Cooperative catalysis by tertiary amino-thioureas: mechanism and basis for enantioselectivity of ketone cyanosilylation.
The mechanism of the enantioselective cyanosilylation of ketones catalyzed by tertiary amino-thiourea derivatives was investigated using a combination of experimental and theoretical methods. The kinetic analysis is consistent with a cooperative mechanism in which both the thiourea and the tertiary amine of the catalyst are involved productively in the rate-limiting cyanide addition step. Density functional theory calculations were used to distinguish between mechanisms involving thiourea activation of ketone or of cyanide in the enantioselectivity-determining step. The strong correlation obtained between experimental and calculated ee's for a range of substrates and catalysts provides support for the most favorable calculated transition structures involving amine-bound HCN adding to thiourea-bound ketone. The calculations suggest that enantioselectivity arises from direct interactions between the ketone substrate and the amino-acid derived portion of the catalyst. On the basis of this insight, more enantioselective catalysts with broader substrate scope were prepared and evaluated experimentally.
Zuend
Stephan J
SJ
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Jacobsen
Eric N
EN
D002384:Catalysis; D003486:Cyanides / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D007700:Kinetics; D019158:N-Acetylneuraminic Acid / Q000737:chemistry*; D013057:Spectrum Analysis; D013237:Stereoisomerism; D013890:Thiourea / Q000737:chemistry*
D003486:Cyanides; D007659:Ketones; D013890:Thiourea; D019158:N-Acetylneuraminic Acid