Enantioselective enzymatic approach to (+)- and (-)-2-acetoxy/hydroxycyclopentanones

Article abstract of DOI:10.1016/S0957-4166(02)00366-X

A new practical enzymatic approach to (+)- and (-)-2-acetoxy/hydroxycyclopentanones with 96-98% ee has been described via enzymatic hydrolysis of the meso-diacetate 2, Swern oxidation of the thus formed (±)-hydroxy acetates 3 and 4, followed by re-enzymatic resolution. Enantiomerically pure (+)- and (-)-2-hydroxycyclopentanones are in equilibrium with enediol 9 and slowly undergo racemisation, a process which could be arrested by protecting the hydroxyl group as the acetate.

Full text of DOI:10.1016/S0957-4166(02)00366-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1367–1371
Enantioselective enzymatic approach to (+)- and
†
(
−)-2-acetoxy/hydroxycyclopentanones
Srinivasan Easwar, Shrivallabh B. Desai, Narshinha P. Argade* and Krishna N. Ganesh*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 14 May 2002; accepted 4 July 2002
Abstract—A new practical enzymatic approach to (+)- and (−)-2-acetoxy/hydroxycyclopentanones with 96–98% ee has been
described via enzymatic hydrolysis of the meso-diacetate 2, Swern oxidation of the thus formed (±)-hydroxy acetates 3 and 4,
followed by re-enzymatic resolution. Enantiomerically pure (+)- and (−)-2-hydroxycyclopentanones are in equilibrium with enediol
9
and slowly undergo racemisation, a process which could be arrested by protecting the hydroxyl group as the acetate. © 2002
Elsevier Science Ltd. All rights reserved.
9
1. Introduction
benzyloxy-substituted oxirane has been reported to
yield the desired enantiomerically pure benzyloxycyclo-
pentanone. It is noteworthy that 2-hydroxycyclo-
pentanones are not very stable compounds and at
ambient conditions they are known to undergo self-
The utilities of (±)-2-hydroxy- and (±)-2-acetoxycyclo-
1
pentanones have been well proven in practice and
several methods for synthesis of them are known in the
2
literature. To date there are five reports on the prepa-
10,11
coupling reactions to form 1,4-dioxane derivatives.
Similarly, in basic aqueous solutions they are known
ration of enantiomerically pure (R)-/(S)-2-hydroxy-
4
3
cyclopentanones. The first reports an enzymatic oxida-
to undergo a decomposition reaction with darkening to
a black colour. Hence the provision of an unambiguous
and facile route to (+)- and (−)-2-hydroxycyclopen-
tanones and their derivatives is a challenging task of
tion of cis-cyclopentanediol using whole cells to obtain
enantiomerically pure 2-hydroxycyclopentanone. The
4
second report describes the preparation of (2R)-
hydroxycyclopentanone by enantioselective reduction
of (±)-2-hydroxycyclopentanone using glucose-6-phos-
phate dehydrogenase (G-6-PDH) or glucose dehydro-
genase with 16–22% yield and 70–86% ee. The third one
2–9
current interest.
In continuation of our earlier
12
studies on the chemo-, regio- and enantioselective
hydrolysis of vicinal diacetyl derivatives by enzymes, we
investigated an enzymatic route to these unstable but
useful building blocks, and we herein report an easy
access to (+)- and (−)-2-acetoxy/hydroxycyclopen-
tanones (Scheme 1).
5
demonstrates an elegant asymmetric oxidation of a
homochiral ketal by rhenium(VII) oxide to obtain the
ketal of enantiomerically pure 2-hydroxycyclopen6-
tanone with 98% yield and >99% ee. The fourth report
illustrates Pseudomonas cepacia lipase (PSL)-induced
transesterification of cis-1,2-cyclopentanediol using
vinyl acetate to obtain (1S)-acetoxy-(2R)-hydroxy7-
cyclopentane with 82% chemical yield and 79% ee,
2
. Results and discussion
which can be oxidized to the desired (2S)-acetoxy-
In our hands the Amano PS-catalyzed biphasic hydro-
lysis of cis diacetate 2 at pH 7 furnished a mixture of
hydroxy acetates 3 and 4 in 65% yield and was found to
8
cyclopentanone using CrO /Py. The fifth report details
3
an enzymatic oxidation of anti-1,2-cyclopentane diol
with Bacillus stearothermophilus diacetyl reductase to
obtain (2S)-hydroxycyclopentanone in 16% yield with
13–15
be optically inactive.
The formation of a racemic
mixture of 3 and 4 could be a result of either non-selec-
tive random enzymatic hydrolysis of both acetates or
alternatively, the enzyme is enantioselective in its
action, but the product mixture is formed by the instan-
taneous in situ intramolecular acyl migration in a
cyclic-cis-vicinal hydroxy acetate system. At this stage,
99% ee. Recently, the asymmetric rearrangement of a
*
Corresponding authors. Tel.: +91-20-5893153; fax: +91-20-5893153;
e-mail: argade@dalton.ncl.res.in
NCL Communication No. 6627.
†
0
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00366-X

1
368
S. Easwar et al. / Tetrahedron: Asymmetry 13 (2002) 1367–1371
Scheme 1. (i) Ac O, Py, rt, 48 h (93%); (ii) petroleum ether/benzene (2:1), Amano PS, rt, 18 h, pH 7.0 (65%); (iii) (COCl) ,
2
2
12
DMSO, TEA, DCM, −60°C, 15 min (86%); (iv) petroleum ether/benzene (2:1), Amano PS (800 U), rt, 22 h, pH 6.5 (6, 28–32%;
, 45%); (v) aq. K CO , MeOH, 0°C, 4 h (77%).
7
2
3
we oxidized the mixture of hydroxy acetates 3 and 4 to
the corresponding keto acetate 5, for enzymatic resolu-
tion with two aims; viz (a) to draw conclusions about
the enantioselectivity of the enzyme and (b) to develop
a new enzymatic route to (+)- and (−)-2-acetoxy/
hydroxycyclopentanones. Upon Swern oxidation, the
mixture of 3 and 4 gave (±)-2-acetoxycyclopentanone 5
in 86% yield, which on Amano PS-catalyzed biphasic
1
6
hydrolysis at pH 6.5 gave a mixture of enantiomeri-
cally pure 2-hydroxycyclopentanone 6 and 2-acetoxycy-
clopentanone 7. Silica gel column chromatographic
separation of the above mixture gave (−)-(2R)-hydroxy-
cyclopentanone 6 in 28–32% yield and (+)-(2S)-ace-
toxycyclopentanone
7
in
45%
yield.
The
2
-hydroxyketone 6 on reaction with (R)-Mosher’s acid
in the presence of DCC gave the corresponding MTPA
1
derivative of 6, the H NMR spectrum of which
revealed that it has an ee of 90–92%. Similarly, enan-
tiomerically pure 6 on treatment with AcOH/DCC gave
the acetyl derivative of 6 with 90–92% ee. The compari-
son of the specific rotation of 7 with the acetyl deriva-
tive of 6 revealed that 7 is obtained with 96–98% ee.
The base-induced hydrolysis of 7 to 8 followed by
MTPA derivatisation of 8 indicated that it possesses
only 40% ee. The decline in the ee of 8 can be due to
Figure 1.
prototropic shifts take place in the formation of ene-
diol-9. The isolation of monodeuterated (−)-6 from
D O and determination of the optical rotation indi-
2
cated that the process of racemisation of (−)-6 was also
relatively slow in D O, possibly because of extensive
17
base-induced racemisation/1,2-carbonyl transposition.
2
During these studies, we also noticed that (−)-6, either
neat or in chloroform solution at 0°C, slowly loses its
enantiomeric purity and becomes completely racemic
over a period of nearly two months, indicating that
these isomers have a two months half life span as
determined by measuring the specific rotations with
intermolecular hydrogen bonding. The (+)-(2S)-ace-
toxycyclopentanone 7 did not show any decline in
enantiomeric purity and hence without chromato-
graphic separation of 6 and 7, the mixture was first
treated with (R)-Mosher’s acid and DCC to form a
mixture of 7 and the MTPA derivative of 6. The H
NMR spectrum of silica gel column-purified MTPA-
ester of 6 revealed that it actually has an ee of 96–98%.
1
time (Fig. 1). Enantiopure (−)-6 was subjected to D O
2
1
treatment at room temperature for 10 days and H
NMR spectra were scanned after each 24 h. Only the
heteroatom proton (-OH) was exchanged. The a-
methine proton did not show any exchange with deu-
terium atom, revealing that only intramolecular
These observations clearly suggest that intramolecular
hydrogen bonding in 6/8 enhances the keto-enol tau-
tomerism and the 2-hydroxycyclopentanones 6 and 8

S. Easwar et al. / Tetrahedron: Asymmetry 13 (2002) 1367–1371
1369
are in equilibrium with enediol 9 (Scheme 1). This is
aqueous layer was extracted with ethyl acetate (15
mL×5). The combined organic layer was washed with
water, brine and dried over Na SO . Concentration of
the organic layer in vacuo followed by silica gel column
chromatographic separation of the residue using a 10–
slowly transformed to the racemic mixture through
1
8
keto-enol tautomerism. These results show that the
enzyme Amano PS is very specific in its hydrolytic
action on the meso-diacatate 2 and the racemic mixture
of products 3 and 4 is formed because of in situ
2
4
1
5% ethyl acetate:petroleum ether mixture as an eluent
1
2b
intramolecular acyl migrations.
gave 2 (840 mg, 30%), 3 and 4 (1.4 g, 65%), respectively
(
increased reaction time resulted in the formation of 1).
1
Thick oil: H NMR (CDCl , 200 MHz) l 1.40–2.05 (m,
3
3. Conclusion
6H), 2.08 (s, 3H), 2.25 (bs, 1H), 4.15 (q, J=5 Hz, 1H),
1
3
4
2
6
.87–5.03 (m, 1H); C NMR (CDCl , 50 MHz) l 19.0,
3
In summary, we have demonstrated a facile and unam-
biguous new practical chemoenzymatic approach to
0.8, 27.7, 30.4, 72.5, 76.4, 171.0. MS (m/e) 101, 84, 73,
7, 57, 55. IR (neat) wmax 3429, 1722 cm .
−1
(
−)-(2R)-hydroxycyclopentanone 6 with 28–32% yield
and 90–92% ee, and (+)-(2S)-acetoxycyclopentanone 7
with 45% yield and 96–98% ee.
4
.4. (±)-2-Acetoxycyclopentanone, 5
To a solution of oxalyl chloride (0.74 mL, 8.4 mmol) in
dry CH Cl (5 mL) under argon at −60°C was added a
2
2
4. Experimental
solution of DMSO (0.8 mL, 11 mmol) in dry CH Cl (5
2
2
mL) in a dropwise fashion over a period of 5 min.
4
.1. General
Hydroxy acetate 3 and 4 (1.0 g, 7 mmol) in dry CH Cl
2
2
was charged dropwise over a period of 5 min and the
1
H NMR spectra were recorded on a Brucker AC 200
200 MHz) NMR spectrometer and Brucker MSL 300
300 MHz) NMR spectrometer. The FT-IR spectra
reaction mixture was stirred at −60°C for 15 min. Et N
3
(
(
(
4.9 mL, 35 mmol) was added and the reaction mixture
was further stirred at rt for 5 min. Water (10 mL) was
added to the reaction mixture and the aqueous layer
was extracted with CH Cl (15 mL×5). The combined
were recorded on a FT-IR-8300 Shimadzu spectrome-
ter. The mass spectra were recorded on a Finnigan Mat
2
2
1
020 mass spectrometer at 70 eV. Column chromato-
organic layer was washed with water, brine and dried
over Na SO . Concentration of the organic layer in
graphic separations were carried out on ACME silica
gel (60–120 mesh). Amano PS-800 U from Amano
Pharmaceuticals, Japan was used. The activity of the
lipase powder used is expressed in terms of units, 1 unit
corresponding to micromoles of butyric acid liberated
2
4
vacuo followed by silica gel column chromatographic
purification of the residue provided 5 (855 mg, 86%).
1
Viscous oil: H NMR (CDCl , 200 MHz) l 1.70–2.00
3
(
m, 2H), 2.13 (s, 3H), 2.20–2.50 (m, 4H), 5.07 (t, J=9
(
estimation by GC) from glyceryl tributyrate per
13
Hz, 1H); C NMR (CDCl , 50 MHz) l 17.0, 20.5,
3
minute per milligram of enzyme powder.
2
8.2, 34.6, 75.5, 169.9, 212.2. MS (m/e) 142, 99, 86, 71.
−
1
IR (neat) wmax 1753, 1744 cm .
4.2. cis-1,2-Diacetoxycyclopentane, 2
4
.5. Amano PS-catalyzed hydrolysis of (±)-5
To a stirred solution of diol 1 (2.04 g, 20 mmol) in
pyridine (10 mL) was added acetic anhydride (8 mL)
and the reaction mixture was kept in the dark for 24 h
at rt. The reaction mixture was poured into water and
extracted with ethyl acetate (15 mL×5). The combined
A solution of (±)-2-acetoxyketone 5 (710 mg, 5 mmol)
in a petroleum ether:benzene (2:1) mixture (30 mL) was
added to a suspension of Amano PS lipase (250 mg) in
aq. sodium phosphate (0.01 M, 10 mL) at pH 6.5. The
reaction mixture was stirred at 25°C for 22 h. The
reaction mixture was filtered through Celite and the
aqueous layer was extracted with ethyl acetate (15
mL×5). The combined organic layer was washed with
water, brine and dried over Na SO . Concentration of
the organic layer in vacuo followed by silica gel column
chromatographic separation using a 10–15% ethyl acet-
ate:petroleum ether mixture as an eluent gave (+)-7 (318
mg, 45%) and (−)-6 (150 mg, 32%), respectively.
organic layer was washed with a CuSO solution, water,
4
brine and dried over Na SO . Concentration of the
2
4
organic layer in vacuo followed by silica gel column
chromatographic purification of the residue using a
5
–10% ethyl acetate:petroleum ether mixture as an elu-
1
ent gave 2 (3.5 g, 93%). Thick oil; H NMR (CDCl ,
2
4
3
2
00 MHz) l 1.50–2.10 (m, 6H), 2.04 (s, 6H), 5.00–5.25
13
(m, 2H); C NMR (CDCl , 50 MHz) l 18.8, 20.6, 27.9,
3
7
3.8, 170.0. MS (m/e) 143, 126, 101, 83, 67, 57. IR
−1
(
neat) wmax 1742 cm .
2
0
1
(
(
−)-6: viscous oil; [h] =−38.4 (c 1.2, CHCl ); H NMR
4.3. (±)-cis-1-Acetoxy-2-hydroxycyclopentane 3 and 4
D
3
CDCl , 200 MHz) l 1.60–1.95 (m, 2H), 1.95–2.60 (m,
3
4
H), 2.92 (bs, 1H, D O exchangeable), 4.09 (t, J=10
A solution of diacetate 2 (2.79 g, 15 mmol) in a
petroleum ether:benzene (2:1) mixture (60 mL) was
added to a suspension of Amano PS lipase (350 mg) in
aq. sodium phosphate (0.01 M, 20 mL) at pH 7.0. The
reaction mixture was stirred at 25°C for 18 h. The
reaction mixture was filtered through Celite and the
2
1
Hz, 1H); H NMR (D O, 200 MHz) l 1.50–2.50 (m,
6H), 4.19 (t, J=10 Hz, 1H); C NMR (CDCl
MHz) l 16.4, 30.7, 33.9, 75.7, 159.8. MS (m/e) 100, 84,
72, 57, 55. IR (neat) w
viscous oil; [h] =+61.0 (c 2.0, CHCl ).
2
13
, 50
3
−
1
3404, 1746 cm . (+)-7:
max
2
0
D
3

1
370
S. Easwar et al. / Tetrahedron: Asymmetry 13 (2002) 1367–1371
4.6. Acetyl derivative of (−)-6
Acknowledgements
To a solution of acetic acid (10 mg), (−)-2-hydroxy-
ketone 6 (10 mg, 0.1 mmol) and DMAP (cat.) in dry
CH Cl (3 mL) was added a solution of DCC (15 mg)
S.E. thanks UGC, New Delhi, for the award of a
research fellowship. N.P.A. thanks the Department of
Science and Technology, New Delhi, for financial sup-
port. We thank Amano Pharmaceuticals Co., Japan for
a generous gift of enzyme Amano PS.
2
2
in dry CH Cl (2 mL) at 0°C. The reaction mixture was
2
2
allowed to warm to rt and stirred for 8 h. The urea
formed was filtered off and the organic layer was
concentrated in vacuo. Silica gel column chromato-
graphic purification of the residue using a 10% ethyl
acetate:petroleum ether mixture as an eluent gave the
acetyl derivative of (−)-6 in quantitative yield. Thick
References
2
0
1
. (a) Brown, M. J.; Harrison, T.; Herrinton, P. M.; Hop-
kins, M. H.; Hutchinson, K. D.; Overman, L. E.; Mishra,
P. J. Am. Chem. Soc. 1991, 113, 5365; (b) Ohno, M.;
Oguri, I.; Eguchi, S. J. Org. Chem. 1999, 64, 8995; (c)
Gatling, S. C.; Jackson, J. E. J. Am. Chem. Soc. 1999,
121, 8655; (d) Hoffmann, T.; Zhong, G.; List, B.; Shabat,
D.; Anderson, J.; Gramatikova, S.; Lerner, R. A.; Bar-
bas, C. F., III J. Am. Chem. Soc. 1998, 120, 2768 and
references cited therein 1a–d.
oil: [h] =−54.9 (c 1.0, CHCl ).
D
3
4.7. (+)-(2S)-Hydroxycyclopentanone 8
To a solution of (+)-acetoxyketone 7 (71 mg, 0.5 mmol)
in MeOH (15 mL) and H O (15 mL) was added K CO
2
2
3
(
70 mg, 0.6 mmol) and the reaction mixture was stirred
at 0°C for 4 h. The reaction mixture was diluted with
water (30 mL) and the aqueous solution was extracted
with CH Cl (15 mL×5). The combined organic layer
2. (a) Yamamoto, H.; Tsuda, M.; Sakaguchi, S.; Ishii, Y. J.
Org. Chem. 1997, 62, 7174; (b) Reddy, D. R.; Thornton,
E. R. J. Chem. Soc., Chem. Commun. 1992, 172; (c)
Moriarty, R. M.; Hou, K.-C. Tetrahedron Lett. 1984, 25,
2
2
was washed with water, brine and dried over Na SO .
2
4
Concentration of organic layer in vacuo followed by
silica gel column chromatographic purification of the
residue using a 15% ethyl acetate:petroleum ether mix-
ture as an eluent gave 8 (39 mg, 77%). Thick oil;
691; (d) Cookson, R. C.; Lane, R. M. J. Chem. Soc.,
Chem. Commun. 1976, 804; (e) Shinada, T.; Kawakami,
T.; Sakai, H.; Takada, I.; Ohfune, Y. Tetrahedron Lett.
1998, 39, 3757; (f) Cummins, C. H.; Coates, R. M. J.
Org. Chem. 1983, 48, 2070; (g) Rubottom, G. M.; Mott,
R. C.; Juve, H. D., Jr. J. Org. Chem. 1981, 46, 2717; (h)
Fry, A. J.; Donaldson, W. A.; Ginsburg, G. S. J. Org.
Chem. 1979, 44, 349; (i) Shono, T.; Okawa, M.;
Nishiguchi, I. J. Am. Chem. Soc. 1975, 97, 6144; (j)
Shono, T.; Matsumura, Y.; Nakagawa, Y. J. Am. Chem.
Soc. 1974, 96, 3532 and references cited therein (2a–j).
. Posternak, Th.; Reymond, D.; Friedli, H. Helv. Chim.
Acta 1955, 38, 205.
2
0
[
h] =+20.3 (c 1.2, CHCl ).
D 3
4.8. General procedure for MTPA-ester preparation
To a solution of (R)-Mosher’s acid (23 mg), (−)-2-
hydroxyketone 6 (10 mg, 0.1 mmol) and DMAP (cat.)
in dry CH Cl (3 mL) was added a solution of DCC (15
2
2
3
mg) in dry CH Cl (2 mL) at 0°C. The reaction mixture
2
2
was allowed to warm to rt and stirred for 8 h. The urea
formed was filtered off and the organic layer was
concentrated in vacuo. Silica gel column chromato-
graphic purification of the residue using a 10% ethyl
acetate:petroleum ether mixture as an eluent gave the
MTPA-ester in quantitative yield.
4
5
. Lee, L. G.; Whitesides, G. M. J. Org. Chem. 1986, 51, 25.
. Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33,
7823.
6
7
. Nicolosi, G.; Patti, A.; Piattelli, M.; Sanfilippo, C. Tetra-
hedron: Asymmetry 1995, 6, 519.
. (1S)-Acetoxy-(2R)-hydroxycyclopentane
suffers
an
appreciable decrease in enantiomeric excess following
work up of the reaction mixture.
8. Bortolini, O.; Casanova, E.; Fantin, G.; Medici, A.; Poli,
S.; Hanau, S. Tetrahedron: Asymmetry 1998, 9, 647.
. Feng, X.; Shu, L.; Shi, Y. J. Am. Chem. Soc. 1999, 121,
1
4
.8.1. MTPA-ester of (±)-2-hydroxycyclopentanone. H
NMR (CDCl , 200 MHz) l 1.70–2.60 (m, 12H), 3.58 (s,
H), 3.64 (s, 3H), 5.25 (t, J=8 Hz, 1H), 5.35 (t, J=8
Hz, 1H), 7.30–7.75 (m, 10H). MS (m/e) 316, 286, 216,
3
3
9
11002.
189, 158, 139, 119, 105, 91, 77, 69, 55.
1
1
0. Sterk, H. Monatsh. Chem. 1968, 99, 2107.
1. Schick, H.; Ballschuh, D. Ger. (East) 124, 300.
(C1.C07D319/14), 16 Feb 1977, Appl. 191, 505, 26 Feb
1976. Chem. Abstr. 1978, 88, 50877.
12. (a) Desai, S. B.; Argade, N. P.; Ganesh, K. N. J. Org.
Chem. 1996, 61, 6730; (b) Desai, S. B.; Argade, N. P.;
Ganesh, K. N. J. Org. Chem. 1999, 64, 8105.
3. The mixture of 2, 3 and 4 did not show any optical
rotation before silica gel column chromatographic
separation.
14. (a) Crout, D. H. G.; Gaudet, V. S. B.; Laumen, K.;
Schneider, M. P. J. Chem. Soc., Chem. Commun. 1986,
808; (b) Xie, Z.-F.; Suemune, H.; Sakai, K. J. Chem.
Soc., Chem. Commun. 1987, 838.
4
6
3
.8.2. MTPA-ester of (−)-(2R)-hydroxycyclopentanone,
. H NMR (CDCl , 300 MHz) l 1.75–2.50 (m, 6H),
.64 (s, 3H), 5.35 (t, J=8 Hz, 1H), 7.30–7.70 (m, 5H).
MS (m/e) 316, 286, 216, 189, 158, 139, 119, 105, 91, 77,
1
3
69, 55.
1
4
8
3
.8.3. MTPA-ester of (+)-(2S)-hydroxycyclopentanone,
. H NMR (CDCl , 200 MHz) l 1.80–2.60 (m, 6H),
.57 (s, 3H), 5.25 (t, J=8 Hz, 1H), 7.35–7.70 (m, 5H).
MS (m/e) 316, 286, 216, 189, 158, 139, 119, 105, 91, 77,
9, 55.
1
3
6

S. Easwar et al. / Tetrahedron: Asymmetry 13 (2002) 1367–1371
1371
1
1
1
5. Kirschning, A.; Kreimeyer, M.; Blanke, H.-P. Tetra-
M. S. J. Org. Chem. 1994, 59, 6395.
hedron: Asymmetry 1993, 4, 2347.
18. To our knowledge this is the first example of an enediol-
induced in situ racemisation. The corresponding six-mem-
bered compound (2R)-hydroxycyclohexanone is known to
6. (±)-2-Acetoxycyclopentanone 5 on Amano PS-catalyzed
hydrolysis at pH 7.0 gave (−)-6 with lower % yield and ee.
7. Hernandez, R.; Velazquez, S. M.; Suarez, E.; Rodriguez,
8
be stable and has been isolated in quantitative yield.