Catalytic Asymmetric Addition of Allyl Cyanide to Ketones
A R T I C L E S
Scheme 1. Catalytic Asymmetric Addition to Ketones with (a)
Reactive Organometallic Reagents and (b) Pronucleophiles
Activated in Situ
Figure 1. Chemoselective activation of allylic cyanides with a soft Lewis
acid/hard Brønsted base catalyst.
use of a soft Lewis acid and a hard Brønsted base to achieve
chemoselective activation/deprotonation of a soft Lewis basic
pronucleophile under mild conditions (Figure 1). Particular focus
was placed on allylic cyanides as potential pronucleophiles for
this purpose because (1) the minimal steric bias of the nitrile
group is beneficial for the highly congested transition state
anticipated for the reaction with ketones; (2) the soft Lewis basic
character of the nitrile functionality allows for chemoselective
activation in the presence of a soft Lewis acid; and (3) the
adjacent vinyl group enhances the acidity of the R-hydrogen of
the nitrile to facilitate deprotonation under mild basic conditions
and serves as a useful handle for further elaboration of the
reaction products.15-19 On the basis of this hypothesis, we
developed a chiral soft Lewis acid/hard Brønsted base catalytic
system consisting of [Cu(CH3CN)4]ClO4/(R,R)-Ph-BPE/LiOAr
that enables direct catalytic asymmetric γ-addition of allyl
cyanide (1a) to ketones,20 producing a tetrasubstituted stereo-
genic center bearing a Z-configured olefin via proton-transfer
conditions in conjunction with C-C bond formation (Scheme
significantly decreases the overall reaction efficiency (Scheme
1a). Catalytic generation of a nucleophile by simple deproto-
nation that is sufficiently active to attack ketones without the
retro-reaction is the key to overcoming the above-mentioned
drawback (Scheme 1b).11-13 Until recently, HCN has been the
only pronucleophile that meets the criteria,14 likely because the
generation of highly active nucleophiles by deprotonation
requires harsh Brønsted basic conditions, which compromise
the catalytic turnover and induce undesirable side reactions. In
this context, we directed our attention toward the cooperative
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Aldrichimica Acta 2004, 37, 3. KOtBu catalyst: (g) Bunlaksananusorn,
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see ref 6d)CpRu(CH3CN)3PF6/DBU/NaPF6 catalyst: (i) Kumagai, N.;
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(20) (a) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009,
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130, 14477.
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