Lipase-catalyzed kinetic resolution of tetronic acid derivatives bearing a chiral quaternary carbon: total synthesis of (S)-(-)-vertinolide

Article abstract of DOI:10.1016/j.tetasy.2006.07.044

We have developed a chemoenzymatic synthesis of (S)-vertinolide 1 with a chiral quaternary carbon atom at C5. In the kinetic resolution of tetronic acid precursor 6, lipase PS-D furnished the recovered alcohol 6 with an (R)-stereochemistry in a ratio of 95% ee, whereas lipase AY gave (S)-alcohol 6 with 93% ee. Chemical transformations of (S)-alcohol 6 provided (S)-vertinolide 1 in 33% yield in five steps with no loss of enantiomeric excess.

Full text of DOI:10.1016/j.tetasy.2006.07.044

Tetrahedron: Asymmetry 17 (2006) 2195–2198
Lipase-catalyzed kinetic resolution of tetronic acid
derivatives bearing a chiral quaternary carbon:
total synthesis of (S)-(ꢀ)-vertinolide
Tetsuo Tauchi, Hiroki Sakuma, Takahiro Ohno, 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 11 July 2006; accepted 28 July 2006
Abstract—We have developed a chemoenzymatic synthesis of (S)-vertinolide 1 with a chiral quaternary carbon atom at C5. In the kinetic
resolution of tetronic acid precursor 6, lipase PS-D furnished the recovered alcohol 6 with an (R)-stereochemistry in a ratio of 95% ee,
whereas lipase AY gave (S)-alcohol 6 with 93% ee. Chemical transformations of (S)-alcohol 6 provided (S)-vertinolide 1 in 33% yield in
five steps with no loss of enantiomeric excess.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
chemical transformation of (S)-6 into (S)-1, as shown in
Scheme 1.
A number of fully substituted tetronic acid derivatives
bearing a quaternary stereocenter at C5, for example,
(S)-(ꢀ)-vertinolide 1,1,2 isogregatin B 2a,3 isoaspertetronin
A 2b,3a,d,4 (S)-gregatin B 3a,5 gregatin A 3b,6,7 graminin A
3c,8 and (ꢀ)-ircinianin 49 as shown in Figure 1, have been
isolated. These naturally occurring tetronic acid derivatives
display important biological properties, which have
aroused great interest in their total synthesis. During our
recent studies on chemoenzymatic total syntheses,10 we
were interested in the versatile synthesis of organic com-
pounds containing quaternary carbon atoms. This is cur-
rently one of the most challenging topics in asymmetric
organic chemistry. (S)-(ꢀ)-Vertinolide 1 is a mycotoxin iso-
lated from Verticillium intertextum, and its structure was
determined by X-ray crystallographic analysis by Dreiding
et al. in 1981.1 Takaiwa et al. established the (S)-absolute
configuration at the quaternary stereogenic C5-center in
1983.2 Previously, five successful syntheses of (S)-1, includ-
ing the precursor synthesis were reported,11 in which the
chiral pool and chiral auxiliary approaches were employed.
Herein, we report the chemoenzymatic total synthesis of
(S)-(ꢀ)-vertinolide (1), that is, efficient lipase-catalyzed
kinetic resolution of tetronic acid precursor 6 and
OH
O
OMe
R
O
O
*
O
O
O
1
2
a: R = Me
b: R = (
E)-CH=CHMe
O
O
O
R
MeO
O
OH
*
O
O
H
3
4
a: R = Me
b: R = (
c: R = (
E
)-CH=CHMe
E
)-CH=CHPrn
Figure 1. Fully substituted tetronic acid derivatives bearing a quaternary
stereocenter at C5.
2. Results and discussion
*
Recently we reported a short synthesis of racemic vertino-
lide rac-1 via the Michael reaction of the anion derived from
Corresponding author. Tel./fax: +81 53 478 1148; e-mail: tcktaka@
ipc.shizuoka.ac.jp
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.044

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T. Tauchi et al. / Tetrahedron: Asymmetry 17 (2006) 2195–2198
dependent upon the nature of the lipase, for instance, Li-
OR
pase OF (Candida cyclindracea, Meito Sangyo Co., Ltd),
ChirazymeÒL-2 (Candida antarctica (lipase B), Roche
Molecular Biochemicals), and Lipozyme IM (Mucor mie-
hei, Novo Nordisk) showed low to moderate enantiomeric
ratio of E16 = 1.9–3.9 (entries 1–3). The enantioselectivity
was improved by using Lipase PS-D (Burkholderia cepacia,
Amano Enzyme Co, Ltd) to give (S)-acetate 9 in 42% yield
with 69% ee along with recovered (R)-alcohol 6 in 44%
yield and 95% ee (entry 4). Interestingly, Lipase AY (Can-
dida rugosa, Amano Enzyme Co, Ltd) reversed the enantio-
selectivity to give the recovered (S)-alcohol 6 with 93% ee
(entry 5). Both enantiomers were obtained with high enan-
tiomeric excess by use of lipase PS-D or AY. Alcohol 6b
also showed similar results (entries 6–8).
(S)-1
O
O
O
(S)-5
OR
OR
Lipase
OH
OH
O
O
O
O
(rac)-6
(
S
)-6
Scheme 1. Chemoenzymatic synthesis of (S)-(ꢀ)-vertinolide 1.
readily available tetronic acid with (E)-5-ethoxyocta-1,6-
dien-3-one.12 Unfortunately, our initial approaches to pre-
pare a enantiopure vertinolide using lipase-catalyzed kinetic
resolution of rac-1 and/or the precursor 5 were unsuccess-
ful. Although the construction of a tetronic acid skeleton
bearing a quaternary stereocenter at C5 was expected to
be difficult, we next examined lipase-catalyzed kinetic reso-
lution of the tetronic acid precursor 6. Starting alcohol 6
was prepared from the readily available tetronic acid deriv-
ative 713 in two steps (Scheme 2). The hydroxy group was
protected with either methoxymethyl12 or methyl14 groups
to give the protected tetronic acid derivative 8 in high yields.
The tetronic acid derivative 8 was treated with LDA at
ꢀ78 °C. The resulting anion was reacted with paraformalde-
hyde in the presence of HMPA to give the desired alcohol 6.
In spite of the (S)-configuration at C5 of naturally occur-
ring vertinolide 1, enantioselectivities of the (S)-acetate 9a
and yields of recovered (S)-alcohol 6a were low (Table 1).
Since we had found that lipase PS-D was favorable for
the (S)-isomer, while lipase AY was unfavorable for it,
the enantiopurity of the acetate 9a (69% ee) was improved
by hydrolysis, followed by lipase-AY catalyzed kinetic res-
olution, as shown in Scheme 3. These reactions provided
the recovered alcohol 6a with 94% ee in 51% yield.
OMOM
OAc
OMOM
OH
1) Hydrolysis
2) Lipase AY
O
O
O
O
OH
OR
OR
(
S
)-9a
(
S
)-6a
(69% ee)
(y. 51%, 94% ee)
a
b
OH
O
O
O
O
O
O
Scheme 3. Reagents and conditions: (1) K2CO3, MeOH, rt, 2 h; (2) lipase
AY, CH2@CHOAc, 25 °C, 3 h.
8
6
7
a: -CH2OCH3, b: -CH3
The preparation of (S)-vertinolide 1 required five steps and
was achieved in a straightforward fashion, as shown in
Scheme 4. Swern oxidation of alcohol 6a (94% ee deter-
mined by HPLC) afforded aldehyde 10 in 83% yield. Wittig
reaction of the formyl group followed by radical hydroge-
nation of the enone 11 furnished ketone 12. An aldol reac-
tion of ketone 12 with crotonaldehyde gave enone 14 in
Scheme 2. Reagents and conditions: (a) CH3OCH2Cl, i-Pr2NEt, 3 h, 99%
for 8a; Bu4NOH, (CH3)2SO4, 3 h, 96% for 8b; (b) LDA, paraformalde-
hyde, THF, HMPA, ꢀ78 °C to rt, 12 h, 89% for 6a, 84% for 6b.
The kinetic resolution of alcohol 6 was next investigated,15
with the results shown in Table 1. Enantioselectivity was
Table 1. Lipase-catalyzed kinetic resolution of the alcohol 6
OR
Lipase
OR
OR
CH2 =CHOAc
+
OH
*
O
OAc
*
O
OH
25 oC
O
O
O
O
(rac)-6
a: -CH2OCH3, b: -CH3
9
recovered 6
Entry
Substrate
Lipase
Time (h)
Acetate 9a yield (ee), config.
Recovered 6a yield (ee), config.
E value
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6b
6b
6b
OF
72
1
6
24
4
5
55 (21), S
43 (46), S
54 (42), S
42 (69), S
46 (78), R
59 (31), S
58 (50), S
61 (19), R
32 (5), R
44 (55), R
29 (85), R
45 (95), R
32 (93), S
26 (78), R
32 (99), R
15 (93), S
1.9
3.7
3.9
8.9
16.0
2.8
6.0
1.9
ChirazymeÒ-L2
Lipozyme IM
PS-D
AY
ChirazymeÒ-L2
PS-D
24
3
AY
a Determined by chiral-phase HPLC analysis (CHIRALPAK AD, hexane–EtOH = 95:5, 0.4 mL/min, k = 254 nm).

T. Tauchi et al. / Tetrahedron: Asymmetry 17 (2006) 2195–2198
2197
OMOM
OMOM
OMOM
OMOM
OH
b
a
c
O
H
O
O
O
O
O
O
O
O
O
O
(
S
)-6a
10 (83% )
11 (78% )
12 (88% )
(94% ee)
OMOM
OH
OMOM
d
f
+
O
O
O
O
O
O
O
OH
O
O
13 (52% )
14 (38%)
(S)-1 (82% , 94% ee)
e
(61%)
Scheme 4. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ60 °C, 2 h; (b) NaH, [CH3COCH2PPh3]+Brꢀ, THF, rt, 14 h; (c) Bu3SnH,
AIBN, benzene, reflux, 1 h; (d) LDA, (E)-CH3CH@CHCHO, THF, ꢀ78 °C, 2 h; (e) basic alumina, CH2Cl2, rt, 1 h; (f) concd HCl, AcOH, rt, 2 h.
38% yield and alcohol 13 in 52% yield, which was readily
dehydrated to enone 14 in the presence of basic alumina.
Finally, removal of the MOM group yielded (S)-vertinolide
enantiomeric excess. We hope that our simple synthesis will
be helpful for solving unidentified properties of (S)-1 in the
future.
1 (94% ee determined by HPLC), which showed a specific
20
rotation of ꢀ25.8 (lit.1 ½aꢁD ¼ ꢀ25:0). No loss of enantio-
purity was observed in the chemical transformation of
(S)-6a into (S)-1. In addition, physical and spectral proper-
ties of synthetic vertinolide 1 matched those of natural
vertinolide 1.1,2,11
Acknowledgments
We would like to thank Amano Enzyme Co., Ltd, Meito
Sangyo Co., Novo Nordisk, and Roche Molecular Bio-
chemicals for a generous gift of enzymes. This work was
supported in part by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, and Cul-
ture of Japan.
Our strategy is easily adaptable to the synthesis of (S)-
dehydrovertinolide 16 as shown in Scheme 5. The highly
conjugated enone 16 was synthesized by a similar proce-
dure to that described above.
References
OMOM
OMOM
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THF, ꢀ78 °C, 8 h; (b) basic alumina, CH2Cl2, rt, 1 h; (c) AcOH, H2O,
60 °C, 3 h.
3. Conclusion
In conclusion, we have developed a chemoenzymatic syn-
thesis of (S)-vertinolide 1 with a chiral quaternary carbon
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tetronic acid derivatives 6 demonstrated good enantioselec-
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15. Typical procedure: To a solution of the alcohol 6 (0.5 mmol)
in vinyl acetate (3 mL), lipase (50 mg) was added, and stirred
at 25 °C for an appropriate time. Lipase was removed
through filtration and washed with ethyl acetate, and the
combined organic filtrates were concentrated to give a crude
oil, which was purified by column chromatography (silica gel,
eluent: hexane–AcOEt) to give the acetate 9 and the recov-
ered alcohol 6.
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