Chemo-, Diastereo-, and Enantioselective Radical Cyclization of Enals to Access Cyclopentanols Bearing an α-Quaternary Center.

Controlling both chemo- and stereoselectivity in reactions of sterically demanding radicals remains a fundamental challenge in the construction of vicinal stereocenters, particularly those bearing an α-quaternary carbon center. Despite their synthetic value, asymmetric radical cyclization of bulky carbon-centered radicals onto enals to access α-quaternary cyclic alcohols remained undeveloped. Here we report a stereoconvergent asymmetric radical alkylation/cyclization cascade of enals with unactivated, sterically congested alkyl iodides, enabled by an earth-abundant chromium catalyst supported by a chiral bisoxazoline ligand. This method provides direct access to cyclopentanol and 2,3-dihydro-1H-inden-1-ol derivatives bearing an α-quaternary stereocenter in good yields with excellent diastereo- and enantioselectivities (>20:1 d.r., up to 99% ee). The reaction proceeds under mild conditions, exhibits broad functional-group tolerance, and completely suppresses the competing direct coupling of alkyl electrophiles with aldehydes. Experimental and DFT studies support a catalytic manifold in which a chiral Cr(II) complex mediates single-electron generation of alkyl radicals for addition to enals and controls the enantiodetermining outer-sphere cyclization of the resulting bulky tertiary radical onto the carbonyl group.