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
References
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with acrylonitrile 6. In spite of its obvious synthetic value, no highly
enantioselective catalytic conjugate addition to acrylonitrile (6) has
been reported. At least due partially to its weak activity as a Michael
acceptor, acrylonitrile (6) appears to be a particular challenging
Michael acceptor for catalytic asymmetric conjugate additions. For
example, although 1a is highly effective for asymmetric conjugate
additions with nitroalkenes,6b,9a R,â-unsaturated sulfones,9b ketones,9c
aldehydes,9d and R-chloroacrylonitrile,4 the addition of R-phenyl
R-cyanoacetate 3e to acrylonitrile (6) with QD-1a produced the
corresponding 1,4-adduct 7e in only 44% ee. Thus, we were delight-
ed to find that 2c was able to promote this challenging asymmetric
conjugate addition in drastically enhanced enantioselectivity (entry
3, Table 3). Furthermore the high efficiency by 2c could be extended
to a range of different Michael donors (Table 3). To our knowledge,
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In conclusion, with readily accessible bifunctional organic
catalysts, we developed an unprecedented highly enantioselective
catalytic conjugate addition with acrylonitrile and an asymmetric
tandem conjugate addition-protonation of high enantioselectivity
and a unique sense of diastereoselectivity. The development of the
latter demonstrates that hydrogen-bonding-based cooperative ca-
talysis not only is applicable to the development of highly
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