Angewandte
Chemie
DOI: 10.1002/anie.200603787
Asymmetric Catalysis
Enantioselective Desymmetrization of meso Epoxides with Anilines
Catalyzed by a Niobium Complex of a Chiral Multidentate Binol
Derivative**
Kenzo Arai, Matthew M. Salter, Yasuhiro Yamashita, and Sh u¯ Kobayashi*
The development of new chiral catalysts for the promotion of
asymmetric reactions is one of the most important tasks in
organic synthesis. New chiral catalysts must not only mediate
reactions with high yields and enantioselectivities, but are also
increasingly required to have the ability to recognize the
precise structure of substrates. For example, a nonenzymatic
catalyst that could recognize the difference between methyl
and ethyl groups in a substrate would be an ideal catalyst in
this field. We now describe homochiral multidentate com-
plexes of binol derivatives and niobium which distinguish
substrate structures strictly and catalyze the desymmetrizaton
of meso epoxides with anilines efficiently.
We conducted the reaction with a
range of different epoxides and ani-
[
5]
lines,
with
striking
results
(Table 1). First, it was found that
the reaction of cis-but-2-ene oxide
(2a) with aniline 3a proceeded very
smoothly to give the corresponding
1,2-hydroxyamine 4aa in quantita-
tive yield with very high enantiose-
[
1]
lectivity (Table 1, entry 1). Subsequent experiments, in which
cis-but-2-ene oxide (2a) was treated with a range of sub-
stituted anilines in the presence of 10 mol% of the catalyst,
further confirmed the utility of the system (Table 1, entries 2–
9). These results showed that the catalyst activity was general
for a broad range of aniline nucleophiles, including both
electron-rich and electron-poor examples, although in the
case of ortho-substituted anilines the chemical yield of the
reaction was slightly lower. Furthermore, from a synthetic
point of view, we could decrease the amount of the catalyst
from 10 mol% to 0.25 mol% without significant loss of
activity. On the other hand, when the reaction was conducted
with the closely related epoxide substrates cis-hex-3-ene
oxide (2b) and cis-oct-4-ene oxide (2c), there was hardly any
turnover, and only traces of the products were formed
(Table 1, entries 10 and 11). However, when we switched to
epoxide substrates derived from cyclic alkenes, the ring-
opened products were obtained in good to very high yields
and with generally high enantioselectivities (Table 1,
entries 12–16). Such outstandingly high levels of molecular
recognition and selectivity are, to the best of our knowledge,
unprecedented in the desymmetrization of meso epoxides and
are a unique characteristic of the niobium–tetradentate-binol
catalyst system.
We previously reported the first example of a highly
enantioselective Lewis acid based on niobium(V) for Man-
[
2]
nich-type reactions of imines with silicon enolates. This
species, prepared from a metal source and a binol-derived
tridentate ligand, was shown to have a unique binuclear
structure in which two niobium atoms were straddled by two
molecules of the ligand. This arrangement, in which the metal
centers are held in a spatially defined array by firm but
flexible ligation, appeared to permit highly substrate-selective
reactions. As niobium(V) has a high affinity for oxygen and is
already heavily coordinated in our metal–ligand system, we
judged that monodentate species would function most
efficiently as substrates and focused accordingly on the
[
3]
[4]
asymmetric ring opening of meso epoxides with anilines.
A series of initial experiments showed that the reaction
proceeded most efficiently when the niobium atom in the
complex was tetracoordinated. This finding led to the
development of a new class of Lewis acid complexes formed
from niobium and the tetradentate ligand 1.
Further investigations revealed that the most effective
catalyst system was Nb(OMe) –1 in the presence of 4-
5
molecular sieves with a 3:2 mixture of toluene and CH Cl as
To investigate the molecular-recognition ability of
2
2
the solvent. Following the optimization of the reaction
conditions, attention was turned to the scope of the reaction.
Nb(OMe) –1 further, we conducted competition reactions
5
in which the parent aniline 3a was treated with an equimolar
mixture of cis-but-2-ene oxide (2a) and another, bulkier
epoxide in the presence of the catalyst (Table 2). As
anticipated given the high absolute and relative reactivity of
[
*] K. Arai, Dr. M. M. Salter, Dr. Y. Yamashita, Prof. Dr. S. Kobayashi
Graduate School of Pharmaceutical Sciences
The University of Tokyo
2
a, these competition reactions proceeded smoothly with
high selectivity for 2a versus the bulkier epoxides 2i, 2j, or 2h
to give predominantly 4aa in high yield and with very high
enantioselectivity. Only traces of the products from the
addition of the nucleophile to the other epoxide 2 were
formed. In all cases, the ratio of 4aa to the product derived
from the other epoxide exceeded 60:1. To our knowledge,
such high levels of chemoselectivity with a metal-based Lewis
acid catalyst are unprecedented.
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-3684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(
JSPS).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 955 –957
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
955
Arai, Kenzo
