Synthesis of enantiomerically pure γ-azidoalcohols by lipase-catalyzed transesterification

Article abstract of DOI:10.1016/j.tetasy.2008.03.028

An enantioselective synthesis of chiral γ-azidoalcohols via lipase-catalyzed resolution is described. The efficiency of various lipases and the effect of different solvents have been studied. Pseudomonas cepacia immobilized on diatomaceous earth (PS-D) in n-hexane catalyzed the transesterification process in an efficient manner providing γ-azidoalcohols in high enantiomeric excess.

Full text of DOI:10.1016/j.tetasy.2008.03.028

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1078–1083
Synthesis of enantiomerically pure c-azidoalcohols
by lipase-catalyzed transesterification
Ahmed Kamal,* M. Shaheer Malik, Ahmad Ali Shaik and Shaik Azeeza
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 7 March 2008; accepted 27 March 2008
Abstract—An enantioselective synthesis of chiral c-azidoalcohols via lipase-catalyzed resolution is described. The efficiency of various
lipases and the effect of different solvents have been studied. Pseudomonas cepacia immobilized on diatomaceous earth (PS-D) in n-hex-
ane catalyzed the transesterification process in an efficient manner providing c-azidoalcohols in high enantiomeric excess.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
oped.4 Furthermore, chiral c-azidoalcohols have been
found to be useful in the ring expansion of symmetrical
cyclohexanones in the asymmetric Schmidt reaction.5 Chi-
ral c-azidoalcohols can be obtained from a lipase-catalyzed
kinetic resolution, which is considered as a powerful tech-
nique for providing access to new chiral synthons with high
enantiopurity.6 A number of chiral b-azidoalcohols have
been prepared by kinetic resolution using hydrolytic en-
zymes;7 however, there is one report on the resolution of
c-azidoalcohol relating to the evaluation of the active site’s
size of lipase from Candida rugosa and Pseudomonas cepa-
cia.8 Moreover, c-azidoalcohols possess a somewhat chal-
lenging structural unit for carrying out a lipase-catalyzed
resolution process. This is because of the increase in the
flexibility of the side chain as an additional methylene unit
is present in comparison to b-azidoalcohols. In view of the
aforementioned importance of c-azidoalcohols as well as in
continuation of our interest for the development of new
chemoenzymatic routes towards biologically active com-
pounds and chiral intermediates,9 we herein report the syn-
thesis of optically active c-azidoalcohols by employing a
lipase-mediated kinetic resolution protocol.
Enantiomerically pure chiral aminoalcohols are of great
interest, owing to their presence in biologically active nat-
ural products and their application as chiral catalysts in
asymmetric synthesis.1 Amongst these, b-aminoalcohols
are more popular than c-aminoalcohols and some other
higher aminoalcohols. Nevertheless, the interest in chiral
c-aminoalcohols has increased, as they are also important
structural units in many natural products, pharmacologi-
cally useful drugs and chiral ligands or auxillaries, which
are useful in stereoselective synthesis.2 Notably, the c-ami-
noalcohol unit is present in many selective serotonin/
norepinephrine reuptake inhibitors such as fluoxetine,
tomoxetine, nisoxetine and duloxetine, which are being
used in the clinic as antidepressant drugs for the treatment
of impulse control disorders.3 Chiral c-azidoalcohols are
the immediate precursors of c-aminoalcohols, in addition
to b-hydroxynitriles, which are not particularly safe as their
preparation involves the use of cyanide salts (Scheme 1).
However, some methods utilizing milder reagents for the
synthesis of b-hydroxynitriles have recently been devel-
OH
OH
OH
CN
R
NH2
R
N3
R
Scheme 1.
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189; e-mail: ahmedkamal@iict.res.in
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.028

A. Kamal et al. / Tetrahedron: Asymmetry 19 (2008) 1078–1083
1079
2. Results and discussion
In order to improve the enantioselectivity of this transeste-
rification process, the effect of various solvents was investi-
gated by employing lipase PS-D with isopropenyl acetate
as the acyl donor. Moreover, these reactions have been per-
formed at slightly higher temperatures (42 °C) with a view
to improve the rate of conversion; the results obtained are
shown in Table 2. It was observed that the rate of lipase-
mediated resolution and enantioselectivity varied with the
type of solvents used. The selectivity as well as the conver-
sion was poor when solvents such as dioxane and THF
were used, whereas the use of toluene or tert-butyl methyl
ether (TBME) provided good selectivity and conversion.
Moreover, when using a more hydrophobic solvent such
as n-hexane, the lipase PS-D has showed very high enanti-
oselectivity providing alcohol (S)-1a with 99% ee and ace-
tate (R)-2a with 92% ee. However, changing the acyl
donor from isopropenyl acetate to vinyl acetate lowered
the enantioselectivity.
Some approaches based on non-enzymatic methods have
already been reported in the literature that provide an ac-
cess to chiral c-aminoalcohols.2f However, a few biocata-
lytic procedures such as the kinetic resolution of b-
hydroxynitriles and microbial reductions of b-keto acid
derivatives involving chemical transformation are also
known for the preparation of chiral c-aminoalcohols.10
Herein, c-azidoalcohols (useful precursors of chiral c-ami-
noalcohols) have been synthesized by lipase-catalyzed enan-
tioselective acylation of racemic 3-azido-1-arylpropanols.
In this investigation, in order to optimize the enantioselec-
tivity of the process, 3-azido-1-phenyl propanol 1a was
chosen as the model substrate for the lipase-mediated ki-
netic resolution process. The selection of lipase is an impor-
tant aspect in the development of an efficient resolution
protocol. Hence, twelve commercially available lipases ob-
tained from different sources have been screened for the
transesterification of c-azidoalcohol 1a employing isopro-
penyl acetate and diisopropyl ether as an acyl donor and
solvent, respectively. The preliminary results obtained for
some selected potential lipases are summarized in Table 1.
Based on the above investigations, various racemic 3-azi-
do-1-arylpropanols 1a–f have been examined for the li-
pase-catalyzed transesterification process employing
lipases from P. cepacia (PS-D) in n-hexane with isopro-
penyl acetate as the acyl donor. The effect of substituents
on the aryl ring has also been studied (Table 3). It is found
that the kinetic resolution of 3-azido-1-phenylpropanol
and its derivatives 1a–d has proceeded efficiently to provide
the resolved alcohols (S)-1a–d with 99% ee and acetates
(R)-2a-d with 92–99% ee, whereas the p-methoxy substi-
tuted phenyl derivative 1e showed very little conversion
even after prolonged reaction time in n-hexane. However,
the use of diisopropyl ether as a solvent afforded the re-
solved alcohol (S)-1e and acetate (R)-2e with >99% ee
and 96% ee, respectively. The results also indicate that in
the presence of different substituents at the para-position
of the aromatic ring, comparatively higher conversion rates
and enantiopurities were observed. Using this protocol, the
It has been observed that the transesterification of c-azido-
alcohol 1a by employing lipases from sources such as Can-
dida antartica, Rhizopus arrhizus, Mucor miehei (lipozyme)
and papain (latex from Carica papaya) did not show signif-
icant conversions even after prolonged reaction time. How-
ever, the lipases from C. rugosa (CRL), Pseudomonas
fluorescens (AK-20), Candida cyclindracea (CCL) and P.
cepacia (immobilized on ceramic particles, PS-C) provide
moderate to good enantioselectivity for the acetate. The re-
sults are significant when employing P. cepacia lipase
(immobilized on diatomaceous earth, PS-D), which
gives 48% ee and 77% ee of the alcohol and acetate,
respectively.
Table 1. Lipase-mediated transesterification of c-azidoalcohol ( )-1aa
O
OH
OH
O
lipase
N3
N3
N3
isopropenyl acetate
+
(RS)-1a
(S)-1a
(R)-2a
Entry
Lipase
Time (h)b
% eec
cd (%)
Ee
Alcohol (S)-1a
Acetate (R)-2a
1
2
3
4
5
PS-C
PS-D
CRL
AK-20
CCL
48
48
48
58
48
10
48
15
15
10
63
77
70
44
55
14
38
18
25
16
<5
12
<10
<5
<5
a Conditions: 30 mg of ( )-1a, 30 mg of lipase (1 equiv w/w), isopropenyl acetate (6 equiv), 3 mL of diisopropyl ether (DIPE).
b Time taken for transesterification at 35 °C.
c Determined by chiral HPLC analysis employing Daicel Chiralcel OD-H column (0.46 ꢀ 25 cm); eluent: hexane/2-propanol = 90:10; flow rate: 0.5 mL/
min; detector: 230 nm.
d Conversion (c) is calculated from the enantiomeric excess of substrate alcohol 1a, (ees) and product acetate 2a (eep) using the formula: c = ees/(ees + eep).
e Enantiomeric ratio calculated with the formula E={ln[1 ꢁ c(1 + eep)]}/{ln[1 ꢁ c(1 ꢁ eep)]}.

1080
A. Kamal et al. / Tetrahedron: Asymmetry 19 (2008) 1078–1083
Table 2. Effect of solvents on enantioselectivity of c-azidoalcohol 1a using lipase PS-D
Entry
Lipase
Time (h)a
% ee
cb (%)
Ec
Alcohol (S)-1a
Acetate (R)-2a
1
2
3
4
5
6
n-Hexane
TBME
Toluene
Dioxane
n-Hexaned
DIPEd
48
42
42
42
48
48
99
88
35
10
94
10
92
69
82
34
85
55
52
56
30
23
53
15
153
15
14
<5
<100
<5
a Time taken for transesterification at 42 °C.
b Conversion.
c Enantiomeric ratio.
d Vinyl acetate used as acyl donor.
Table 3. Lipase-catalyzed kinetic resolution of racemic c-azidoalcohols 1a
O
OH
OH
O
lipase PS-D
+
R
N3
R
N3
R
N3
isopropenyl acetate, n-hexane
2a-f
1a-f
(rac)-1a-f
Entry
Substrate
R
Time (h)
48
% ee
cb (%)
Ec
Alcohol-1
Acetate-2
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
99d
>99e
99d
92d
94e
93d
99e
96e
76g
52
51
51
50
51
56
153
147
115
>200
>200
26
p-Me–C6H4
p-Cl–C6H4
p-Br–C6H4
p-MeO–C6H4
2-Thienyl
40
20
23
42f
16
99e
>99e
96g
a Conditions: 30 mg of rac-1, 30 mg of lipase (1 equiv w/w), isopropenyl acetate (6 equiv), 3 mL of n-hexane, 40–42 °C.
b Conversion.
c Enantiomeric ratio.
d Determined by chiral HPLC analysis employing Daicel Chiralcel OD-H column (0.46 ꢀ 25 cm); eluent: hexane/2-propanol = 90:10; flow rate: 0.5 mL/
min; detector: 230 nm.
e Determined by chiral HPLC analysis employing Daicel Chiralcel AD-H column (0.46 ꢀ 25 cm); eluent: hexane/2-propanol = 90:10; flow rate: 0.5 mL/
min; detector: 230 nm.
f Diisopropyl ether used as solvent.
g Determined by chiral HPLC analysis employing Daicel Chiralcel OB-H column (0.46 ꢀ 25 cm); eluent: hexane/2-propanol = 90:10; flow rate: 0.5 mL/
min; detector: 230 nm.
heteroaromatic c-azidoalcohol 1f has also been resolved
efficiently but with lower enantiomeric ratios in compari-
son to the aryl substituted ones. Attempts to improve the
enantioselectivity in this case by employing diisopropyl
ether instead of n-hexane did not provide any significant
enhancement in the selectivity.
3. Conclusion
In conclusion, we have developed a simple and efficient
enantioselective method for the synthesis of enantiomeri-
cally enriched c-azidoalcohols by employing a lipase-med-
iated kinetic resolution process. The present method could
find extensive applications for the preparation of various
biologically active c-aminoalcohols.
Finally, the absolute configuration of the enantiomerically
pure unreacted c-azidoalcohol 1a obtained by the enzy-
matic reaction was assigned an (S)-configuration on the
basis of the comparison of the specific rotation of c-amino-
alcohol (prepared by the reduction of 1a) reported in the
literature.11a Similarly, the configuration of the resolved
substituted phenyl azidoalcohols 1b–e has been assigned
based on the comparison of the sign of the specific rotation
with that of the parent azidoalcohol 1a. Azidoalcohol 1f
was assigned an (S)-configuration by comparing the spe-
cific rotation of its ethyl carbamate derivative (prepared
from aminoalcohol, which was obtained by the reduction
of 1f) with that reported in the literature.11b
4. Experimental
4.1. Material and methods
Enzymatic reactions were carried out on an ‘Innova-4080
incubator-shaker’ at 200 rpm. Infrared spectra of neat sam-
ples are reported in wave numbers (cmꢁ1). H NMR was
1
recorded as solutions in CDCl3 and chemical shifts are re-
ported in parts per million (PPM, d) on a 300 MHz instru-
ment. Coupling constants are reported in Hertz (Hz). ESI

A. Kamal et al. / Tetrahedron: Asymmetry 19 (2008) 1078–1083
1081
spectra were recorded on Micro mass, Quattro LC using
4.4. General procedure for the synthesis of chiral azido-
alcohols 1a–f and azidoacetates 2a–f
ESI+ software with capillary voltage 3.98 kV and ESI
mode positive ion trap detector. Elemental analyses were
performed on an elemental analyzer, Model: VARIO EL,
Elementar, Germany. HPLC analysis was performed on
an instrument that consisted of a Shimadzu SCL-10A sys-
tem controller, SPA-M10A Diode array detector. Specific
rotations were recorded on SEPA-300 Horiba high sensi-
tive polarimeter, fixed with sodium lamp of wavelength
589 nm.
To a solution of racemic c-azidoalcohol 1 (1 mmol) dis-
solved in n-hexane (15 mL) under ultrasonication were
added lipase (1 equiv w/w) and isopropenyl acetate
(6 mmol) and the reaction mixture was shaken at 40–
42 °C in an orbital shaker. The progress of the reaction
was monitored by chiral HPLC and after about 50% con-
version, the reaction mixture was filtered and the residue
washed with ethyl acetate. The organic solvent was evapo-
rated under reduced pressure and purified by column chro-
matography. The enantiopure products 1 and 2 obtained
were analyzed by chiral HPLC and compared with the cor-
responding racemic products.
4.2. Chemicals and enzymes
Chemicals and solvents were obtained commercially and
used without purification. P. cepacia lipase immobilized
on diatomaceous earth (PS-D) was purchased from Amano
(Nagoya, Japan).
4.4.1. (S)-3-Azido-1-phenyl-1-propanol 1a. Yield: 46%;
30
99% ee (tmajor ¼ 14:87, tminor ¼ 16:01 min); ½aꢂD ¼ ꢁ33:5
(c 6.0, CHCl3); IR (neat): 3408, 2097, 1261, 761 cmꢁ1; H
1
4.3. General procedure for the synthesis of racemic
azidoalcohols 1a–f
NMR (300 MHz, CDCl3): d 1.40 (1H, s), 1.83–2.07 (2H,
m), 3.31–3.55 (2H, m), 4.77–4.84 (1H, m), 7.22–7.38 (5H,
m); 13C NMR (100 MHz, CDCl3): d 37.61, 48.15, 71.46,
125.60, 127.71, 128.50, 143.90; ESIMS m/z: 200
(M+Na)+; Anal. Calcd for C9H11N3O: C, 61.00; H, 6.26.
Found: C, 61.03; H, 6.23.
The racemic azidoalcohols were prepared by Friedel–Crafts
acylation on aryl/thienyl compounds using chloropropio-
nyl chloride and anhydrous aluminium chloride to provide
the corresponding ketochlorides in quantitative yields.
These substituted ketochlorides were transformed into
ketoazides using sodium azide in the presence of catalytic
18-crown-6. The crude substituted ketoazides were reduced
to racemic azidoalcohols 1a–f employing sodium borohy-
dride in methanol in quantitative yields.
4.4.2. (R)-3-Azido-1-phenylpropyl acetate 2a. Yield: 45%;
30
92% ee (tmajor ¼ 10:65, tminor ¼ 12:03 min); ½aꢂD ¼ þ56:4
1
(c 3.0, CHCl3); IR (neat): 2096, 1737, 1231, 757 cmꢁ1; H
NMR (300 MHz, CDCl3): d 1.93–2.24 (2H, m), 2.06 (3H,
s), 3.17–3.36 (2H, m), 5.77–5.83 (1H, m), 7.23–7.36 (5H,
m); ESIMS m/z: 242 (M+Na)+; Anal. Calcd for
C11H13N3O2: C, 60.26; H, 5.98. Found: C, 60.22; H, 5.94.
4.3.1. General procedure for Friedel–Crafts acylation. To
a solution of aluminium chloride (12 mmol) in dry CH2Cl2,
3-chloropropionyl chloride (11 mmol) was added dropwise
at 0 °C. To the resulting mixture, aryl or thienyl compound
(10 mmol) was added and allowed to warm to room tem-
perature and stirred overnight. The reaction mixture was
quenched by slowly adding crushed ice pieces at 0 °C and
the aqueous layer was extracted with CH2Cl2. The organic
layer was washed with brine solution, dried over anhydrous
Na2SO4, evaporated under reduced pressure and purified
by column chromatography. Yield: 87–92%.
4.4.3. (S)-3-Azido-1-p-tolylpropan-1-ol 1b. Yield: 45%;
30
>99% ee (tminor ¼ 14:31, tmajor ¼ 15:90 min); ½aꢂD ¼ ꢁ26:9
1
(c 0.5, CHCl3); IR (neat): 3397, 2096, 1260, 814 cmꢁ1; H
NMR (300 MHz, CDCl3): d 1.40 (1H, s), 1.82–2.05 (2H,
m), 2.35 (3H, s), 3.28–3.52 (2H, m), 4.75 (1H, dd,
J = 4.5, J = 8.3 Hz), 7.12 (2H, d, J = 7.5 Hz), 7.20 (2H,
d, J = 7.5 Hz); 13C NMR (150 MHz, CDCl3): d 21.06,
37.52, 48.16, 71.30, 125.57, 129.18, 137.51, 140.60; ESIMS
m/z: 214 (M+Na)+; Anal. Calcd for C10H13N3O: C, 62.81;
H, 6.85. Found: C, 62.79; H, 6.81.
4.3.2. General procedure for the synthesis of racemic
azidoalcohols. To a stirred solution of substituted keto-
chlorides (10 mmol) in dry CH2Cl2 was added sodium
azide (15 mmol) followed by 18-crown-6 (1 mmol) and stir-
red for 8–10 h. To the reaction mixture, cold water was
added and the aqueous layer extracted with CH2Cl2. The
organic layer was washed with brine solution, dried over
anhydrous Na2SO4, evaporated under reduced pressure
to give crude substituted ketoazides, which were dissolved
in methanol. Sodium borohydride (10 mmol) was added
in portions at 0 °C and stirred at room temperature for
2 h. The solvent was evaporated, water was added followed
by extraction with ethyl acetate. The organic layer was
washed with brine solution, dried over anhydrous Na2SO4
and the solvent removed under reduced pressure and puri-
fied by column chromatography to give racemic azidoalco-
hols 1a–f. Yield: 75–82%.
4.4.4. (R)-3-Azido-1-p-tolylpropyl acetate 2b. Yield: 46%;
30
94% ee (tmajor ¼ 8:86, tminor ¼ 9:82 min); ½aꢂD ¼ þ62:1 (c
1
0.6, CHCl3); IR (neat): 2097, 1740, 1233, 813 cmꢁ1; H
NMR (300 MHz, CDCl3): d 1.92–2.24 (2H, m), 2.06 (3H,
s), 2.34 (3H, s), 3.17–3.36 (2H, m), 5.73–5.79 (1H, m),
7.12 (2H, d, J = 7.5 Hz), 7.19 (2H, d, J = 7.5 Hz); ESIMS
m/z: 256 (M+Na)+; Anal. Calcd for C12H15N3O2: C, 61.79;
H, 6.48. Found: C, 61.75; H, 6.45.
4.4.5.
(S)-3-Azido-1-(4-chlorophenyl)propan-1-ol
1c.
.Yield: 44%; 99% ee (tmajor ¼ 13:28, tminor ¼ 14:75 min);
30
½aꢂD ¼ ꢁ20:3 (c 0.7, CHCl3); IR (neat): 3400, 2099, 1086,
1
827 cmꢁ1; H NMR (300 MHz, CDCl3): d 1.38 (1H, s),
1.80–2.00 (2H, m), 3.31–3.57 (2H, m), 4.77–4.84 (1H, m),
7.27 (2H, d, J = 9.0 Hz), 7.31 (2H, d, J = 9.0 Hz); 13C
NMR (150 MHz, CDCl3): d 37.58, 48.04, 70.82, 126.96,
128.62, 133.25, 142.08; ESIMS m/z: 234 (M+Na)+; Anal.

1082
A. Kamal et al. / Tetrahedron: Asymmetry 19 (2008) 1078–1083
Calcd for C9H10ClN3O: C, 51.07; H, 4.76. Found: C, 51.08;
H, 4.75.
4.4.12. (R)-3-Azido-1-(2-thienyl)propyl acetate 2f. Yield:
30
46%; 76% ee (tmajor ¼ 16:75, tminor ¼ 18:10 min); ½aꢂD
¼
þ67:3 (c 1.1, CHCl3); IR (neat): 2929, 2099, 1739,
1
4.4.6. (R)-3-Azido-1-(4-chlorophenyl)propyl acetate 2c.
.Yield: 46%; 93% ee (tminor ¼ 10:43, tmajor ¼ 11:10 min);
1229 cmꢁ1; H NMR (300 MHz, CDCl3): d 2.06 (3H, s),
2.07–2.33 (2H, m), 3.24–3.42 (2H, m), 6.09–6.15 (1H, m),
6.93–6.97 (1H, m), 7.04 (1H, d, J = 3.0 Hz), 7.25 (1H, d,
J = 3.0 Hz); ESIMS m/z: 248 (M+Na)+; Anal. Calcd for
C9H11N3O2S: C, 47.99; H, 4.92. Found: C, 47.95; H, 4.90.
30
½aꢂD ¼ þ55:4 (c 1.0, CHCl3); IR (neat): 2098, 1739, 1232,
1
823 cmꢁ1; H NMR (300 MHz, CDCl3): d 1.86–2.26 (2H,
m), 2.06 (3H, s), 3.16–3.41 (2H, m), 5.76 (1H, dd,
J = 5.4, J = 6.2 Hz), 7.20–7.36 (4H, m); ESIMS m/z: 276
(M+Na)+; Anal. Calcd for C11H12ClN3O2: C, 52.08; H,
4.77. Found: C, 52.09; H, 4.77.
Acknowledgement
4.4.7.
(S)-3-Azido-1-(4-bromophenyl)propan-1-ol
1d.
The authors (M.S.M., A.A.S. and S.A.) are thankful to
CSIR, New Delhi, for the award of research fellowship.
.Yield: 46%; 99% ee (tminor ¼ 15:88, tmajor ¼ 16:56 min);
30
½aꢂD ¼ ꢁ23:1 (c 1.0, CHCl3); IR (neat): 3408, 2095, 1072,
821 cmꢁ1; H NMR (200 MHz, CDCl3): d 1.42 (1H, s),
1
1.81–1.98 (2H, m), 3.27–3.59 (2H, m), 4.72–4.84 (1H, m),
7.15–7.28 (2H, m), 7.41–7.51 (2H, m); 13C NMR
(150 MHz, CDCl3): d 37.58, 48.05, 70.81, 122.72, 127.80,
128.95, 141.20; ESIMS m/z: 279 (M+Na)+; Anal. Calcd
for C9H10BrN3O: C, 42.21; H, 3.94. Found: C, 42.20; H,
3.93.
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B.; Mercier, P.; Belanger, M. C. Psychopharmacol. Bull. 1985,
21, 73; (f) Wong, D. T.; Robertson, D. W.; Bymaster, F. P.;
Krushinski, J. H.; Reid, L. R. Life Sci. 1988, 43, 2049; (g)
Liu, H.; Hoff, B. H.; Anthonsen, T. Chirality 2000, 12, 26.
4. (a) Mirmashhori, B.; Azizi, N.; Saidi, M. R. J. Mol. Catal. A:
Chem. 2006, 247, 159, and references cited therein; (b)
Konno, H.; Toshiro, E.; Hinoda, N. Synthesis 2003, 2161.
5. Sahasrabudhe, K.; Gracias, V.; Furness, K.; Smith, B. T.;
Katz, C. E.; Reddy, D. S.; Aube, J. J. Am. Chem. Soc. 2003,
125, 7914.
4.4.8. (R)-3-Azido-1-(4-bromophenyl)propyl acetate 2d.
.Yield: 47%; 99% ee (tminor ¼ 7:91, tmajor ¼ 10:05 min);
30
½aꢂD ¼ þ40:8 (c 1.2, CHCl3); IR (neat): 2099, 1739, 1232,
1
820 cmꢁ1; H NMR (300 MHz, CDCl3): d 1.70–2.18 (2H,
m), 2.05 (3H, s), 4.05–4.32 (2H, m), 5.52–5.59 (1H, m),
7.17 (2H, d, J = 8.3 Hz), 7.44 (2H, d, J = 8.3 Hz); ESIMS
m/z: 321 (M+Na)+; Anal. Calcd for C11H12BrN3O2: C,
44.32; H, 4.06. Found: C, 44.31; H, 4.04.
4.4.9. (S)-3-Azido-1-(4-methoxyphenyl)propan-1-ol 1e.
.Yield: 45%; >99% ee (tminor ¼ 19:94, tmajor ¼ 21:89 min);
30
½aꢂD ¼ ꢁ18:4 (c 0.6, CHCl3); IR (neat): 3410, 2097, 1513,
1247, 832 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.40
;
(1H, s), 1.81–2.10 (2H, m), 3.25–3.55 (2H, m), 3.79 (3H,
s), 4.69–4.79 (1H, m), 6.78–6.88 (2H, m), 7.18–7.27 (2H,
m); 13C NMR (150 MHz, CDCl3): d 37.58, 48.24, 55.19,
71.12, 113.76, 126.93, 135.70, 158.95; ESIMS m/z: 230
(M+Na)+; Anal. Calcd for C10H13N3O2: C, 57.96; H,
6.32. Found: C, 57.95; H, 6.30.
4.4.10. (R)-3-Azido-1-(4-methoxyphenyl)propyl acetate
(tmajor ¼ 11:26, tminor ¼
2e. Yield: 46%; 96% ee
30
12:93 min); ½aꢂD ¼ þ77:4 (c 1.0, CHCl3); IR (neat): 2097,
1
1737, 1513, 1234, 830 cmꢁ1; H NMR (300 MHz, CDCl3):
6. Selected examples: (a) Santaniello, E.; Ferraboschi, P.;
Grisenti, P.; Manzocchi, A. Chem. Rev. 1992, 92, 1071; (b)
Ferrero, M.; Gotor, V. Chem. Rev. 2000, 100, 4319; (c)
Bornscheuer, U. T.; Kazlauskas Hydrolases in Organic
Synthesis; Wiley-VCH: Weinheim, 1999; (d) Pamies, O.;
Backvall, J.-E. Chem. Rev. 2003, 103, 3247; (e) Garcia-
Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105,
313.
d 1.91–2.26 (2H, m), 2.04 (3H, s), 3.16–3.36 (2H, m), 3.79
(3H, s), 5.71–5.79 (1H, m), 6.83 (2H, d, J = 9.0 Hz), 7.22
(2H, d, J = 9.0 Hz); ESIMS m/z: 272 (M+Na)+; Anal.
Calcd for C12H15N3O3: C, 57.82; H, 6.07. Found: C,
57.81; H, 6.06.
4.4.11. (S)-3-Azido-1-(2-thienyl)-1-propanol 1f. Yield:
7. (a) Ader, U.; Schneider, M. P. Tetrahedron: Asymmetry 1992,
3, 205; (b) Theil, F.; Lemke, K.; Ballschuh, S.; Kunath, A.;
Schick, H. Tetrahedron: Asymmetry 1995, 6, 1323; (c)
Foelsche, E.; Hickel, A.; Ho¨nig, H.; Wasserthal, P. S. J.
Org. Chem. 1990, 55, 1749; (d) Pchelka, B. K.; Loupy, A.;
Plenkiewicz, J.; Blanco, L. Tetrahedron: Asymmetry 2000, 11,
2719; (e) Brenelli, E. C. S.; Fernandes, J. L. N. Tetrahedron:
Asymmetry 2003, 14, 1255; (f) Kamal, A.; Shaik, A. A.;
Sandbhor, M.; Malik, M. S. Tetrahedron: Asymmetry 2004,
42%; 96% ee
(tmajor ¼ 21:58, tminor ¼ 22:81 min);
30
½aꢂD ¼ ꢁ17:8 (c 1.7, CHCl3); IR (neat): 3407, 2098, 1263,
1
703 cmꢁ1; H NMR (300 MHz, CDCl3): d 1.96–2.15 (2H,
m), 3.32–3.58 (2H, m), 5.01–5.12 (1H, m), 6.91–6.99 (2H,
m), 7.19–7.24 (1H, m); 13C NMR (100 MHz, CDCl3): d
37.84, 48.00, 67.26, 123.85, 124.75, 126.64, 147.82; ESIMS
m/z: 206 (M+Na)+; Anal. Calcd for C7H9N3OS: C, 45.89;
H, 4.95. Found: C, 45.85; H, 4.96.

A. Kamal et al. / Tetrahedron: Asymmetry 19 (2008) 1078–1083
1083
15, 935; (g) Pamies, O.; Ba¨ckvall, J. E. J. Org. Chem. 2001, 66,
4022.
8. Khadwaji, M. G.; Ho¨nig, H. Biocatal. Biotransform. 1994, 9,
249.
9. (a) Kamal, A.; Malik, M. S.; Shaik, A. A.; Azeeza, S.
Tetrahedron: Asymmetry 2007, 18, 2547; (b) Kamal, A.;
Krishnaji, T.; Khan, M. N. A. J. Mol. Catal. B: Enzym. 2007,
47, 1; (c) Kamal, A.; Shaik, A. A.; Azeeza, S.; Malik, M. S.;
Sandbhor, M. Tetrahedron: Asymmetry 2006, 17, 2890; (d)
Kamal, A.; Shaik, A. A.; Sandbhor, M.; Malik, M. S.;
Azeeza, S. Tetrahedron: Asymmetry 2006, 17, 2876; (e)
Kamal, A.; Ramana, K. V.; Rao, M. V. J. Org. Chem.
2001, 66, 997.
metry 2001, 12, 405; (c) Santianello, E.; Ferraboschi, P.;
Grisenti, P.; Manzocchi, A. Chem. Rev. 1992, 92, 1071; (d)
Quiros, M.; Rebolledo, F.; Gotor, V. Tetrahedron: Asymme-
try 1999, 10, 473, and references cited therein; (e) Smallridge,
A. J.; Ten, A.; Trewhella, M. A. Tetrahedron Lett. 1998, 39,
5121; (f) Ito, T.; Takagi, Y.; Fuyisawa, T. Tetrahedron Lett.
1989, 30, 3811; (g) Padhi, S. K.; Titu, D.; Pandian, N. G.;
Chadha, A. Tetrahedron 2006, 62, 5133; (h) Zhu, D.; Ankati,
H.; Mukherjee, C.; Yang, Y.; Biehl, E. R.; Hua, L. Org. Lett.
2007, 9, 2561, and references cited therein.
11. (a) Kamal, A.; Khanna, G. B. R.; Ramu, R. Tetrahedron:
Asymmetry 2002, 13, 2039; (b) Kamal, A.; Khanna, G. B. R.;
Ramu, R.; Krishnaji, T. Tetrahedron Lett. 2003, 44,
4783.
10. (a) Pamies, O.; Baeckvall, J. E. Adv. Synth. Catal. 2001, 343,
726; (b) Kamal, A.; Khanna, G. B. R. Tetrahedron: Asym-