Organocatalytic Asymmetric Construction Of Chiral Sulfur-Containing Compounds

Enantiomerically enriched sulfur-containing compounds are the core structural elements prevalent in natural products and biologically active molecules, and also have broad applications in many research areas of chemistry and biology. Therefore, considerable attention has been paid to developing catalytic asymmetric protocols for the synthesis of chiral sulfur compounds. Among the existing approaches, enantioselective addition of thiol nucleophiles to electrophilic acceptors is one of the most profound and reliable C-S bond-forming reactions in organic synthesis. Organocatalysis has proven to be one of the most rapidly developing and competitive research areas in asymmetric catalysis over the past decade. In order to develop novel methods for the construction of optically active sulfur-containing molecules, we designed several different types of organocatalytic asymmetric reactions, and my research work mainly contains the following three parts:1) We have reported the first highly efficient organocatalytic asymmetric addition of thiols to trifluoromethyl aldimine for the construction of chiral trifluoromethylated N,S-acetals in high yields (up to 99%) and excellent enantioselectivities (up to 95% ee) with 1 mol% of a bifunctional squaramide-based organocatalyst. Moreover, a plausible dual activation model accounting for the observed stereoselectivity of the addition reaction was proposed.2) We have successfully developed an effective and unprecedented DABCO-catalyzed [3+3] cycloaddition of 1,4-dithiane-2,5-diol with azomethine imines to afford highly functionalized six-membered dinitrogen-fused heterocycles in high yield (up to 96%) with excellent diastereoselectivity (>20:1 dr), which was controlled by anomeric effect. Furthermore, a possible stepwise sulfa-addition/intramolecular cyclization mechanism was proposed for the current [3+3] cycloaddition.3) We have described an asymmetric sulfa-Michael addition of thiols to a variety of ?,?-unsaturated hexafluoroisopropyl esters catalyzed by a bifunctional amine-thiourea bearing multiple hydrogen-bonding donors developed by our group for the first time. This organocatalytic system exhibited a broad substrate scope, high reactivity, and excellent enantioselectivity (90->99% ee). Introduction of an electron-withdrawing hexafluoroisopropyl ester moiety was revealed to be the key point in enhancing the electrophilicity of ?,?-unsaturated esters as Michael acceptors. In addition, the current methodology was successfully applied to the concise synthesis of (R)-Thiazesim in a one-pot protocol.