Enantioselective epoxidation of allylic alcohols by a chiral complex of vanadium: An effective controller system and a rational mechanistic model

Article abstract of DOI:10.1002/anie.200500938

(Chemical Equation Presented) Bishydroxamic acid derivatives are used as ligands for a vanadium catalyst in the preparation of epoxy alcohols (see scheme). The methodology uses aqueous tert-butyl hydroperoxide (TBHP) as an achiral oxidant, low catalyst loading, low reaction temperatures (0°C to room temperature), and simple workup procedures. The reaction is applied to the kinetic resolution of a secondary allylic alcohol and the preparation of small epoxy alcohols. R¹, R², R³: alkyl, aryl, H.

Full text of DOI:10.1002/anie.200500938

Angewandte
Chemie
Asymmetric Catalysis
coordination with the metal center. Furthermore, the attach-
ment of additional ligands to the vanadium center will also be
restricted because of steric reasons. Thus, doubly or triply
coordinated species, which are believed to be inactive, should
not be generated from the bishydroxamic acid ligand, and
consequently a ligand deceleration effect within the vana-
dium/1 catalytic system should not be problematic.[8]
Enantioselective Epoxidation of Allylic Alcohols
by a Chiral Complex of Vanadium: An Effective
Controller System and a Rational Mechanistic
Model**
We devised a synthetic protocol for 1 from a readily
available diamine tartrate salt (Scheme 1) so that the veracity
Wei Zhang, Arindrajit Basak, Yuji Kosugi,
Yujiro Hoshino, and Hisashi Yamamoto*
The asymmetric epoxidation of allylic alcohols by metal
catalysts,[1] though a widely used synthetic method, could
gain even more practical applications if the following
were realized: 1) employment of a ligand designed to
achieve high enantioselectivity for Z olefins, 2) catalyst
loading of less than 1 mol%, 3) reaction temperatures of
08C to room temperature over a shorter time, 4) use of
aqueous tert-butyl hydroperoxide (TBHP) as an achiral
oxidant instead of anhydrous TBHP, and 5) simple
workup procedures for small epoxy alcohols. Many
important improvements have been made to the meth-
odology developed by Sharpless and co-workers for the
titanium tartarate catalyzed asymmetric epoxidation.[2–4]
Nonetheless, each of these approaches fails to fulfil the
above criteria.[1–5] Herein, we report our recent progress
on all five fronts.
Recently, we developed a series of hydroxamic acid
ligands and demonstrated that they were effective for
the vanadium-catalyzed asymmetric epoxidation of
allylic alcohols.[6,7] These results suggested that several
structural features of the hydroxamic acid significantly
enhanced the rate and enantioselectivity of the reaction.
However, the ligand deceleration effect was still
observed in these cases.[6–8] To exclude this effect, we planned
to design a new C2-symmetric bishydroxamic acid 1 that
incorporated the following features: 1) an additional binding
site with which 1 can chelate as a bidentate ligand to the metal
center to complete the generation of a chiral vanadium/ligand
complex more efficiently than the monohydroxamic acid and
2) an R group of the amide in 1 that is sufficiently large so the
oxygen atom of the carbonyl group is directed towards the
cyclohexane ring to minimize steric interaction and restrict its
Scheme 1. Preparation of bishydroxamic acid. DIEA=N,N-diisopropylethylamine,
Bn=benzyl, DMAP=4-dimethylaminopyridine, TESCl=triethylsilyl chloride.
of our hypothesis could be proved.[9] These reaction sequen-
ces can be carried out with satisfactory yields and without any
purification to provide 4, from which we have prepared an
array of diverse ligands 1a–c.
As expected, the use of a complex of vanadium with
ligand 1 provided epoxy alcohols both in good yields with high
enantioselectivities (Table 1).[9] The catalyst 5a, derived from
vanadium and 1a, invariably induced excellent enantioselec-
tivities during the epoxidation of trans-disubstituted and
-trisubstituted allylic alcohols. The most gratifying aspect of
this catalytic system was the excellent enantioselectivity
observed during the epoxidation of cis-substituted allylic
alcohols with catalyst 5b, which was derived from vanadium
and 1b. It is of note that 1) the slow reactivity of some
substrates were surmounted by performing the epoxidation at
08C or room temperature without significant loss of enantio-
selectivity, 2) the catalyst loading could be as low as
0.2 mol%, 3) all the reactions were performed in air and in
the presence of aqueous TBHP; the use of anhydrous TBHP
increased neither the yield nor the enantioselectivity.[9] Also
as expected, the negative effect of a dynamic ligand exchange
was not observed in the vanadium/bishydroxamic acid
catalytic system. The high reactivity of the vanadium/ligand
complex was maintained, even if the ratio of ligand/vanadium
was increased to more than 3:1.[9]
[*] W. Zhang, Dr. A. Basak, Dr. Y. Hoshino, Prof. Dr. H. Yamamoto
Department of Chemistry
The University of Chicago
5735 South Ellis Avenue, Chicago, IL 60637 (USA)
Fax: (+1)773-702-0805
E-mail: yamamoto@uchicago.edu
Y. Kosugi
Graduate School of Engineering
Nagoya University, Furo-cho
Chikusa, Nagoya 464-8603 (Japan)
[**] Support of this work by the SORSTproject of the Japan Science and
Technology Agency (JST), the National Institutes of Health (NIH;
GM068433-01), and a starter grant from the University of Chicago is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 4389 –4391
DOI: 10.1002/anie.200500938
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4389

Communications
Table 1: Enantioselective epoxidation of allylic alcohols
Table 2: Enantioselective epoxidation of small allylic alcohols
Catalyst
Product
T [8C] t [h] Yield [%] ee [%]
Catalyst
Product
Yield [%]
78
ee [%]
À20
À20
À20
À20
À20
0
48 91
48 84
60 53
72 56
72 51
48 73
97
97
97
95
95
95
5c
97
5a
5b
5a
5c
50
71
68
73
93
92
95
94
To explain the reaction enantioselectivity, we have
proposed a possible intermediate during the epoxidation[10]
(Figure 1). If 1a is divided into four sections, as indicated by
À20
48 79
95
À20
48 68
72 60
95[a]
0
95
97
96
À20 120 24
À20
À20
48 64
48 62
Figure 1. Postulated model of the epoxidation of allylic alcohols cata-
lyzed by the vanadium/1a complex. a) Chiral cyclohexyl bishydroxamic
acid 1a and b) the proposed reaction intermediate. The circle repre-
sents the division of the bishydroxamic acid into quarters to explain its
stereochemistry. The shaded sections of the circle represent the parts
of the bishydroxamic acid in bold.
95
[a] Catalyst was 5c.
the circle in Figure 1, it is seen that the second and fourth
quadrants of 1a (corresponding to the shaded sections) are
more crowded than the first and third quadrants (correspond-
ing to the unshaded quarters) because of the structural
features of the chiral cyclohexyl bishydroxamic acid (Fig-
ure 1a), especially when the vanadium center is introduced.
[VO(OiPr)3] coordinates with 1a by displacement of two
iPrOH units with two hydroxy groups from the bishydroxamic
acid (Figure 1b). Another iPrOH unit of [VO(OiPr)3] is then
displaced by TBHP, which occupies the less-crowded third
quadrant. Finally, when the allylic alcohol forms, it will
coordinate with the vanadium center through its oxygen atom
from the top. During the reaction, the oxygen atom of TBHP
is spiro overlapped with the olefin and attacks it from the
bottom. Steric bulk at the a position of the carboxylate group,
which is greater in the case of 1a, plays an important role and
is suitable for trans-substituted allylic alcohols as the sub-
This method was applied to the asymmetric synthesis of
small epoxy alcohols, which is a long-standing problem in
asymmetric oxidation. Thus, after the reaction, the product
was extracted with water to give the enantiopure epoxy
alcohols (Table 2).[2,9]
Finally, the method was also applied to the kinetic
resolution of a secondary allylic alcohol. As expected, both
the epoxy alcohol and the allylic alcohol were isolated with
high enantioselectivities [Eq. (1)].[9]
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Angewandte
Chemie
strate. On the other hand, the additional flexibility of 1b
allows the cis-substituted allylic alcohols enough space to fit
into the chiral pocket, thus resulting in high selectivity.
In conclusion, we have developed a new catalytic system
for the asymmetric epoxidation of allylic alcohols. Investiga-
tions into the mechanism and further applications of bishy-
droxamic acid ligands in asymmetric catalysis is in progress.
Experimental Section
Representative experimental procedure: [VO(OiPr)3] (0.0025 mL,
0.0104 mmol) was added to a solution of 1a (11.2 mg, 0.0210 mmol) in
CH2Cl2 or toluene (1 mL), and the reaction mixture was stirred for 1 h
at RT. The resulting solution was cooled to 08C, and 70%aqueous
TBHP (0.22 mL, 1.59 mmol) and a-phenylcinnamyl alcohol (220 mg,
1.05 mmol) were added. The mixture was stirred at the same
temperature for 12 h. The process of epoxidation was monitored by
TLC. Saturated aqueous Na2SO3 was added, and the reaction mixture
was stirred for 1 h at 08C. The reaction mixture was then allowed to
warm to RT, extracted with Et2O, dried over Na2SO4, and concen-
trated under reduced pressure. The remaining residue was purified by
flash column chromatography on silica gel to provide the epoxy
alcohol (93%, 94% ee). Determination of the ee values of the epoxy
alcohols is provided in the Supporting Information.
Received: March 14, 2005
Published online: June 8, 2005
Keywords: asymmetric catalysis · chirality · epoxidation ·
.
ligand design · vanadium
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