First synthesis of (R)-(-)-5-hydroxy-3-methyl-3-pyrrolin-2-one (jatropham) by lipase-catalyzed kinetic resolution

Article abstract of DOI:10.1016/S0957-4166(99)00513-3

Jatropham, (R)-(-)-5-hydroxy-3-methyl-3-pyrrolin-2-one, is synthesized in three steps from citraconic anhydride. Highly regioselective reduction of citraconimide gives racemic jatropham in high yield. Kinetic resolution of racemic jatropham using lipase is also described. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00513-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4469–4471
First synthesis of (R)-(−)-5-hydroxy-3-methyl-3-pyrrolin-2-one
jatropham) by lipase-catalyzed kinetic resolution
(
∗
Nobuyuki Mase, Toshiki Nishi, Yasuaki Takamori, Hidemi Yoda and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
Received 15 October 1999; accepted 9 November 1999
Abstract
Jatropham, (R)-(−)-5-hydroxy-3-methyl-3-pyrrolin-2-one, is synthesized in three steps from citraconic anhy-
dride. Highly regioselective reduction of citraconimide gives racemic jatropham in high yield. Kinetic resolution
of racemic jatropham using lipase is also described. © 1999 Elsevier Science Ltd. All rights reserved.
Jatropham, (R)-(−)-5-hydroxy-3-methyl-3-pyrrolin-2-one (R)-3, is an antitumor alkaloid isolated from
1,2
Jatropha macrohiza (Euphorbiaceae) in 1973 by Cole et al. The synthesis of (±)-jatropham has
3
4
included the conversion of lactone to lactam, the autoxidation of 2-furylcabamate, and selenoxide syn
5
6
elimination etc.; however, several steps are needed for the preparation and the yields are relatively low
in these reports. Moreover, the synthesis of homochiral natural jatropham 3 has not yet been reported.
We now report herein the first synthesis of natural jatropham (R)-3 from citraconic anhydride 1 in three
steps (Scheme 1), of which the regioselective reduction of citraconimide 2 and the kinetic resolution of
racemic jatropham 3 are the key steps for the successful synthesis.
Scheme 1.
∗
Corresponding author. Tel & fax: +81-53-478-1148; e-mail: tcktaka@ipc.shizuoka.ac.jp
0
957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00513-3
tetasy 3148

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N. Mase et al. / Tetrahedron: Asymmetry 10 (1999) 4469–4471
Citraconimide 2 was prepared from citraconic anhydride 1, which is commercially available and
7
inexpensive, by the procedure reported in the literature. Previously, the regioselective reduction of
5
citraconimide 2 using NaBH was examined by Nagasaka et al., where only 5-hydroxy-4-methyl-3-
4
pyrrolin-2-one 4 was obtained. Indeed, our experiment also showed high regioselectivity caused by attack
of the hydride anion at the C2 carbon to give the regioisomer 4 in 96% yield (Table 1, entry 1). On the
8
other hand, in the presence of CeCl a considerable amount of jatropham 3 was obtained (entry 2).
3
Furthermore, reduction using DIBAL afforded only jatropham 3 in 95% yield (entry 3); probably, the
bulky DIBAL approached the C5 carbon to avoid steric influence.
Table 1
Regioselective reduction of citraconimide 2
9
Next, the lipase-catalyzed kinetic resolution of (±)-jatropham 3 was examined (Table 2). (±)-
Jatropham 3 was treated with vinyl acetate in the presence of lipases. In the case of lipases M and
A, the transesterification did not occur (entries 1 and 2). On the other hand, the reaction using lipase PS
smoothly proceeded to give (R)-jatropham 3 and the (S)-acetate 5 (entries 3–5). The reactivity as well as
enantioselectivity was improved by using lipase PL, and (R)-jatropham 3 was obtained in 35% yield with
9
8% e.e. along with the (S)-acetate 5 in 53% yield with 50% e.e. (entry 6).10
Table 2
Kinetic resolution of (±)-jatropham 3

N. Mase et al. / Tetrahedron: Asymmetry 10 (1999) 4469–4471
4471
In summary, we have shown the regioselective reduction of citraconimide 2 and the kinetic resolution
of (±)-jatropham 3. These reactions have provided a simple and inexpensive preparation of (R)-jatropham
3.
Acknowledgements
We are grateful to Amano Pharmaceutical Co., Ltd, and Meito Sangyo Co., Ltd, for a generous gift
of some enzymes. This work was supported in part by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports, and Culture of Japan.
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. Isolation of reduction product 3 from the crude product was relatively difficult in the case of NaBH /CeCl reduction.
4 3
. A solution of (±)-jatropham 3 and lipase (0.5 gram equivalent) in vinyl acetate (10 equivalent) was stirred at 25°C, then
lipase was removed by filtration, and concentrated to give a crude oil, which was purified by column chromatography (silica
gel) to give (R)-jatropham (R)-3 and the acetate 5.
2
a
1
0. Previously, the absolute configuration of (−)-jatropham 3 was deduced from CD spectrum analysis. We confirmed the
absolute configuration by comparison of the known value of the specific rotation of 1-benzyl-3-methylpyrrolidine-2,5-dione
22
(
R)-7 (lit. [α]
negative value ([α]
Puertas, S.; Rebolledo, F.; Gotor, V. Tetrahedron 1995, 51 (5), 1495–1502.
D
=+14.4 (c 1.39, CHCl
3
, 80% ee)) after transformations of (R)-3 (37% ee) obtained in Table 2, entry 4. A
18
D
=−6.1 (c 1.24, CHCl )) of (S)-7 was observed; therefore, (−)-jatropham 3 had (R) configuration, see:
3