One-pot synthesis of optically active allyl esters via lipase-vanadium combo catalysis

Article abstract of DOI:10.1021/ol102053a

The combination of vanadium-oxo compounds (3 or 4) with a lipase produced the regio- and enantioconvergent transformation of racemic allyl alcohols (1 or 2) into optically active allyl esters. In this system, the vanadium compounds catalyzed the continuous racemization of the alcohols along with the transposition of the hydroxyl group, while the lipase effected the chemo- and enantioselective esterification to achieve the dynamic kinetic resolution.

Full text of DOI:10.1021/ol102053a

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4900-4903
One-Pot Synthesis of Optically Active
Allyl Esters via Lipase-Vanadium
Combo Catalysis
Shuji Akai,*,† Ryosuke Hanada,† Noboru Fujiwara,† Yasuyuki Kita,‡,§ and
Masahiro Egi†
School of Pharmaceutical Sciences, UniVersity of Shizuoka, 52-1, Yada, Suruga-ku,
Shizuoka, Shizuoka 422-8526, Japan, and Graduate School of Pharmaceutical
Sciences, Osaka UniVersity, 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan
akai@u-shizuoka-ken.ac.jp
Received August 30, 2010
ABSTRACT
The combination of vanadium-oxo compounds (3 or 4) with a lipase produced the regio- and enantioconvergent transformation of racemic
allyl alcohols (1 or 2) into optically active allyl esters. In this system, the vanadium compounds catalyzed the continuous racemization of the
alcohols along with the transposition of the hydroxyl group, while the lipase effected the chemo- and enantioselective esterification to achieve
the dynamic kinetic resolution.
Optically active secondary allyl alcohols and their derivatives
are one of the most vital classes of compounds in modern
organic synthesis because of their ubiquity and wide ap-
plications in the synthesis of optically active molecules
including natural products, pharmaceutical and agrochemical
products, and functional materials.1 Therefore, various
synthetic methods have been developed over the past
decades. The popular ones include the kinetic resolution of
racemic allyl alcohols,1c,2 asymmetric reduction of vinyl
ketones by optically active catalysts1a,b,3 or enzymes,4 and
the enantioselective addition of alkenyl metal reagents to
aldehydes.5 Nevertheless, the development of different
approaches that enable an environmentally benign production
is still in need.
On the other hand, the 1,3-transposition of allyl alcohols has
been studied over several decades mainly using metal-oxo
catalysts.6 It basically produces an equilibrium between the
substrates and their regioisomers, and the product distribution
depends on the relative thermodynamic stabilities of the two
isomers.7-9 The chiral integrity of optically active allyl
alcohols is not always maintained.8,9a,b Because of these
(3) For a review, see: Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed.
2001, 40, 40.
† University of Shizuoka.
(4) For an example, see: Krausser, M.; Hummel, W.; Gro¨ger, H. Eur.
J. Org. Chem. 2007, 5175.
‡ Osaka University.
§ Current address: School of Pharmaceutical Sciences, Ritsumeikan
University, 1-1-1 Noji Higashi, Kusatsu, Shiga 525-8577, Japan.
(1) For a review, see: (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int.
Ed. 1998, 37, 1986. For some recent examples, see: (b) Fujioka, H.; Matsuda,
S.; Horai, M.; Fujii, E.; Morishita, M.; Nishiguchi, N.; Hata, K.; Kita, Y.
Chem.sEur. J. 2007, 13, 5238. (c) Sawama, Y.; Sawama, Y.; Krause, N.
Org. Biomol. Chem. 2008, 6, 3573.
(5) For examples, see: (a) Cozzi, P. G.; Kotrusz, P. J. Am. Chem. Soc.
2006, 128, 4940. (b) Sokeirik, Y. S.; Mori, H.; Omote, M.; Sato, K.; Tarui,
A.; Kumadaki, I.; Ando, A. Org. Lett. 2007, 9, 1927.
(6) For reviews, see: (a) Chabardes, P.; Kuntz, E.; Varagnat, J.
Tetrahedron 1977, 33, 1775. (b) Bellemin-Laponnaz, S.; Le Ny, J.-P.;
Dedieu, A. Chem.sEur. J. 1999, 5, 57.
(7) For a review, see: Bellemin-Laponnaz, S.; Le Ny, J.-P. Compt. Rend.
(2) For a review, see: (a) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed.
2005, 44, 3974. For an example, see (b) Birman, V. B.; Li, X. Org. Lett.
Chim. 2002, 5, 217
(8) Matsubara, S.; Okazoe, T.; Oshima, K.; Takai, K.; Nozaki, H. Bull.
Chem. Soc. Jpn. 1985, 58, 844
.
2006, 8, 1351
.
.
10.1021/ol102053a  2010 American Chemical Society
Published on Web 10/11/2010

uncertain natures, the 1,3-transposition reaction has received
less attention from a synthetic point of view.10,11 We report
herein an asymmetric synthesis of optically active allyl esters
5 from racemic allyl alcohols (1 or 2) by the combination
of the vanadium (3 or 4)-catalyzed 1,3-transposition reaction
and the lipase-catalyzed kinetic resolution (schemes in the
Abstract and Table 1). In this system, the vanadium-catalyzed
perature, many are hardly compatible with the lipases. On
the contrary, we initially reported that OdV(OSiPh3)3 (3)
and the lipases were tolerant in acetone at 35 °C for a few
days and their combined use accomplished the dynamic
kinetic resolution (DKR) of (()-1 (R1 ) R2) to give (R)-
5;18 however, this method was not effective for the unsym-
metrically substituted (()-1 (R1 * R2) (see the following
examples of 1a). Therefore, our first challenge was the
discovery of a more powerful racemization protocol for 1
(R1 * R2) while maintaining the compatibility with the
lipases. It is worth noting that no one has positively promoted
the racemization of optically active allyl alcohols during the
transposition, although the prevention of the racemization
has been investigated.9a,b
Table 1. Conversion of (()-1a-c and (()-2a-c into (R)-5 by
the Lipase-Vanadium (3, 4) Combo Catalysis
The racemization was studied using (R)-1a (98% ee) as the
test substrate (Scheme 1). Under our previous conditions [use
Scheme 1
.
Vanadium-Catalyzed Racemization of Optically
Active 1a,b
substrate
entry (1 or 2) V catalyst conditions
product 5
1
2
3
4
5
6
7
8
(()-1a
(()-1a
(()-1b
(()-1b
(()-1c
(()-2a
(()-2b
(()-2c
3a
4
3
4
4
4
3
4
50 °C, 3 d (R)-5a 95% ee, 70%
35 °C, 1 d (R)-5a 92% ee, 80%
35 °C, 1 d (R)-5b >99% ee, 97%
35 °C, 1 d (R)-5b 99% ee, 27%
50 °C, 1 d (R)-5c
92% ee, 71%
35 °C, 1 d (R)-5a 94% ee, 77%
35 °C, 1 d (R)-5b 96% ee, 99%
50 °C, 1 d (R)-5c
94% ee, 74%
of 3 (10 mol %) in acetone at 35 °C],18 the racemization was
very slow to give (R)-1a (86% ee) after 72 h. We then screened
the solvents, the reaction temperature, and the vanadium
compounds: (1) Raising the temperature to 50 °C in acetone or
changing the solvent to MeCN at 35 °C significantly enhanced
the racemization to give the racemic 1a after 8 h. (2) Com-
mercially available OdVSO4·nH2O (10 mol %) was very
reactive and produced the complete racemization within 1 h in
MeCN at 35 °C; however, a mixture of diastereomeric ethers
6 was also obtained in approximately 50% yield. A further study
disclosed its fatal incompatibility with lipases.19 (3) While the
use of OdVPO4·2H2O (10 mol %) in MeCN at 35 °C was less
effective in producing a 2:1 mixture of (R)-1a (86% ee) and 6
after 13 h, a polymer-bound vanadyl phosphate 420 (10 mol
a 20 mol % of 3 was used.
1,3-transposition of 1 or 2 generates a dynamic equilibrium
between them with continuous racemization, while the lipase
effects the chemo- and enantioselective esterification to give
optically active 5.
One of the most difficult obstacles to achieve this idea was
the incompatibility of artificial metallic compounds and natural
enzymes in a single reaction pot. Although several transition
metal-oxo compounds that include V,8,11 W,12 Mo,13,14 and
Re9,10,15-17 have been developed to effectively catalyze the
1,3-transposition of the allyl alcohols below ambient tem-
(9) For recent trials to control the regio- and stereoselectivities of the
1,3-transposition of allyl alcohols, see: (a) Morrill, C.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 2842. (b) Morrill, C.; Beutner, G. L.; Grubbs, R. H.
J. Org. Chem. 2006, 71, 7813. (c) Herrmann, A. T.; Saito, T.; Stivala, C. E.;
(16) (a) Bellemin-Laponnaz, S.; Gisie, H.; Le Ny, J. P.; Osborn, J. A.
Angew. Chem., Int. Ed. Engl. 1997, 36, 976. (b) Bellemin-Laponnaz, S.;
Le Ny, J. P.; Osborn, J. A. Tetrahedron Lett. 2000, 41, 1549.
(17) (a) Jacob, J.; Espenson, J. H.; Jensen, J. H.; Gordon, M. S.
Organometallics 1998, 17, 1835. (b) Wang, G.; Jimtaisong, A.; Luck, R. L.
Organometallics 2004, 23, 4522.
Tom, J.; Zakarian, A. J. Am. Chem. Soc. 2010, 132, 5962
(10) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 11262
(11) For the use of allenic alcohols, see: Trost, B. M.; Jonasson, C.
Angew. Chem., Int. Ed. 2003, 42, 2063
(12) Hosogai, T.; Fujita, Y.; Ninagawa, Y.; Nishida, T. Chem. Lett. 1982,
.
.
.
(18) Akai, S.; Tanimoto, K.; Kanao, Y.; Egi, M.; Yamamoto, T.; Kita,
Y. Angew. Chem., Int. Ed. 2006, 45, 2592.
357.
(19) Jacobs also reported the incompatibility of OdVSO4·nH2O with
C. antarctica lipase, B; see: Wuyts, S.; Wahlen, J.; Jacobs, P. A.; De Vos,
D. E. Green Chem. 2007, 9, 1104.
(13) (a) Belgacem, J.; Kress, J.; Osborn, J. A. J. Am. Chem. Soc. 1992,
114, 1501. (b) Belgacem, J.; Kress, J.; Osborn, J. A. J. Mol. Catal. 1994,
86, 267
(14) Fronczek, F. R.; Luck, R. L.; Wang, G. Inorg. Chem. Commun.
2002, 5, 384
.
(20) The polymer reagent 4 is commercially available from STREM as
PhosphonicS POVO and has been used only for the oxidation of allyl
alcohols; see: Jurado-Gonzalez, M.; Sullivan, A. C.; Wilson, J. R. H.
Tetrahedron Lett. 2004, 45, 4465.
.
(15) Narasaka, K.; Kusama, H.; Hayashi, Y. Tetrahedron 1992, 48, 2059
.
Org. Lett., Vol. 12, No. 21, 2010
4901

%) in MeCN at 35 °C produced the racemic 1a (89% yield)
and 6 (11% yield) after only 2 h. This implied some beneficial
nature of the polymer reagent on the compatibility with lipases.21
The racemization of the p-methoxy derivative (S)-1b (99%
ee) was much faster than that of 1a. It was completed by 3 (10
mol %) in MeCN within 2 h at 35 °C to give (()-1b; however,
its yield was 28%, and 6b was formed in 72% yield (Scheme
1). These results indicated that the racemization took place via
a cationic intermediate B similar to the cases using the rhenium-
oxo compounds.9,15 This is also consistent with the fact that
the use of the more polar solvent, MeCN, accelerated the
process. However, the formation of dimeric ethers 6 has
emerged as another serious problem.
and Z-isomers) quantitatively afforded a mixture of (E)- and
(Z)-2b (E/Z ) 23:77), which was then converted into (R)-
5b (99% ee, 94% yield) with exclusive E-selectivity. Thus,
the overall process enabled the two-step preparation of the
optically and geometrically pure 5b starting from commercial
raw materials in a 94% overall yield (Scheme 2).
Scheme 2. Two-Step Synthesis of (R)-5b from Anisaldehyde
We next examined the DKR of (()-1a-c by the combined
use of a lipase with 3 or 4. First, (()-1b was treated with the
commercially available immobilized C. antarctica lipase, B,
and 3 (10 mol %) in MeCN at 35 °C for 1 day to provide the
corresponding (R)-5b (>99% ee) in 97% isolated yield (Table
1, entry 3). This result demonstrated that the presence of a
lipase sufficiently depressed the formation of the dimer 6b. The
selection of a racemization catalyst suitable for each substrate
was found to be essential for the efficient DKR. Thus, for the
racemization resistant (()-1a, the use of 4 (10 mol %) gave
slightly better results [(R)-5a: 92% ee, 80% yield at 35 °C in 1
day] (entry 2) than that of 20 mol % of 3 [(R)-5a: 95% ee,
70% yield at 50 °C in 3 days] (entry 1). In a like manner, (()-
1c was converted into (R)-5c (92% ee, 71% yield) using 4 (10
mol %) (entry 5). Because the developed method generates an
equilibrium between 1 and 2, a similar treatment of (()-2a-c
also provided the same products (R)-5a-c in comparable optical
and chemical yields (entries 6-8).
The combo-catalysis was applied to a variety of allyl
alcohols (()-2d-n to give (R)-5d-n (Table 2). For the
substrates with electron-rich aromatic rings, such as 2e,g-i,
the use of 3 yielded the corresponding (R)-5e,g-i in good-
to-excellent optical and chemical yields (entries 2 and 4-6).
For the nonconjugated aliphatic alcohols (2j and 2k), 4 was
more suitable to provide 5j (96% ee) and 5k (95% ee) in
68-71% yields (entries 7 and 8). Starting from the tertiary
cyclic alcohols 2l-n, the secondary alcohols (R)-5l-n were
obtained in good yields (entries 9-11). The acylates of 2
were not obtained at all in these reactions.
(R)-3-Undecyl-2-cyclohexen-1-ol 7, derived from (R)-5m,
served as a key synthetic intermediate of (+)-tanikolide.1b
It had been synthesized from 3-ethoxy-2-cyclohexen-1-one
via the CBS asymmetric reduction of 2-iodo-3-undecyl-2-
cyclohexen-1-one in 31% overall yield in five steps, while
this method provided (R)-7 (96% ee) from the simpler and
The following is another practical advantage of this
method: the reaction of anisaldehyde with the commercially
available 1-propenylmagnesium bromide (a mixture of E-
Table 2. Asymmetric Synthesis of (R)-5 from (()-2 by the Lipase-Vanadium Combo Catalysis
a 20 mol % of 3 was used. b Vinyl butyrate was used instead of vinyl acetate.
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Org. Lett., Vol. 12, No. 21, 2010

less expensive 2-cyclohexen-1-one in a 46% overall yield22
and features the high step-, atom-, and redox-economies.23
An additional outstanding aspect of the developed method
was demonstrated by the reactions of the dienols [(()-8o,p],
each of which is a mixture of several stereoisomers, to
produce the single products [(R,E,E)-5o,p]. In these cases,
3 generated a dynamic equilibrium including different regio-
and stereoisomers [(()-8, (()-2, and (()-1], while the lipase
catalyzed the chemo-, stereo-, and enantioselective esterifi-
cation of (R,E,E)-1. The alcohol 2q having a hydroxyl group
between two olefins produced (R)-5q. The cyclic dienols
[(()-1r,s] were converted into their optically active acetates
[(R)-5r,s] with excellent optical purities (Scheme 3).
Scheme 4. Asymmetric Synthesis of the Optically Active Allyl
Esters (R)-5 and Some Examples of Their Further
Transformation
Scheme 3.
Asymmetric Synthesis of Dienyl Acetates (R)-5o-sa
overall process provides a few-step synthesis of optically
active olefins (Scheme 4).
In conclusion, the combined use of the vanadium-oxo
compounds (3 and 4) and the lipase produced the regio- and
enantioconvergent transformation of racemic allyl alcohols (1,
2 or 8) into optically active allyl esters. This method features a
multistep one-pot reaction26 involving the 1,3-transposition of
the hydroxyl group, the continuous racemization of the optically
active allyl alcohols, and the enantio-, chemo-, and diastereo-
selective esterification. Its value also lies in the fact that such a
transformation has never been achieved using each catalyst
separately. Moreover, this method is different from the well-
known dynamic kinetic resolution using a combination of Ru
complexes and lipases27 and offers the following synthetic
advantages: (1) all possible regioisomers are available as
equivalent substrates to give the same allyl esters in a single
step; (2) the best synthetic route to the substrates can be selected
among various candidates; and (3) the overall process offers a
new methodology for the asymmetric synthesis of the optically
active allyl esters from easily obtainable prochiral raw materials
in only a few steps. The application of other kinds of hydrolases
having different enantio- and chemoselectivities to this combo
catalysis is under investigation in our laboratory to expand the
availability range of the optically active allyl esters.
a Use of 3 (20 mol %).
The racemic allyl alcohols (1 and 2) were prepared by the
common reactions of carbonyl compounds and carbanions,
which are classified into three groups based on the carbon-
carbon bond to make (methods A-C) (for details, see the
Supporting Information). In some cases, the preparation of 2 is
more convenient and effective than that of 1 due to the
availability and cost of the precursors, efficiency and safety of
the reactions, etc. The fact that both 1 and 2 serve as equivalent
substrates of the developed method increases flexibility in
choosing the most effective synthetic route to (R)-5. Because
the stereo- and regioselective transformations of the allyl esters
to various valuable compounds have been developed,24,25 the
Acknowledgment. This work was supported by KAK-
ENHI (No. 21390005) and the Asahi Glass Foundation.
Roche Diagnostics K. K., Japan, is thanked for the generous
gift of the lipase.
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) For the detailed time-course of these racemization reactions, see
the Supporting Information.
(22) For the detailed comparison of the two methods, see the Supporting
Information.
OL102053A
(23) For an example, see: Burns, N. Z.; Baran, P. S.; Hoffmann, R. W.
Angew. Chem., Int. Ed. 2009, 48, 2854.
(26) For reviews of the multistep one-pot reactions using cooperative
catalysis, see: (a) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008,
41, 222. (b) Shao, Z.; Zhang, H. Chem. Soc. ReV. 2009, 38, 2745.
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Org. Synth. Enz. 2008, 89. (b) Karvembu, R.; Prabhakaran, R.; Tamizh,
M.; Natarajan, K. Compt. Rend. Chim. 2009, 12, 951. (c) Lee, J. H.; Han,
K.; Kim, M.-J.; Park, J. Eur. J. Org. Chem. 2010, 999. (d) Turner, N. J.
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