Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: transition state stabilization via multiple non-covalent interactions.
An experimental and computational investigation of amido-thiourea promoted imine hydrocyanation has revealed a new and unexpected mechanism of catalysis. Rather than direct activation of the imine by the thiourea, as had been proposed previously in related systems, the data are consistent with a mechanism involving catalyst-promoted proton transfer from hydrogen isocyanide to imine to generate diastereomeric iminium/cyanide ion pairs that are bound to catalyst through multiple noncovalent interactions; these ion pairs collapse to form the enantiomeric alpha-aminonitrile products. This mechanistic proposal is supported by the observation of a statistically significant correlation between experimental and calculated enantioselectivities induced by eight different catalysts (P << 0.01). The computed models reveal a basis for enantioselectivity that involves multiple stabilizing and destabilizing interactions between substrate and catalyst, including thiourea-cyanide and amide-iminium interactions.
Harvard University, Department of Chemistry & Chemical Biology, Cambridge, Massachusetts 02138, USA.
Stephan J
SJ
Zuend
Eric N
EN
Jacobsen
D000588:Amines / Q000737:chemistry*; D002384:Catalysis; D006860:Hydrogen Bonding; D006856:Hydrogen Cyanide / Q000737:chemistry*; D007097:Imines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013890:Thiourea / Q000737:chemistry*
D000588:Amines; D007097:Imines; D006856:Hydrogen Cyanide; D013890:Thiourea