New chemoenzymatic pathway for β-adrenergic blocking agents

Article abstract of DOI:10.1016/j.tetasy.2005.02.015

The lipase mediated kinetic resolution of pharmaceutically important β-hydroxy nitriles is described in high enantiomeric excesses and good yields. Some of the chiral β-hydroxy nitriles have been employed in the synthesis of β-adrenergic blocking agents such as propranolol, alprenolol and moprolol. This protocol has also been extended for the enantiopure preparation of 5-(4-tosyloxymethyl)-1,3-oxazolidine-2-one and 3-hydroxy-4-tosyloxybutanenitrile, chiral intermediates of high synthetic value.

Full text of DOI:10.1016/j.tetasy.2005.02.015

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1485–1494
New chemoenzymatic pathway for b-adrenergic blocking agents
Ahmed Kamal,* G. B. Ramesh Khanna, T. Krishnaji, Venkatesh Tekumalla and R. Ramu
Biotransformation Laboratory, Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 13 January 2005; accepted 14 February 2005
Abstract—The lipase mediated kinetic resolution of pharmaceutically important b-hydroxy nitriles is described in high enantiomeric
excesses and good yields. Some of the chiral b-hydroxy nitriles have been employed in the synthesis of b-adrenergic blocking agents
such as propranolol, alprenolol and moprolol. This protocol has also been extended for the enantiopure preparation of 5-(4-tosyl-
oxymethyl)-1,3-oxazolidine-2-one and 3-hydroxy-4-tosyloxybutanenitrile, chiral intermediates of high synthetic value.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
OH
H
N
O
R
Enantiomerically pure b-amino alcohols1 are an impor-
tant class of organic compounds whose structures are
present in numerous natural products, such as amino
sugars,1a
antibiotics,1b–d
b-adrenergic
blocking
Figure 1.
agents,1e–h etc. They play an increasingly important role
in both the treatment of a wide variety of human disor-
ders and as chiral auxiliaries1i–l in organic synthesis.
b-Adrenergic blocking agents (b-blockers)1e–h mostly
comprising of b-amino alcohols are of pharmaceutical
significance and have received major attention due to
their utility in the management of cardiovascular disor-
ders,2 including hypertension,3 anginapectoris, cardiac
arrhythmias and also other disorders4 related to the
sympathetic nervous system. After three decades of their
evolution, more than 50different compounds having b-
adrenergic blocking activity have been brought to a
stage of commercial development with about two dozen
of the b-adrenergic blocking agents being approved for
medicinal use. The most important ones are proprano-
lol, atenolol, metoprolol and alprenolol.
For example, (S)-propranolol is 130times as active as its
(R)-enantiomer, which effectively means that the latter is
inactive.6 Moreover, contraceptive activity is believed to
be associated with the (R)-enantiomer.5b,7 Most of the
b-adrenergic blocking agents are marketed as racemates;
this has been probably influenced by the fact that they
are difficult to separate by classical methods and that
the distomer exhibits no serious side-effects (or no more
than the eutomer). However, over a period of time the
situation has been changing rapidly, although the dis-
tomers generally exhibit no serious side-effects, they
are still considered an unnecessary isomeric ballast8 as
they produce the same side-effects as the eutomer with-
out contributing to the desired therapeutic effect. In this
connection several methods have been reported for their
synthesis in enantiopure form.
b-Adrenergic blocking agents are chiral aryloxy propa-
nol amines, which have the general structure as shown
in Figure 1. Their therapeutic effect is mostly due to
the (S)-enantiomer that bears a strong structural resem-
blance to the adrenergic hormone noradrenaline. The
eudismic ratios of the various b-adrenergic blocking
agents vary considerably, but in all cases, the (S)-enan-
tiomer is the active enantiomer.5
Owing to the high biological importance associated with
these compounds, many research groups have carried
out extensive research over a period of three decades
for their preparation. Until the early 1980s only a few
methods, all non-enzymatic, have been described for
the preparation of optically active b-adrenergic blocking
agents. They have been prepared from D-mannitol,9 (R)-
glyceraldehyde10 and from racemic b-adrenergic block-
ing agents by resolution.5b,7d,11 Subsequently, enzyme
*
Corresponding author. Tel.: +91 402719 3157; fax: +91 402719
3189; e-mail: ahmedkamal@iict.res.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.015

1486
A. Kamal et al. / Tetrahedron: Asymmetry 16 (2005) 1485–1494
mediated processes12–14 for chiral intermediates to b-
adrenergic blocking agents have been emerging and
gaining prominence.
OH
O
N
O
O
i
R
R
4 - 6
1 - 3
2. Results and discussion
R = 2,3-(CH=CH-CH=CH)- 1; 2-(CH2-CH=CH2) 2; 4-OCH3 3
Reagents and conditions : i. NaCN, EtOH-H2O, room temp.
2.1. Preparation of enantiomerically pure b-hydroxy
nitriles
ð1Þ
In continuation of our earlier efforts towards the prepa-
ration of biologically important compounds or their
intermediates by employing enantiomerically pure b-hy-
droxy nitriles,15 we herein report an efficient chemoenzy-
matic preparation of some b-adrenergic blocking agents
and more importantly a favourable common intermedi-
ate14 for the preparation of a wide range of b-adrenergic
blocking agents. Previously we investigated the synthesis
of various chiral propanolamines16 by stereoselective
ring opening of epoxides with amines in the presence
of rat liver microsomes and various lipases. We have
also synthesized (R)-propranolol from 3-isopropyl-5-
(1-naphthyloxymethyl)-oxazolidine with post mitochon-
drial supernatant from rat liver in phosphate buffer.16e
The racemic b-hydroxy nitriles 4–6 thus obtained have
been independently studied for lipase-catalyzed resolu-
tion (Eq. 2). In the first series of experiments, the effi-
ciency of the different commercially available lipases17
to catalyze the transesterification of cyanohydrins has
been investigated. As the solvent variation in many cases
of lipase-catalyzed kinetic resolution influences the
enantiomeric or enantiotopic selectivity as well as the
reaction rate, the effect of the solvents18 on these sub-
strates has also been studied. The important results of
these studies are illustrated in Table 1.
O
OH
OH
N
H3C
O
O
N
N
O
O
i
+
R
R
R
ð2Þ
4-6
(S)-4-6
(R)-7-9
R = 2,3-(CH=CH-CH=CH)- 4; 2-(CH2-CH=CH2) 5; 4-OCH3 6
Reagents and conditions: i. lipase from Pseudomonas cepacia (Burkholderia cepacia),
vinyl acetate, diisopropyl ether.
This study represents a facile preparation of 4-aryloxy-
3-hydroxybutanenitriles, their successful enzymatic res-
olution employing lipases and their application towards
the synthesis of enantiomerically pure b-adrenergic
blocking agents viz., propranolol, alprenolol and
moprolol. In our earlier report15a we presented a facile
preparation of some b-hydroxy nitriles and their
enzymatic resolution. Herein the present investigation
3-hydroxy-4-(1-naphthyloxy)butanenitrile 4, 4-(2-allyl-
phenoxy)-3-hydroxybutanenitrile 5 and 3-hydroxy-4-
(4-methoxyphenoxy)butanenitrile 6 have been envis-
aged as substrates of special interest as these can be
converted into (S)-propranolol, (S)-alprenolol and
(S)-moprolol by simple reaction sequence in high enan-
tiomeric excess and good yields. The racemic b-hydro-
xy nitriles have been prepared by the ring opening
of their corresponding epoxides 1–3 using NaCN in
aqueous-alcoholic conditions with high regioselectivity
(Eq. 1). The presence of water in the reaction media
makes the reaction slightly basic and also facilitates
the availability of the cyanide nucleophile, thus helping
us to obtain a complete regioselective, opening resul-
ting in good yields.
The enantiomeric excess was calculated from the enan-
tiomeric ratios obtained by employing chiral HPLC. Ini-
tially, the absolute configurations of the alcohol and
acetate obtained after enzymatic resolution were arbi-
trarily assigned as the (S)-alcohol and (R)-acetate from
the enantio-preference for the lipase and from our ear-
lier experiences.15a This was later confirmed by the com-
parison of the chiroptical properties. Comparison of the
specific rotations of the compounds derived, with those
of the compounds known in the literature, established
an (S)-configuration for the alcohol and (R)-configura-
tion for the acetate.
Racemic 3-hydroxy-4-(1-naphthyloxy)butanenitrile
4
was subjected to transesterification by employing vari-
ous lipases and vinyl acetate in diisopropyl ether. Pseu-
domonas cepacia lipase was the most suited lipase for
this reaction. Immobilization provided a revolutionary
change in the enantioselectivity (Table 1: entries 1 and
3) and the reaction rate of this transesterification reac-
tion (Table 1: entries 2 and 3). P. cepacia lipase (PS-D)
catalyzed the reaction at 20–24 ꢁC affording enantiomer-
ically pure (S)-alcohol (S)-4 and (R)-acetate (R)-7 in

A. Kamal et al. / Tetrahedron: Asymmetry 16 (2005) 1485–1494
1487
Table 1. Lipase-catalyzed transesterification of 4-aryloxy-3-hydroxybutanenitriles in diisopropyl ether
Entry
Compound
Lipasea
Time (h)
Alcohol
Yieldb (%)
Acetate
Yieldb (%)
E19
ee%
ee%
1d
2e
3f
4g
5g
6g
7g
8i
4
4
4
5
5
5
5
6
6
6
PS-D
PS-C
PS
48
9
44
44
92.6c
43
46
29
44
45
44
25
44
46
41
>98c
89.2c
>98c
94.3h
90.7h
>99h
93h
>99k
83.4k
>99k
311
75.5c
41
139
127
65
c
12063
9
37
35.0
PS-C
PS-D
Lipozyme
PS
46
45
94.3h
90.3h
87.6h
36.8h
>99j
111
114
12
49
68
581
41
PS-D
PS-C
PS
43
44
1057
31
9i
10i
05
31
87.2j
j
5081.6
501
a Pseudomonas cepacia lipase immobilized on diatomite (PS-D) (Amano Pharmaceutical Company), Pseudomonas cepacia lipase immobilized on
modified ceramic particles (PS-C) (Amano Pharmaceutical Company), Pseudomonas cepacia (PS) (Amano Pharmaceutical Company), immobilized
lipase from Mucor meihei (Lipozyme) (Fluka).
b Isolated yields.
c Determined by chiral HPLC (chiral OJ-H column; Diacel) employing hexane–isopropanol (82:18) as mobile phase at 0.5 mL/min and monitored by
UV (254 nm).
d Reaction carried out at 20–24 ꢁC.
e Reaction carried out at 30 ꢁC.
f Reaction carried out at 40 ꢁC.
g Reaction carried out at 35 ꢁC.
h Determined by chiral HPLC (chiral OD column; Diacel) employing hexane–isopropanol (88:12) as mobile phase at 0.5 mL/min and monitored by
UV (254 nm).
i Reaction carried out at 25–28 ꢁC.
j Determined by chiral HPLC (chiral OD column; Diacel) employing hexane–isopropanol (85:15) as mobile phase at 0.75 mL/min and monitored by
UV (245 nm).
k Determined by chiral HPLC (chiral OJ-H column; Diacel) employing hexane–isopropanol (88:12) as mobile phase at 1.0mL/min and monitored by
UV (245 nm).
high enantiomeric excess and good yields as shown in
Table 1. Enantiomerically pure alcohol (S)-4, which
was obtained after enzymatic resolution, was effectively
employed in the preparation of (S)-propranolol.
pyl ether, hexane, diethyl ether and toluene are the
solvents of choice offering remarkable enantioselectivi-
ties whereas, in hydrophilic solvents such as acetone, tet-
rahydrofuran and acetonitrile, the reaction proceeded
with low conversion rates. The summarized data is illus-
trated in Table 2.
Among the various lipases screened, lipases from vari-
ous sources like P. cepacia, Mucor mehie and Pseudo-
monas fluorescens gave satisfactory results for the
resolution of 4-(2-allylphenoxy)-3-hydroxybutanenitrile
5. Lipase from P. cepacia lipase (PS-C) provided excel-
lent yields with high enantiomeric excess in a short
period of time. Furthermore, the transesterification
process by this immobilized lipase is comparatively
much faster than the use of lipase PS (unimmobilized)
as seen from the detailed data given in Table 1 (entries
4 and 7). The resolved (S)-5 was been later employed
in the preparation of alprenolol.
2.2. Preparation of b-adrenergic blocking agents
The general schematic representation for the prepara-
tion of these b-adrenergic blocking agents is shown in
Scheme 1.
The b-hydroxy nitriles obtained after resolution are one
homologue higher than the target propanol amines. In
order to decrease the aliphatic chain length by one car-
bon, b-hydroxy nitriles (S)-4–6 were treated with H2O2
in aqueous ammonia to afford 4-aryloxy-3-hydroxy
butanamides (S)-10–12. These hydroxyl amides were
then subjected to a Hoffmann type of rearrangement
using Pb(OAc)4 in pyridine to provide 5-aryloxy-
methyl-1,3-oxazolidine-2-one (S)-13–15. Amongst the
number of solvents studied for this rearrangement reac-
tion, pyridine has given good results as it also acts as a
base, thus increasing the rate of the reaction. In this pro-
cess, the vicinal hydroxyl group acts as a nucleophile on
the isocyanate resulting in cyclization to form an oxazo-
lidinone ring system. Oxazolidinones (S)-13–15 were
treated with aqueous NaOH in EtOH to afford b-amino
alcohols as a clean product. These amino alcohols are
the precursors for the preparation of b-adrenergic
blocking agents, their treatment with acetone and
3-Hydroxy-4-(4-methoxyphenoxy)butanenitrile 6 is an-
other substrate of high interest and was effectively re-
solved by transesterification catalyzed by lipase PS-D
at 25–28 ꢁC. This substrate shows faster conversion
rates in better enantiomeric excess than other substi-
tuted substrates probably due to the presence of a para
electron donating substituent.15a Lipase PS-D provides
excellent results with high enantiomeric excess and in
good yields. The thus obtained enantiopure (S)-6 was
employed in the preparation of moprolol.
In this process of resolution, the effect of solvents on the
rate of conversion and enantioselectivity on each sub-
strate was also examined. It was observed that diisopro-

1488
A. Kamal et al. / Tetrahedron: Asymmetry 16 (2005) 1485–1494
Table 2. Effects of solvents on the transesterification of 4-aryloxy-3-hydroxy-butanenitrile by lipases
Sl. no
Compd
Lipase
Solvent
Time (h)
Alcohol
%
Acetate
%
Yielda
ee%
Yielda
ee%
1
4
4
4
4
5
5
5
5
6
6
6
6
PS-D
PS-D
PS-D
PS-D
PS-C
PS-C
PS-C
PS-C
PS-D
PS-D
PS-D
PS-D
Diisopropyl etherb
Tolueneb
48
92
44
52
92.6d
43
35
13
06
44
45
31
15
44
43
>98b
>98d
>98d
>98d
94.3f
90.9f
94.4f
15.7f
>99i
2
70.4d
d
3
Acetonec
120.707
12084
9
20
d
4
Tetrahydrofuranc
Diisopropyl ethere
Hexanee
13.1
46
45
5
94.3f
91.1f
30.7f
3.9f
>99h
>99h
62.9h
40.9h
6
8
7
Acetonee
108
108
12
62
76
8
Acetonitrilee
Diisopropyl etherg
Tolueneg
9
43
44
10
11
12
13
62
>99i
Tetrahydrofurang
Acetonitrileg
63
65
20>99
16
i
62
>99i
a Isolated yields.
b Reaction carried out at 20–24 ꢁC.
c Reaction carried out at 40 ꢁC.
d Determined by chiral HPLC (chiral OJ-H column; Diacel) employing hexane–isopropanol (82:18) as mobile phase at 0.5 mL/min and monitored by
UV (254 nm).
e Reaction carried out at 35 ꢁC.
f Determined by chiral HPLC (chiral OD column; Diacel) employing hexane–isopropanol (88:12) as mobile phase at 0.5 mL/min and monitored by
UV (254 nm).
g Reaction carried out at 25–28 ꢁC.
h Determined by chiral HPLC (chiral OD column; Diacel) employing hexane–isopropanol (85:15) as mobile phase at 0.75 mL/min and monitored by
UV (245 nm).
i Determined by chiral HPLC (chiral OJ-H column; Diacel) employing hexane–isopropanol (88:12) as mobile phase at 1.0mL/min and monitored by
UV (245 nm).
O
OH
OH
O
O
N
ii
i
O
R
NH
O
O
R
NH2
R
(S)-13-15
(S)-4-6
(S)-10-12
iii
OH
O
OH
H
NH2
iv
N
O
R
R
(S)-16-18
(S)-19-21
Scheme 1. R = 2,3-(CH@CH–CH@CH) 4; 2-(CH2–CH@CH2) 5; 4-OCH3 6. Reagents: (i) H2O2, aq NH3; (ii) Pb(OAc)4, pyridine; (iii) NaOH,
EtOH–H2O; (iv) NaBH4, acetone, absolute EtOH.
NaBH4 under anhydrous condition providing the re-
quired b-adrenergic blocking agents (S)-19–21 in high
enantiomeric excess and almost quantitative yield.
exploited in the preparation of intermediates for the syn-
thesis of GABOB and carnitine and also paved the way
for a common intermediate useful in the preparation of
various b-blockers (Scheme 2).
2.3. Preparation of chiral intermediates of synthetic
importance
5-(4-Methoxyphenoxymethyl)-1,3-oxazolidine-2-one (S)-
15 on treatment with a ceric ammonium nitrate (CAN)
in acetonitrile–water system, led to the formation of 5-
hydroxymethyl-1,3-oxazolidine-2-one (S)-22, which in
turn has been converted to 5-(4-methylphenylsulfonyl-
oxymethyl)-1,3-oxazolidine-2-one (S)-23 when treated
with p-toluenesulfonyl chloride and Et3N. As most of
the b-blockers have same chemical structure differing
only in the aryl group, 5-(4-methylphenylsulfonyloxy-
Another interesting aspect of this investigation is that
one of the substrates, 3-hydroxy-4-(4-methoxyphen-
oxy)butanenitrile 6, contains an anisyl group,20 which
has been generally used as a protecting group for pri-
mary alcohols and survives through a series of acidic,
basic, oxidative and reductive reactions and yet can be
readily cleaved under mild conditions. This has been

A. Kamal et al. / Tetrahedron: Asymmetry 16 (2005) 1485–1494
1489
O
O
NH
O
O
NH
i
O
O
ii
O
NH
HO
TsO
H3CO
(S)-15
(S)-22
(S)-23
Scheme 2. Reagents and condition: (i) CAN, CH3CN–H2O, 10min; (ii) p-toluenesulfonyl chloride, Et3N.
methyl)-1,3-oxazolidine-2-one14 is a favourable common
intermediate for the synthesis of various b-adrenergic
blocking agents as the tosyl group can be easily dis-
placed with various phenols leading to the formation
of various b-adrenergic blocking agents. On the other
hand, (R)-3-hydroxy-4-(4-methoxyphenoxy)butanenit-
rile (R)-6 prepared from (R)-3-acetyloxy-4-(4-methoxy-
phenoxy)butanenitrile (R)-15 was treated with CAN
in acetonitrile–water system to afford (R)-3,4-di-
hydroxybutanenitrile, which in turn was transformed
to (R)-3-hydroxy-4-(4-methylphenylsulfonyloxy)butane-
nitrile21 (R)-24 an intermediate for synthesis of (R)-GA-
BOB and (R)-carnitine, compounds of pharmacological
importance (Scheme 3).
and are uncorrected. Infrared spectra were recorded
on Perkin–Elmer model 683 or 1310spectrometers and
are reported in wave numbers (cmÀ1). 1H 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 tet-
ramethylsilane (TMS) as an internal standard. Spectral
patterns are designated as s, singlet; d, doublet; dd, dou-
ble 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 Micromass mass spectrometers.
Analytical TLC of all reactions was performed on
Merck prepared plates (silica gel 60F-254 on glass). Col-
umn 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 sys-
tem controller with a SPD-10A fixed wavelength UV
monitor as detector. Optical rotations were measured
on SEPA-300 (Horiba) digital polarimeter.
3. Conclusion
An efficient and practical preparation of b-hydroxy nitr-
iles and their successful enzymatic kinetic resolution
using lipases has been demonstrated, which has been
further extended for the preparation of biologically
important compounds like b-adrenergic blocking
agents. Furthermore, some chiral intermediates of high
synthetic importance in the preparation of biologically
important compounds have also been prepared from
these b-hydroxy nitriles.
4.2. General procedure for the oxirane ring opening
The epoxide (20mmol) was dissolved in ethanol (20mL)
and to this was added water (100 mL). After stirring for
5 min, NaCN (28 mmol) was added and stirring contin-
ued at room temperature. On completion of the reaction
as indicated by TLC, the reaction mixture was concen-
trated to about half the volume under reduced pressure.
The residue was extracted with ethyl acetate, washed
with brine and dried over anhydrous Na2SO4. Evapora-
tion and purification by column chromatography
employing EtOAc–hexane (3:7) as the eluent afforded
pure b-hydroxy nitriles.
4. Experimental
4.1. General
Unless specified all solvents and reagents were reagent
grade and used without further purification. Reactions
involving moisture-sensitive reagents were performed
under an inert atmosphere of nitrogen in glassware,
which had been oven dried. Melting points were re-
corded on an electrothermal melting point apparatus
4.2.1. 3-Hydroxy-4-(1-naphthyloxy)butanenitrile 4. 3-
(1-Naphthyloxy)-1,2-epoxy-propane 1 when treated
with NaCN for 18 h as described in the above general
OAc
N
OH
N
OH
O
O
i
ii
N
HO
H3CO
H3CO
(R)-9
(R)-6
OH
(R)-GABOB
N
TsO
&
(R)-CARNITINE
(R)-24
Scheme 3. Reagents and condition: (i) K2CO3, methanol; (ii) CAN, CH3CN–H2O, 10min; (iii) p-toluenesulfonyl-chloride, Et3N, dibutyltinoxide,
DCM.

1490
A. Kamal et al. / Tetrahedron: Asymmetry 16 (2005) 1485–1494
procedure for the ring opening of oxiranes resulted in
white solid 4 and is previously reported.15a
4.3.3.
3-Acetyloxy-4-(4-methoxyphenoxy)butanenitrile
9. 3-Hydroxy-4-(4-methoxyphenoxy)butanenitrile was
acetylated using acetic anhydride and pyridine employ-
ing the above general procedure to obtain 9 in almost
quantitative yield. 1H NMR (200 MHz, CDCl3) 2.14
(s, 3H), 2.86 (d, 2H, J = 5.8 Hz), 3.76 (s, 3H), 3.99–
4.16 (m, 2H), 5.19–5.31 (m, 1H), 6.75–6.81 (m, 4H);
Mass (EI) 249 (M+), 207, 167, 149, 139, 124, 123, 77.
4.2.2. 3-Hydroxy-4-(2-allylphenoxy)butanenitrile 5. 3-
(2-Allylphenoxy)-1,2-epoxy-propane
2 when treated
with NaCN for 12 h as described in the above general
procedure for the ring opening of oxiranes resulted in
5. Yield 86%; IR (neat): 3443, 3059, 3035, 2988, 2915,
2862, 2235, 1490, 1239, 1106, 1051 cmÀ1 1H NMR
;
(200 MHz, CDCl3) d 2.62–2.84 (m, 2H), 3.15 (br s,
1H), 3.41 (d, 2H, J = 6.8 Hz), 4.04–4.15 (m, 2H), 4.24–
4.36 (m, 1H), 4.98–5.11 (m, 2H), 5.88–6.06 (m, 1H),
6.83 (d, 1H, J = 7.9 Hz), 6.90–6.99 (m, 1H), 7.13–7.29
(m, 2H); Mass (EI) 217 (M+), 147, 134, 119, 117, 103,
91, 77, 43.
4.4. General procedure for the resolution of b-hydroxy
nitriles
b-Hydroxy nitriles (5 mmol) were dissolved in diisopro-
pyl ether (50mL) and to this, lipase and vinyl acetate
(12.5 mmol) were added successively and shaken in an
orbital shaker. After about 50% completion of the reac-
tion, as indicated by the HPLC, the reaction mixture
was filtered and washed with EtOAc. Solvents were
evaporated and purification accomplished by column
chromatography employing EtOAc–hexane (25:75) as
the eluent to afford the corresponding (R)-acetate fol-
lowed by the unreacted (S)-b-hydroxy nitrile.
4.2.3.
3-Hydroxy-4-(4-methoxyphenoxy)butanenitrile
6. 3-(4-Methoxyphenoxy)-1,2-epoxy-propane 3 when
treated with NaCN for 12 h as described in the above
general procedure for the ring opening of oxiranes re-
sulted in white crystalline solid 6. Yield 85%; mp 66–
69 ꢁC; 1H NMR (300 MHz, CDCl3) d 2.61–2.77 (m,
2H), 3.75 (s, 3H), 3.98 (d, 2H, J = 5.7 Hz), 4.24–4.29
(m, 1H), 6.75–6.83 (m, 4H); Mass (EI) 207 (M+), 180,
166, 149, 137, 124, 123, 77.
4.4.1.
(R)-3-Acetyloxy-4-(1-naphthyloxy)butanenitrile
(R)-7. Resolution of 3-hydroxy-4-(1-naphthyloxy)-
butanenitrile 4 by employing the typical procedure using
P. cepacia lipase immobilized on diatomite (PS-D)
4.3. General procedure for preparation of 3-acetyloxy-4-
aryloxybutanenitrile
afforded (R)-7 in 43% yield and >98% ee after 48 h.
25
D
tral data are identical to 7.
½aŠ ¼ þ26:84 (c 1.0, CHCl3); IR, NMR and mass spec-
To 4-aryloxy-3-hydroxybutanenitrile (5.00 mmol) under
N2 was added acetic anhydride (20.00 mmol) and pyri-
dine (5.50mmol) and the resultant mixture stirred at
room temperature overnight. After completion of the
reaction (TLC), the reaction mixture was diluted with
ethyl acetate (25 mL) and treated with 1 M HCl
(20mL). The organic layer was separated, washed with
brine and dried over anhydrous Na2SO4. The solvent
was evaporated and the residue was purified by column
chromatography employing EtOAc–hexane (15:85) as
eluent to afford the required 3-acetyloxy-4-aryloxybu-
tanenitrile in nearly quantitative yield.
4.4.2. (S)-3-Hydroxy-4-(1-naphthyloxy)butanenitrile (S)-
4. Resolution of 3-hydroxy-4-(1-naphthyloxy)butane-
nitrile 4 by employing the above general procedure for
the resolution of b-hydroxy nitriles by employing P.
cepacia lipase immobilized on diatomite (PS-D) in diiso-
propyl ether at 22 ꢁC afforded (S)-4 in 44% yield and
26
92.6% ee after 48 h. Mp 65–68 ꢁC; ½aŠ ¼ À15:2 (c
D
1.05, CHCl3); IR, NMR and mass spectral data are
identical to 4.
4.4.3.
(R)-3-Acetyloxy-4-(2-allylphenoxy)butanenitrile
4.3.1. 3-Acetyloxy-4-(1-naphthyloxyphenoxy)butanenit-
rile 7. 3-Hydroxy-4-(1-napthyloxy)butanenitrile was
acetylated using acetic anhydride and pyridine employ-
ing the above general procedure to obtain 7 in almost
quantitative yield. IR (neat) 3059, 2937, 2255, 1742,
(R)-8. The resolution of 3-hydroxy-4-(2-allylphenoxy)-
butanenitrile 5 was carried out by employing the typical
procedure at 35 ꢁC using P. cepacia lipase immobilized
on modified ceramic particles (PS-C) to afford (R)-8
26
in 44% yield and 94.3% ee after 9 h. ½aŠ ¼ þ28:7 (c
D
1.25, CHCl3); NMR and mass spectral data are identical
to 8.
1
1393, 1218, 1105 cmÀ1; HNMR (200 MHz, CDCl3) d
8.13–8.20(m, 1H), 7.75–7.83 (m, 1H), 7.25–7.52 (m,
4H), 6.8 (d, J = 7.14 Hz, 1H), 5.41–5.52 (m, 1H), 4.26–
4.40(m, 2H), 2.97 (d, J = 4.76 Hz, 2H), 2.18 (s, 3H);
Mass (EI) 269, 164, 126.
4.4.4. (S)-3-Hydroxy-4-(2-allylphenoxy)butanenitrile (S)-
5. The resolution of 3-hydroxy-4-(2-allylphenoxy)-
butanenitrile 5 was carried out by employing the typical
procedure at 35 ꢁC using P. cepacia lipase immobilized
4.3.2. 3-Acetyloxy-4-(2-allylphenoxy)butanenitrile 8. 3-
Hydroxy-4-(2-allylphenoxy)butanenitrile was acetylated
using acetic anhydride and pyridine employing the
above general procedure to obtain 8 in almost quantita-
on modified ceramic particles (PS-C) to afford ((S)-5)
26
in 46% yield and 94.3% ee after 9 h. ½aŠ ¼ À1:9 (c
D
2.6, CHCl3); IR, NMR and mass spectral data are
identical to 5.
1
tive yield. H NMR (200 MHz, CDCl3) d 2.14 (s, 3H),
2.87 (d, 2H, J = 4.5 Hz), 3.35 (d, 2H, J = 6.3 Hz),
4.06–4.22 (m, 2H), 4.94–5.03 (m, 2H), 5.25–5.36 (m,
1H), 5.83–6.00 (m, 1H), 6.81 (d, 1H, J = 7.9 Hz), 6.88–
6.95 (m, 1H), 7.10–7.25 (m, 2H); Mass (EI) 259 (M+),
126, 91, 43.
4.4.5. (R)-3-Acetyloxy-4-(4-methoxyphenoxy)butanenit-
rile (R)-9. The resolution of 3-hydroxy-4-(4-methoxy-
phenoxy)butanenitrile 6 was carried out by employing
the typical procedure using P. cepacia lipase

A. Kamal et al. / Tetrahedron: Asymmetry 16 (2005) 1485–1494
1491
immobilized on diatomite (PS-D) to afford (R)-9 in 44%
yield and >99% ee after 12 h. ½aŠ ¼ þ24:1 (c 1.3,
4-(2-allylphenoxy)-3-hydroxy butanenitrile (4.00 g,
18.43 mmol), aqueous NH3 (60mL) and H 2O2 (100
vol) (42 mL, 368.00 mmol). ½aŠ ¼ À18:1 (c 1.0, CHCl3);
27
D
CHCl3); NMR and mass spectral data are identical to 9.
27
D
IR (neat): 3388, 3075, 2973, 2925, 2871, 1671, 1490,
1
4.4.6. (S)-3-Hydroxy-4-(4-methoxyphenoxy)butanenitrile
(S)-6. The resolution of 3-hydroxy-4-(4-methoxyphen-
oxy)butanenitrile 6 was carried out by employing the
typical procedure using P. cepacia lipase immobilized
1435, 1239, 1114, 1035; H NMR (200 MHz, CDCl3) d
2.47–2.54 (m, 2H), 3.36 (d, 2H, J = 5.9 Hz), 3.95 (d,
2H, J = 5.3 Hz), 4.23–4.40(m, 1H), 4.94–5.05 (m, 2H),
5.75–6.00 (m, 1H), 6.79 (d, 1H, J = 8.1 Hz), 6.85–6.92
(m, 1H), 7.08–7.25 (m, 2H); Mass (EI) 235 (M+), 218,
208, 133, 131, 102, 91, 77, 44.
on diatomite (PS-D) to afford (S)-6 in 43% yield and
27
D
CHCl3); NMR and mass spectral data are identical to 6.
>99% ee after 12 h. Mp 57–60 ꢁC; ½aŠ ¼ À5:5 (c 1.2,
4.8. (S)-3-Hydroxy-4-(4-methoxyphenoxy)butanamide
(S)-12
4.5. (R)-3-Hydroxy-4-(4-methoxyphenoxy)butanenitrile
(R)-6
The title compound was prepared using a similar proce-
dure to that of the preparation of 10 employing 3-hydr-
oxy-4-(4-methoxyphenoxy)butanenitrile (2.86 g, 13.82
mmol), 10–15 mL of ethanol, aq NH3 (48 mL) and
To a stirring solution of (R)-3-acetyloxy-4-(4-methoxy-
phenoxy)butanenitrile (5.00 g, 20.08 mmol) in 80 mL
of methanol was added K2CO3 (11.08 g, 80.32 mmol)
at room temperature and the reaction progress moni-
tored by TLC. After completion of the reaction (1 h),
methanol was evaporated and the residue was separated
between ethyl acetate (60mL) and water (40mL). The
aqueous layer was then extracted with EtOAc
(3 · 50mL) and the combined organic layers were
washed with brine and dried over anhydrous Na2SO4.
The organic solvent was evaporated to leave a residue
H2O2 (100 vol) (32 mL, 276.40 mmol) and carrying out
27
D
the reaction for 2 h. Mp 126–127 ꢁC; ½aŠ ¼ À7:1 (c
1
0.95, EtOH); H NMR (200 MHz, DMSO(d6)) d 2.21–
2.40(m, 2H), 3.66 (s, 3H), 3.68–3.82 (m, 2H), 4.90–
4.19 (m, 1H), 4.99 (d, 1H (OH), J = 4.3 Hz), 6.52 (br
s, 1H), 6.67–6.79 (m, 4H), 7.18 (br s, 1H); Mass (EI)
225 (M+), 207, 137, 124, 123, 109, 77.
of (R)-3-hydroxy-4-(4-methoxyphenoxy)butanenitrile in
4.9. (S)-5-(1-Naphthyloxymethyl)-1,3-oxazolidine-2-one
(S)-13
27
almost quantitative yield. Mp 56–59 ꢁC; ½aŠ ¼ þ5:1 (c
D
1.2, CHCl3); NMR and mass spectral data are identical
to 6.
To a solution of 3-hydroxy-4-(1-naphthyloxy)butana-
mide (S)-10 (3.60g, 14.70mmol) in pyridine (35 mL)
was added Pb(OAc)4 (9.10g, 20.50mmol) and the resul-
tant reaction mixture was stirred under N2 at room tem-
perature for 1 h. After completion of the reaction as
indicated by TLC, the reaction mixture was taken up
in CH2Cl2 (100 mL) and then treated with 10% HCl
(125 mL). The resultant reaction mixture was filtered
through a celite pad and the residue washed three times
with CH2Cl2 (50mL). The organic layer from the com-
bined filtrates and washings were separated and the
aqueous layer extracted with CH2Cl2 (2 · 100 mL).
The organic layer, free from pyridine, was washed with
brine, dried over anhydrous Na2SO4 and concentrated
to leave a residue of crude oxazolidinone (S)-13, which
was purified by column chromatography employing
EtOAc–hexane (40:60) as eluent to afford pure 5-(1-
4.6. (S)-3-Hydroxy-4-(1-naphthyloxy)butanamide (S)-10
3-Hydroxy-4-(1-naphthyl-oxy)butanenitrile (4.54 g, 20.00
mmol) was dispersed in 15 mL of ethanol and aq NH3
(65 mL) was added to it at room temperature. To the
resulting mixture was added H2O2 (100 vol) (45 mL,
400 mmol) in portions, while maintaining the tempera-
ture of the reaction mixture below 25 ꢁC. After complete
addition, the resultant reaction mixture was stirred vig-
orously at 25–30 ꢁC and the reaction progress moni-
tored by TLC. After completion of the reaction
(45 min), the reaction volume was concentrated to about
50% of the original volume under reduced pressure and
the resultant mixture was extracted with dichlorometh-
ane (3 · 80mL). The combined organic layers were
dried over anhydrous Na2SO4 and the solvent was evap-
orated to leave a residue, which was purified by column
chromatography employing EtOAc–hexane (80:20) as
eluent to afford 3-hydroxy-4-(1-naphthyloxy)butana-
naphthyloxymethyl)-1,3-oxazolidine-2-one (S)-13 in
24
D
85% yield. Mp 152–154 ꢁC; ½aŠ ¼ À20:4 (c 0.75,
1
CHCl3); H NMR (200 MHz, CDCl3) d 3.66–3.96 (m,
2H), 4.31 (d, 2H, J = 5.0Hz), 5.02–5.20 (m, 1H), 5.73
(br s, 1H), 6.80(d, 1H, J = 6.8 Hz), 7.29–7.58 (m, 4H),
7.73–7.87 (m, 1H), 8.13–8.26 (m, 1H); Mass (EI) 243
(M+), 144, 127, 115, 57, 43.
mide in almost quantitative yield. Mp 123–125 ꢁC;
25
½aŠ ¼ À7:5 (c 1.0, MeOH); 1H NMR (200 MHz,
D
DMSO (d6)) d 2.39–2.58 (m, 2H), 3.97–4.12 (m, 2H),
4.33–4.42 (m, 1H), 5.10(br s, 1H), 6.42 (br s, 1H),
6.77 (d, 1H, J = 6.6 Hz), 7.16 (br s, 1H), 7.23–7.40(m,
4H), 7.67–7.71 (m, 1H), 8.21–8.26 (m, 1H); Mass (EI)
227 (M+À18), 218, 167, 149, 144, 127, 115, 102, 71,
57, 43.
4.10. (S)-5-(2-Allylphenoxymethyl)-1,3-oxazolidine-2-one
(S)-14
The title compound was prepared using a similar proce-
dure to that of the preparation of 13 employing 4-(2-
allylphenoxy)-3-hydroxy butanamide (1.80g, 7.66
4.7. (S)-4-(2-Allylphenoxy)-3-hydroxybutanamide (S)-11
mmol), pyridine (18 mL) and Pb(OAc)4 (4.76 g, 10.73
25
D
IR (neat) 3286, 3075, 2980, 2915, 1741, 1498, 1239,
The title compound was prepared using a similar pro-
cedure to that of the preparation of 10 employing
mmol). Yield 88% yield; ½aŠ ¼ þ8:1 (c 1.1, CHCl3);

1492
A. Kamal et al. / Tetrahedron: Asymmetry 16 (2005) 1485–1494
28
D
1098; 1H NMR (200 MHz, CDCl3) d 3.34 (d, 2H,
J = 6.1 Hz), 3.60–3.87 (m, 2H), 4.14 (d, 2H,
J = 5.4 Hz), 4.94–5.03 (m, 3H), 5.81–5.99 (m, 1H), 6.25
(br s, 1H), 6.79 (d, 1H, J = 7.5 Hz), 6.83–6.97 (m, 1H),
7.10–7.26 (m, 2H); Mass (EI) 234 (M++1), 206, 190,
173, 159, 145, 133, 131, 91, 56, 43.
tion for 80 min. Yield 80%; mp 100–103 ꢁC; ½aŠ ¼ À5:5
1
(c 0.85, EtOH); H NMR (200 MHz, CDCl3) d 2.70–
3.00 (m, 2H), 3.75 (s, 3H), 3.85–4.00 (m, 3H), 6.75–
6.90(m, 4H); Mass (EI) 197 (M +), 167, 150, 137, 124,
109.
4.15. (S)-1-Isopropylamino-3-(1-naphthyloxy)-2-propanol
(propranolol) (S)-19
4.11. (S)-5-(4-Methoxyphenoxymethyl)-1,3-oxazolidine-
2-one (S)-15
To a solution of 1-amino-3-(1-naphthyloxy)-2-propanol
(0.44 g, 2.03 mmol) in 10 mL of absolute ethanol was
added 0.8 mL of acetone under N2 at room temperature.
To the resultant reaction mixture, NaBH4 (0.20 g,
5.26 mmol) was added slowly over a period of 3 min in
three portions. Five minutes later, the entire set of
NaBH4 additions were repeated after adding another
0.8 mL of acetone. After complete additions, the reac-
tion mixture was flushed with N2, stirred at room tem-
perature and the reaction progress was monitored by
TLC. After completion of the reaction (45 min) H2O
(20mL) was added to the reaction mixture and then ex-
tracted with CH2Cl2 (3 · 30mL). The combined organic
layers were washed with brine and dried over anhydrous
Na2SO4. Evaporation of the solvent under reduced pres-
sure and purification of the residue by column chroma-
tography employing MeOH–CHCl3 (5:95) as eluent
afforded propranolol in 85–90% yield. Mp 70–72 ꢁC;
The title compound was prepared using a similar proce-
dure to that of the preparation of 13 employing 3-hydro-
xy-4-(4-methoxyphenoxy)butanamide (2.60g, 11.56
mmol), pyridine (25 mL) and Pb(OAc)4 (7.18 g, 16.20
mmol) and carrying out the reaction for 90min. Yield
26
80%; mp 118–120 ꢁC; ½aŠ ¼ þ16:8 (c 1.05, CHCl3);
D
1H NMR (200 MHz, CDCl3) d 3.42–3.50(m, 1H),
3.60–3.66 (m, 1H), 3.72 (s, 3H), 3.98–4.10 (m, 2H),
4.76–4.89 (m, 1H), 6.71–6.82 (m, 4H), 7.26 (br s, 1H);
Mass (EI) 223 (M+), 137, 124, 109, 77.
4.12. (S)-1-Amino-3-(1-naphthyloxy)-2-propanol (S)-16
To
a
solution of oxazolidinone (S)-13 (1.46 g,
6.00 mmol) in 15 mL of ethanol was added NaOH
(1.20 g, 30.00 mmol) dissolved in 8 mL of water at room
temperature and the resultant reaction mixture refluxed
for 1 h. After completion of the reaction (TLC) ethanol
was evaporated and the resultant mixture was diluted
with water and then extracted with CH2Cl2 (3 · 50mL).
The organic layer was washed with brine, dried over
anhydrous Na2SO4 and concentrated to leave a residue,
which was purified by column chromatography employ-
ing MeOH–CHCl3 (10:90) as eluent to afford
25
25
½aŠ ¼ À9:8 (c 1.0, EtOH); lit.12e ½aŠ ¼ À10:2 (c 1.02,
D
D
EtOH); 1H NMR (200 MHz, CDCl3) d 1.15 (d, 6H,
J = 6.4 Hz), 2.80–3.01 (m, 3H), 3.42 (br s, 1H), 4.06–
4.20(m, 3H), 6.75 (d, 1H, J = 6.9 Hz), 7.25–7.45 (m,
4H), 7.71–7.77 (m, 1H), 8.16–8.22 (m, 1H); Mass (EI)
+
260(M +1), 216, 145, 128, 116, 72, 57, 43.
pure 1-amino-3-(1-naphthyloxy)-2-propanol in 80%
4.16. (S)-3-(2-Allylphenoxy)-1-isopropylamino-2-propa-
nol (alprenolol) (S)-20
25
D
yield. Mp 113–116 ꢁC; ½aŠ ¼ À10:4 (c 0.9, EtOH); lit.12c
25
D
½aŠ ¼ À7:3 (c 0.51, CHCl3). 1H NMR (200 MHz,
DMSO (d6)) d 2.92–3.20 (m, 2H), 4.00–4.22 (m, 3H),
6.80(d, 1H, J = 6.9 Hz), 7.28–7.55 (m, 4H), 7.70–7.80
(m, 1H), 8.18–8.30(m, 1H); Mass (EI) 217 (M +), 169,
155, 144, 115, 74, 43.
The title compound was prepared using a similar proce-
dure to that of the preparation of 19 employing 3-(2-
allylphenoxy)-1-amino-2-propanol (0.68 g, 3.29 mmol),
10–12 mL of absolute ethanol, 1.2 mL of acetone and
27
D
NaBH4 (0.31 g, 8.23 mmol). Yield 88%; ½aŠ ¼ À15:7
1
4.13. (S)-3-(2-Allylphenoxy)-1-amino-2-propanol (S)-17
(c 1.1, CHCl3); H NMR (200 MHz, CDCl3) d 1.25 (d,
6H, J = 6.0Hz), 2.94–3.19 (m, 3H), 3.34 (d, 2H,
J = 6.9 Hz), 3.85–4.04 (m, 2H), 4.22–4.25 (m, 1H),
4.93–5.01 (m, 2H), 5.80–6.01 (m, 1H), 6.75 (d, 1H,
J = 7.4 Hz), 6.80–6.88 (m, 1H), 7.05–7.14 (m, 2H); Mass
The title compound was prepared using a similar proce-
dure to that of the preparation of 16 employing 5-
(2-allylphenoxymethyl)-1,3-oxazolidine-2-one (1.20g,
5.15 mmol), 15 mL of ethanol and NaOH (1.03 g,
+
(EI) 250(M +1), 91, 77.
25.75 mmol) in 8 mL of water. Yield 82%; mp
25
D
41–42 ꢁC; ½aŠ ¼ À8:3 (c 1.8, CHCl3); 1H NMR
4.17. (S)-1-Isopropylamino-3-(4-methoxyphenoxy)-
2-propanol (moprolol) (S)-21
(200 MHz, DMSO (d6)) 2.80–3.04 (m, 2H), 3.36 (d,
2H, J = 5.9 Hz), 3.80–3.96 (m, 3H), 4.95–5.04 (m, 2H),
5.80–6.01 (m, 1H), 6.77–6.90 (m, 2H), 7.07–7.17 (m,
2H); Mass (EI) 207 (M+), 190, 134, 133, 102, 91, 77.
The title compound was prepared using a similar
procedure to that of the preparation of 19 employing
1-amino-3-(4-methoxyphenoxy)-2-propanol (0.50 g, 2.54
mmol), 10mL of absolute ethanol, 0.9 mL of acetone
4.14. (S)-1-Amino-3-(4-methoxyphenoxy)-2-propanol
(S)-18
and NaBH4 (0.24 g, 6.40 mmol) and carrying out the
28
D
reaction for 1 h. Yield 88%; mp 50–53 ꢁC; ½aŠ ¼ À7:5
1
The title compound was prepared using a similar proce-
dure to that of the preparation of 16 employing 5-(4-
methoxyphenoxymethyl)-1,3-oxazolidine-2-one (1.20g,
5.38 mmol), 15 mL of ethanol and NaOH (1.08 g,
27.00 mmol) in 8 mL of water and carrying out the reac-
(c 0.9, CHCl3); H NMR (200 MHz, CDCl3) d 1.11 (d,
6H, J = 6.8 Hz), 2.32 (br s), 2.68–2.94 (m, 3H), 3.76 (s,
3H), 3.94 (d, 2H, J = 4.2 Hz), 3.98–4.07 (m, 1H), 6.84–
7.27 (m, 4H); Mass (EI) 239 (M+), 195, 166, 150, 137,
124, 123, 109, 77.

A. Kamal et al. / Tetrahedron: Asymmetry 16 (2005) 1485–1494
1493
26
D
4.18. (S)-5-Hydroxymethyl-1,3-oxazolidine-2-one (S)-22
oxy)butanenitrile in 65% yield. ½aŠ ¼ þ13:5 (c 1.45,
1
EtOH); H NMR (300 MHz, CDCl3) d 2.48 (s, 3H),
2.52–2.67 (m, 2H), 4.06 (d, 2H, 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.
To a stirred solution of 5-(4-methoxyphenoxymethyl)-
1,3-oxazolidine-2-one (0.60 g, 2.69 mmol) in 30 mL of
CH3CN-H2O (4:1) at 0 ꢁC was added ceric ammonium
nitrate (2.95 g, 5.38 mmol) and the progress of the reac-
tion monitored by TLC. After completion of the reac-
tion (10min) the reaction mixture was filtered through
a silica pad and the filtrate was concentrated to leave a
residue, which was purified by column chromatography
employing MeOH–EtOAc (5:95) as eluent to afford
5-hydroxymethyl-1,3-oxazolidine-2-one in 45% yield. Mp
Acknowledgements
The authors G.B.R.K., T.K., T.V. and R.R. thanks
CSIR, New Delhi for the award of research fellowship.
27
D
1
70–73 ꢁC; ½aŠ ¼ þ32:8 (c 0.6, EtOH); H NMR (200
References
MHz, DMSO (d6)) d 3.35–3.75 (m, 4H), 4.50–4.64 (m,
1H), 4.85 (br s, 1H).
1. (a) Horri, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano,
N.; Matsui, K. J. Med. Chem. 1986, 29, 1038; (b)
Hashiguchi, S.; Kawada, A.; Natsugari, H. J. Chem.
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B. G.; Tucker, H. In Medicinal Chemistry: The role of
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Crowther, A. F.; Smith, L. H. J. Med. Chem. 1968, 11,
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R. P.; Vandenbossche, C. P.; Wald, S. A. Tetrahedron
Lett. 1993, 40, 819.
4.19. (S)-5-(4-Methylphenylsulfonyloxymethyl)-1,3-oxaz-
olidine-2-one (S)-23
p-Toluene-sulfonyl chloride (0.30 g, 1.60 mmol) and
Et3N (0.16 g, 1.60 mmol) were added to 5-hydroxy-
methyl-1,3-oxazolidine-2-one (0.12 g, 1.03 mmol) dis-
persed in 8 mL of CH2Cl2 and stirred overnight at
room temperature under N2. After completion of the
reaction (TLC), the solvent in the reaction mixture
was evaporated and the residue purified by column chro
matography employing EtOAc–hexane (75:25) as eluent
to afford 5-(4-methylphenylsulfonyloxymethyl)-1,3-oxaz-
27
D
(c 1.25, CHCl3); IR (KBr) 3247, 2933, 2886, 2824,
olidine-2-one in 80% yield. Mp 96–99 ꢁC; ½aŠ ¼ þ44:4
1741, 1012, 949 cmÀ1 1H NMR (200 MHz, CDCl3)
;
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.
2. (a) Powell, J. R.; Wainer, I. W.; Drayer, D. E. Drug
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4.20. (R)-3-Hydroxy-4-(4-methylphenylsulfonyl-
oxy)butanenitrile (R)-24
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To a stirring solution of (R)-3-hydroxy-4-(4-methoxy-
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100 mL of CH3CN–H2O (4:1) at 0 ꢁC was added ceric
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gress of the reaction monitored by TLC. After comple-
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room temperature and under N2. The resultant reaction
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and organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (3 · 150mL) and the combined
organic layers were dried over anhydrous Na2SO4, con-
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