Rhodium-catalyzed enantioselective and diastereodivergent access to diaxially chiral heterocycles

N-N axially chiral biaryls represent a rarely explored class of atropisomers. Reported herein is construction of diverse classes of diaxially chiral biaryls containing N-N and C-N/C-C diaxes in distal positions in excellent enantioselectivity and diastereoselectivity. The N-N chiral axis in the products provides a handle toward solvent-driven diastereodivergence, as has been realized in the coupling of a large scope of benzamides and sterically hindered alkynes, affording diaxes in complementary diastereoselectivity. The diastereodivergence has been elucidated by computational studies which revealed that the hexafluoroisopropanol (HFIP) solvent molecule participated in an unusual manner as a solvent as well as a ligand and switched the sequence of two competing elementary steps, resulting in switch of the stereoselectivity of the alkyne insertion and inversion of the configuration of the C-C axis. Further cleavage of the N-directing group in the diaxial chiral products transforms the diastereodivergence to enantiodivergence. Molecules with axial chirality are of intense focus to the synthetic organic community, but the axes most commonly explored are carbon-carbon and carbon-heteroatom. Here the authors report the syntheses of diaxially chiral biaryls containing N-N and C-N/C-C axes, achieved via rhodium catalysis.

Automated summary

Here, the authors report the construction of diverse classes of diaxially chiral biaryls containing N-N and C-N/C-C diaxes in excellent stereo- and diastereoselectivity. The N-N chiral axis in the products allows for solvent-driven diastereodivergence, as demonstrated in the coupling of benzamides and sterically hindered alkynes. The mechanism of diastereodivergence is elucidated through computational studies, revealing the role of hexafluoroisopropanol (HFIP) as a solvent and ligand.