Regiospecific acetylation of substituted α,α′- benzylidenedimethanols with vinyl acetate using porcine pancreas lipase

Article abstract of DOI:10.1080/00397910701544760

Acetylation of substituted α,α′-benzylidenedimethanols with 10 equivalents of vinyl acetate in the presence of 50 w/w% of porcine pancreas lipase (PPL) type II regiospecifically proceeded to afford only the corresponding E-monoacetates in excellent yields

Full text of DOI:10.1080/00397910701544760

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Regiospecific Acetylation of Substituted
α,α′‐Benzylidenedimethanols with Vinyl
Acetate using Porcine Pancreas Lipase
Tsuyoshi Miura a , Yuya Kawashima a , Mauko Takahashi a , Yasuoki Murakami
a & Nobuyuki Imai a
a Faculty of Pharmacy , Chiba Institute of Science , Chiba, Japan
Published online: 10 Sep 2007.
To cite this article: Tsuyoshi Miura , Yuya Kawashima , Mauko Takahashi , Yasuoki Murakami & Nobuyuki Imai
(2007) Regiospecific Acetylation of Substituted α,α′‐Benzylidenedimethanols with Vinyl Acetate using Porcine
Pancreas Lipase, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:18, 3105-3109, DOI: 10.1080/00397910701544760
To link to this article: http://dx.doi.org/10.1080/00397910701544760
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Synthetic Communicationsw, 37: 3105–3109, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701544760
Regiospecific Acetylation of Substituted
a,a0-Benzylidenedimethanols with Vinyl
Acetate using Porcine Pancreas Lipase
Tsuyoshi Miura, Yuya Kawashima, Mauko Takahashi,
Yasuoki Murakami, and Nobuyuki Imai
Faculty of Pharmacy, Chiba Institute of Science, Chiba, Japan
Abstract: Acetylation of substituted a,a0-benzylidenedimethanols with 10 equivalents
of vinyl acetate in the presence of 50 w/w% of porcine pancreas lipase (PPL) type II
regiospecifically proceeded to afford only the corresponding E-monoacetates in
excellent yields without Z-monoacetates, diacetate, or the starting materials.
Keywords: acylation, diol, enzyme, lipase, regioselectivity
INTRODUCTION
The acetyl group is one of the most popular protecting groups and plays an
important role in organic synthesis.[1] Therefore, development of highly
selective acetylation is an attractive research field. Among the many
methods for selective acetylation, the enzymatic acetylation using lipase and
vinyl acetate is an excellent methodology. Although many articles reported
enantioselective acetylation of racemic alcohols in the presence of lipase,[2]
there is only one example where researchers have developed a highly regiose-
lective acetylation of a,a0-alkylidenedimethanols using several kinds of
lipases such as AK and PS-D.[3] In this method, diacetates and Z-monoacetates
were obtained as by-products in all cases, and exactly 1 equivalent of vinyl
acetate has to be used to avoid production of diacetates. Regioselective acety-
lation of a,a0-alkylidenedimethanols is very difficult with common conditions
Received in the USA November 16, 2006
Address correspondence to Nobuyuki Imai, Faculty of Pharmacy, Chiba Institute of
Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan. E-mail: nimai@cis.ac.jp
3105

3106
T. Miura et al.
using acetic anhydride/pyridine.[3] In this article, we describe a regiospecific
acetylation of substituted a,a0-benzylidenedimethanols 1a–h with vinyl
acetate using 50 w/w% of porcine pancreas lipase (PPL) type II.
Porcine pancreas lipase (PPL) type II is commercially available from
Sigma.
RESULTS AND DISCUSSION
a,a0-Alkylidenedimethanols 1 were easily prepared from diethyl alkylidene-
dicarboxylates 3, which can be obtained by Knoevenagel condensation of
the corresponding aldehydes with diethyl malonate,[4] followed by diisobutyl-
aluminium hydride (DIBAH) reduction in 20–62% yields as shown in
Scheme 1.[5]
In a preliminary investigation, the reaction of 2-benzylidenepropane-1,3-
diol (1a) with vinyl acetate in the presence of 50 w/w% of porcine pancreas
lipase (PPL) in 1,4-dioxane afforded the corresponding E-isomer 2a as a sole
product in 95% yield as indicated in entry 1 of Table 1. The overacetylated
1
product and the Z-isomer were not detected from H NMR analysis of the
crude product. The regioselective acetylation of a,a0-benzylidenedimethanols
substituted on the benzene ring by electron-donating or electron-withdrawing
groups was then examined: the results from the acetylation of various substi-
tuted a,a0-benzylidenedimethanols 1b–h and a,a0-alkylidenedimethanol 1i
with vinyl acetate in the presence of 50 w/w% of PPL in 1,4-dioxane are
collected in Table 1. We selected methoxy and methyl substituents as repre-
sentative electron-donating groups (see entries 2 and 5–8), trifluoromethyl
and chloro substituents as electron-withdrawing groups (see entries 3 and
4), and 2-(3-phenylpropylidene)propane-1,3-diol (1i) for an aliphatic species
(see entry 9). Fortunately, all para-monosubstituted a,a0-benzylidenedi-
methanols 1b–e were reacted with vinyl acetate in the presence of 50 w/
w% of PPL in 1,4-dioxane to afford the corresponding E-monoacetylated
products in excellent yields with complete regioselectivities. The high regios-
electivities were also observed in the reaction of substrates (1f and 1g) with the
methyl group at meta- and ortho-positions on the benzene ring (see entries 6
Scheme 1. Preparation of a,a0-alkylidenedimethanols 1.

Benzylidenedimethanols with Vinyl Acetate
3107
Table 1. E-Acetylation of substituted a,a0-benzylidenedimethanols 1a–h
and
a,a0-alkylidenedimethanol
1i
in
the
presence
of
PPLa
Entry
1
R
Reaction time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
23
23
47
48
31
20
26
72
28
95
94
4-MeOC6H4
4-CF3C6H4
4-ClC6H4
90
94
4-MeC6H4
3-MeC6H4
2-MeC6H4
2,4,6-Me3C6H2
PhCH2CH2
97
92
1g
1h
1i
95
30b
80c
aAll reactions were carried out with 1 equivalent of substituted a,a0-benzylidenedi-
methanol 1, 10 equivalents of vinyl acetate, and 50 w/w% of PPL in 3 mL of 1,4-
dioxane at rt.
bThe starting material was recovered in 61% yield.
cThe starting material was recovered in 3.7% yield, and the Z-isomer 4 and the
diacetate 5 were obtained in 4.6% and 5.6% yields, respectively.
and 7, respectively). 2-(2,4,6-Trimethylbenzylidene)propane-1,3-diol (1h)
was a poor substrate for acetylation using PPL, probably because of its
steric hindrance by ortho-substituents on the benzene ring, and the corre-
sponding E-monoacetate 2h was obtained in 30% yield. The reaction of the
2-(3-phenylpropylidene)propane-1,3-diol (1i in entry 9) afforded E-monoace-
tate in lower regioselectivity than ones of substituted a,a0-benzylidenedi-
methanols 1a–h. Although the corresponding E-isomer 2i was obtained in
80% yield, the Z-isomer 4 and the diacetate 5 were produced as by-products
in 4.6% and 5.6% yields, respectively (Fig. 1).
Figure 1. By-products in acetylation of 1i.

3108
T. Miura et al.
Figure 2. Determination of the structure of 2b.
The structure of monoacetate 2b was determined to be the E-isomer by
nuclear overhauser effect spectroscopy (NOESY) analysis as shown in Fig. 2.
The NOESY correlationships were observed between the olefin and the
methylene protons adjacent to the acetate group and between the aromatic
and the methylene protons adjacent to the hydoroxyl group. All other monoace-
tates (2a, 2c–i) were also determined to be E-isomer by NOESY analysis.
In summary, porcine pancreas lipase (PPL) efficiently works as a catalyst
in acetylation of substituted a,a0-benzylidenedimethanols 1a–h and a,a0-
alkylidenedimethanol 1i. Although a large excess of vinyl acetate (10
equiv) was used, the corresponding E-monoacetates were obtained as a sole
product in high yields without overacetylation. Monoacetates of a,a0-alkyli-
denedimethanols are potential useful intermediates in organic synthesis and
may be used as building blocks in syntheses of natural products. In our
procedure, it is possible to prepare various E-monoacetates of a,a0-benzylide-
nedimethanols and a,a0-alkylidenedimethanols. We are now working on pre-
paration of Z-monoacetates these diols.
EXPERIMENTAL
Compound 2b Data
Compound 2b: 1H NMR (CDCl3) d 2.13 (3H, s), 2.23 (1H, brs), 3.82 (3H, s),
4.33 (2H, s), 4.80 (2H, s), 6.67 (1H, s), 6.89 (2H, d, J ¼ 8.7 Hz), 7.26 (2H, d,
J ¼ 8.7 Hz); 13C NMR (CDCl3) d 21.1, 55.3, 59.4, 67.8, 113.8, 128.2, 130.3,
132.8, 133.8, 159.2, 171.4; HRMS (ESI-TOF): calcd. for C13H16O4
(M þ Naþ): 259.0941; found: 259.0958.
Typical Acetylation Procedure
A typical procedure of acetylation using PPL is as follows. To a pale yellow
suspension of 194 mg (1.00 mmol, 1 equiv) of 2-(4-methoxybenzylidene)pro-
pane-1,3-diol 1b, 0.92 mL (10.0 mmol, 10 equiv) of vinyl acetate and 97 mg

Benzylidenedimethanols with Vinyl Acetate
3109
(50 w/w%) of PPL in 3 mL of 1,4-dioxane was stirred at rt for 23 h. The
reaction suspension was diluted with 10 mL of ethyl acetate and dried over
anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was
evaporated. The crude product was chromatographed on silica gel with a
2:3 mixture of ethyl acetate and hexane to afford 222 mg (94% yield) of 2b.
ACKNOWLEDGMENT
This work was supported in part by Ajinomoto Award in Synthetic Organic
Chemistry, Japan, and Grants-in-Aid for Scientific Research (C) (No.
18590014) from the Japan Society for the Promotion of Science. This work
was performed through the Scientific Research Project by CIS (Chiba
Institute of Science).
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