
Amongst all lipases examined, it was observed that the
lipase from Pseudomonas cepacia (Burkholderia cepacia)
provided better conversions. However, the lipase from P.
cepacia immobilized on ceramic particles (PS-C) gave both
the required (S)-alcohol and (R)-acetate in 45% yields with
more than 99% enantiomeric excess (Table 1, entry 1).
Moreover, this transesterification takes place in about
60 h in comparison to other lipases, which required longer
durations.
Entry
Bases
Time
(h)
Alcohol
Acetate
Yielda
eeb
Yielda
eeb
(%)
(%)
(%)
(%)
1
2
3
4
DMAP
Et3N
2,6-Lutidine
Pyridine
24
40
40
51
45
46
49
53
>99
98
89
45
44
42
38
>99
>99
>99
>99
75
a Isolated yields.
Furthermore, the effect of solvents has also been investi-
gated and it was observed that the transesterification in
hydrophobic solvents such as diisopropyl ether, toluene
and hexane not only provided good yields, but also high
enantiomeric excess for both (S)-alcohol and (R)-acetate.
However, the hydrophilic solvents such as THF or di-
oxane gave low yields, particularly the (R)-acetate and
as a result the enantiomeric excess of (S)-alcohol was
also greatly reduced. Therefore, diisopropylether appears
to be the solvent of choice for this type of a transesterifi-
cation with regard to yields and enantiomeric excess
(Table 2).
b Determined by chiral HPLC (chiral column OD; Diacel) employing
hexane–isopropanol (90:10) as mobile phase at 0.5 mL/min and moni-
tored by UV (254 nm).
2.3. Preparation of the intermediate for b-adrenergic
blocking agents
b-Adrenergic blocking agents are well-established pharma-
ceutical products used in the treatment of cardiovascular
disorder17 or angina pectoris.18 After three decades of their
use, more than 50 different compounds possessing b-block-
ing activity have been brought to a stage of commercial
development. A large number of these compounds are in
clinical usage and all of them possess a stereogenic centre
with a general structure of 3-aryloxypropanol amine
(Fig. 2).
In addition to the screening of lipases and effect of solvents,
in this investigation the role of certain additives in the
transesterification of 3-hydroxy-4-trityloxybutanenitrile 3
was also studied. It is known that the addition of crown
ethers,16a,b amino alcohols16c–e and certain bases16f influ-
ence the enzymatic resolution process. In this context, the
effect of DMAP, Et3N, 2,6-lutidine and pyridine as addi-
tives in the transesterification of 3-hydroxy-4-trityloxy-
butanenitrile 3 was examined and it was observed that all
these bases enhanced the rate of transesterification process
as shown in Table 3. DMAP in particular, enhances the
reaction rate considerably (Table 3, entry 1).
OH
H
O
R
N
Figure 2.
It is interesting to note that in all the experiments con-
ducted,24 there is no instance wherein the (S)-enantiomer
(less reactive enantiomer) has been acetylated. This clearly
suggests that the identity of the protecting group on the
primary hydroxyl group is very important and the steric
bulk of the trityl group may abrogate the binding of its
(S)-enantiomer to the enzyme active site leading to very
effective kinetic resolution process as seen from the very
high enantiomeric excess values.
Therefore, it was of interest to prepare an intermediate that
could provide compounds with different aryl substitutions.
In view of the above objective, an intermediate (S)-5-tosyl-
oxymethyl-1,3-oxazolidine-2-one (S)-8 has been designed
and prepared wherein different b-blockers can be synthe-
sized by simple displacement of the tosyloxy group with
sodium salt of various phenols. In the present investigation,
Table 2. Effects of solvents on the transesterification of 3-hydroxy-4-trityloxybutanenitrile 3 by lipase PS-C between 45 and 47 ꢁC
Entry
Solvent
LogP
Time (h)
Alcohol
Acetate
Yielda (%)
eeb (%)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
Diisopropyl ether
Hexane
Toluene
Acetonitrile
Tetrahydrofuran
Acetone
1.9
3.5
2.5
ꢀ0.33
0.49
ꢀ0.23
ꢀ1.1
2.0
60
64
72
232
232
232
232
232
45
50
54
75
80
86
90
93
>99
83
73
24
15
11
<5
—
45
42
38
17
12
08
<5
—
>99
>99
>99
>99
>99
>99
>99
—
Dioxane
Chloroform
a Isolated yields.
b Determined by chiral HPLC (chiral column OD; Diacel) employing hexane–isopropanol (90:10) as mobile phase at 0.5 mL/min and monitored by UV
(254 nm).

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A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 1281–1289
(S)-3-hydroxy-4-trityloxybutanenitrile (S)-3 was effectively
employed for the preparation of this oxazolidinone
intermediate.
the tosyloxy group with NaN3. The intermediates (R)-7
and (R)-9 can be utilized for the preparation of various
antimicrobial agents containing oxazolidinone ring system
by simple arylation of the oxazolidinone ring.21
In this process, the nitrile functionality of the enantiomeri-
cally pure (S)-3-hydroxy-4-trityloxybutanenitrile (S)-3 was
hydrolyzed to provide the corresponding amide (S)-5
employing H2O2 in aqueous ammonia. A Hoffmann-like
rearrangement of the amide using Pb(OAc)4 resulted in
the formation of (S)-5-trityloxymethyl-2-oxazolidinone
(S)-6. The trityloxy group of this oxazolidinone was trans-
formed to its tosyloxy group by using PTSA and TsCl to
obtain the required (S)-5-tosyloxymethyl-1,3-oxazolidine-
2-one (S)-8 as shown in Scheme 3. This common inter-
mediate (S)-8 has been utilized in a straightforward manner
and is well documented in the literature19 in the prepara-
tion of b-adrenergic blocking agents.
2.5. Enantioconvergent synthesis of (R)-GABOB
In yet another application, the enantiomerically pure (S)-
3-hydroxy-4-trityloxybutanenitrile (S)-3 and (R)-3-acetyl-
oxy-4-trityloxybutanenitrile (R)-4, obtained by enzymatic
resolution have been employed in an enantioconvergent
synthesis of (R)-GABOB by functional group switching,
as illustrated in Scheme 5.
The activated alcohol group (tosyloxygroup) of (S)-5-tosyl-
oxymethyl-1,3-oxazolidine-2-one (S)-8 was displaced by a
cyanide group using NaCN in aqueous-methanol system
leading to a functional group switching. Hydrolysis of the
nitrile group of (R)-10 to carboxylic acid and cleavage of
the oxazolidinone ring has been achieved by using concd
HCl at 80–90 ꢁC to afford (R)-GABOB.22
2.4. Preparation of the intermediate for oxazolidinone based
antimicrobials
In another application, some common intermediates for a
variety of antimicrobials possessing an oxazolidinone ring
structure20 have been designed and developed starting from
(R)-4, wherein the synthesis of a wide divergent 3-aryl
substituted oxazolidinones from a common intermediate
is feasible. This process proceeds with high efficiency from
commercially available glycidol and is represented in
Scheme 4.
In an alternative approach, (R)-3-acetyloxy-4-trityloxy-
butanenitrile (R)-4 has been treated with K2CO3 in methanol
and then by PTSA in methanol to afford 3,4-dihydroxy-
butanenitrile, which without purification has been trans-
formed to (R)-3-hydroxy-4-tosyloxybutanenitrile (R)-12.
This upon treating with aqueous ammonia in refluxing eth-
anol and then treating with concd HCl at 80 ꢁC afforded
the desired (R)-GABOB (R)-11 in high yield with excellent
enantiomeric excess. The above two processes in combina-
tion is an illustrative example of an enantioconvergent syn-
thesis of (R)-GABOB.
(R)-5-Tosyloxymethyl-1,3-oxazolidine-2-one (R)-8 was
prepared as shown in Scheme 4, which was then trans-
formed to azidooxazolidinone (R)-9 by displacement of
O
O
OH
OH
O
ii
i
N
NH
TrO
TrO
TrO
85%
75%
NH2
(S)-3
(S)-5
(S)-6
(88%)
iii
O
O
O
NH
O
iv
O
O
NH
NH
TsO
HO
ArO
β-blockers
80%
(S)-8
(S)-7
Scheme 3. Reagents and conditions: (i) H2O2, aq NH3, rt; (ii) Pb(OAc)4, pyridine, rt; (iii) PTSA, MeOH, rt; (iv) TsCl, Et3N, CH2Cl2.
O
O
O
OAc
O
N
O
O
i
ii
TrO
NH
NH
HO
NH
N3
TsO
80%
80%
(R)-7
(R)-4
(R)-8
(R)-9
Antimicrobials
Scheme 4. Reagents and conditions: (i) TsCl, Et3N, CH2Cl2; (ii) NaN3, DMF, 60–70 ꢁC.

A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 1281–1289
1285
O
O
OH
O
O
i
N
NH
NH
(80%)
ii
TrO
TrO
TsO
NC
70%
(S)-3
OH
(S)-8
(R)-10
H2N
COOH
(R)-11 (R)-GABOB
OH
ii
(80%)
OAc
OH
vi
80%
N
iii, iv, v
N
N
TsO
H2N
51% for
3 steps
(R)-4
(R)-12
(R)-13
Scheme 5. Reagents and conditions: (i) NaCN, MeOH–H2O, reflux; (ii) concd HCl, 80 ꢁC; (iii) K2CO3, MeOH; (iv) PTSA, MeOH, rt; (v) TsCl, Et3N,
Bu2SnO, CH2Cl2; (vi) aq NH3, EtOH, reflux.
3. Conclusion
SEPA-300 (Horiba) digital polarimeter. Enantiomeric
excess has been determined by chiral HPLC (chiral column
OD; Diacel).
An efficient method for the preparation of ( )-3-hydroxy-
4-trityloxybutanenitrile and its successful enzymatic
resolution have been described. This lipase-mediated
transesterification process has been optimized with respect
to different lipases, solvents and additives. Furthermore,
enantiomerically pure (S)-3-hydroxy-4-trityloxybutane-
nitrile and (R)-3-acetyloxy-4-trityloxybutanenitrile have
been employed in the preparation of common intermedi-
ates for b-adrenergic blocking agents and antimicrobials
possessing oxazolidinone ring system. Furthermore, the
present investigation also describes an enantioconvergent
synthesis of (R)-GABOB.
4.1.1. 3-Trityloxy-1,2-epoxypropane 2. To a stirred solu-
tion of glycidol (5.00 g, 67.57 mmol) in 150 mL of dry
CH2Cl2 under N2 was added trityl chloride (18.82 g,
67.57 mmol) and pyridine (5.87 g, 74.33 mmol) at room
temperature, and the progress of the reaction was moni-
tored by TLC. After completion of the reaction (over-
night), 100 mL of 1 M HCl was added and the organic
layer separated. The aqueous layer was extracted with
CH2Cl2 (3 · 125 mL) and the combined organic layers
washed with brine, dried over anhydrous Na2SO4 and con-
centrated to give a residue of crude 2. Purification of the
crude epoxide was accomplished by column chromatogra-
phy employing EtOAc–hexane (10:90) as eluent to afford
4. Experimental
4.1. General
1
2 in 71% yield. H NMR (300 MHz, CDCl3) d 3.26 (dd,
1H, J1 = 3 Hz, J2 = 9.4 Hz), 3.29 (dd, 1H, J1 = 4.9 Hz,
J2 = 9.4 Hz), 3.60 (dd, 1H, J1 = 6.0 Hz, J2 = 10.9 Hz),
3.68 (dd, 1H, J1 = 5.4 Hz, J2 = 10.0 Hz), 3.83–3.92 (m,
1H), 7.18–7.38 (m, 9H), 7.38–7.42 (m, 6H); mass (EI)
259, 243, 165, 77.
Reactions involving moisture-sensitive reagents were per-
formed under an inert atmosphere of nitrogen in glassware,
which had been oven dried. Melting points were recorded
on an electrothermal melting point apparatus and are
uncorrected. Infrared spectra were recorded on Perkin–
Elmer model 683 or 1310 spectrometers and are reported
4.1.2. ( )-3-Hydroxy-4-triphenylmethoxybutanenitrile 3.
To a stirred solution of 2 (15.80 g, 50.00 mmol) in 50 mL
of ethanol were added 150 mL of H2O and NaCN
(2.94 g, 60.00 mmol). The resultant reaction mixture was
stirred overnight at room temperature and on completion
of the reaction (TLC), the reaction mixture was concen-
trated to about 50% of the total volume under reduced
pressure. The residue was extracted with ethyl acetate
(3 · 125 mL), washed with brine and dried over anhydrous
Na2SO4. Evaporation of the solvent and purification of the
residue by column chromatography employing EtOAc–
hexane (25:75) as eluent afforded 3-hydroxy-4-tri-
phenylmethoxybutanenitrile in 82% yield. IR (neat) 3506,
1
in wave numbers (cmꢀ1). H NMR spectra were recorded
as solutions in CDCl3, or DMSO-d6 and chemical shifts
reported in parts per million (ppm, d) on a Gemini 200 MHz,
AV 300 MHz, instrument using tetramethylsilane (TMS)
as an internal standard. Spectral patterns unless specified
all solvents and reagents were of reagent grade and used
without further purification. Spectral patterns are desig-
nated as s, singlet; d, doublet; dd, double doublet; t, triplet;
br, broad, m, multiplet. Coupling constants are reported in
hertz (Hz). Low resolution mass spectra were recorded on
CEC-21-100B Finnigan Mat 1210 or VG 7070H Micro-
mass mass spectrometers. Analytical TLC of all reactions
was performed on Merck prepared plates (silica gel 60F-
254 on glass). Column chromatography was performed
using Acme silica gel (100–200 mesh). Percentage yields
are given for compounds. HPLC analysis was performed
on an instrument that consisted of a Shimadzu LC-10AT
system controller with a SPD-10A fixed wavelength UV
monitor as detector. Optical rotations were measured on
1
3043, 2996, 2918, 2855, 2275, 1106, 1051 cmꢀ1; H NMR
(200 MHz, CDCl3) d 2.45–2.56 (m, 2H), 3.27 (d, 2H,
J = 5.2 Hz), 3.92–4.02 (m, 1H), 7.23–7.41 (m, 15H); mass
(EI) 259, 243, 165, 105, 77.
4.1.3. ( )-3-Acetyloxy-4-triphenylmethoxybutanenitrile 14.
To ( )-3-hydroxy-4-triphenylmethoxybutanenitrile 3 (1.03 g,
3.00 mmol) under N2 were added acetic anhydride (1.53 g,

1286
A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 1281–1289
15.00 mmol) and pyridine (0.26 g, 3.30 mmol), and the
resultant mixture stirred overnight at room temperature.
After completion of the reaction (TLC), the reaction
mixture was diluted with ethyl acetate (25 mL) and treated
with 1 M HCl (20 mL). The organic layer was separated,
washed with brine and dried over anhydrous Na2SO4.
The solvent was evaporated and the residue purified by
column chromatography employing EtOAc–hexane
(15:85) as eluent to afford the required 3-acetyloxy-4-tri-
phenylmethoxybutanenitrile in nearly quantitative yield.
IR (KBr) 3466, 3066, 3019, 2925, 2863, 2235, 1741, 1223,
4.1.8. (R)-3-Hydroxy-4-triphenylmethoxy butanamide (R)-
5. (R)-3-Hydroxy-4-triphenylmethoxy butanamide was
prepared from (R)-3-acetyloxy-4-triphenylmethoxy butane-
nitrile (3.85 g, 10.00 mmol), aqueous NH3 (60 mL) and
H2O2 (45 mL, 400.00 mmol) employing a similar procedure
as that of the preparation of (S)-3-hydroxy-4-triphenyl-
27
methoxy butanamide. Mp 98–100 ꢁC; ½aꢁD ¼ þ18:9 (c 0.9,
MeOH); IR, NMR and mass spectral data are identical
to that of (S)-5.
4.1.9. (S)-5-Triphenylmethoxymethyl-1,3-oxazolidine-2-one
(S)-6. To a solution of (S)-3-hydroxy-4-triphenylmethoxy
butanamide (S)-5 (4.33 g, 12.00 mmol) in pyridine (25 mL)
was added Pb(OAc)4 (7.45 g, 16.80 mmol) and the resultant
reaction mixture stirred under N2 at room temperature for
1 h. On completion of the reaction as indicated by the
TLC, the reaction mixture was taken up in CH2Cl2
(100 mL) and then treated with 1 M HCl (125 mL). The
resultant reaction mixture was filtered through a Celite
pad and the residue washed three times with CH2Cl2
(50 mL). The organic layer from the combined filtrates
and washings was separated while the aqueous layer was
extracted with CH2Cl2 (2 · 100 mL). The organic layer free
from pyridine was washed with brine, dried over anhy-
drous Na2SO4 and concentrated to leave a residue of crude
oxazolidinone (S)-6, which was purified by column chro-
matography employing EtOAc–hexane (50:50) as eluent to
1
1004 cmꢀ1; H NMR (300 MHz, CDCl3) d 2.09 (s, 3H),
2.76 (d, 2H, J = 5.69), 3.92–4.02 (m, 1H), 7.23–7.41
(m, 15H); mass (EI) 259, 243, 165, 105, 77.
4.1.4. Procedure for resolution of 3-hydroxy-4-triphenyl-
methoxybutanenitrile 3. To a solution of 3-hydroxy-4-tri-
tyloxybutanenitrile 3 (1.50 g) in diisopropyl ether (160 mL)
was successively added lipase (1.50 g) and vinyl acetate
(6 equiv). The reaction mixture was shaken at room tem-
perature in an orbital shaker. After about 50% completion
of the reaction as indicated by the HPLC analysis the reac-
tion mixture was filtered and the residue washed three
times with diisopropyl ether. The combined organic layers
were evaporated under reduced pressure and purification
was accomplished by column chromatography employing
EtOAc–hexane (20:80) as eluent to afford the correspond-
ing (R)-acetate (R)-4 followed by (S)-alcohol (S)-3.
afford pure 5-triphenylmethoxymethyl-1,3-oxazolidine-2-
26
one in 85% yield. ½aꢁD ¼ þ25:0 (c 1.0, MeOH); lit.23
25
4.1.5. (S)-3-Hydroxy-4-triphenylmethoxybutanenitrile (S)-
½aꢁD ¼ þ35:5 (c 1.0, MeOH); IR (KBr) 3247, 2933, 2886,
29
1
3. Mp 144–146 ꢁC; ½aꢁD ¼ ꢀ7:6 (c 1.5, CHCl3); IR, NMR
2824, 1741, 1012, 949 cmꢀ1; H NMR (300 MHz, CDCl3)
and mass spectral data are identical to that of 3.
d 3.24 (dd, 1H, J1 = 4.5 Hz, J2 = 10.4 Hz), 3.36–3.48 (m,
3H), 3.57–3.64 (m, 1H), 4.71–4.77 (m, 1H), 5.27 (br, s,
1H), 7.21–7.44 (m, 9H), 7.46–7.47 (m, 6H); mass (EI)
274, 258, 243, 183, 165, 105, 77.
4.1.6. (R)-3-Acetyloxy-4-triphenylmethoxybutanenitrile (R)-
29
4. Mp 155–158 ꢁC; ½aꢁD ¼ þ24:4 (c 1.35, CHCl3); IR,
NMR and mass spectral data are identical to that of 14.
4.1.10. (R)-5-Triphenylmethoxymethyl-1,3-oxazolidine-2-one
(R)-6. (R)-5-Triphenylmethoxymethyl-1,3-oxazolidine-
2-one was prepared from (R)-5 (3.61 g, 10.00 mmol),
pyridine (25 mL) and Pb(OAc)4 (6.21 g, 14.00 mmol)
4.1.7. (S)-3-Hydroxy-4-triphenylmethoxy butanamide (S)-
5. To a stirred solution of (S)-3-hydroxy-4-triphen-
ylmethoxybutanenitrile (5.15 g, 15.01 mmol) in 15 mL of
ethanol at room temperature was added aqueous NH3
(50 mL), after which H2O2 (34 mL, 300.00 mmol) was
added in portions while maintaining the temperature of
the reaction mixture below 25 ꢁC. After complete addition,
the resultant reaction mixture was stirred vigorously at 25–
30 ꢁC and the progress of the reaction monitored by TLC.
On completion of the reaction (overnight) as indicated by
the TLC, the reaction volume was concentrated to about
50% of the original volume under reduced pressure, and
the resultant mixture extracted with CH2Cl2 (3 · 75 mL).
The combined organic layers were dried over anhydrous
Na2SO4 and the solvent evaporated to give a residue, which
was purified by column chromatography employing
EtOAc–hexane (80:20) as eluent to afford (S)-3-hydroxy-
4-triphenylmethoxy butanamide (S)-5 in 75% yield.
employing a similar procedure to that of the preparation
26
of (S)-6. ½aꢁD ¼ ꢀ25:5 (c 1.0, MeOH); IR, NMR and
mass spectral data are identical to that of (S)-6.
4.1.11. (S)-5-Hydroxymethyl-1,3-oxazolidine-2-one (S)-
7. To a stirred solution of (S)-5-triphenylmethoxy-
methyl-1,3-oxazolidine-2-one (7.18 g, 20.00 mmol) in 60 mL
of methanol at room temperature was added p-toluenesulf-
onic acid (7.16 g, 40.00 mmol) and stirring was continued
overnight. After completion of the reaction (TLC), the sol-
vent in the reaction mixture was evaporated and the residue
purified by column chromatography employing MeOH–
EtOAc (5:95) as eluent to afford pure 5-hydroxymethyl-
1,3-oxazolidine-2-one in 88% yield. Mp 70–73 ꢁC;
27
½aꢁD ¼ þ32:8 (c 0.6, EtOH); 1H NMR (200 MHz,
27
25
Mp 96–100 ꢁC; ½aꢁD ¼ ꢀ18:1 (c 1.0, MeOH); lit.23½aꢁD
¼
DMSO-d6) d 3.35–3.75 (m, 4H), 4.50–4.64 (m, 1H), 4.85
ꢀ53:5 (c 0.5, MeOH); IR (KBr) 3467, 3349, 3012, 2980,
(br s, 1H).
1
2918, 2839, 1671, 1098, 1076 cmꢀ1; H NMR (300 MHz,
CDCl3) d 2.36 (d, 2H, J = 6.5 Hz), 3.13–3.16 (m, 2H),
3.28 (S, 1H), 4.11–4.15 (m, 1H), 5.44 (br, s, 1H), 7.18–
7.38 (m, 9H), 7.39–7.42 (m, 6H); mass (EI) 361, 259, 243,
165, 77.
4.1.12. (R)-5-Hydroxymethyl-1,3-oxazolidine-2-one (R)-
7. (R)-5-Hydroxymethyl-1,3-oxazolidine-2-one was pre-
pared in 85% yield analogous to the preparation of (S)-7
employing (R)-5-triphenylmethoxymethyl-1,3-oxazolidine-

A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 1281–1289
1287
2-one (2.87 g, 8.00 mmol) and p-toluenesulfonic acid
as eluent to afford pure 5-cyanomethyl-1,3-oxazolidine-2-
27
(3.04 g, 16.00 mmol). Mp 70–73 ꢁC; ½aꢁD ¼ ꢀ33:3 (c 0.45,
25
26
one in 70% yield. ½aꢁD ¼ þ4:5 (c 1.0, MeOH); IR (neat)
1
EtOH); lit.21c ½aꢁD ¼ ꢀ29:6 (c 2.7, EtOH); NMR spectral
3349, 2918, 2839, 2243, 1710, 1255, 1051 cmꢀ1; H NMR
data is identical to that of (S)-7.
(200 MHz, CD3OD) d 2.57 (d, 2H, J = 6.6 Hz), 3.20–3.55
(m, 2H), 4.00–4.18 (m, 1H).
4.1.13. (S)-5-(4-Methylphenylsulfonyloxymethyl)-1,3-oxazol-
idine-2-one (S)-8. p-Toluenesulfonyl chloride (2.74 g,
14.36 mmol) and Et3N (1.45 g, 14.36 mmol) were added
to 5-hydroxymethyl-1,3-oxazolidine-2-one (1.40 g, 11.97
mmol) dispersed in 20 mL of CH2Cl2 and stirred overnight
at room temperature under N2. After completion of the
reaction (TLC), the reaction mixture was evaporated and
the residue obtained, was purified by column chromato-
graphy employing EtOAc–hexane (70:30) as eluent to
4.1.17. (R)-3-Hydroxy-4-(4-methylphenylsulfonyloxy)butane-
a solution of (R)-3-acetyloxy-4-
nitrile (R)-12. To
triphenylmethoxybutanenitrile (R)-5 (3.85 g, 10.00 mmol)
in methanol (40 mL) was added K2CO3 (6.90 g,
50.00 mmol) and stirred at room temperature for 2 h. After
completion of the reaction, K2CO3 was filtered and the
residue washed with 20 mL of methanol. To the combined
filtrates was added p-toluenesulfonic acid (7.61 g,
40.00 mmol) and the reaction stirred overnight at room
temperature. After completion of the reaction, the solvent
in the reaction mixture was evaporated and the residue
purified by column chromatography to obtain 3,4-
dihydroxybutanenitrile. To this, were added dry CH2Cl2
(100 mL), dibutyltinoxide (0.50 g, 2.00 mmol) and p-tolu-
enesulfonyl chloride (2.29 g, 12.00 mmol) and stirred for
about 1 h. The reaction mixture was treated with water
(100 mL), then the organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (125 mL). The
combined organic layers were dried over Na2SO4 and
evaporated to give a residue, which was purified by column
afford
5-(4-methylphenylsulfonyloxymethyl)-1,3-oxazol-
27
idine-2-one in 80% yield. Mp 96–99 ꢁC; ½aꢁD ¼ þ45:4 (c
1.25, CHCl3); IR (KBr) 3302, 2980, 2925, 2871, 1757,
1694, 1357, 1184, 1090, 996, 965 cmꢀ1
;
1H NMR
(200 MHz, CDCl3) d 2.47 (s, 3H), 3.40–3.50 (m, 1H),
3.64–3.74 (m, 1H), 4.14 (d, 2H, J = 4.4 Hz), 4.71–4.82
(m, 1H), 7.35 (d, 2H, J = 8.2 Hz), 7.78 (d, 2H,
J = 8.2 Hz); mass (EI) 271, 207, 173, 155, 139, 91.
4.1.14. (R)-5-(4-Methylphenylsulfonyloxymethyl)-1,3-oxazol-
idine-2-one
(R)-8. (R)-5-(4-Methylphenylsulfonyloxy-
methyl)-1,3-oxazolidine-2-one was prepared from p-
toluenesulfonyl chloride (1.17 g, 6.14 mmol), Et3N
(0.62 g, 6.14 mmol) and 5-hydroxymethyl-1,3-oxazolidine-
2-one (0.60 g, 5.13 mmol), employing a similar approach
chromatography employing EtOAc–hexane (30:70) as
26
eluent to afford (R)-12 in 51% yield. ½aꢁD ¼ þ13:5 (c 1.45,
25
EtOH); lit.15 ½aꢁD ¼ ꢀ14:2 (c 1.72, EtOH) for (S)-isomer;
to the preparation of (S)-5-(4-methylphenylsulfonyloxy-
IR (neat) 3474, 3059, 2933, 2902, 2220, 1584, 1349,
27
methyl)-1,3-oxazolidine-2-one. Mp 96–99 ꢁC; ½aꢁD ¼ ꢀ44:4
27
1169, 1098, 996 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
(c 1.25, CHCl3); ½aꢁD ¼ ꢀ38:75 (c 1.2, EtOH); IR, NMR
d 2.48 (s, 3H), 2.52–2.67 (m, 2H), 4.06 (d, 2H,
and mass spectral data are identical to that of (S)-8.
J = 5.4 Hz), 4.15–4.22 (m, 1H), 7.38 (d, 2H, J = 8.3 Hz),
7.80 (d, 2H, J = 8.3 Hz); mass (EI) 255 (M+), 173, 155,
139, 122, 91.
4.1.15. (R)-5-Azidomethyl-1,3-oxazolidine-2-one (R)-9. To
a stirred solution of (R)-5-(4-methylphenylsulfonyloxy-
methyl)-1,3-oxazolidine-2-one (2.17 g, 8.00 mmol) in 20 mL
of DMF equipped with a calcium chloride guard tube
was added NaN3 (3.12 g, 48.00 mmol) at room temperature
and the resultant mixture heated to 60–70 ꢁC. The progress
of the reaction was monitored by TLC, and on completion
of the reaction (10 h), the reaction mixture was diluted with
40 mL of ice-cold water and then extracted with ethyl ace-
tate (4 · 40 mL). The organic layer was washed with brine,
dried over anhydrous Na2SO4 and concentrated to leave a
residue, which on purification by column chromatography
4.1.18. (R)-4-Amino-3-hydroxybutanoic acid (R)-11.
A
mixture of (R)-5-cyanomethyl-1,3-oxazolidine-2-one
(0.15 g, 1.2 mmol) and concd HCl (15 mL) was stirred
and heated to 80–90 ꢁC for 6 h. After completion of the
reaction, as indicated by the TLC the solvent in the reac-
tion mixture was evaporated and the residue purified by
an ion exchange column chromatography (Amberlite IR
120 H+). The column was first eluted with water until the
fractions collected were neutral and later with 10%
NH4OH. The solvent in the basic fractions was evaporated
and redissolved in minimum amount of H2O and triturated
employing EtOAc–hexane (50:50) as eluent afforded 5-azido-
29
methyl-1,3-oxazolidine-2-one in 80% yield. ½aꢁD ¼ ꢀ62:2
with EtOH to obtain (R)-GABOB as a white solid after
28
(c 1.12, CHCl3); IR (neat) 3302, 2941, 2886, 2839, 2102,
evaporation of the solvent. Mp 211–213 ꢁC; ½aꢁD ¼ ꢀ20:7
1
1
1749, 1231, 1074, 957 cmꢀ1; H NMR (200 MHz, CDCl3)
(c 1.0, H2O); H NMR (200 MHz, D2O) d 2.43 (d, 2H,
d 3.42 (dd, 1H, J1 = 6.2 Hz, J2 = 8.8 Hz), 3.52–3.59 (m,
2H), 3.63–3.88 (m, 1H), 4.66–4.79 (m, 1H); mass (EI) 86,
87.
J = 5.9 Hz), 2.95 (dd, 1H, J1 = 9.66 Hz, J2 = 13.38 Hz),
3.18 (dd, 1H, J1 = 3.72 Hz, J2 = 13.38 Hz), 4.10–4.30 (m,
1H); 13C NMR (50 MHz, D2O) d 42.3, 44.0, 65.5, 178.5;
mass (EI) 118 (M+ꢀH), 74, 60, 43.
4.1.16. (R)-5-Cyanomethyl-1,3-oxazolidine-2-one (R)-10.
To a stirred solution of (S)-5-(4-methylphenylsulfonyl-
oxymethyl)-1,3-oxazolidine-2-one (0.54 g, 1.99 mmol) in
MeOH (15 mL)–water (3 mL) was added NaCN (0.39 g,
8.00 mmol) at room temperature and then heated at reflux
for 4 h. After completion of the reaction, the reaction mix-
ture was completely evaporated and the residue purified by
column chromatography employing EtOAc–hexane (70:30)
4.1.19. (R)-4-Amino-3-hydroxybutanoic acid (R)-11. To a
solution of (R)-3-hydroxy-4-tosyloxybutanenitrile (4.07 g,
13.70 mmol) in ethanol (40 mL), was added excess aq
NH3, refluxed overnight and the solvent in the reaction
mixture was evaporated. To the resulting residue was
added concd HCl and heated to 80 ꢁC for 6 h. After
evaporation of the solvent, the residue containing crude

1288
A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 1281–1289
8. (a) Narasaka, K.; Pai, F.-C. Tetrahedron 1984, 40, 2233; (b)
Evans, D. A.; Chapman, K. T.; Carreira, M. J. Am. Chem.
Soc. 1988, 110, 3560.
9. (a) Haddad, M.; Dorbais, J.; Larcheveque, M. Tetrahedron
Lett. 1997, 38, 5981; (b) Narasaka, K.; Ukaji, Y.; Yamazaki,
S. Bull. Chem. Soc. Jpn. 1986, 59, 525.
10. (a) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M.
J. Am. Chem. Soc. 1982, 104, 6465; (b) Hashiguchi, S.;
Kawada, A.; Natsugari, H. J. Chem. Soc., Perkin Trans. 1
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11. (a) Hayashi, Y.; Rode, J. J.; Corey, E. J. J. Am. Chem. Soc.
1996, 118, 5502; (b) Senanayake, C. H.; Fang, K.; Grover, P.;
Bakale, R. P.; Vandenbossche, C. P.; Wald, S. A. Tetrahedron
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(R)-GABOB was purified over an ion exchange column
chromatography (Amberlite IR-120 H+). The column
was first eluted with water until the fractions were neutral
and later with 10% NH4OH. Evaporation of the basic frac-
tions gave a thick oil, which was dissolved in minimum
amount of water and absolute ethanol was added to pro-
vide (R)-GABOB as a white solid after evaporation of
28
the solvent (80% yield). Mp 211–213 ꢁC; ½aꢁD ¼ ꢀ20:7 (c
1.0, H2O); 1H NMR (200 MHz, D2O) d 2.43 (d, 2H,
J = 5.9 Hz), 2.95 (dd, 1H, J1 = 9.66 Hz, J2 = 13.38 Hz),
3.18 (dd, 1H, J1 = 3.72 Hz, J2 = 13.38 Hz), 4.10–4.30 (m,
1H); 13C NMR (50 MHz, D2O) d 42.3, 44.0, 65.5, 178.5;
mass (EI) 118 (M+ꢀH), 74, 60, 43.
12. (a) Kamal, A.; Khanna, G. B. R. Tetrahedron: Asymmetry
2001, 12, 405; (b) Kamal, A.; Khanna, G. B. R.; Ramu, R.
Tetrahedron: Asymmetry 2002, 13, 2039; (c) Kamal, A.;
Khanna, G. B. R.; Ramu, R.; Krishnaji, T. Tetrahedron
Lett. 2003, 44, 4783; (d) Kamal, A.; Khanna, G. B. R.;
Krishnaji, T.; Ramu, R. Bioorg. Med. Chem. Lett. 2005, 15,
613.
Acknowledgement
The authors G.B.R.K., T.K. and R.R. thank CSIR, New
Delhi, for the award of research fellowship.
13. (a) Itoh, T.; Takagi, Y.; Fujisawa, T. Tetrahedron Lett. 1989,
30, 3811; (b) Fuganti, C.; Pedrocchi-Fantoni, G.; Servi, S.
Tetrahedron Lett. 1990, 31, 4195; (c) Smallridge, A. J.; Ten,
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