One-pot synthesis and resolution of chiral allylic alcohols

Article abstract of DOI:10.1016/S0957-4166(03)00598-6

Substituted α,β-unsaturated ketones were selectively reduced to the corresponding allylic alcohols under mild reaction conditions. The allylic alcohols thus obtained were kinetically resolved by lipase catalyzed transesterification in the same pot to affo

Full text of DOI:10.1016/S0957-4166(03)00598-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2839–2844
One-pot synthesis and resolution of chiral allylic alcohols
Ahmed Kamal,* Mahendra Sandbhor, Ahmad Ali Shaik and V. Sravanthi
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
Received 11 July 2003; accepted 24 July 2003
Abstract—Substituted a,b-unsaturated ketones were selectively reduced to the corresponding allylic alcohols under mild reaction
conditions. The allylic alcohols thus obtained were kinetically resolved by lipase catalyzed transesterification in the same pot to
afford chiral allylic alcohols in excellent enantioselectivity. Various lipases were screened for this one-pot transesterification of
allylic alcohols. Effects of different solvent have also been studied under these conditions. Pseudomonas cepacia lipase immobilized
on ceramic particles (PS-C) and on diatomaceous earth (PS-D) catalyzes this transesterification in diisopropyl ether in a highly
efficient manner.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
lectivity in reducing a,b-unsaturated ketone and give
saturated alcohols, saturated ketones and b-hydroxy
ketones as side products.6b Moreover, these methods
need high pressure, longer reaction time and expensive
metal catalysts. In lipase catalyzed transesterification of
(RS)-trans-4-phenyl-3-butene-2-ol 2 using dimethyl-
malonate as the acyl donor the enantiomeric excess did
not exceed 93% for the unsaturated alcohol and the
condition applied such as reaction under reduced pres-
sure and use of KHCO3 limit its application at a large
scale.2a In continuation of our earlier work on the
one-pot synthesis and lipase catalyzed resolution of
enantiopure secondary alcohols7a and their applications
for the synthesis of biologically important
intermediates7b and chiral g- and d-lactones,7c herein we
report stereoselective syntheses of chiral allylic alcohols
using one-pot reduction and lipase resolution protocols.
Chiral allylic alcohols represent an important structural
motif and have attracted synthetic chemists for their
wide range of applications.1 They are useful chiral
synthons in sigmatropic reactions2a as well as for the
synthesis of natural products viz. octalactin A, (−)- and
(+)-cis-a-irone.2b,c They have been used as chiral pre-
cursors for the synthesis of (S)- and (R)-verapamil,3 a
calcium channel blocker used for the treatment of
classical angina pectoris and superventricular tachycar-
dia. Allylic alcohols are synthesized in enantiomerically
pure form from prochiral ketones by microbial reduc-
tion, and chemically by stereoselective reduction or
hydrogenation processes.4 Among the methods cur-
rently available for the synthesis of enantiopure allylic
alcohols, two of the most practical are the dynamic
kinetic resolution of racemic allylic alcohols,5a asym-
metric epoxidation5b and enzymatic acylation6 in
organic solvents and in ionic liquids.6d These methods
have some limitations which make them unsuitable for
the practical synthesis of chiral allylic alcohols. Whole
cell reductions of a,b-unsaturated ketones are less
applicable because of low yields and poor enantioselec-
tivities and needs the complementary approaches of
metal catalyzed asymmetric hydrogenation.4a Whereas
chemical hydrogenation methods afford poor chemose-
2. Result and discussion
In the selective reduction of carbonyls considerable
progress has been made in the development of reducing
agents derived from NaBH4.8 We report NaBH4/acti-
vated alumina9 mediated selective reduction of carbonyl
group of a,b-unsaturated ketone quantitatively under
mild conditions. The racemic alcohol thus obtained was
subjected to lipase catalyzed transesterification in the
same pot. Both the enantiomers of the chiral allylic
alcohol were obtained in good enantioselectivity by
using this one-pot lipase resolution process.
* Corresponding
author.
Fax:
91-40-27193189;
e-mail:
ahmedkamal@iict.ap.nic.in
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00598-6

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A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2839–2844
2.1. Lipase screening
enantiomeric ratios12 E=278. Pseudomonas fluorescens
lipase (Amano AK-20) and P. fluorescens lipase immobi-
lized in Sol-Gel-AK on sintered glass offered acetate 3a
with high enantioselectivity (98 to >99%) at longer
reaction time. There was no significant conversion in this
one-pot transesterification with Candida antarctica lipase
immobilized on glass beads, Candida rugosa, and Candida
cylindracea lipase.
The efficiency of different commercially available lipases
to catalyze the transesterification of the racemic allylic
alcohol 2a after the one-pot reduction of the correspond-
ing a,b-unsaturated ketone 1a was investigated. trans-4-
(3-Phenoxyphenyl)-3-butene-2-one was chosen as a
model substrate for lipase screening because of good
separation of the enantiomers of allylic alcohol 2a and
acylated product 3a in an OD column. Substrate 1a was
treated with NaBH4 and activated alumina in diisopropyl
ether at 40°C. The reduction was complete in 3 h, lipase
from various sources and isopropenyl acetate were then
added. The transesterification was monitored on chiral
HPLC.11b The results of the one-pot reduction and
lipase-catalyzed transesterifications of 1a are summarized
in Table 1. Pseudomonas cepacia lipase immobilized on
ceramic particles (PS-C) and on diatomaceous earth
(PS-D) displayed high enantioselectivity for 2a with equal
2.2. Solvent effect
The effect of solvent on substrate specificity, enantiomeric
or enantiotopic selectivity and rate of reaction and rate
of lipase-catalyzed kinetic resolution is well documented
in the literature.10 One-pot reduction of a,b-unsaturated
ketone, 1a and further acetylation of racemic alcohol, 2a
with isopropenyl acetate at 40°C in presence of immobi-
lized P. cepacia lipase ‘Amano’ PS-C were performed in
various organic solvents.
Table 1. One-pot reduction of a,b-unsaturated ketone, 1a to (RS)-2a and resolution of (RS)-2a by lipase catalyzed
transesterificationa
Lipase
Timeb (h)
(S)-2a e.e.c (%)
(R)-3a e.e.c (%)
(%) Conversiond
Ed
P. fluorescens (Amano AK-20)
P. cepacia (Amano PS)
P. cepacia (Amano PS-C)
P. cepacia (Amano PS-D)
P. fluorescens (Fluka)
36
72
12
16
96
96
94
46
>99
>99
93
98
97
97
97
>99
>99
49
32
50
50
48
13
356
103
278
278
645
230
M. miehei (Fluka)
15
a Conditions: 0.25 mmol of 1, 2.5 mL of diisopropyl ether, 0.25 g activated alumina, 2 eq. NaBH4; after 3 h lipase 1 equiv. w/w, 1.5 mmol
isopropenyl acetate at 40°C.
b Time taken for transesterification.
c Determined by chiral HPLC.11b
d Conversion c=e.e.2/e.e.2+e.e.3, enantiomeric ratio E={ln[1−c(1+e.e.3)]/{ln[1−c(1−e.e.3)]}.12
Table 2. Effect of solvent on one-pot reduction and transesterification of 1a using immobilized P. cepacia lipase ‘Amano’
PS-Ca
Solvent
log P
Timeb (h)
(S)-2a e.e.c (%)
(R)-3a e.e.c (%)
(%) Conversiond
Ed
Diisopropyl ether
n-Hexane
Toluene
Ethyl acetate
THF
Acetonitrile
1,4-Dioxane
1.9
3.5
2.5
12
15
15
15
72
72
72
>99
97
99
>99
>99
97
97
82
98
98
88
49
92
50
54
50
50
53
66
13
278
40
458
458
85
–
0.49
−0.33
−1.1
10
27
14
a Conditions: 0.25 mmol of 1, 2.5 mL of solvent, 0.25 g activated alumina, 2 eq. NaBH4; after 3 h lipase Amano PS-C (1 equiv. w/w), 1.5 mmol
isopropenyl acetate at 40°C.
b Time taken for transesterification.
c Determined by chiral HPLC.11b
d Conversion c=e.e.2/e.e.2+e.e.3, enantiomeric ratio E={ln[1−c(1+e.e.3)]/{ln[1−c(1−e.e.3)]}.12

A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2839–2844
2841
Scheme 1. Reagents and conditions: (i) NaBH4, activated alumina, diisopropyl ether; (ii) Lipase PS-C ‘Amano’ II, isopropenyl
acetate.
The results summarized in Table 2 show that lipase PS-C
affords higher activity for the one-pot transesterification
in solvent of low polarity as indicated by their Log P (the
logarithm of the partition coefficient of a given solvent
between 1-octanol and water). Diisopropyl ether, n-hex-
ane, toluene, (log P=1.9–3.5) and ethyl acetate catalyze
this transesterification with high enantioselectivity (>99%
e.e.) for 2a at faster reaction rates (12–15 h). On the other
hand solvents such as acetonitrile, and dioxane (log P=
−1.1 and 0.49) provide poor enantioselectivity at longer
reaction times. The one-pot transesterification of allylic
alcohols in THF solvent afforded >99% e.e. for 2a.
Table 3. Synthesis of chiral allylic alcohol by lipase mediated one-pot reduction resolution processa

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A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2839–2844
2.3. Synthesis of chiral allylic alcohol
tivity in organic media such as diisopropyl ether pro-
vides a practical in situ synthesis and biocatalytic
resolution process for allylic alcohols from their car-
bonyl precursors.
Various chiral allylic alcohols have been synthesized in
high enantiopurity based on this one-pot reduction
followed by resolution protocol. P. cepacia lipase
immobilized on ceramic particles (PS-C) is the lipase of
choice employing diisopropyl ether as solvent. Five
a,b-unsaturated ketones have been studied, and are
selectively reduced to a corresponding racemic allylic
alcohols in a quantitative manner in 3 h using NaBH4
and active neutral alumina in diisopropyl ether. The
racemic allylic alcohol thus obtained is kinetically
resolved by lipase ‘Amano’ PS-C catalyzed transesterifi-
cation at 40°C in the same pot (Scheme 1).
4. Experimental
4.1. Material and methods
Enzymatic reactions were carried out on ‘Lab-line envi-
ron-shaker’ at 150 rpm. Infrared spectra of neat sample
1
are reported in wave numbers (cm−1). H NMR was
recorded as solutions in CDCl3 and chemical shifts are
reported in parts per million (ppm, l) on a 200 MHz
instrument. Coupling constants are reported in hertz
(Hz). Low resolution mass spectra were recorded on
VG 7070H Micromass mass spectrometer at 200°C, 70
eV with a trap current of 200 mA and 4 kV acceleration
voltage. HPLC analysis was performed on an instru-
ment that consisted of a Shimadzu LC-10AT system
controller, SPD-10A fixed wavelength UV monitor as
detector. Specific rotation were recorded on SEPA-300
Horiba high sensitive polarimeter, fixed with sodium
lamp of wavelength 589 nm.
Both the unsaturated chiral allylic alcohols and acetates
are obtained in high enantiomeric purity in a short
reaction time (9–12 h), see Table 3. It is interesting to
note that unsaturated allylic alcohols, 2a, 2c and 2d, are
obtained in 98 to >99% enantiomeric excess. Moreover,
the acetates 3a, 3b and 3e are obtained in 97 to >99%
enantiomeric excess. The importance of this one-pot
reduction–resolution protocol for the synthesis of chiral
allylic alcohol has been ascertained by comparison of
the enantiopurity of alcohol 2a–e and acetate 3a–e with
earlier reports. Lindner et al.6b have synthesized chiral
allylic alcohols by using two consecutive approaches,
asymmetric hydrogenation of a,b-unsaturated ketone
by ruthenium metal complex and lipase catalyzed
kinetic resolution of the hydrogenated product. In this
method unsaturated acetate 3b has been prepared by
asymmetric reduction of ketone 1b to chiral alcohol 2b
which was further resolved to obtain chiral unsaturated
acetate 3b in 91–92% e.e. by employing ‘Amano’ PS-D
lipase. In another attempt allylic alcohol 2b and acetate
3b were obtained in 95% e.e. in 12 h by lipase Amano
AK-20 catalyzed kinetic resolution employing vinyl ace-
tate in hexane. Whereas the present method provides
92% enantiomeric excess for 2b and 98% for 3b in a
short time (5 h). From the practical point of view, this
one-pot reduction-transesterification process has been
carried out on a 2 gram scale for the substrate 1a, and
interestingly the results obtained are consistent with
those observed on the milligram scale reaction of this
substrate. This shows the potential of the present
method for the large scale preparation of chiral allylic
alcohols in high enantiopurity.
4.2. Chemicals and enzymes
Sodium borohydride, neutral alumina and solvents
were obtained commercially and used without purifica-
tion. Activated neutral alumina was prepared by homo-
geneous addition of 1.1 mL water to 10 g of neutral
alumina (preheated in oven at 200°C).7a Lipase from P.
cepacia (PS), P. fluorescens (AK), P. cepacia immobi-
lized on ceramic particles (PS-C), P. cepacia immobi-
lized on diatomaceous earth (PS-D), were purchased
from Amano (Nagoya, Japan). P. fluorescens lipase
immobilized in Sol-Gel-AK on sintered glass, C.
antarctica, Lipozyme, immobilized from Mucor miehei
were purchased from Fluka. Candida rugosa lipase type
VII, C. cylindracea lipase type VII were purchased from
Sigma.
4.3. Synthesis of the substrates
a,b-Unsaturated ketones 1a–e were prepared by well
known aldol condensation of the corresponding
ketones, purified by column chromatography and were
fully characterized by 1H NMR, IR, and E.I. mass
spectroscopy. Racemic unsaturated allylic alcohol 2a–e
were prepared by reduction of corresponding a,b-unsat-
urated ketone 1a–e by NaBH4 and activated alumina
and the corresponding racemic acetates were prepared
from racemic allylic alcohol 2a–e by a well known
acetylation procedure using acetic anhydride, triethyl
amine and DMAP in dry DCM.
3. Conclusion
A new efficient enzymatic pathway has been developed
for the synthesis of both (R) and (S) enantiopure allylic
alcohols from the corresponding a,b-unsaturated
ketone. The carbonyl functionality of a,b-unsaturated
ketones has been reduced selectively in a quantitative
manner to the corresponding alcohols under mild reac-
tion conditions. We have described for the first time,
the reduction of a,b-unsaturated ketones with alumina-
assisted sodium borohydride followed by the lipase-cat-
alyzed in situ transesterification of the racemic allylic
alcohol in one-pot. The enhanced reaction rates in the
presence of alumina with high regio- and enantioselec-
4.4. General procedure for one-pot synthesis of enantiop-
ure allylic alcohol 2a–e and acetate 3a–e
To a solution of the a,b-unsaturated ketone (1 mmol)
in diisopropyl ether (10 mL) was added activated alu-
mina (1.0 g) and NaBH4 (2 mmol). The suspension was

A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2839–2844
2843
shaken at 150 rpm at 40°C in a conical flask for 3–4 h
and monitored by TLC for the complete reduction to
racemic alcohol. Then lipase ‘Amano’ PS-C (1 equiv.
w/w) and isopropenyl acetate (1.1 mL) were added to
the reaction mixture. The reaction was monitored on
chiral HPLC analysis until it reaches 50% conversion
(9–12 h, as indicated in Table 3). The reaction was
filtered through a pad of Celite and thoroughly washed
with ethyl acetate. The combined filtrate was washed
with water, followed by brine. The organic layer was
dried over anhydrous sodium sulfate, concentrated
under reduced pressure and purified by silica gel
column chromatography. The enantiopure products 2
and 3, were analyzed by chiral HPLC11,13,14 and com-
pared with corresponding racemic products.
4.4.6. (R)-(E)-2-Acetoxy-4-chlorophenyl-3-butene 3c5a.
Yield: 52%; 78% e.e.13(tR=12.84 min); [h]2D5 +103 (c 2.0
CHCl3); IR (neat): 1730 cm−1; 1H NMR (200 MHz,
CDCl3): l 1.4 (3H, d, J=6.68 Hz), 2.0 (3H, s), 5.4 (1H,
q, J=6.68 Hz), 6.0–6.2 (1H, dd, J=15.60, 5.94 Hz),
6.4–6.6 (1H, d, J=15.60 Hz), 7.2–7.4 (5H, m); EIMS
(m/z): 224 (M+), 182 (M+−42). Anal. calcd for
C12H13ClO2: C, 64.15; H, 5.83; Cl, 15.78. Found: C,
64.03; H, 5.62; Cl, 15.21%.
4.4.7. (S)-(E)-4-(1-Naphthyl)-3-butene-2-ol 2d. Yield:
44%; 98% e.e.11b (tR=15.63 min); [h]2D5 −10.4 (c 2.0,
CHCl3); IR (neat): 3480 cm−1; 1H NMR (200 MHz,
CDCl3): l 1.4 (3H, d, J=6.68 Hz), 4.6 (1H, q, J=6.68
Hz), 6.2 (1H, dd, J=15.60, 6.68 Hz), 7.2–7.6 (5H, m),
7.8 (2H, m), 8.1 (1H, m); EIMS (m/z): 198 (M+), 155
(M+−43). Anal. calcd for C14H14O: C, 84.81; H, 7.12.
Found: C, 84.64; H, 7.0%.
4.4.1. (S)-(E)-4-(3-Phenoxyphenyl)-3-buten 2-ol 2a.
Yield: 46%; >99% e.e.11a (tR=36.75 min); [h]2D5 −10.4 (c
1
2, CHCl3); IR (neat): 3400 cm−1; H NMR (200 MHz,
CDCl3): l 1.2–1.6 (3H, d, J=6.69 Hz), 4.5 (1H, q,
J=6.69 Hz), 6.2 (1H, dd, J=16.68, 6.69 Hz), 6.5 (1H,
d, J=16.68 Hz), 6.8–7.6 (9H, m); EIMS (m/z): 240
(M+), 197 (M+−43). Anal. calcd for C16H16O2: C, 79.97;
H, 6.71. Found: C, 79.60; H, 6.50%.
4.4.8. (R)-(E)-2-Acetoxy-4-(1-naphthyl)-3-butene 3d5a.
Yield: 47%; 91% e.e.14 (tR=16.13 min); [h]2D5 +63.3 (c
1.4, CHCl3); IR (neat): 1730 cm−1; 1H NMR (200 MHz,
CDCl3): l 1.5 (3H, d, J=6.67 Hz), 2.1 (3H, s), 5.6 (1H,
q, J=6.68 Hz), 6.2 (1H, dd, J=15.60, 6.68 Hz), 7.2–7.6
(5H, m), 7.8 (2H, m), 8.1 (1H, m); EIMS (m/z): 240
(M+), 198 (M+−42). Anal. calcd for C16H16O2: C, 79.97;
H, 7.12. Found: C, 79.8; H, 7.04%.
4.4.2. (R)-(E)-2-Acetoxy-4-(3-phenoxyphenyl)-3-butene
3a. Yield: 49%; 97% e.e.11a (tR=12.42 min); [h]D25 +91.7
1
(c 1.6, CHCl3); IR (neat): 1730 cm−1; H NMR (200
MHz, CDCl3): l 1.4 (3H, d, J=6.69 Hz), 2.1 (3H, s),
5.5 (1H, q, J=6.69 Hz), 6.2 (1H, dd, J=16.68, 6.69
Hz), 6.5 (1H, d, J=16.68 Hz), 6.8–7.4 (9H, m); EIMS
(m/z): 282 (M+), 240 (M+−42), 197 (M+−85). Anal.
calcd for C18H18O3: C, 76.57; H, 6.43. Found: C, 76.40;
H, 6.15%.
4.4.9. (S)-2-[1-Phenyl-(E)-methylidene]-1-cyclohexanol
2e. Yield: 43%; 92% e.e.11b (tR=10.91 min); [h]D25 −12.9
1
(c 1.0, CHCl3); IR (neat): 3400 cm−1; H NMR (200
MHz, CDCl3): l 1.4–1.8 (6H, m), 2.0 (1H, m), 2.6 (1H,
m), 4.2 (1H, m), 6.5 (1H, s), 7.1–7.4 (5H, m); EIMS
(m/z): 184 (M+−4). Anal. calcd for C13H16O: C, 82.94;
H, 8.57. Found: C, 82.64; H, 8.12%.
4.4.3. (S)-(E)-4-Phenyl-3-butene-2-ol 2b5a. Yield: 42%;
96% e.e.11b (tR=15.76 min); [h]D25 −29.6 (c 2.0, CHCl3)
[lit. [h]2D5 −29.2 (c 2.0, CHCl3), e.e. 95%];6c IR (neat):
4.4.10.
(R)-2-[1-Phenyl-(E)-methylidene]-1-cyclohexyl
acetate 3e. Yield: 42%; >99% e.e.13 (tR=8.37 min); [h]2D5
1
3450, cm−1; H NMR (200 MHz, CDCl3): l 1.4 (3H, d,
+36.0 (c 0.8, CHCl3); IR (neat): 1730 cm−1; H NMR
1
J=6.69 Hz), 4.4 (1H, q, J=6.69 Hz), 6.2 (1H, dd,
J=16.68, 6.69 Hz), 6.5 (1H, d, J=16.68 Hz), 7.2–7.4
(5H, m); EIMS (m/z): 148 (M+), 105 (M+−43). Anal.
calcd for C10H12O: C, 81.04; H, 8.16. Found: C, 80.60;
H, 7.85%.
(200 MHz, CDCl3): 1.2–1.8 (6H, m), 2.0 (3H, s), 2.2–2.6
(2H, m), 5.4 (1H, m), 6.5 (1H, s), 7.1–7.4 (5H, m);
EIMS (m/z): 230 (M+), 188 (M+−42). Anal. calcd for
C15H18O2: C, 78.23; H, 7.88. Found: C, 78.02; H,
7.46%.
4.4.4. (R)–(E)-2-Acetoxy-4-phenyl-3-butene 3b. Yield:
45%; 98% e.e.13 (tR=13.59 min); [h]2D5 +138 (c 1.1,
CHCl3); IR (neat): 1730 cm−1; 1H NMR (200 MHz,
CDCl3): l 1.4 (3H, d, J=6.69 Hz), 2.1 (3H, s), 5.5 (1H,
q, J=6.69 Hz), 6.0–6.2 (1H, dd, J=16.68, 6.69 Hz), 6.6
(1H, d, J=16.68 Hz), 7.2–7.4 (5H, m); EIMS (m/z):
190 (M+), 148 (M+−42). Anal. calcd for C12H14O2: C,
75.76; H, 7.42. Found: C, 75.6; H, 7.05%.
Acknowledgements
We are thankful to the Department of Science and
Technology, New Delhi for the financial support for
Grants-in-Aid project under SERC (No. SP/S1/G-47/
99). Two of the authors M.S. and A.A.S. are thankful
to CSIR, New Delhi for the award of research
fellowship.
4.4.5. (S)-(E)-4-Chlorophenyl-3-butene-2-ol 2c. Yield:
40%; >99% e.e.13 (tR=8.97 min); [h]2D5 −18.8 (c 1.3,
CHCl3); IR (neat): 3450 cm−1; 1H NMR (200 MHz,
CDCl3): l 1.4 (3H, d, J=6.68 Hz), 4.4 (1H, q, J=6.68
Hz), 6.2 (1H, dd, J=15.60, 5.94 Hz), 6.5 (1H, d,
J=15.60 Hz), 7.2–7.4 (4H, m); EIMS (m/z): 182 (M+).
Anal. calcd for C10H11ClO: C, 65.76; H, 6.07; Cl, 19.41
Found: C, 65.56; H, 6.0; Cl, 19.01%.
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14. Determined by chiral HPLC (Chiracel, OJ-H column,
Daicel) at 254 nm wavelength employing hexane–iso-
propanol (90:10) as mobile phase, 0.5 mL/min and 18 kgf
pressure.