In this communication, we report an asymmetric Friedel-Crafts reaction of indoles with imines catalyzed by a bifunctional cinchona alkaloid catalyst. This is the first efficient organocatalytic asymmetric Friedel-Crafts reaction of indoles with imines. This reaction is operationally simple and, unprecedentedly, affords high enantioselectivity for a wide range of indoles and both aryl and alkyl imines. This establishes a direct, convergent, and versatile approach to optically active 3-indolyl methanamines, a structural motif embedded in numerous indole alkaloids and synthetic indole derivatives.

The development of broadly applicable and practical catalytic approaches for the enantioselective creation of quaternary stereocenters remains a highly desirable yet challenging goal. In this Communication, we describe a highly enantioselective cyanosilylation of acetal ketones (alpha,alpha-dialkoxy ketones) catalyzed by modified cinchona alkaloids. This reaction is the first highly enantioselective cyanosilylation of ketones catalyzed by an organic chiral Lewis base and is found to be highly efficient with acetal ketones bearing a broad range of alkyl, aryl, alkenyl, and alkynyl substituents. This new catalytic asymmetric reaction, coupled with the versatility of the acetal functionality, provides a broadly useful synthetic method for chiral building blocks bearing quaternary stereocenters. Acetal ketones, readily accessible but previously unexplored in asymmetric synthesis, demonstrate unusual reactivity and selectivity toward the nucleophilic cyanosilylation, thereby suggesting that they may be interesting substrates for other catalytic enantioselective reactions.

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The aldehyde is arguably the most versatile carbonyl functionality. Furthermore, it is more active than any other carbonyl functionality toward a plethora of nucleophilic reactions. This unique combination of functional versatility and activity renders chiral aldehydes highly valuable intermediates in asymmetric synthesis. The emergence of numerous catalytic enantioselective reactions that involve aldehydes as either nucleophiles or electrophiles further enhances the synthetic value of chiral aldehydes. Enantioselective transformations of the readily available prochiral aldehydes are now emerging as a fundamentally important approach toward optically active aldehydes. In particular, great strides have been made in the development of enantioselective bond formations with the a-carbon atom of prochiral aldehydes with chiral enamine catalysis, [1,2] enantioselective cycloadditions and Friedel-Crafts reactions with chiral immonium catalysis, [3] and conjugate additions of aryl boronic acids and silyl nitronates to a,b-unsaturated aldehydes by chiral transition-metal catalysis [4] and chiral phase-transfer catalysts, [5] respectively. Despite its synthetic importance, the highly enantioselective and general conjugate addition of carbonyl donors to a,b-unsaturated aldehydes remains elusive, even with considerable efforts. [6][7][8] Herein, we wish to report significant progress toward the development of such a reaction with cinchona-alkaloid-derived organic catalysts.At the outset of our investigations, we were concerned that the decomposition of 3 a could be triggered by cinchona alkaloids as nucleophilic catalysts (Scheme 1) in light of the well-documented nucleophilic catalysis of 1,4-diazabicyclo-[2.2.2]octane (DABCO) and quinuclidine in the MoritaBaylis-Hillman (MBH) reaction.[9] Indeed, 3 a was found to rapidly undergo decomposition to form insoluble oligomers or polymers in the presence of DABCO, quinuclidine, or bisocupreidine. On the other hand, mechanistic studies by us established that cinchona alkaloids, such as dihydroquinidine