Lipase AK-mediated synthesis of both antipodes of 2-phenyl- and 2-(1-naphthyl)cyclohexanols in enantiomerically pure form

Article abstract of DOI:10.1055/s-2005-861819

Both (R,S)- and (S,R)-enantiomers of 2-phenylcyclohexanol and 2-(1-naphthyl)cyclohexanol were prepared in enantiomerically pure form and in excellent chemical yields by lipase AK (Pseudomonas fluorescens)-catalyzed kinetic acetylation of racemic alcohols

Full text of DOI:10.1055/s-2005-861819

PAPER
749
Lipase AK-Mediated Synthesis of Both Antipodes of 2-Phenyl- and 2-(1-Naph-
thyl)cyclohexanols in Enantiomerically Pure Form
S
ynthesis of 2-Phe
i
nyl- an
-
d
2-(1-N
H
aphthyl)cyclohexa
s
nols uan She, Chen-Fan Wu, Kak-Shan Shia, Jen-Dar Wu, Rama Krishna Peddinti, Hsing-Jang Liu*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300, P. R. of China
E-mail: hjliu@mx.nthu.edu.tw
Received 18 October 2004; revised 6 December 2004
Abstract: Both (R,S)- and (S,R)-enantiomers of 2-phenylcyclohex-
anol and 2-(1-naphthyl)cyclohexanol were prepared in enantiomer-
ically pure form and in excellent chemical yields by lipase AK
OH
OH
OH
(Pseudomonas fluorescens)-catalyzed kinetic acetylation of racem-
ic alcohols with vinyl acetate in t-butyl methyl ether at 35 °C. The
enantioselectivity of this biocatalytic transformation was found to
be independent of reaction time.
Key words: lipase AK, kinetic acetylation, pure enantiomers, 2-
phenylcyclohexanol, 2-(1-naphthyl)cyclohexanol
3
1
2
Figure 1 Cyclohexyl-based chiral auxiliaries
naphthylmagnesium bromide, respectively. The trans-
esterification of ( )-2 was performed using a lipase with
vinyl acetate as acetyl donor in t-butyl methyl ether
(Scheme 1). Lipases Rhizopus oryzae (lipase N, Amano),
Rhizomucor miehei (lipase MAP-10, Amano), Candida
rugosa (lipases MY and OF-360, Sangyo), and
Pseudomonas fluorescens (lipase AK, Amano) were test-
ed under the present acetyl transfer reaction. The progress
of the reaction was monitored by TLC analysis and the
enantioselectivity of the alcohol was judged by HPLC
analysis using a chiral column. No reaction was observed
with lipase N after a reaction time of 50 hours, while li-
pase MAP-10 could not differentiate the enantiomers sat-
isfactorily. However, lipases OF-360 and AK provided
encouraging results when the reactions were carried out at
35 °C. Thus, lipases OF-360 and AK produced acetate
(–)-4 in >99% ee and alcohol (+)-2 in 44% and 79% ee,
respectively, in a reaction time of 50 hours (Table 1). Af-
ter considerable experimentation, it was found that lipase
AK catalyzes the reaction to afford both antipodes in op-
tically pure form and in quantitative yield in five days
when the amount of the lipase used was increased. The
transesterification is highly selective and formation of
(+)-4 was not observed even after the reaction time was
extended to 10 days. The catalytic activity of the recov-
ered enzyme was tested and its activity was found to be
the same as it had been prior to the initial transesterifica-
tion. When lipase PS30 was used for this transformation,
we were able to reproduce the results reported by Carpen-
ter et al.12a However, when the reaction time for the trans-
esterification of ( )-2 using PS30 was extended, the
(1S,2R)-2 formed reacted further, albeit slowly, resulting
in the formation of both enantiomers in lower optical pu-
rities (Table 1, entries 6 and 7).
Due to their versatility and the high levels of stereocontrol
achieved, cyclohexyl-based chiral auxiliaries1 such as Co-
rey’s (–)-8-phenylmenthol (1)2 and Whitesell’s (–)-2-phe-
nylcyclohexanol (2)3 (Figure 1), have a unique place in
the construction of a large variety of chiral target mole-
cules. The asymmetric induction achieved is a conse-
quence of selective facial shielding of the functional
group to be transformed by the aryl moiety of the
auxiliary1 and the occurrence of interactions4,5 between
them. The prominence of enantiomerically pure 2 as ef-
fective inducers of chirality has prompted the develop-
ment of both non-enzymatic as well as enzymatic routes
towards both antipodes.1 Several non-enzymatic synthetic
routes via asymmetric hydroboration,6 epoxidation,7 and
dihydroxylation8 of 1-phenylcyclohexene and non-enzy-
matic kinetic resolutions9,10 have been reported for the
preparation of optically active alcohol 2. Among the vari-
ous enzymes11,12 employed for the kinetic resolution of 2,
lipases Pseudomonas sp,11c,12b PS30,12a Candida rugosa11a
were found to yield best results. Nevertheless, carefully
controlled reaction conditions, in particular the reaction
time, are necessary to obtain both enantiomers in opti-
mum chemical and optical yields. 2-(1-Naphthyl)cyclo-
hexanol (3, Figure 1) is another promising chiral auxiliary
as it bears a bulkier aryl moiety. Recently, non-
enzymatic10 and enzymatic11b,13 methods were reported
for the kinetic resolution of 3. Herein, we report a highly
efficient kinetic acetylation of 2 and 3 using lipase AK
(Pseudomonas fluorescens) that allows for convenient ac-
cess to optically pure antipodes of these compounds.
The racemic trans-alcohols ( )-211d and ( )-313 were pre-
pared via a copper-catalyzed ring opening of epoxycyclo-
hexane with phenylmagnesium bromide and 1-
We have also separated the enantiomers ( )-2-(1-naph-
thyl)cyclohexanol (3) by kinetic resolution using several
lipases. Again, lipase AK was found to yield optimum re-
SYNTHESIS 2005, No. 5, pp 0749–0752
Advanced online publication: 09.02.2005
DOI: 10.1055/s-2005-861819; Art ID: F14904SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
5

750
Y.-H. She et al.
PAPER
OH
The above experimental results clearly reveal that lipase
AK is a superior enzyme to those previously reported for
kinetic acetylation of 2-phenyl- (2) and 2-(1-naphthyl)cy-
clohexanols (3). By the use of this enzyme, each of the
enantiomeric pairs was cleanly resolved, and each enanti-
omer was obtained in optically pure form. The complete
enantioselectivity observed using lipase AK was shown to
be totally independent of the reaction time. Consequently,
the tedious monitoring of the reaction becomes unneces-
sary. An added advantage is the low cost of lipase AK,
which is considerably less expensive than the commonly
used lipase PS 30. The low cost, reaction time indepen-
dency, and reusability of lipase AK make it a viable asset
for large-scale preparations of pure enantiomers of 2 and
3, which have found extensive use (the former in particu-
lar) as chiral auxiliaries for asymmetric synthesis.
OH
OAc
lipase
+
vinyl acetate
t-BuOMe
( )-2
(1S,2R)-2
(1R,2S)-4
K2CO3
MeOH
(1R,2S)-2
Scheme 1
OH
OH
OAc
lipase
+
vinyl acetate
t-BuOMe
(1S,2R)-3
( )-3
(1R,2S)-5
1
The spectral properties (IR, H NMR, 13C NMR, and MS) of the
compounds were found to be in good agreement with those report-
ed.11b,13 FTIR spectra were recorded on a Nicolet Magna 750 instru-
ment. 1H and 13C NMR spectra were measured using a Varian Inova
300 instrument with chemical shifts reported in d (ppm) downfield
from TMS (d = 0.00) using the residual solvent signal of CDCl3 (1H
NMR: d = 7.26, singlet; 13C NMR: d = 77.0, triplet) as an internal
standard. HRMS were recorded using a Kratos MS-50 mass spec-
trometer (electron impact). Analytical TLC was performed using
Merck 60 F254 precoated silica gel plates (0.25 mm thickness). Flash
chromatography was performed using silica gel (Kieselgel 60, 230–
400 mesh, Merck). Determination of ee was done by HPLC (Waters
K2CO3
MeOH
(1R,2S)-3
Scheme 2
sults. The transesterification catalyzed by this lipase pro-
ceeded efficiently, and in 10 days both enantiomers were
obtained in optically pure form and in virtually quantita-
tive yield (Scheme 2 and Table 2). As in the previous 2410) using chiral column ChiraCel OD, and specific rotation was
measured on a Jasco P-1020 polarimeter.
case, lipase AK is very specific to the (1R,2S)-enantiomer
and the (1S,2R)-enantiomer was not esterified under these
Optically Pure (+)- and (–)-2-Phenylcyclohexanol
conditions even after 20 days.
A suspension of ( )-2 (1.76 g, 10 mmol), vinyl acetate (9.3 mL, 100
mmol), and lipase AK on Celite (3.52 g, Amano) in t-BuOMe (30
Table 1 Lipase-Mediated Kinetic Resolution of ( )-2a
Entry
Enzymeb
Reaction Time
(1S,2R)-2
(1R,2S)-4
Yield (%)c
ee (%)d
44
Yield (%)c
ee (%)e
99
1
2
3
4
5f
6
7
OF
AK
AK
AK
AK
PS
50 h
50 h
5 d
69
29
50
79
42
99
49.5
49.5
49.5
49
>99
>99
>99
85
49.5
49.5
49.5
40
>99
>99
>99
97
10 d
5 d
3 d
PS
5 d
40
81
47
79
a All reactions were carried out in t-BuOMe (0.333 M concentration) with 10 equiv of vinyl acetate at 35 °C. For entries 1, 2, 6, and 7, ( )-2/
enzyme = 0.85 mmol/80 mg; for entries 3–5, ( )-2/enzyme = 10 mmol/3.52 g.
b OF: lipase OF-360, AK: lipase AK, PS: lipase PS 30.
c All yields are for the isolated compound. For entries 1, 2, 6, and 7, various amounts of the enantiomer were detected in the isolated material.
d Determination of ee was done by HPLC analysis using chiral column ChiralCel OD (i-PrOH–hexane, 1:99; flow rate: 2 mL/min, tR 14.51 min
for (+)-2; tR 3.94 min for (–)-4; UV: l = 254 nm).
e Determination of ee was by HPLC analysis of the corresponding alcohol using chiral column ChiralCel OD (i-PrOH–hexane, 1:99; flow rate:
2 mL/min; tr 15.87 min for (–)-2, l = 254 nm).
f Recovered enzyme was used.
Synthesis 2005, No. 5, 749–752 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Phenyl- and 2-(1-Naphthyl)cyclohexanols
751
Table 2 Lipase-Mediated Kinetic Resolution of ( )-3a
Entry
Enzymeb
Reaction Time
(1S,2R)-3
(1R,2S)-5
Yield (%)c
ee (%)d
<50
Yield (%)c
ee (%)e
99
1
OF
14 d
7 d
90
9
2f
3
AK
AK
AK
AK
66
<50
29
>98
>99
>99
>99
10 d
20 d
10 d
49.5
49.5
49.5
>99
49.5
49.5
49.5
4
>99
5g
>99
a All reactions were carried out in t-BuOMe (0.285 M concentration) with 10 equiv of vinyl acetate at 35 °C unless otherwise mentioned. For
entries 1 and 2, ( )-3/enzyme = 0.22 mmol/44 mg; for entries 3–5, ( )-3/enzyme = 10 mmol/4.52 g.
b OF: lipase OF-360, AK: lipase AK.
c All yields are for the isolated compound. For entries 1 and 2, various amounts of the enantiomer were detected in the isolated material.
d ee was determined by HPLC analysis using a chiral column ChiralCel OD (i-PrOH–hexane, 1: 99; flow rate: 2 mL/min; tR 23.01 min for (+)-
3; 7.66 min for (+)-5, l = 254 nm).
e ee was determined by the HPLC analysis of the corresponding alcohol using a chiral column, ChiralCel OD (i-PrOH–hexane, 1:99; flow rate:
2 mL/min; tR 28.42 min for (–)-3, l = 254 nm).
f Reaction was carried out at r.t.
g Recovered enzyme was used.
mL) was stirred at 35 °C for 5 d. To determine the completion of the
reaction, aliquots were taken and purified by flash chromatography
on silica gel (EtOAc–hexanes, 5:95), and the optical purity was de-
termined by HPLC using chiral column chiralcel OD (i-PrOH–hex-
ane, 1:99; flow rate: 2 mL/min). After completion of the reaction,
the mixture was cooled to r.t., filtered through a sintered-glass fun-
nel, and rinsed with EtOAc (100 mL). The combined organic layers
were dried over anhyd MgSO4, concentrated in vacuo and chro-
matographed on silica gel (EtOAc–hexane, 5:95 to 10:90) to furnish
(+)-2 (0.87 g) as white crystals and (–)-4 (1.08 g) as a pale yellow
oil.
(+)-3
Mp 99.5–100.5 °C (Lit.13 100–101 °C); [a]D25 +72.2 (c 1.0, EtOH)
{Lit.13 [a]D26 +78.8 (c 1.0, CHCl3)}.
(+)-5
[a]D25 +34.9 (c 1.0, EtOH) {Lit.13 [a]D26 +36.2 (c 1.05, CHCl3)}.
Hydrolysis of (+)-5 (1.33 g, 4.9 mmol) using the same method de-
scribed in the preceding experiment gave pure (–)-3 (1.11 g).
(–)-3
Mp 99.5–100.5 °C (Lit.13 100–100.5 °C); [a]D25 –71.9 (c 1.1, EtOH)
{Lit.13 [a]D26 –72.6 (c 1.0, CHCl3)}.
(+)-2
25
Mp 63.5–64.5 °C (Lit.14 64–65 °C); [a]D +56.9 (c 1.0, EtOH)
{Lit.14 [a]D23 +55.0 (c 0.10, MeOH)}.
Acknowledgment
We thank the National Science Council of the Republic of China for
financial support.
(–)-4
[a]D25 –6.5 (c 0.32, EtOH) [Lit.15 [a]D –6.2].
The optically active ester (–)-4 was chemically hydrolyzed. To a so-
lution of (–)-4 (0.99 g, 4.5 mmol) in MeOH (10 mL), was added
K2CO3 (1.86 g, 13.5 mmol). After stirring at r.t. for 10 h, the reac-
tion mixture was concentrated in vacuo, and the residue was parti-
tioned between EtOAc (50 mL) and H2O (20 mL). The organic layer
was washed with brine (20 mL), dried over anhyd MgSO4, the
EtOAc evaporated under reduced pressure and the residue was
chromatographed on silica gel (EtOAc–hexanes, 10:90) to afford
pure (–)-2 (0.78 g).
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Optically Pure (+)- and (–)-2-(1-Naphthyl)cyclohexanol
A suspension of ( )-3 (2.26 g, 10 mmol), vinyl acetate (9.3 mL, 100
mmol), and lipase AK on Celite (4.52 g, Amano) in t-BuOMe (35
mL) was stirred at 35 °C for 10 d. The reaction was worked up as
mentioned above. Chromatography of the crude product on silica
gel (EtOAc–hexanes, 5:95 to 10:90) furnished (+)-3 (1.12 g) as
white crystals and (+)-5 (1.33 g) as a pale yellow oil.
Synthesis 2005, No. 5, 749–752 © Thieme Stuttgart · New York

752
Y.-H. She et al.
PAPER
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Synthesis 2005, No. 5, 749–752 © Thieme Stuttgart · New York