A facile preparation of (±)-β-hydroxy nitriles and their enzymatic resolution with lipases

Article abstract of DOI:10.1016/S0957-4166(01)00058-1

A simple and efficient method for the preparation of racemic 4-aryloxy-3-hydroxybutanenitriles is described. Lipase mediated kinetic resolution in organic media was then utilised to effect enantioseparation. Lipases from different sources were screened in the resolution reaction using a number of organic solvents. Enantiomeric excesses of up to 99% were obtained by employing lipase from Pseudomonas cepacia in di-iso-propyl ether medium.

Full text of DOI:10.1016/S0957-4166(01)00058-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 405–410
A facile preparation of ( )-b-hydroxy nitriles and their
enzymatic resolution with lipases
Ahmed Kamal* and G. B. Ramesh Khanna
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
Received 18 December 2000; accepted 5 February 2001
Abstract—A simple and efficient method for the preparation of racemic 4-aryloxy-3-hydroxybutanenitriles is described. Lipase
mediated kinetic resolution in organic media was then utilised to effect enantioseparation. Lipases from different sources were
screened in the resolution reaction using a number of organic solvents. Enantiomeric excesses of up to 99% were obtained by
employing lipase from Pseudomonas cepacia in di-iso-propyl ether medium. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
when the substrate was suitably modified, particularly
when sulphur functionalities were incorporated.8 How-
ever, the mechanism of this enhancement is unclear.
The incubation of a-cyanoketones in the presence of
baker’s yeast under typical enzymatic reaction condi-
tions produced mainly the reduced alkylated product;9
more recently, the yeast mediated reduction10 of a-
cyanoketones at 4°C over 7 days afforded (S)-3-
hydroxy nitrile in 59% yield.
b-Hydroxy nitriles have importance both as reagents
and as technical products in organic chemistry and
have been extensively investigated and employed in
synthetic chemistry for the preparation of intermediates
of many naturally occurring bioactive compounds.1,2
Chiral non-racemic b-hydroxy nitriles are useful chiral
building blocks in asymmetric synthesis, as the cyano
group is a precursor of both amino and carbonyl
groups. Furthermore, the stereogenicity at the hydroxyl
group can be used to control the generation of new
stereocentres, thus offering potential routes to
homochiral 1,3-diols3 and 1,3-amino alcohols.4 The
synthesis of homochiral 1,3-amino alcohols still remains
an attractive target because of their versatility as syn-
thetic intermediates for a large number of natural prod-
ucts, antibiotics5 and chiral auxiliaries.6
2. Results and discussion
2.1. Synthesis of b-hydroxy nitriles
The method reported herein describes the stereoselec-
tive acylation of 4-aryloxy-3-hydroxybutanenitrile with
lipases by a transesterification process. These nitriles
have been described in the literature11 as precursors for
compounds having different pharmaceutical properties,
namely cardiovascular, anti-arrhythmic and sympa-
tholytic. The ( )-b-hydroxy nitriles required as sub-
strates for the enzymatic resolution were obtained by
the facile ring opening of oxiranes, a direct and simple
method for b-hydroxy nitriles.
There are few reports on the preparation of homochiral
b-hydroxy nitriles and in continuation of our earlier
efforts towards the synthesis of biologically important
compounds employing enzymatic methodologies,7 we
herein report a simple practical preparation of b-
hydroxy nitriles and their resolution employing lipases.
Earlier enzymatic methods described for the prepara-
tion of homochiral b-hydroxy nitriles are mainly based
on lipase catalysed hydrolysis reactions.8 An enhance-
ment in the enantioselectivity of the reaction was seen
In the literature, ring opening of epoxides with cyanide
as a nucleophile has been carried out by employing
volatile and toxic HCN,12 non-volatile alkali cyanides
in the presence of perchlorate salts13 or Yb(CN)3.13,14
Some methods employ acetone cyanohydrin in the pres-
ence of a base15 or lanthanide alkoxides,16 alkyl alu-
minium cyanides17 and Ce(OTf)4.18 In most literature
* Corresponding author. Fax: +91 40 7173387; e-mail: ahmedkamal
@iict.ap.nic.in
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00058-1

406
A. Kamal, G. B. Ramesh Khanna / Tetrahedron: Asymmetry 12 (2001) 405–410
2.2. Enzymatic resolution of b-hydroxy nitriles
OH
O
O
N
O
NaCN
The enantioselective resolution of racemic b-hydroxy
nitriles has been carried out by employing different
lipases such as Pseudomonas cepacia (Amano), Candida
rugosa (Sigma), Candida cylindracea (Sigma), Lipozyme
(Mucor meihei, Novo Nordisk) and porcine pancreas
(Sigma) in a number of organic solvents including
di-iso-propyl ether, tetrahydrofuran, tert-butyl methyl
ether and toluene. It was observed that lipase from P.
cepacia produced good conversions in di-iso-propyl
ether, as shown in Scheme 2.
EtOH/H2O
R
R
1a-g
2a-g
Scheme 1.
methods the reaction conditions are usually severe,
some reagents are commercially unavailable and have
to be prepared from alkali cyanides, whilst the use of
alkyl aluminium cyanides presents a difficulty in large
scale reactions. Trimethylsilylcyanide (TMSCN)14,17b,19
has been used in the preparation of b-hydroxy nitriles,
but a problem with this is that the isonitrile can be
formed14,19d as the main product. To overcome these
limitations we developed a new approach of oxirane
ring opening with sodium cyanide in aqueous–alcoholic
conditions to afford b-hydroxy nitriles (Scheme 1) in
good to excellent yields, as shown in Table 1.
E.e.s were calculated from the enantiomeric ratios mea-
sured using a Chiralcel OD column. The absolute
configuration of the enantiomerically pure (S)-4-aryl-
oxy-3-hydroxybutanenitriles was assigned by preparing
standards from enantiomerically pure 1-chloro-3-aryl-
oxy-2-propanol using lipase from Pseudomonas sp. as
described in the literature.20 Comparison of the specific
rotation established the (S)-configuration of the alcohol
and the (R)-configuration of the acetate. The configura-
tions were further confirmed by comparison of the
chiral HPLC data. In this study, all acetates were
obtained in high enantiomeric purities. The substrates
with para-substitution (2c–2e), as given in Table 2,
show comparatively higher conversion rates with better
e.e. In the case of 2b, 2f and 2g as the reaction proceeds
slowly, efforts have been made to shorten the reaction
time by increasing the temperature to 40°C, which
improved the conversion rates.
Table 1. Ring opening of racemic epoxides with sodium
cyanide
Substrate 1
R
Time (h)
Yielda (%)
a
b
c
d
e
f
H
2-CH3
4-CH3
4-Cl
12
12
12
10
10
15
18
80
86
87
90
82
70
55
4-Br
3. Conclusion
2,3-(CHꢀCHꢁCHꢀCH)ꢁ
3,4-(CHꢀCHꢁCHꢀCH)ꢁ
g
In summary, we have demonstrated an efficient and
practical preparation of b-hydroxy nitriles and their
a Isolated yields.
OH
OH
OAc
O
N
O
N
O
N
Lipase PS
AcO
+
R
R
R
2a-g
(R)-3a-g
(S)-2a-g
Scheme 2.
Table 2. Kinetic resolution of 4-aryloxy-3-hydroxybutanenitriles
Substrate 2
R
Time (h)
Alcohol
Acetate
E.e.a (%)
Yieldb (%)
E.e.a (%)
Yieldb (%)
a
H
2-CH3
4-CH3
4-Cl
98
102
50
46
44
82.7
71.0
91.8
92.2
93.8
35.0
44.0
52
51
46
42
41
60
62
\99.0
91.1
\99.0
92.1
88.7
\98.0
\99.0
42
42
45
45
55
36
34
bc
c
d
e
4-Br
fc
gc
2,3-(CHꢀCHꢁCHꢀCH)ꢁ
3,4-(CHꢀCHꢁCHꢀCH)ꢁ
116
105
a Determined by chiral HPLC (Chiralcel OD column; Daicel) employing hexane–isopropanol (85:15) as mobile phase at 0.5 mL/min and
monitored by UV (254 nm).
b Isolated yields.
c Reaction carried out at 40°C.

A. Kamal, G. B. Ramesh Khanna / Tetrahedron: Asymmetry 12 (2001) 405–410
407
enzymatic resolution using lipase from P. cepacia (PS).
This method affords biologically important 4-aryloxy-
3-hydroxybutanenitriles in good yields and high enan-
tiomeric excesses.
procedure for the ring opening of oxiranes, resulted in
a white crystalline solid of 2c. Yield 87%; mp 57–59°C;
IR (KBr): 3401, 3023, 2938, 2274, 1240, 1102, 1052
1
cm−1; H NMR (200 MHz, CDCl3): l 7.08 (d, J=7.62
Hz, 2H), 6.79 (d, J=7.62 Hz, 2H), 4.21–4.34 (m, 1H),
4.01 (d, J=3.57 Hz, 2H), 2.74 (dd, J1=3.81 Hz, J2=
11.90 Hz, 1H), 2.64 (dd, J1=4.76 Hz, J2=15.47 Hz,
1H), 2.29 (s, 3H); MS: m/z 191, 121, 108, 91.
4. Experimental
4.1. General
4.2.4. 4-(4-Chlorophenoxy)-3-hydroxybutanenitrile 2d. 3-
(4-Chlorophenoxy)-1,2-epoxypropane 1d when stirred
with NaCN for 10 h, as described in the above general
procedure for the ring opening of oxiranes, resulted in
a white crystalline solid of 2d. Yield 90%; mp 65–68°C;
IR (KBr): 3438, 3098, 2879, 2255, 1242, 1092, 1043
Column chromatography was carried out using 100–
200 mesh silica gel (Acme India Ltd.). TLC analyses
were performed on Merck 60 PF254 silica gel plates.
Melting points were taken on electrothermal melting
point apparatus and are uncorrected. Infrared (IR)
spectra were recorded on Perkin–Elmer model 683 or
1
cm−1; H NMR (200 MHz, CDCl3): l 7.24 (d, J=6.90
1
Hz, 2H), 6.84 (d, J=6.90 Hz, 2H), 4.24–4.34 (m, 1H),
3.99 (d, J=4.60 Hz, 2H), 3.19 (br. s, 1H), 2.79 (dd,
J1=3.45 Hz, J2=11.49 Hz, 1H), 2.63 (dd, J1=4.60 Hz,
J2=16.09 Hz, 1H); MS: m/z 211, 141, 128, 94.
1310 spectrometers. H NMR spectra were recorded on
a Varian Gemini 200 MHz spectrometer using tetra-
methylsilane (TMS) as an internal standard. Mass spec-
tra were recorded on CEC-21-100B Finnigan Mat 1210
or Micromass 7070 spectrometers. Optical rotations
were measured on a Jasco Dip 360 digital polarimeter.
HPLC was performed on a Chiralcel OD column
(Daicel) and monitored by UV (254 nm).
4.2.5. 4-(4-Bromophenoxy)-3-hydroxybutanenitrile 2e. 3-
(4-Bromophenoxy)-1,2-epoxypropane 1e when stirred
with NaCN for 10 h, as described in the above general
procedure for the ring opening of oxiranes, resulted in
a white crystalline solid of 2e. Yield 82%; mp 79–81°C;
4.2. General procedure for oxirane ring opening
1
IR (KBr): 3496, 3092, 2926, 2252, 1250, 1107 cm−1; H
NMR (200 MHz, CDCl3): l 7.35 (d, J=8.43 Hz, 2H),
6.76 (d, J=8.43 Hz, 2H), 4.20–4.33 (m, 1H), 3.99 (d,
J=4.82 Hz, 2H), 2.74 (dd, J1=4.82 Hz, J2=14.46 Hz,
1H), 2.61 (dd, J1=6.02 Hz, J2=9.64 Hz, 1H); MS: m/z
255, 257, 187, 185, 174, 172.
To a solution of epoxide (20 mmol) in ethanol (20 mL)
was added water (100 mL). After stirring for 5 min,
NaCN (28 mmol) was added and stirring was continued
overnight at room temperature. On completion of the
reaction as indicated by TLC, the reaction mixture was
concentrated to about half the volume under reduced
pressure. The residue was extracted with ethyl acetate,
washed with brine and dried over anhydrous Na2SO4.
Evaporation and purification by column chromatogra-
phy employing EtOAc–hexane (3:7) as the eluent
afforded pure b-hydroxy nitriles.
4.2.6. 3-Hydroxy-4-(1-naphthyloxy)butanenitrile 2f. 3-(1-
Naphthyloxy)-1,2-epoxypropane 1f when stirred with
NaCN for 15 h, as described in the above general
procedure for the ring opening of oxiranes, resulted in
a white crystalline solid of 2f. Yield 70%; mp 89–92°C;
1
IR (KBr): 3503, 3050, 2929, 2244, 1272, 1095 cm−1; H
NMR (200 MHz, CDCl3): l 8.10–8.20 (m, 1H), 7.76–
7.81 (m, 1H), 7.25–7.51 (m, 4H), 6.8 (d, J=5.13 Hz,
1H), 4.39–4.50 (m, 1H), 4.21 (d, J=3.85, 2H), 2.70–
2.91 (m, 2H); MS: m/z 227, 144, 127.
4.2.1. 3-Hydroxy-4-phenoxybutanenitrile 2a. 3-Phenoxy-
1,2-epoxypropane 1a was stirred with NaCN for 12 h,
as described in the above general procedure for the ring
opening of oxiranes, to afford 2a in 80% yield. IR
(film): 3437, 3066, 2930, 2256, 1228, 1047 cm−1; 1H
NMR (200 MHz, CDCl3): l 7.14–7.29 (m, 2H), 6.77–
7.00 (m, 3H), 4.20–4.31 (m, 1H), 3.96 (d, J=5.12 Hz,
2H), 2.73 (dd, J1=5.12 Hz, J2=17.95 Hz, 1H), 2.60
(dd, J1=5.12 Hz, J2=11.50 Hz, 1H); MS: m/z 177, 119,
107, 94, 77.
4.2.7. 3-Hydroxy-4-(2-naphthyloxy)butanenitrile 2g. 3-
(2-Naphthyloxy)-1,2-epoxypropane 1g when stirred
with NaCN for 18 h, as described in the above general
procedure for the ring opening of oxiranes, resulted in
a white crystalline solid of 2g. Yield 55%; mp 134–
138°C; IR (KBr): 3399, 3045, 2927, 2268, 1217, 1103
1
cm−1; H NMR (200 MHz, CDCl3): l 7.66–7.78 (m,
4.2.2. 3-Hydroxy-4-(2-methylphenoxy)butanenitrile 2b.
3-(2-Methylphenoxy)-1,2-epoxypropane 1b was stirred
with NaCN for 12 h, as described in the above general
procedure for the ring opening of oxiranes, to afford 2b
in 86% yield. IR (film): 3477, 3028, 2931, 2255, 1193,
3H), 7.26–7.55 (m, 2H), 7.14–7.20 (m, 2H), 3.99–4.33
(m, 3H), 2.84 (dd, J1=3.41 Hz, J2=12.50 Hz, 1H), 2.69
(dd, J1=5.68 Hz, J2=14.77 Hz, 1H); MS: m/z 227, 144,
115.
1
1044 cm−1; H NMR (200 MHz, CDCl3): l 7.06–7.19
4.3. General procedure for the resolution of b-hydroxy
nitriles
(m, 2H), 6.73–6.94 (m, 2H), 4.23–4.40 (m, 1H), 3.93–
4.10 (m, 2H), 3.16 (d, J=4.76 Hz, 2H), 2.60–2.84 (m,
2H), 2.22 (s, 3H); MS: m/z 191, 139, 108, 91, 77.
The b-hydroxy nitrile (5 mmol) was dissolved in di-iso-
propyl ether (50 mL) and to this P. cepacia lipase (750
mg) and vinyl acetate (12.5 mmol) were added succes-
sively and shaken at 25°C in an orbital shaker. After
about 50% completion of the reaction, as indicated by
4.2.3. 3-Hydroxy-4-(4-methylphenoxy)butanenitrile 2c. 3-
(4-Methylphenoxy)-1,2-epoxypropane 1c when stirred
with NaCN for 12 h, as described in the above general

408
A. Kamal, G. B. Ramesh Khanna / Tetrahedron: Asymmetry 12 (2001) 405–410
HPLC analysis, the reaction mixture was filtered and
washed with EtOAc. Solvents were evaporated and
purification was accomplished by column chromatogra-
phy employing EtOAc–hexane (25:75) as the eluent to
afford the corresponding (R)-acetate, followed by the
unreacted (S)-b-hydroxy nitrile.
(d, J=8.43 Hz, 2H), 6.76 (d, J=8.43 Hz, 2H), 4.20–
4.33 (m, 1H), 3.99 (d, J=4.82 Hz, 2H), 2.74 (dd,
J1=4.82 Hz, J2=14.46 Hz, 1H), 2.61 (dd, J1=6.02 Hz,
J2=9.64 Hz, 1H); MS: m/z 255, 257, 187, 185, 174, 172.
4.3.6. 3-Hydroxy-4-(1-naphthyloxy)-(S)-butanenitrile
(S)-2f. Resolution of 3-hydroxy-4-(1-naphthyloxy)-
butanenitrile 2f by employing the above general proce-
dure for the resolution of b-hydroxy nitriles at 40°C
afforded (S)-2f in 60% yield and 35.0% e.e. Mp 89–
92oC; [h]D25=−2.25 (c 1.0, CHCl3); IR (KBr): 3503,
3050, 2929, 2244, 1272, 1095 cm−1; 1H NMR (200
MHz, CDCl3): l 8.10–8.20 (m, 1H), 7.76–7.81 (m, 1H),
7.25–7.51 (m, 4H), 6.8 (d, J=5.13 Hz, 1H), 4.39–4.50
(m, 1H), 4.21 (d, J=3.85, 2H), 2.70–2.91 (m, 2H); MS:
m/z 227, 144, 127.
4.3.1. 3-Hydroxy-4-phenoxy-(S)-butanenitrile (S)-2a.
Resolution of 3-hydroxy-4-phenoxybutanenitrile 2a by
employing the above general procedure for the resolu-
tion of b-hydroxy nitriles afforded (S)-2a in 52% yield
and e.e.=82.7%; [h]D25=−6.4 (c 1.0, CHCl3); IR (film):
1
3437, 3066, 2930, 2256, 1228, 1047 cm−1; H NMR (200
MHz, CDCl3): l 7.14–7.29 (m, 2H), 6.77–7.00 (m, 3H),
4.20–4.31 (m, 1H), 3.96 (d, J=5.12 Hz, 2H), 2.73 (dd,
J1=5.12 Hz, J2=17.95 Hz, 1H), 2.60 (dd, J1=5.12 Hz,
J2=11.50 Hz, 1H); MS: m/z 177, 119, 107, 94, 77.
4.3.7. 3-Hydroxy-4-(2-naphthyloxy)-(S)-butanenitrile
(S)-2g. Resolution of 3-hydroxy-4-(2-naphthyloxy)-
butanenitrile 2g by employing the above general proce-
dure for the resolution of b-hydroxy nitriles at 40°C
afforded (S)-2g in 62% yield and 44.0% e.e. Mp 134–
138°C; [h]2D5=−4.7 (c 0.5, CHCl3); IR (KBr): 3399,
3045, 2927, 2268, 1217, 1103 cm−1; 1H NMR (200
MHz, CDCl3): l 7.66–7.78 (m, 3H), 7.26–7.55 (m, 2H),
7.14–7.20 (m, 2H), 3.99–4.33 (m, 3H), 2.84 (dd, J1=
3.41 Hz, J2=12.50 Hz, 1H), 2.69 (dd, J1=5.68 Hz,
J2=14.77 Hz, 1H); MS: m/z 227, 144, 115.
4.3.2. 3-Hydroxy-4-(2-methylphenoxy)-(S)-butanenitrile
(S)-2b. Resolution of 3-hydroxy-4-(2-methylphen-
oxy)butanenitrile 2b by employing the above general
procedure for the resolution of b-hydroxy nitriles at
40°C afforded (S)-2b in 51% yield and 71.0% e.e.
[h]2D5=−8.0 (c 1.0, CHCl3); IR (film): 3477, 3028, 2931,
1
2255, 1193, 1044 cm−1; H NMR (200 MHz, CDCl3): l
7.06–7.19 (m, 2H), 6.73–6.94 (m, 2H), 4.23–4.40 (m,
1H), 3.93–4.10 (m, 2H), 3.16 (d, J=4.76 Hz, 2H),
2.60–2.84 (m, 2H), 2.22 (s, 3H); MS: m/z 191, 139, 108,
91, 77.
4.3.3. 3-Hydroxy-4-(4-methylphenoxy)-(S)-butanenitrile
(S)-2c. Resolution of 3-hydroxy-4-(4-methylphe-
noxy)butanenitrile 2c by employing the above general
procedure for the resolution of b-hydroxy nitriles
afforded (S)-2c in 46% yield and 91.8% e.e. Mp 57–
59°C; [h]2D5=−7.2 (c 1.0, CHCl3); IR (KBr): 3401, 3023,
2938, 2274, 1240, 1102, 1052 cm−1; 1H NMR (200
MHz, CDCl3): l 7.08 (d, J=7.62 Hz, 2H), 6.79 (d,
J=7.62 Hz, 2H), 4.21–4.34 (m, 1H), 4.01 (d, J=3.57
Hz, 2H), 2.74 (dd, J1=3.81 Hz, J2=11.90 Hz, 1H), 2.64
(dd, J1=4.76 Hz, J2=15.47 Hz, 1H), 2.29 (s, 3H); MS:
m/z 191, 121, 108, 91.
4.3.8. 3-Acetyloxy-4-phenoxy-(3R)-butanenitrile (R)-3a.
Resolution of 3-hydroxy-4-phenoxybutanenitrile 2a by
employing the above general procedure for the resolu-
tion of b-hydroxy nitriles afforded (R)-3a in 42% yield
and >99.0% e.e. [h]2D5=+30.5 (c 1.0, CHCl3); IR (film):
3041, 2939, 2255, 1745, 1373, 1222, 1047 cm−1; 1H
NMR (200 MHz, CDCl3): l 7.2–7.34 (m, 2H), 6.81–
7.02 (m, 3H), 5.21–5.34 (m, 1H), 4.18 (dd, J1=4.76 Hz,
J2=9.52 Hz, 1H), 4.09 (dd, J1=5.95 Hz, J2=7.14 Hz,
1H), 2.88 (d, J=4.76 Hz, 2H), 2.13 (s, 3H); MS: m/z
219, 126, 94, 77.
4.3.9. 3-Acetyloxy-4-(2-methylphenoxy)-(3R)-butane-
nitrile (R)-3b. Resolution of 3-hydroxy-4-(2-methylphen-
oxy)butanenitrile 2b by employing the above general
procedure for the resolution of b-hydroxy nitriles at
40°C afforded (R)-3b in 42% yield and 91.1% e.e.
[h]2D5=+23.4 (c 1.0, CHCl3); IR (film): 3028, 2918, 2254,
1775, 1312, 1188, 1128, 1023 cm−1; 1H NMR (200
MHz, CDCl3): l 7.04–7.16 (m, 2H), 6.72–6.90 (m, 2H),
5.25–5.37 (m, 1H), 4.02–4.21 (m, 2H), 2.89 (d, J=4.82
Hz, 2H), 2.20 (s, 3H), 2.13 (s, 3H); MS: m/z 233, 126,
91, 77.
4.3.4. 4-(4-Chlorophenoxy)-3-hydroxy-(S)-butanenitrile
(S)-2d. Resolution of 4-(4-chlorophenoxy)-3-hydroxy-
butanenitrile 2d by employing the above general proce-
dure for the resolution of b-hydroxy nitriles afforded
(S)-2d in 42% yield and 92.2% e.e. Mp 65–68°C; [h]2D5=
−7.0 (c 1.0, CHCl3); IR (KBr): 3438, 3098, 2879, 2255,
1
1242, 1092, 1043 cm−1; H NMR (200 MHz, CDCl3): l
7.24 (d, J=6.90 Hz, 2H), 6.84 (d, J=6.90 Hz, 2H),
4.24–4.34 (m, 1H), 3.99 (d, J=4.60 Hz, 2H), 3.19 (br. s,
1H), 2.79 (dd, J1=3.45 Hz, J2=11.49, 1H), 2.63 (dd,
J1=4.60 Hz, J2=16.09 Hz, 1H); MS: m/z 211, 141,
128, 94.
4.3.10. 3-Acetyloxy-4-(4-methylphenoxy)-(3R)-butane-
nitrile (R)-3c. Resolution of 3-hydroxy-4-(4-methylphen-
oxy)butanenitrile 2c by employing the above general
procedure for the resolution of b-hydroxy nitriles
afforded (R)-3c in 45% yield and >99.0% e.e. [h]2D5=
+27.05 (c 1.0, CHCl3); IR (film): 3033, 2939, 2254,
4.3.5. 4-(4-Bromophenoxy)-3-hydroxy-(S)-butanenitrile
(S)-2e. Resolution of 4-(4-bromophenoxy)-3-hydroxy-
butanenitrile 2e by employing the above general proce-
dure for the resolution of b-hydroxy nitriles afforded
(S)-2e in 41% yield and 93.8% e.e. Mp 79–81°C; [h]2D5=
−3.2 (c 1.0, CHCl3); IR (KBr): 3496, 3092, 2926, 2252,
1
1755, 1372, 1232, 1052 cm−1; H NMR (200 MHz, CD-
1
1250, 1107 cm−1; H NMR (200 MHz, CDCl3): l 7.35
Cl3): l 7.06 (d, J=7.14 Hz, 2H), 6.78 (d, J=7.14 Hz,

A. Kamal, G. B. Ramesh Khanna / Tetrahedron: Asymmetry 12 (2001) 405–410
409
2H), 5.20–5.33 (m, 1H), 4.14 (dd, J1=3.57 Hz, J2=9.52
References
Hz, 1H), 4.05 (dd, J1=4.76 Hz, J2=10.71 Hz, 1H), 2.88
(d, J=4.76 Hz, 2H), 2.28 (s, 3H), 2.13 (s, 3H); MS: m/z
233, 126, 108, 91.
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4.3.11.
3-Acetyloxy-4-(4-chlorophenoxy)-(3R)-butane-
nitrile (R)-3d. Resolution of 4-(4-chlorophenoxy)-3-
hydroxybutanenitrile 2d by employing the above gen-
eral procedure for the resolution of b-hydroxy nitriles
afforded (R)-3d in 45% yield and 92.1% e.e. [h]2D5=+
26.7 (c 1.0, CHCl3); IR (film): 3071, 2938, 2255, 1742,
1373, 1212, 1047 cm−1; H NMR (200 MHz, CDCl3): l
1
7.21 (d, J=7.69 Hz, 2H), 6.80 (d, J=7.69 Hz, 2H),
5.20–5.31 (m, 1H), 4.00–4.20 (m, 2H), 2.73–2.97 (m,
2H), 2.11 (s, 3H); MS: m/z 253, 148, 125.
4.3.12.
3-Acetyloxy-4-(4-bromophenoxy)-(3R)-butane-
nitrile (R)-3e. Resolution of 4-(4-bromophenoxy)-3-
hydroxybutanenitrile 2e by employing the above gen-
eral procedure for the resolution of b-hydroxy nitriles
afforded (R)-3e in 55% yield and 88.7% e.e. [h]2D5=+
29.45 (c 0.5, CHCl3); IR (film): 3023, 2937, 2255, 1755,
1373, 1246, 1045 cm−1; H NMR (200 MHz, CDCl3): l
1
7.38 (d, J=6.02 Hz, 2H), 6.76 (d, J=6.02 Hz, 2H),
5.20–5.30 (m, 1H), 4.00–4.19 (m, 2H), 2.74–2.95 (m,
2H), 2.11 (s, 3H); MS: m/z 297, 299, 187, 185, 174, 172.
7. (a) Kamal, A.; Damayanthi, Y.; Reddy, B. S. N.; Laxmi-
narayana, B.; Reddy, B. S. P. Chem. Commun. 1997,
1015; (b) Kamal, A.; Damayanthi, Y.; Rao, M. V. Tetra-
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2158.
4.3.13. 3-Acetyloxy-4-(1-naphthyloxy)-(3R)-butanenitrile
(R)-3f. Resolution of 3-hydroxy-4-(1-naphthyloxy)-
butanenitrile 2f by employing the general procedure at
40°C afforded (R)-3f in 36% yield and >98.0% e.e.
[h]2D5=+26.8 (c 1.0, CHCl3); IR (film): 3059, 2937, 2255,
1742, 1393, 1218, 1105 cm−1; 1H NMR (200 MHz,
CDCl3): l 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); MS: m/z 269, 164, 126.
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4.3.14. 3-Acetyloxy-4-(2-naphthyloxy)-(3R)-butanenitrile
(R)-3g. Resolution of 3-hydroxy-4-(2-naphthyloxy)-
butanenitrile 2g by employing the general procedure for
the resolution of b-hydroxy nitriles at 40°C afforded
(R)-3g in 34% yield and >99.0% e.e. Mp 77–80°C;
[h]2D5=+34.13 (c 0.8, CHCl3); IR (KBr): 3073, 2926,
2250, 1739, 1374, 1249, 1037 cm−1; 1H NMR (200
MHz, CDCl3): l 7.68–7.75 (m, 3H), 7.24–7.46 (m, 2H),
7.08–7.13 (m, 2H), 5.28–4.00 (m, 1H), 4.16–4.31 (m,
2H), 2.91 (d, J=3.61 Hz, 2H), 2.16 (s, 3H); MS: m/z
267, 144, 115.
10. Florey, P.; Smallridge, A. J.; Ten, A.; Trewhella, M. A.
Org. Lett. 1999, 1, 1879.
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1973, Feb 15; (c) Orsymonde, S. A. Fr. Demande
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Erzsebet, M.; Jozsef, S. Ger. Offen. 2,506,355 1975, Aug
21; (e) Victor, L. (Orsymonde, S. A.) Ger. Offen.
2,166,869 1976, May 06.
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Acknowledgements
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The authors are grateful to Amano Pharmaceutical Co.
and Novo Nordisk for providing the gift samples of
Amano PS lipase and Lipozyme, respectively. One of
the authors (G.B.R.K.) thanks CSIR, New Delhi for
the award of a research fellowship.
15. Mitchell, D.; Koenig, T. M. Tetrahedron Lett. 1992, 33,

410
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