Development of Amino Thiourea Catalysts as an Artificial Enzyme: Their Application to Catalytic Enantioselective Reactions

Abstract

Bifunctional thiourea-catalyzed asymmetric addition of several nucleophiles with nitrones, imines, and electron-deficient unsaturated compounds is described. These urea and thiourea catalysts were designed and synthesized based on the mechanism of hydrolytic enzymes. By taking advantage of the strong hydrogen-bonding ability of diaryl thioureas, several electrophiles such as nitrones and aldehydes were revealed to be activated in the reactions with TMSCN and ketene silyl acetals. In addition, we discovered that use of bifunctional thioureas bearing a tertiary amino group significantly expanded the applicability of the thiourea-catalyzed enantioselective nucleophilic addition by the simultaneous activation of both nucleophiles and electrophiles. These organocatalyzed asymmetric reactions were successfully applied to the concise asymmetric synthesis of natural products and medical supplies such as epibatidine, baclofen, and CP-99, 994.