Stereodivergent Rhodium(III)-Catalyzed cis-Cyclopropanation Enabled by Multivariate Optimization

The design of stereodivergent transformations is of great interest to the synthetic community as it allows funneling of a given reaction pathway toward one stereochemical outcome or another by only minor adjustments of the reaction setup. Herein, we present a physical organic approach to invert the sense of induction in diastereoselective cyclopropanation of alkenes with N -enoxyphthalimides through rhodium(III) catalysis. Careful parametrization of catalyst–substrate molecular determinants allowed us to interrogate linear-free energy relationships and establish an intuitive and robust statistical model that correlates an extensive number of data points in high accuracy. Our multivariate correlations-steered mechanistic investigation culminated with a robust and general diastereodivergent cyclopropanation tool where the switch from trans - to cis -diastereoinduction is attributed to a mechanistic dichotomy. Selectivity might be determined by the flexibility of rhodacyclic intermediates derived from ring-opened versus -unopened phthalimides, induced by both their respective ring size and the Sterimol B 1 parameter of the Cp X ligand on rhodium.