Stereoselective Synthesis of anti-2,4-Disubstituted Tetrahydrofurans via a Pd-Catalyzed Hayashi–Heck Arylation and Rh-Catalyzed Hydroformylation Sequence

Abstract

A catalytic, two-step protocol for the expedient synthesis of anti-2,4-disubstituted tetrahydrofurans is described. In the first step, an enantioselective and regioselective Pd-catalyzed Hayashi−Heck arylation was developed using (R)-hexaMeOBiphep to generate 5-aryl-2,3-dihydrofurans. A subsequent Rh-catalyzed hydroformylation step proceeds at low Rh loading with high regio-and diastereoselectivity for the anti-2,4-disubstituted tetrahydrofuran isomer. Key to the development of the hydroformylation reaction was the utilization of either (R)-Me-i-Pr-INDOLphos or (R,R)-Ph-BPE to control the regioselectivity and provide the kinetic product isomer.