Preparation of chiral 4-benzyloxymethyldihydrofuran-2-one using lipase-catalyzed kinetic resolution: Synthesis of (-)-virginiae butanolide C (VB C)

Article abstract of DOI:10.1016/S0960-894X(02)00458-4

Lipase-catalyzed kinetic resolution of the N,N-dialkyl-3-benzyloxymethyl-4-hydroxybutanamide 10a,b afforded the acetate 11a,b with (R) configuration, whereas the N-monoalkyl-3-benzyloxymethyl-4-hydroxybutanamide 10c-e gave the acetate 11c-e with (S) configuration. The butanamide 10 smoothly cyclized to give chiral 4-benzyloxymethyldihydrofuran-2-one 9 without racemization, which was effectively transformed into highly stereocontrolled virginiae butanolide C (VB C).

Full text of DOI:10.1016/S0960-894X(02)00458-4

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2295–2297
Preparation of Chiral 4-Benzyloxymethyldihydrofuran-2-one
Using Lipase-Catalyzed Kinetic Resolution: Synthesis of
(ꢀ)-Virginiae Butanolide C (VB C)
Kunihiko Takabe,a,* Nobuyuki Mase,a Hidetoshi Matsumura,a Takehiro Hasegawa,a
Yasuhiro Iida,a Hisashi Kuribayashi,a Kenji Adachi,a Hidemi Yodaa and Masato Aob
aDepartment of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
bNagoya Municipal Industrial Institute, 3-4-41 Rokuban, Atsuta-ku, Nagoya 456-0058, Japan
Received 15 April 2002; accepted 7 June 2002
Abstract—Lipase-catalyzed kinetic resolution of the N,N-dialkyl-3-benzyloxymethyl-4-hydroxybutanamide 10a,b afforded the ace-
tate 11a,b with (R) configuration, whereas the N-monoalkyl-3-benzyloxymethyl-4-hydroxybutanamide 10c–e gave the acetate 11c–e
with (S) configuration. The butanamide 10 smoothly cyclized to give chiral 4-benzyloxymethyldihydrofuran-2-one 9 without race-
mization, which was effectively transformed into highly stereocontrolled virginiae butanolide C (VB C). # 2002 Elsevier Science
Ltd. All rights reserved.
The chiral 3-alkoxymethyl butanolides 4 are the most
useful precursors for the synthesis of A-factor 1 iso-
lated from Streptomyces griseus,1,2 virginiae butanolides
(VB) 2 [VB A: R=CH2CH2CH2CH(CH3)2,VB B:
R=CH2CH2CH (CH3)CH2CH3, VB C: R=CH2CH2
CH2CH2CH3, VB D: R=CH2CH2CH2CH2CH2CH3,VB
E: R=CH2CH2 CH(CH3)2] isolated from Streptomyces
virginiae,2c,3 and IM-2 3 isolated from Streptomyces
FRI-54 (Fig. 1). They have attractive bioactivities, for
instance, A-factor is an autoregulator of differentiation
and antibiotic biosynthesis in various streptomycetes.2
Moreover, they are structurally homologous com-
pounds, which have an alkyl group at the 2-position and
a hydroxymethyl group at the 3-position based on the
butanolide skeleton.
Thus, we concluded that even under the neutral condi-
tions racemization occurred in the transformation of 6
to 7 due to an intramolecular transesterification. We
now report herein a practical preparation of the chiral
butanolide 9 using kinetic resolution of the butanamide
10, and the synthesis of virginiae butanolide C.
Enantioselective acylation6 of the butanamide 10 was
investigated.7 Results are shown in Table 1. Lipase PS
(Pseudomonas cepacia, Amano) was marked best
enantioselectivity among lipases tested.8 Phenyl acetate
was most effective acylating agent to give the acetate 11a
and the recovered alcohol 10a in a good enantiomeric
ratio of E 9=18.6 (entry 3) The absolute configuration of
Recently, we reported that the lipase-catalyzed asym-
metric desymmetrization of the 2-carbamoylmethyl-1,3-
propanediol 5 afforded the (S)-acetate 6 with >99%
ee.5 For construction of the butanolide skeleton, the
hydroxy group was protected with a benzyl group under
the usual conditions to give the acetate 7. Hydrolysis
and cyclization of 7 smoothly proceeded to give the
3-benzyloxymethyl butanolide 9; however, the racemate
was obtained from a chiral HPLC analysis (Scheme 1).
*Corresponding author. Tel.: +81-53-478-1148; fax: +81-53-478-
1148; e-mail: tcktaka@ipc.shizuoka.ac.jp
Figure 1. Chiral 3-alkoxymethyl butanolides.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00458-4

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K. Takabe et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2295–2297
10a was determined to be (R) by comparison of the
value of the optical rotation of 4-(phenylsulfanyl-
methyl)dihydrofuran-2-one after acid-catalyzed lactoni-
zation.5 Simplified isolation from the reaction mixture
was accomplished by using succinic anhydride as an
acylating agent; only washing the reaction mixture with
a saturated NaHCO3 solution gave the alcohol (R)-10 in
99% ee (entry 5).10 Interestingly, kinetic resolution of
the N-monoalkyl-butanamide 10c–e showed the opposite
enantioselectivity compared with N,N-dialkyl-butan-
amide 10a,b. The absolute configuration of 11c–e and
10c–e was found to be (S). Thus, the (R)-enantiomer
was more likely to be obtained from N,N-dialkylbutan-
amide (entries 1–7), while the (S)-enantiomer was
Scheme 1. Attempts to synthesis of 3-benzyloxymethyl butanolide 9 from the (S)-acetate 6.
Table 1. Kinetic resolution of the butanamide 10 by lipase-catalyzed acylation
Entry
Substrate
Acylating agenta
Time (h)
11 Yieldb (ee)c (%)
Config.
10 Yieldb (ee)d (%)
Config.
E
1
2
3
4
5e
6
7e
8
9e
10
11
10a
10a
10a
10a
10a
10b
10b
10c
10c
10d
10e
Isopropenyl acetate
Vinyl acetate
Phenyl acetate
9
2
3
2
4
2
8
20 (84)
37 (80)
33 (85)
53 (32)
43 (11)
38 (71)
48 (43)
R
R
R
R
R
R
R
S
75 (25)
51(62)
60 (39)
20 (95)
31(99)
54 (54)
35 (63)
32 (59)
41(55)
49 (18)
53 (9)g
R
R
R
R
R
R
R
S
14.1
14.3
18.6
2.7
—
9.0
—
4.1
—
Phenyl acetate
Succinic anhydridef
Phenyl acetate
Succinic anhydridef
Phenyl acetate
)
138 (51
Succinic anhydridef
Phenyl acetate
Phenyl acetate
5
12
10
54 (39)
26 (38)
40 (6)g
S
S
S
S
S
S
2.5
1.2
aAcylating agent (2 equiv) was used unless otherwise noted.
bIsolated yields.
cDetermined by HPLC analysis using Chiralpak AD after methanolysis of 11 to 10.
dDetermined by HPLC analysis using Chiralpak AD.
ei-Pr2O was used as the solvent.
fSuccinic anhydride (1equiv) was used.
gDetermined by optical rotation after transformation into 9.
Scheme 2. Synthesis of virginiae butanolide C (VB C).

K. Takabe et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2295–2297
2297
obtained from N-monoalkylbutanamide (entries 8–11).
References and Notes
These tendencies were in good accord with the results of
stereoselectivity in the lipase-catalyzed asymmetric
desymmetrization of the 2-carbamoylmethyl-1,3-diols 5.5
1. Isolation: Kleiner, E. M.; Pilner, S. A.; Soifer, V. S.; Ono-
prienko, V. V.; Balasheva, T. A.; Rozynov, B. V.; Khoklov,
S. A. Bioorg. Khim. 1976, 2, 1142.
2. (a) Asymmetric synthesis: Crawforth, J. M.; Fawcett, J.;
Rawlings, B. J. J. Chem. Soc., Perkin Trans. 1 1998, 1721. (b)
Parsons, P. J.; Lacrouts, P.; Buss, A. D. J. Chem. Soc., Chem.
Commun. 1995, 437. (c) Mori, K.; Chiba, N. Liebigs Ann.
Chem. 1990, 31. (d) Posner, G. H.; Weitzberg, M.; Jew, S.-s.
Synth. Commun. 1987, 17, 611. (e) Mori, K.; Yamane, K.
Tetrahedron 1982, 38, 2919.
3. (a) Kondo, K.; Higuchi, Y.; Sakuda, S.; Nihira, T.;
Yamada, Y. J. Antibiotics 1989, 42, 1873. (b) Nihira, T.; Shi-
mizu, Y.; Kim, H. S.; Yamada, Y. J. Antibiotics 1988, 41,
1828. (c) Yamada, Y.; Sugamura, K.; Kondo, K.; Yanagi-
moto, M.; Okada, H. J. Antibiotics 1987, 40, 496.
4. Sato, K.; Nihira, T.; Sakuda, S.; Yanagimoto, M.;
Yamada, Y. J. Ferment. Bioeng. 1989, 68, 170.
5. Takabe, K.; Iida, Y.; Hiyoshi, H.; Ono, M.; Hirose, Y.;
Fukui, Y.; Yoda, H.; Mase, N. Tetrahedron: Asymmetry 2000,
11, 4825.
6. Typical procedure: a solution of the butanamide 10a
(100 mg, 0.358 mmol) and Lipase PS (10.7 mg, 30 mg/mmol of
10a) in vinyl acetate (2equiv) was stirred at 25 ꢁC for an appro-
priate time; then, Lipase PS was removed through filtration, and
concentrated to give a crude oil, which was purified by column
chromatography (silica gel, eluent: hexane–AcOEt) to give the
monoacetate 11a and the recovered alcohol 10a.
The enantiomerically pure alcohol (S)-10a was obtained
by kinetic resolution repeatedly (11a: 1st 60% ee; 2nd
94% ee, 3rd >99%ee, total yield 21%) followed by
hydrolysis, which was employed in the synthesis of vir-
giniae butanolide C (VB C) as shown in Scheme 2.
Cyclization of the (S)-alcohol 10a gave (R)-3-benzyloxy-
methyl-4-butanolide (R)-9 in 77% yield without race-
mization as revealed by a chiral HPLC analysis. The
butanolide (R)-9 was treated with LDA at ꢀ78 ꢁC, and
the resulting anion was reacted with hexanoyl chloride
to give the butanolide (3R)-12 in 68% yield. An ana-
logue of A-factor (3R)-13 was obtained by deprotection
of the benzyl group in 78% yield. Reduction/deprotec-
tion of (3R)-12 gave a diastereomeric mixture of 14,
which was readily separated by column chromato-
graphy to afford VB C (2R,3R,10S)-14 and its epimer
(2R, 3R,10R).11 A higher value of the optical rotation of
synthetic VB C was observed compared with that
reported in the literature,2c therefore, it is suggested that
partial racemization via NaBH4 reduction of 13 might
have occurred in a previous preparation of VB C.2c
7. We also examined the enantioselective hydrolysis and
transesterification of the acetate 11a,b in the presence of
Lipase PS in a buffer and ethanol solution, respectively; how-
ever, low enantioselectivities (11–57% ee) was observed.
8. The enantioselectivities were dependent upon the nature of
the lipase used, for instance, Lipase A (Aspergillus niger,
Amano) showed reverse enantioselectivity to give (S)-acetate
11a (57% ee).
In conclusion, we have shown high enantioselectivity in
the kinetic resolution of the butanamide 10. This pres-
ent reaction would provide a practical strategy for
asymmetric synthesis of natural products including
3-alkoxymethyl butanolide skeleton.
9. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 104, 7294.
Acknowledgements
10. High enantiomeric excess of the acetate 11 was not
obtained, because acetylation of the alcohol 10 slowly pro-
ceeded in the absence of Lipase PS. See Hyatt, J. A.; Skelton,
C. Tetrahedron: Asymmetry 1997, 8, 523.
11. Revised structure of the virginiae butanolides is reported
by Yamada et al.; see: Sakuda, S.; Yamada, Y. Tetrahedron
Lett. 1991, 32, 1817.
We thank Professor Yasuhiro Yamada of Osaka Uni-
versity for scientific discussion. We are also grateful to
Amano Pharmaceutical Co., Ltd. for a generous gift of
some enzymes. This work was supported by a Grant-in-
Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture of Japan.