Enantioselective Cleavage of Cyclobutanols Through Ir-Catalyzed C-C Bond Activation: Mechanistic and Synthetic Aspects

The Ir-catalyzed conversion of prochiral tert-cyclobutanols to beta-methyl-substituted ketones proceeds under comparably mild conditions in toluene (45-110 degrees C) and is particularly suited for the enantioselective desymmetrization of beta-oxy-substituted substrates to give products with a quaternary chirality center with up to 95 % ee using DTBM-SegPhos as a chiral ligand. Deuteration experiments and kinetic isotope effect measurements revealed major mechanistic differences to related Rh-I-catalyzed transformations. Supported by DFT calculations we propose the initial formation of an Ir-III hydride intermediate, which then undergoes a beta-C elimination (C-C bond activation) prior to reductive C-H elimination. The computational model also allows the prediction of the stereochemical outcome. The Ir-catalyzed cyclobutanol cleavage is broadly applicable but fails for substrates bearing strongly coordinating groups. The method is of particular value for the stereo-controlled synthesis of substituted chromanes related to the tocopherols and other natural products.

Automated summary

The Ir-catalyzed conversion of prochiral tert-cyclobutanols to beta-methyl-substituted ketones in toluene under mild conditions is effective for the enantioselective desymmetrization of substrates, yielding products with quaternary chirality centers with high ee values. The mechanistic differences compared to related Rh-I-catalyzed transformations were revealed through deuterium experiments and kinetic isotope effect measurements. The computational model proposed the initial formation of an Ir-III hydride intermediate and its subsequent beta-C elimination, allowing prediction of the stereochemical outcome.