Highly regioselective lipase-catalyzed acetylation and hydrolysis of acyclic α,α′-alkenediols and their diacetates

Article abstract of DOI:10.1016/j.tetlet.2005.07.039

Highly regioselective transformation of acyclic α,α′- alkenediols and their corresponding diacetates to monoacetates using lipase was accomplished. The acetylation of the α,α′-alkenediol regioselectively gave (E)-monoacetate, whereas the (Z)-monoacetate were obtained by hydrolysis of the α,α′-diacetate.

Full text of DOI:10.1016/j.tetlet.2005.07.039

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6293–6295
Highly regioselective lipase-catalyzed acetylation and hydrolysis
of acyclic a,a0-alkenediols and their diacetates
Takaya Hisano, Kotoko Onodera, Yasuhiro Toyabe, Nobuyuki Mase,
Hidemi Yoda and Kunihiko Takabe*
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
Received 24 June 2005; revised 8 July 2005; accepted 11 July 2005
Abstract—Highly regioselective transformation of acyclic a,a0-alkenediols and their corresponding diacetates to monoacetates using
lipase was accomplished. The acetylation of the a,a0-alkenediol regioselectively gave (E)-monoacetate, whereas the (Z)-monoacetate
were obtained by hydrolysis of the a,a0-diacetate.
Ó 2005 Elsevier Ltd. All rights reserved.
The differentiation of sterically and electronically similar
functional groups is a challenging research for organic
synthetic chemists. Generally, it is more difficult to differ-
entiate similar functional groups, as the difference of
physical properties of those groups become smaller.
For example, acetylation of acyclic a,x-terpenediols with
acetic anhydride under standard conditions resulted in
the mixture of a-monoacetoxyterpene, x-monoacetoxy-
terpene and a,x-terpenediacetate.1 Therefore, synthesis
of either the a or x-monoacetoxyterpene was previously
achieved by multi-step transformation.2 The best and
simplest approach to such acyclic terpenes is one-step
transformation of terpenes having the same a- and
x-functional groups (Fig. 1). Recently, Itoh et al.
reported highly regioselective partial hydrolysis of (E)-
4-acetoxy-2-methylbut-2-enyl acetate, in which thia-
crown ether remarkably accelerated the lipase-catalyzed
hydrolysis.3 Their pioneering work encouraged us to
investigate highly regioselective acetylation and hydroly-
sis of the unsymmetrical a,x-terpenediols and their
acetates using lipase, which enables the direct synthesis
of a,x-functionalized terpenoids.1
In order to develop broadly useful enzymes4 for this
class of differentiation, we investigated a regioselective
acetylation and hydrolysis of unsymmetrical a,a0-alkene-
diols and acetates using lipase (Fig. 2). To the best of
our knowledge, this study represents the first example
of a direct transformation of unsymmetrical a,a0-alkene-
diols bearing two primary hydroxy groups with a high
level of regioselectivity.5
a,a0-Alkendiol 2 was prepared from 1,3-bis[(tetrahydro-
2H-pyran-2-yl)oxy]-2-propanone (1) by Wittig reaction
following deprotection as shown in Scheme 1. The
two-step synthesis afforded various acyclic a,a0-alkendi-
ols 2 in 37–71% yield.
At first, acetylation of the acyclic a,a0-alkendiols 2 was
examined under standard conditions. The acetylation
is carried out using acetic anhydride (1 equiv) and
pyridine (1 equiv) in a solution of dichloromethane.
Lipase
Lipase
A
A
B
B
A
A
n
n
n
A
B
A A
B A
A
D
B
C
A
A
B
C
D
A
B
C
Figure 1. Lipase-catalyzed one-step transformation of terpenes bear-
ing different functional groups.
Lipase
Lipase
AD=BC
AA=BC
DA=BC
Keywords: Lipase-catalyzed reaction; Regioselectivity; Building block.
*
Figure 2. Lipase-catalyzed one-step transformation of alkenes bearing
Corresponding author. Tel./fax: +81 53 478 1148; e-mail:
different functional groups.
tcktaka@ipc.shizuoka.ac.jp
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.039

6294
T. Hisano et al. / Tetrahedron Letters 46 (2005) 6293–6295
Chemical yields of the monoacetate 3 were less than
1) RCH2PPh3Br
base, THF
THPO
THPO
HO
HO
59%, and poor regioselectivity was observed (Table 1).
Control of over acetylation was very difficult, and then
diacetates 4 are obtained in 5–25% yields.
O
2) p-TsOH
R
MeOH-H2O, 40 o
C
1
2
Next, the regioselective lipase-catalyzed acetylation of
a,a0-alkenediols 2 was investigated as shown in Table
2.6 Reactions were carried out in a shaking apparatus
at 25 °C. During lipase library screening, lipase PS-D
(Pseudomonas cepacia, Amano) and AY (Candida rug-
osa, Amano) gave high regioselectivity (entries 1–5).
The acetylation of 2-ethylidenepropane-1,3-diol (2a)
regioselectively proceeded to give the monoacetate 3a
in a (E)-3/(Z)-3 ratio of 90/10 (entry 5). Alkyl and alk-
enyl substituents showed higher regioselectivity using
lipase PS-D (entries 6–8). Similarly, aryl-substituted
a,a0-alkenediols 2e–f were acetylated within 4 h to afford
the (E)-monoacetate 3e–f with excellent regioselectivity
(entries 10–11). A significant change of regioselectivity
HO
HO
HO
HO
HO
HO
2a (57%)
2b (71%)
2c (71%)
HO
HO
HO
HO
HO
HO
OBn
O
2d (57%)
2e (42%)
2f (37%)
Scheme 1. Preparation of a,a0-alkendiols 2.
Table 1. Standard acetylation of a,a0-alkendiols 2 using acetic anhydride and pyridinea
Ac2O
HO
HO
AcO
HO
HO
AcO
AcO
pyridine
+
+
CH2Cl2
0 °C tort
R
R
AcO
R
R
(E)-3
(Z)-3
2
4
Entry
Diol 2
Time (h)
3 Yieldb (%)
Ratioc E:Z
4 Yieldb (%)
2 yieldb (%)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
7
44
31
2
4
9
48
55
59
47
54
48
55:45
50:50
46:54
38:62
70:30
65:35
12
13
10
2512
17
5
37
15
21
24
32
a The acetylation was carried out using acetic anhydride (1.0 equiv) and pyridine (1.0 equiv).
b Isolated yield.
c Determined by 1H NMR analysis (entries 1–2) and HPLC analysis (entries 3–6).
Table 2. Lipase-catalyzed acetylation of a,a0-alkendiols 2a
Lipase
HO
HO
AcO
HO
HO
AcO
AcO
AcOCH=CH2
+
+
25 oC
R
R
AcO
R
R
(E)-3
(Z)-3
2
4
Entry
Diol 2
Lipase
Time (h)
3 Yieldb (%)
Ratioc E:Z
4 Yieldb (%)
2 Yieldb (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2b
2c
2d
2e
2e
2f
—
24
21
4
4
24
9
20
8
2
4
4
0
21
36
29
27
74
82
68
81
90
71
—
—
7
16
1541
4
10
8
7
Quant.
45
30
Chirazyme
AK
PS-D
AY
PS-D
PS-D
PS-D
PS-D
AK
57:43
65:35
84:16
90:10
95:5
97:3
97:3
80:20
96:4
99:1
52
6
0
20
8
5
9
10
11
9
4
8
PS-D
0
a The acetylation was carried out using vinyl acetate (1.0 equiv) and lipase (0.1 g equiv).
b Isolated yield.
c Determined by 1H NMR analysis (entries 1–6) and HPLC analysis (entries 7–11).

T. Hisano et al. / Tetrahedron Letters 46 (2005) 6293–6295
Table 3. Lipase-catalyzed hydrolysis of a,a0-alkendiacetates 4a
6295
AcO
AcO
AcO
HO
HO
HO
HO
Lipase
+
+
R
R
AcO
R
R
Buffer
25 oC
(E)-3
(Z)-3
4
2
Entry
Diacetate 4
Lipase
Time (h)
3 Yieldb (%)
Ratioc E:Z
2 Yieldb (%)
4 Yieldb (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
AY
AY
AY
PS-D
AK
33
72
44
24
48
26
24
51
41
49
52
50
28:72
21:79
15:85
9:91
4:96
4:96
18
28
6
26
7
31
17
25
21
30
38
PS-D
7
a The hydrolysis was carried out using lipase (0.1 g equiv).
b Isolated yield.
c Determined by 1H NMR analysis (entries 1–2) and HPLC analysis (entries 3–6).
as well as chemical yield was observed. The (E)-mono-
acetates 3 are obtained in over 68% yield, and the diacet-
ylated product 4 was reduced to less than 10% yield,
with the exception of 2a. Standard conditions for the
chemical acetylation of a,a0-alkenediols 2 result in no
regioselectivity and chemoselectivity. However, such dif-
ficulties are resolved by regioselective lipase-catalyzed
acetylation, even of methyl-substituted alkenediol 2a.
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 Lipases. We gratefully acknowledge Dr. D. D.
Steiner for a scientific discussion.
Lipase-catalyzed hydrolysis of a,a0-alkendiacetates 4
was investigated as shown in Table 3. Reactions are car-
ried out in a similar manner to the reactions in Table 2.
The hydrolysis proceeds slowly to give monoacetate 3
with high regioselectivity but lower chemical yield
compared with that of acetylation. Interestingly, the
(Z)-regioisomer is obtained as a major product in the
lipase-catalyzed hydrolysis. The (E)-regioisomer is selec-
tively obtained by lipase-catalyzed acetylation, there-
fore, we can regioselectively synthesize both of the
regioisomers.
References and notes
1. Takabe, K.; Mase, N.; Hisano, T.; Yoda, H. Tetrahedron
Lett. 2003, 44, 3267–3269.
2. (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;
(c) Ferroud, D.; Gaudin, J. M.; Genet, J. P. Tetrahedron
Lett. 1986, 27, 845–846.
3. (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.; Takagi,
Y. Tetrahedron Lett. 1996, 37, 91–92.
The structure of monoacetate 3 cannot be directly deter-
mined by 1H NMR analysis, since signals of the methyl-
ene protons were overlapped. Structure determination
of monoacetate 3e is performed by 13C NMR analysis,
after derivatization of 3e to 5e as shown in Scheme 2.
Mesylation following reduction furnished alcohol 5e in
76% yield. 13C NMR spectra of 5e is in accordance with
the reported data for (E)-2-methyl-3-phenylprop-2-en-1-
ol (E)-5e ((E)-isomer 15.2, 68.8 ppm, (Z)-isomer 21.7,
62.2 ppm).7
4. (a) Aehle, W. Enzymes in Industry: Production and Appli-
cations; Wiley-VCH: Weinheim, 2004; (b) Drauz, K.;
Waldmann, H. Enzyme Catalysis in Organic Synthesis: A
Comprehensive Handbook; Wiley-VCH: Weinheim, 2002;
(c) Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic
Organic Chemistry; Pergamon: Oxford, 1994.
5. Enzyme-catalyzed hydrolysis of the a,a0-alkenedioate, see
the following report: Schirmeister, T.; Otto, H. H. J. Org.
Chem. 1993, 58, 4819–4822.
In conclusion, we have shown high regioselectivity in
lipase-catalyzed reactions of a,a0-alkendiols and their
acetates. These acetates may now be used directly as
building blocks in natural product synthesis. Although
6. Typical procedure (Table 2, entry 10): To a solution of the
a,a0-alkenediols 2e (164 mg, 1.0 mmol, 1.0 equiv) and vinyl
acetate (92 lL, 1.0 mmol, 1.0 equiv) in 1,4-dioxane
(1.0 mL) was added Lipase AK (16 mg), and stirred for
4 h at 25 °C. The reaction mixture was filtrated to remove
the Lipase AK, concentrated to give the crude acetate. The
crude product was purified by column chromatography
(silica gel, hexane/AcOEt = 70/30) to give the mono-
acetates 3e (186 mg, 90%), the diacetate 4e (12 mg, 5%)
and the recovered diol 2e (8 mg, 5%).
69.0 ppm
HO
AcO
HO
1) MsCl, Et3N
2) LiAlH4
Ph
Ph
7. Daub, G. W.; Edwards, J. P.; Okada, C. R.; Allen, J. W.;
Maxey, C. T.; Wells, M. S.; Goldstein, A. S.; Dibley, M. J.;
Wang, C. J.; Ostercamp, D. P.; Chung, S.; Cunningham, P.
S.; Berliner, M. A. J. Org. Chem. 1997, 62, 1976–1985.
15.2 ppm
5e (76%)
3e
E:Z = 94:6
Scheme 2. Determination of structure.