As an organic molecule with hydrogen-bond donor capability, thiourea-based organocatalyst evolved as an efficient class due to its unique characteristic of dual hydrogen-bonding donor. A number of research groups have proven that catalysts with bifunctional moieties could promote asymmetric transformations more efficiently. The concept of bifunctionality was realized when a Lewis basic functional group was introduced into the catalyst along with hydrogen-bond donors (Figure 1), which work synergistically to achieve the activation of both nucleophile and electrophile in a catalytic asymmetric reaction.

Regarding the significance of the double hydrogen-bonding interactions between thiourea motif and substrate in amine-thiourea catalyzed enantioselective transformations, we envisaged that amine-thiourea catalysts bearing multiple hydrogen-bonding donors could facilitate the formation of additional hydrogen bonds,11 and thus remarkably improve their catalytic activity (Figure 2).

The attractive features of the newly designed fine-tunable amine-thiourea catalysts include: 1) multiple hydrogen-bonding donors and up to four stereogenic centers, 2) enhanced adjustability of the electronic effect and steric effect, and 3) commercial availability of enantioenriched diamines and amino alcohols. The bifunctional amine-thiourea catalysts I and II (Figure 3) showed excellent performances in the catalytic asymmetric Michael addition, nitro-Mannich reaction, and amination reaction, resulting in high stereoselectivity with broad substrate scope. Furthermore, we developed the catalytic enantioselective sulfa-Michael addition of thiols to (Z)-ethyl 4,4,4-trifluorocrotonate, (E)-4,4,4-trifluorocrotonoylpyrazole, (E)-3,3,3-trifluoropropenyl phenyl sulfone, spiro cyclohexadienone oxindoles, and a,b-unsaturated hexafluoroisopropyl esters. The synthetic applications of these new protocols were demonstrated by the concise synthesis of the key intermediate of the potent inhibitor of MMP-3 (stromelysin-1), and (R)-thiazesim, an antidepressant agent.