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 B1 parameter of the CpX ligand on rhodium.