Application of Amide Reductive Alkynylation and Reductive Alkylation in the Rapid Synthesis of Schwarzinicines A~C and Ficusnotins B, F

Ficusnotins B and F, along with Schwarzinicines A～C, are 1,4-diarylbutanoids reported in recent years.Despite their simple structure, preliminary structure-activity relationship studies of Schwarzinicine A analogs for vasorelaxant activity have led to the discovery of four analogs of Schwarzinicine A with significant potency improvement and a simplified analogs with a similar pharmacological profile as Schwarzinicine A. The application of two reactions previously developed by Huang's group, reductive alkynylation and reductive alkylation of amides, in the synthesis of these five natural products is reported.A two-step synthesis of Schwarzinicines A and C was established through iridium-catalyzed hydrosilylation of secondary amides followed by in situ Grignard addition, yielding two alkaloids in overall yields of 74% and 75%, respectively.A "two-pot" synthesis of Schwarzinicine B was achieved using the iridium-copper relay-catalyzed reductive alkynylation of tertiary amide followed by tandem palladium-catalyzed hydrogenation, resulting in the formation of the alkaloid with an overall yield of 79%.By applying the latter method, a three-step synthesis of Ficusnotins B and F was developed with overall yields of 75% and 68%, respectively.Using iridium-copper and organocatalyst relay/synergistic catalysis, a two-step catalytic asymmetric synthesis of Schwarzinicines A～C was preliminarily developed.Although the enantioselectivities were only 2.4∶1, 2∶1, and 2.4∶1, respectively, the enantiomerically enriched products thus obtained allowed a tentative assign of the previously unknown absolute configurations of Schwarzinicines A～C.