Double Activation Catalysis for α′-Alkylidene Cyclic Enones with Chiral Amines and Thiols

5 years ago

Double Activation Catalysis for α′-Alkylidene Cyclic Enones with Chiral Amines and Thiols

Zhi Zhou, Ying-Chun Chen, Wei Xiao, Wei Du, Qin Ouyang, Zhou-Xiang Wang

Cooperative catalysis has contributed greatly to the progress of asymmetric synthesis. However, double-activation catalysis has been less explored, especially for covalently tethered species. Here, we present a double-activation strategy for α′-alkylidene cyclic enone substrates that uses a chiral primary amine and 2-mercaptobenzoic acid to promote regio- and chemoselective addition to generate the complex interrupted iminium ion species. Significantly enhanced reactivity and enantioselectivity were observed for β-regioselective Michael addition and Friedel–Crafts alkylation with malononitriles and indoles, respectively, which produced a spectrum of chiral cyclic adducts with an exo-alkylidene group. Moreover, a HRMS study detected a few key covalently tethered intermediates among the substrates and catalysts, which helped elucidate the catalytic mechanism. Double activation: Complex iminium ion species were generated regio- and chemoselectively from α′-alkylidene cyclic enones, a chiral primary amine, and 2-mercaptobenzoic acid, which led to significantly enhanced reactivity and enantioselectivity in subsequent β-regioselective Michael addition with malononitriles and Friedel–Crafts alkylations with indoles (see scheme).

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201702183