Control of diastereoselectivity in tandem asymmetric reactions generating nonadjacent stereocenters with bifunctional catalysis by cinchona alkaloids

Article abstract of DOI:10.1021/ja0670409

We report the manipulation of hydrogen-bonding-based cooperative catalysis to control the diastereoselectivity for a tandem asymmetric reaction creating two nonadjacent stereocenters. This ability to control both the enantioselectivity and diastereoselect

Full text of DOI:10.1021/ja0670409

Published on Web 01/03/2007
Control of Diastereoselectivity in Tandem Asymmetric Reactions Generating
Nonadjacent Stereocenters with Bifunctional Catalysis by Cinchona Alkaloids
Baomin Wang, Fanghui Wu, Yi Wang, Xiaofeng Liu, and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received October 1, 2006; E-mail: deng@brandeis.edu
Scheme 1. Proposed Model for the Modified Cinchona
Alkaloid-Catalyzed Conjugate Additions
Highly enantioselective and diastereoselective reactions or reac-
tion cascades generating in one step chiral products with multiple
stereocenters are unusually valuable for asymmetric synthesis. The
full power of such reactions lies in their ability to provide, starting
from the same simple prochiral precursors, selective pathways to
any of the possible array of stereoisomers of a complex chiral
product of interest. Ideally, this could be accomplished with a set
of readily available chiral catalysts that afford complementary sense
of diastereoselectivity and enantioselectivity. While complementary
enantioselectivity can be readily provided by a pair of enantiomeric
or pseudoenantiomeric chiral reagents, how to establish comple-
mentary diastereoselectivity in these reactions remains an important
but challenging problem in asymmetric synthesis.
Significant progress has been made on the establishment of
complementary diastereoselectivity with catalytic asymmetric reac-
tions creating adjacent stereocenters.1,2 In contrast, enantioselective
and diastereoselective reactions that provide stereoselective access
to all stereoisomers of a chiral product with nonadjacent stereo-
centers are extremely rare even for those employing a stoichiometric
amount of chiral reagents.3 In particular, to our knowledge, no such
reaction mediated by a chiral catalyst has been reported. We
document here the development of a new, catalytic asymmetric
tandem conjugate addition-protonation reaction that generates
nonadjacent stereocenters with a complementary sense of diaste-
reoselectivity relative to that reported with the 6′-OH cinchona
alkaloids 1 (Scheme 1).4 Consequently, it is now possible to
accomplish one-step and stereoselective construction of 1,3-
tertiary-quaternary stereocenters in any of the four possible
absolute configurations with catalytic control.
Table 1. Optimization of Reaction Conditions Using Model
Substratesa,b
a Only one enantiomer was drawn for 5a and 5′a. b See Supporting
Information (SI) for experimental detail. c ee of 5′a.
We previously reported a highly enantioselective and diastereo-
selective catalytic tandem conjugate addition-protonation of trisub-
stituted carbon nucleophiles to R-chloroacrylonitrile 4 using 6′-
OH cinchona alkaloid catalyst 1 (Scheme 1). As rationalized by the
transition-state model illustrated in Scheme 1,4 the stereochemical
outcome of this asymmetric tandem reaction resulted from a net-
work of hydrogen-bonding interactions between 1 with the reacting
Michael donor X and acceptor Y in the nucleophilic addition step
and, subsequently, with the putative enol intermediate I in the proton-
ation step. This led us to hypothesize that, by exploring bifunctional
catalysts bearing the hydrogen bond donor and acceptor motifs in
altered spatial relationships, an asymmetric tandem conjugate
addition-protonation with a complementary sense of diastereose-
lectivity with respect to that promoted by 1 could be developed.
Accordingly, we investigated the reaction of 2-cyanoindanone
3a and 4 with readily available cinchona alkaloids bearing a
hydrogen bond donor at C9 (Scheme 1 and Table 1).5 While both
natural cinchona alkaloids and their C9-epimers afforded poor
diastereoselectivity and enantioselectivity (entries 1-4, Table 1),
the 9-thiourea cinchona alkaloids 2 were found to afford dramati-
cally enhanced diastereoselectivity and enantioselectivity (entries
5-7, Table 1). Upon optimizations the reaction with Q-2c furnished
5a in 10:1 diastereomeric ratio (dr) and 97% ee. Most importantly,
the sense of diastereoselectivity by 1 and 2 were found to be
complementary to each other (entry 7 vs entry 8, Table 1).
These results obtained with a cyclic Michael donor implied that
the switch of the sense of diastereoselectivity between the two
reactions catalyzed by Q-1a and Q-2c, respectively, is independent
of the geometric configuration of the double bond in the enolic
form of the Michael donor 3. Instead, it may arise from a reversal
of the face of the Michael donor being exposed to the Michael
acceptor in the nucleophilic addition step as a result of replacing
1a with 2c as the catalyst. This hypothesis received validation from
analysis of the absolute configurations of the major diastereomers
5a and 5′a generated from reactions with Q-2c and Q-1a,
respectively, which were found to have the same configuration (1S
vs 1S) at the tertiary stereocenter but opposite configuration (3S vs
3R) at the quaternary stereocenter. The stereochemical outcome of
the asymmetric tandem reaction catalyzed by Q-2c could be
rationalized by a proposed transition-state model (Table 1), in which
the putative enolic Michael donor approaches the Michael acceptor
with its si face.6
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10.1021/ja0670409 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction Scopea
Table 3. Asymmetric Michael Addition of 3 to Acrylonitrile 6a
entry
donor
yield/%
ee/%
entry
donor
yield/%
ee/%
1
2
3
4
5
6
3a
3b
3e
3f
3g
3h
100
92
95(93)
84(87)
96(96)
89(82)
93b
94
89(90)
88(90)
88(89)
89(89)
7
8
3i
3j
3j
3k
3l
92
85
97
89
80
82
90
90
87
89
93b
91
9c
10
11
12
3m
a
b
See SI for experimental details. For absolute configuration deter-
c
mination, see SI for details. This reaction was run at 50 °C.
enantioselective and diastereoselective tandem reactions but also
could be manipulated to achieve diastereoselective control in such
reactions, thereby allowing catalyst-controlled, direct and stereo-
selective construction of two nonadjacent stereocenters in any of
the possible configurations from simple precursors.
a See SI for experimental details. b For absolute configuration determi-
nation, see SI for details. c This reaction was run at -20 °C.
Under the optimized conditions the 2c-catalyzed reactions with
a variety of cyclic R-substituted cyanoketones 3a-d and acyclic
R-substituted cyanoesters 3e-m proceeded in high diastereoselec-
tivity (9-25:1 dr), enantioselectivity (94-99% ee), and excellent
yield (94-100%) (Table 2). Moreover, quinine(Q)- and quinidine-
(QD)-derived 2c afforded similarly high stereoselectivities and
yields (entries 1-5, 7, 9, 11, 13-14, Table 2). Thus, with the
complementary diastereoselectivities afforded by 1 and 2c, respec-
tively, for reactions with a variety of Michael donors (3a-d, 3e,
3h, 3l),7 the asymmetric tandem conjugate addition-protonation
allowed the stereoselective construction of the 1,3-tertiary-
quaternary stereocenters in any of the possible configurations from
the same starting materials.7 To our knowledge, these results
constitute the first example of such a complete stereocontrol for a
catalytic asymmetric transformation creating nonadjacent stereo-
centers. Such catalyst-controlled constructions of 1,3-tertiary-
quaternary centers have been applied by us to accomplish the
asymmetric total syntheses of manzacidins A4 and C8 via a common
sequence of reactions.
Acknowledgment. We are grateful for the generous financial
support from the National Institutes of Health (GM-61591).
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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conjugate addition with R-chloroacrylonitrile 4 prompted us to ex-
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with acrylonitrile 6. In spite of its obvious synthetic value, no highly
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