BCSJ : Vol. 81 (2008) , No. 7 pp.785-795

Discovery and Application of Asymmetric Reaction by Multi-Functional Thioureas

Hideto Miyabe¹⁾²⁾ and Yoshiji Takemoto¹⁾

1) Graduate School of Pharmaceutical Sciences, Kyoto University
2) School of Pharmacy, Hyogo University of Health Sciences

(Received March 5, 2008)

Novel bifunctional organocatalysts, which possess a thiourea moiety and an amino group, were designed and synthesized. We discovered that bifunctional thiourea bearing a tertiary amino group significantly accelerated several nucleophilic addition reactions of active methylene compounds to electron-deficient double bonds. In these reactions, the double hydrogen-bonding activation of electrophiles bearing nitro, imide, and carbamate groups by the thiourea moiety and simultaneous deprotonation of nucleophiles by the dimethylamino group of bifunctional thiourea proved to play a crucial role for enhancing both reaction rate and enantioselectivity. We have demonstrated the utility of PEG-bound thiourea as a homogeneous catalyst. Although the reaction rate was somewhat decreased with PEG-bound thiourea, immobilization to a PEG support proved to facilitate the recovery and reuse of thiourea catalyst without affecting the chemical yield and enantioselectivity. A newly designed thiourea catalyst provided sufficient activation of organoboronic acids to facilitate the enantioselective Petasis transformation of quinolines even at low temperatures. A high degree of stereocontrol was achieved in the reaction of various quinolines and organoboronic acids by using a combination of H₂O and NaHCO₃ as additives.

Bifunctional thiourea catalysts were designed and synthesized. Catalyst having an amino group accelerated several nucleophilic additions of active methylene compounds and catalyst having a chelating functionality provided sufficient activation of organoboronic acids to facilitate the Petasis transformation of quinolines.