Combined Enzyme- and Transition Metal-Catalyzed Strategy for the Enantioselective Syntheses of Nitrogen Heterocycles: (−)-Coniine, DAB-1, and Nectrisine

Abstract

The enantioselective syntheses of (−)-coniine, DAB-1, and nectrisine have been developed, utilizing a complementary strategy of enzyme- and transition metal-catalyzed reactions. The initial stereocenter was set with >99% enantioselectivity via an enzyme-catalyzed hydrocyanation reaction. Substrate incompatibilities with the natural enzyme were overcome by tactical utilization of ruthenium-catalyzed olefin metathesis to functionalize an enzyme-derived (R)-allylic fragment. The piperidine and pyrrolidine alkaloid natural products were obtained by a route that leveraged regio- and stereoselective palladium-catalyzed 1,3-substitutive reactions.

Chemical insights into the synthetic chemistry of five-membered saturated heterocycles—a transition metal–catalyzed approach

“…The substituent methyl at position four of cyclohexamines delivered good to excellent yield (trans: 77%, cis: 91%) ( Scheme 4A ). Deardorff et al, 2020 reported the enantioselective synthesis of the N-containing natural product DAB 36 through an alkene cross-metathesis reaction catalyzed using a combined enzyme and transition metal strategy ( Deardorff et al, 2020 ). The incompatibilities of the substrates with oxynitrilase were overcome via the utilization of a palladium-catalyzed olefine metathesis to functionalize an enzyme-derived (R) allylic fragment ( Scheme 4B ).…”