Stephan J Zuend1, Eric N Jacobsen. 1. Harvard University, Department of Chemistry & Chemical Biology, Cambridge, Massachusetts 02138, USA.
Abstract
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.
An experimental and computational investigation of n class="Chemical">amido-thiourean> 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.
Authors: David D Ford; Lars P C Nielsen; Stephan J Zuend; Charles B Musgrave; Eric N Jacobsen Journal: J Am Chem Soc Date: 2013-10-07 Impact factor: 15.419