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

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posted on 23.07.2018 by Tiffany Piou, Fedor Romanov-Michailidis, Melissa A. Ashley, Maria Romanova-Michaelides, Tomislav Rovis
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.