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

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.