Communications
DOI: 10.1002/anie.200903479
Enantioselectivity
Reversal of Enantioselectivity between the Copper(I)- and Silver(I)-
Catalyzed 1,3-Dipolar Cycloaddition Reactions Using a Brucine-
Derived Amino Alcohol Ligand**
Hun Young Kim, Hui-Ju Shih, William E. Knabe, and Kyungsoo Oh*
The development of asymmetric methods which lead to both
enantioenriched products by using a single chiral source is a
long-standing interest in organic chemistry.[1] This concept of
asymmetric catalysis represents not only a highly attractive
synthetic tool using readily available single enantiomeric
natural products, but also provides valuable mechanistic
information for reaction processes. Several notable methods
have been reported to produce both enantiomerically
enriched products by simply changing the reaction parame-
ters (i.e., solvent, temperature, metal counterion, and addi-
tive) without employing the antipode of the chiral source.
However, most of these reaction parameters are difficult to
incorporate from the inception of catalysis design, and most
often lack substrate generality. Whereas it is widely viewed
that examination of diverse sets of metals in asymmetric
catalysis leads to potential avenues for effective stereocontrol
in an absolute sense,[2] a vast array of available metal sources
together with potentially different catalytic cycles of varied
metal oxidation states adds mulitple variables to the rational
catalysis design. Recently, the structural modification of chiral
sources has provided some significant breakthroughs, leading
to a switch in the enantioselectivity of a reaction by using
intricate hydrogen-bonding networks[3] and pseudoenantio-
meric pairs of ligands.[4] Nevertheless, the design of effective
catalytic asymmetric methods to induce a switch in the
enantioselectivity of a reaction still remains a significant
challenge.[1c]
achieved by judicious choice of a metal having the appro-
priate ionic radius.[6]
For the generation of coordinationally stable metal–ligand
complexes, the readily available strychnos-alkaloid-derived
amino alcohol 1a was utilized as a structurally rigid scaffold.[7]
Additionally, copper(I) and silver(I) sources were chosen as
model catalysts because of their distinctive ionic radii and
their impressive versatilities in catalytic asymmetric 1,3-
dipolar cycloaddition reactions, which depends on their
distinctive ionic radii.[8] To explore the possibility of the
reversal of enantioselectivity, we selected the 1,3-dipolar
cycloaddition of azomethine ylides[9] because of the biological
significance of pyrrolidine derivatives, as well as their
potential as organocatalysts (Table 1).[10] The attractive fea-
ture of our resulting pyrrolidines includes orthogonal reac-
tivity of two ester groups, which allows selective synthetic
manipulation.[11]
We first examined the copper(I)-catalyzed reaction of
imine 2a with 1.5 equivalents of tert-butyl acrylate (3) in the
presence of 10 mol% brucine derivative 1a at room temper-
ature. Whereas the optimal copper(I) source and solvents
were swiftly identified in our preliminary studies,[12] the
observed reactivity as well as the enantioselectivity were
highly sensitive to the nature of base employed (Table 1). For
instance, aromatic bases displayed low enantioselectivities
(Table 1, entries 1 and 2), but tertiary amine bases drastically
improved the observed enantioselectivity to 75% (Table 1,
entry 3). The yield and enantioselectivity of 4a could be
additionally improved to a 98% yield and 95% ee, respec-
tively, by changing the solvent from CH2Cl2 to CHCl3
(Table 1, entry 6). Although the catalyst loading could be
lowered to 5 mol% without an appreciable drop in reactivity
and enantioselectivity (Table 1, entry 7), the optimal reaction
conditions were established using 10 mol% of CuI and 1a.
To address the scope of reversal of enantioselectivity, we
next explored AgI/1a catalytic system by examining different
Herein we present our efforts to design a new asymmetric
approach to the reversal of enantioselectivity in a catalytic
asymmetric 1,3-dipolar cycloaddition reaction. Our strategy
for the development of catalytic systems to induce reversal of
enantioselectivity was based on the premise that chiral amino
alcohol ligands[5] should display different binding modes with
different metals. Moreover, we envisioned that the various
binding modes of amino alcohols to metal centers could be
[*] Dr. H. Y. Kim, H.-J. Shih, W. E. Knabe, Prof. Dr. K. Oh
Department of Chemistry and Chemical Biology, Indiana University
Purdue University Indianapolis (IUPUI)
Indianapolis, IN 46202 (USA)
Fax: (+1)317-274-4701
E-mail: ohk@iupui.edu
[**] This research was supported by IUPUI. Undergraduate fellowships
were provided by UROP and SROP (H.J.S.). The Bruker 500 MHz
NMR was purchased using funds from an NSF-MRI award (CHE-
0619254).
Supporting information for this article is available on the WWW
7420
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 7420 –7423