Highly regioselective lipase-catalyzed acetylation and hydrolysis of acyclic α,ω-terpenediols and their diacetates

Article abstract of DOI:10.1016/S0040-4039(03)00626-9

Highly regioselective transformations of the acyclic α,ω-terpenediols and their diacetates to the monoacetates using lipase were accomplished. The acetylation of the α,ω-terpenediols gave regioselectively the ω-monoacetates 3, whereas the α-monoacetates 2 were obtained by hydrolysis of the α,ω-diacetates.

Full text of DOI:10.1016/S0040-4039(03)00626-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3267–3269
Highly regioselective lipase-catalyzed acetylation and hydrolysis
of acyclic a,v-terpenediols and their diacetates
Kunihiko Takabe,* Nobuyuki Mase, Takaya Hisano and Hidemi Yoda
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
Received 14 February 2003; revised 3 March 2003; accepted 5 March 2003
Abstract—Highly regioselective transformations of the acyclic a,v-terpenediols and their diacetates to the monoacetates using
lipase were accomplished. The acetylation of the a,v-terpenediols gave regioselectively the v-monoacetates 3, whereas the
a-monoacetates 2 were obtained by hydrolysis of the a,v-diacetates. © 2003 Elsevier Science Ltd. All rights reserved.
Acyclic terpenes having different a- and v-functional
groups are valuable building blocks for the synthesis of
natural products.1 The best and simplest approach to
such acyclic terpenes is one-step transformation of the
terpenes having the same a- and v-functional groups
(Fig. 1), though this approach is rarely found in the
literature. Recently, Itoh et al. reported highly regiose-
lective partial hydrolysis of (E)-4-acetoxy-2-methylbut-
2-enyl acetate, in which thiacrown ether remarkably
accelerated the lipase-catalyzed hydrolysis.2 Their pio-
neering work encouraged us to investigate the above
challenge. We report herein regioselective lipase-cata-
lyzed monoesterification of various acyclic a,v-terpene-
diols and their diacetates.
Next, regioselective lipase-catalyzed acetylation of the
acyclic a,v-terpenediols 1 was investigated as shown in
Table 1. Reactions were carried out in shaking appara-
tus at 25°C.3,4 Lipase PS-D (Pseudomonas cepacia,
Amano) marked the best regioselectivity among the
lipases tested.5 Acetylation of (Z)-2-methylbut-2-ene-
1,4-diol 1a regioselectively proceeded to give the v-
monoacetate 3a in a 2a/3a ratio of <1/>99 (entry 1).6
The stereoisomer 1b also showed high regioselectivity
(entry 2). Similarly, acyclic mono- and sesqui-terpene-
diols 1c–e were acetylated in shorter reaction time to
afford the v-monoacetate 3c–e with high regioselectiv-
ity (entries 3–5). Generally, the synthesis of the v-
monoacetate 3 was more difficult than that of the
At first, standard chemical acetylation of the acyclic
a,v-terpenediols 1 using acetic anhydride and pyridine
was examined, in which no regioselectivity was
observed (Scheme 1).
Figure 1. One-step transformation to different functional
group-substituted terpenes.
Scheme 1. Standard chemical acetylation of the acyclic a,v-
terpenediols 1.
* Corresponding author. Tel.: +81-53-478-1148; fax: +81-53-478-1148;
e-mail: tcktaka@ipc.shizuoka.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00626-9

3268
K. Takabe et al. / Tetrahedron Letters 44 (2003) 3267–3269
Table 1. Lipase-catalyzed acetylation of acyclic a,v-terpenediols 1a
Entry
Substrate
Time (h)
Yield (2+3, %)b
2+3:4:1 Ratioc
2:3 Ratioc
1
2
3
4
5
1a
1b
1c
1d
1e
24
0.5
2.5
1
27
36
22
43
45
31:32:37
40:49:11
24:76:0
49:41:10
49:27:24
B1:\99
8:92d
B1:\99
B1:\99
B1:\99
2
a Lipase PS-D/substrate=1/10 (w/w), vinyl acetate/substrate=2/1 (mol/mol).
b Isolated yield.
c Determined by GC using Shimadzu GC-17A fused silica capillary column (J&W Scientific DB-1, 30 m×0.25 mm).
d Determined by 1H NMR analysis.
a-monoacetate 2,7 which were prepared by SeO2 oxida-
Table 2. Competitive acetylation of 2a and 3a
tion of prenyl, geranyl, neryl, and farnesyl acetates,
respectively.1 However, it has been found that such
difficulties are solved by our regioselective lipase-cata-
lyzed acetylation.
Interestingly, competitive lipase-catalyzed acetylation of
2-buten-1-ol (5) and 2-methyl-2-propen-1-ol (6) resulted
in no chemoselectivity as shown in Scheme 2, that is,
lipase PS-D could not differentiate between g- and
b-methyl groups to the hydroxyl group. The similar
acetylation of a mixture of the monoacetates (2a:3a=
56:44) gave a mixture of the diacetate 4a and recovered
monoacetates, the ratio of recovered 2a and 3a was
remarkably changed as shown in Table 2. It became
clear that the monoacetate 2a was acetylated faster than
3a. We, therefore, suggested that the first acetylation of
the diol 1 to the monoacetate 2,3 was non-regioselec-
tive, while the second acetylation of 2,3 to the diacetate
4 was regioselective (Scheme 3). Since the acetylation
was a reversible reaction, the hydrolysis of the diacetate
4 would give rise to high regioselectivity as well as high
yield.
Time (min)
2a:3a Ratioa
2a+3a:4a Ratioa
0
56:44
47:53
40:60
19:81
6:94
100:0
95:5
51:49
30:70
18:82
12:88
10
30
50
70
90
B1:\99
a Determined by GC using Shimadzu GC-17A fused silica capillary
column (J&W Scientific DB-1, 30 m×0.25 mm).
ried out in a similar manner to acetylation. As would
be expected, the hydrolysis effectively proceeded to give
the monoacetate 2 with better yield than in the case of
acetylation. (Z)-4-Hydroxy-3-methyl-but-2-enyl acetate
(2a) was obtained by the hydrolysis of the diacetate 4a
with high regioselectivity in a ratio of 97:3 (entry 1);
however, the hydrolysis of mono- and sesqui-terpene
diacetate 4b–e slightly decreased the regioselectivity
(entries 2–5).
Lipase-catalyzed hydrolysis of the a,v-diacetates 4 was
investigated as shown in Table 3. Reactions were car-
Scheme 2. Competitive acetylation of 5 and 6.
Scheme 3. Proposed mechanism of regioselectivity.

K. Takabe et al. / Tetrahedron Letters 44 (2003) 3267–3269
3269
Table 3. Lipase-catalyzed hydrolysis of the acyclic a,v-ter-
penediacetates 4a
References
1. (a) Lan, J.; Liu, Z.; Yuan, H.; Peng, L.; Li, W.-D. Z.;
Li, Y.; Li, Y.; Chan, A. S. C. Tetrahedron Lett. 2000,
41, 2181–2184; (b) Xiangjun, Y.; Jiong, L.; Jing, L.;
Zuosheng, L.; Yulin, L. Tetrahedron 1999, 55, 133–140;
(c) Kodama, M.; Maeda, H.; Hioki, H. Chem. Lett.
1996, 809–810; (d) Shibuya, H.; Ohashi, K.; Narita, N.;
Ishida, T.; Kitagawa, I. Chem. Pharm. Bull. 1994, 42,
293–299; (e) Li, W.; Li, Y.; Li, Y. Synthesis 1994, 267–
269.
2. (a) Itoh, T.; Mitsukura, K.; Kaihatsu, K.; Hamada, H.;
Takagi, Y.; Tsukube, H. J. Chem. Soc., Perkin Trans. 1
1997, 2275–2278; (b) Itoh, T.; Uzu, A.; Kanda, N.; Tak-
agi, Y. Tetrahedron Lett. 1996, 37, 91–92.
3. Typical procedure: a suspension of (Z)-2-methylbut-2-
ene-1,4-diol 1a (100 mg, 0.979 mmol) and Lipase PS-D
(10 mg) in vinyl acetate (169 mg, 1.96 mmol) was stirred
at 25°C for an appropriate time; then, Lipase PS-D 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 monoac-
etates 2a, 3a, the diacetate 4 and the recovered diol 1a.
4. All compounds were identified by comparing its spec-
trum with the reported value. Registry No. 1a: 40560-13-
2, 1b: 53627-41-1, 1c: 26488-97-1, 1d: 26488-98-2, 1e:
69809-46-7, 2a:132032-87-2, 2b: 70473-55-1, 2c: 37905-03-
6, 2d: 70238-37-8, 2e: 93787-91-8, 3a: 104411-04-3, 3b:
53170-98-2, 3c: 177408-49-0, 3d: 156700-81-1, 4a: 59055-
00-4, 4b: 59054-99-8, 4c: 67604-16-4, 4e: 71135-55-2.
5. The regioselectivities were dependent upon the nature of
the lipase catalysts, for instance, Lipase AY (Candida
rugosa, Amano) showed reverse regioselectivity in a 2a/
3a ratio of 79/21.
6. (Z) or (E)-4-Hydroxy-2-methylbut-2-enyl acetate 3a or
3b has been difficult to prepare regioselectively a pure
form according to reported procedure, see: Ferroud, D.;
Gaudin, J. M.; Genet, J. P. Tetrahedron Lett. 1986, 27,
845–846.
7. Commonly, the synthesis of the v-monoacetate 3 was
achieved by protection/deprotection method, see: (a)
Aldrich, J. R.; Oliver, J. E.; Waite, G. K.; Moore, C.;
Waters, R. M. J. Chem. Ecol. 1996, 22, 729–738; (b)
Hiroi, K.; Hirasawa, K. Chem. Pharm. Bull. 1994, 42,
1036–1040.
Entry
Substrate
Yield
2+3:1:4
2:3
(2+3, %)b
Ratioc
Ratioc
1
2
3
4
5
4a
4b
4c
4d
4e
62
63
43
58
34
78:15:7
75:14:11
44:5:51
74:17:9
34:13:53
97:3
92:8d
89:11
91:9
75:25
a Lipase PS-D/substrate=1/10 (w/w).
b Isolated yield.
c Determined by GC using Shimadzu GC-17A fused silica capillary
column (J&W Scientific DB-1, 30 m×0.25 mm).
d Determined by 1H NMR analysis.
We have shown the high regioselectivity attained in
lipase-catalyzed reactions of the unsymmetrical a,v-ter-
penediols and their acetates, which may enable the
direct and ready synthesis of terpenoids. Although the
detailed mechanism of the regioselectivity is not
presently obvious, the results described here will lead to
further application of the methodology.
Acknowledgements
We are grateful to Amano Enzyme Inc. for a generous
gift of Lipase PS-D.