A Practical Method for Optical Resolution of Racemic Alcohols or Esters via Lipase-Catalyzed Transformation and Sulfation

Article abstract of DOI:10.1246/cl.2000.448

Optically active esters were conveniently obtained from the corrasponding racemic alcohols or esters by lipase-catalyzed transformation, followed by sulfation. Sulfation by sulfurtrioxide pyridine complex enabled facile isolation of optically active esters by extraction instead of laborious column chromatography. The method would be especially adventageous on a large scale.

Full text of DOI:10.1246/cl.2000.448

448
Chemistry Letters 2000
A Practical Method for Optical Resolution of Racemic Alcohols or
Esters via Lipase-Catalyzed Transformation and Sulfation
Toru Yamano,* Fumio Kikumoto, Shozo Yamamoto, Katsuhiko Miwa, Mitsuru Kawada,
Tatsuya Ito,† Tomomi Ikemoto,† Kiminori Tomimatsu,† and Yukio Mizuno†
Technology Development Department, Takeda Chemical Industries, Ltd. 17-85, Juso-honmachi, 2-Chome, Yodogawa-ku, Osaka, 532-8686
†Chemical Development Laboratories, Takeda Chemical Industries, Ltd. 17-85, Juso-honmachi, 2-Chome, Yodogawa-ku, Osaka, 532-8686
(Received January 7, 2000; CL-000027)
Optically active esters were conveniently obtained from the
corresponding racemic alcohols or esters by lipase-catalyzed
transformation, followed by sulfation. Sulfation by sulfurtriox-
ide pyridine complex enabled facile isolation of optically active
esters by extraction instead of laborious column chromatogra-
phy. The method would be especially advantageous on a large
scale.
The lipase-catalyzed transformation of racemic alcohols or
esters has been recognized to be an indispensable method for
synthesis of optically active compounds.1 The method relies on
stereoselectivities accomplished by lipases, and a subsequent
skillful trick, which enables physically identical enantiomers to
be switched physically distinguishable compounds, alcohols
and esters. The separation of alcohols and esters is, in general,
carried out by laborious column chromatography, which is
extremely difficult and inefficient to carry out on a large scale.
In some cases, these difficulties may be avoided by using cyclic
acid anhydrides as acyl donors to form a water-soluble
monoester of dibasic acid, which is separable with an aqueous
alkaline solution.2 Facile and efficient methods suitable for a
large-scale production, however, remain poorly developed.
We wish here to describe a convenient method to separate
alcohols and esters by a simple and practical procedure. We
assumed that extraction, instead of column chromatography,
would be the procedure of choice. To this end, alcohols were
converted into water-soluble compounds by simple derivatiza-
tions. Among various derivatizations evaluated, sulfation using
sulfurtrioxide pyridine complex was found to be the most prom-
ising.
Accordingly, as depicted in Eq.1, racemic alcohols or
esters were subjected to lipase-catalyzed transformation to give
the mixtures consisting of optically active alcohols and esters.
The resulting mixtures were treated with sulfurtrioxide pyridine
complex to give mixtures consisting of esters and pyridinium
salts of monoalkyl sulfates. After dilution with hydrophobic
solvents such as diisopropyl ether, the mixtures were washed
with water to remove pyridinium salts of monoalkyl sulfates to
accomplish substantial separation of esters.3
The procedure has proved to be widely applicable (Table
1). High enantiomer excesses, accomplished by the lipase-cat-
alyzed transformation, were not affected by sulfation. The puri-
ty of esters was appreciably high and the contents of their coun-
terparts, alcohols, were kept below 1%.
Optically active esters thus obtained from the organic layer
could be smoothly converted to the corresponding alcohols by
acid- or base-catalyzed hydrolysis under mild conditions. It is
noteworthy that pyridinium salts of monoalkyl sulfates thus
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
449
obtained from aqueous layer could be also converted to the cor-
responding alcohols by acid hydrolysis (Eq.2). Therefore, both
enantiomeric alcohols could be obtained readily and effectively
by the present procedure. The procedure, thus, will be applica-
ble to the synthesis of a variety of optically active alcohols.
h, diisopropyl ether 70 ml was added. The mixture was
washed with successive water, dilute hydrochloric acid and
brine, then dried over sodium sulfate. The filtrate was con-
centrated under reduced pressure to afford methyl (S)-(+)-
2-(acetyloxy)-2-phenylacetate 0.559 g (45%, 92% ee) as an
oil. The combined aqueous layers were concentrated and
treated with 10% methanolic hydrochloric acid. A similar
work up afforded methyl (R)-(–)-2-hydroxy-2-phenylac-
etate 0.341 g (34%, 96% ee).
4
The acetate was hydrolyzed to give an alcohol, which was
subjected to HPLC analysis. Column: CHIRALCEL OD
(Daicel Chemical Industries, Ltd.), Mobile phase: hexa-
ne/2-propanol (97/3), Flow rate: 1.0 ml/min, Detection:
UV (280 nm), Temperature: room temperature.
5
6
7
8
9
Column: CHIRALCEL OD (Daicel Chemical Industries
Ltd.), Mobile phase: hexane/2-propanol (99/1), Flow rate:
1.2 ml/min, Detection: UV (254 nm), Temperature: room
temperature.
Column: CHIRALCEL OJ (Daicel Chemical Industries,
Ltd.), Mobile phase: hexane/2-propanol (98/2), Flow rate:
1.2 ml/min, Detection: UV (220 nm), Temperature: room
temperature.
Column: CHIRALCEL OB (Daicel Chemical Industries,
Ltd.), Mobile phase: hexane/2-propanol (1000/5), Flow
rate: 1.0 ml/min, Detection: UV (254 nm), Temperature:
room temperature.
Column: CHIRALCEL OD two pieces (Daicel Chemical
Industries, Ltd.), Mobile phase: hexane/2-propanol
(1000/5), Flow rate: 1.0 ml/min, Detection: UV (254 nm),
Temperature: room temperature.
References and Notes
1
a) “Enzymatic Reactions in Organic Media,” ed by A. M.
P. Koskinen and A. M. Klibanov, Blackie Academic &
Professional, Glasgow (1996). b) “Hydrolases in Organic
Synthesis,” ed by U. T. Bornscheuer and R. J. Kazlauskas,
Wiley-VCH, Weinheim (1999).
2
3
a) Y. Terao, K. Tsuji, M. Murata, K. Achiwa, T. Nishio, N.
Watanabe, and K. Seto, Chem. Pharm. Bull., 37, 1653
(1989). b) A. L. Gutman, D. Bernner, and A. Boltanski,
Tetrahedron: Asymmetry, 4, 839 (1993).
Preparation of (+)-methyl 2-acetyloxy-2-phenylacetate and
(–)-methyl 2-hydroxy-2-phenylacetate was performed as
follows: A suspension of lipase (LIP, Toyobo Co. Ltd.)
1.50 g, ( )-methyl 2-hydroxy-2-phenylacetate 1.00 g,
Molecular sieves 4A 5.0 g, and vinyl acetate 3.0 ml in
diisopropyl ether 100 ml was stirred at 35 °C for 3 h. After
the lipase was removed by filtration, the filtrate was con-
centrated under reduced pressure to give a residue contain-
ing methyl (S)-(+)-2-(acetyloxy)-2-phenylacetate (93% ee)
and methyl (R)-(–)-2-hydroxy-2-phenylacetate (99% ee).
The residue was dissolved in pyridine 10 ml and DMF 2
ml, and to this solution sulfur trioxide pyridine complex
1.95 g was added. After stirring at room temperature for 1
(GLC) Column: Chirasil Dex-CB (25 m × 0.25 mm I.D.,
Chrompack), Oven temperature: 80 °C ~ 150 °C, Injection
temperature: 200 °C, Detection temperature: 200 °C,
Carrier gas: Helium.
10 Y. Hirose, Y. Imada, Y. Yamashita, M. Kamori, H. Ozaki,
and J. Takahashi, presented at 9th International
Symposium on Chiral Discrimination, Nagoya, 1997,
Abstr., PP1-46, p.67.
11 M.-J. Kim and Y. K. Choi, J.Org.Chem., 57, 1605 (1992).
12 T. Ohtani, H. Nakatsukasa, M. Kamezawa, H. Tachibana,
and Y. Naoshima, J. Mol. Catal. B: Enzymatic, 4, 53 (1998).