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

Abstract

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 parameter of the Cp ligand on rhodium.

Rhodium(III) Complex with a Bulky Cyclopentadienyl Ligand as a Catalyst for Regioselective Synthesis of Dihydroisoquinolones through C−H Activation of Arylhydroxamic Acids

“…This methodology is particularly useful for directed search for drugs candidates and other biologically active molecules . However, the control of chemo‐ and regioselectivity of the CH‐activation reactions is often challenging . For example, the reaction of O ‐pivaloyl derivative of phenylhydroxamic acid 1 with terminal alkenes 2 in the presence of rhodium catalyst can give two isomeric dihydroisoquinolones 3 and 4 (Scheme ).…”

“…[2,3] However,t he control of chemo-and regioselectivityo ft he CH-activationr eactions is often challenging. [4][5][6][7][8] For example, the reaction of Opivaloyl derivativeo fp henylhydroxamic acid 1 with terminal alkenes 2 in the presence of rhodiumcatalyst can give two isomeric dihydroisoquinolones 3 and 4 (Scheme 1). The classical catalyst[ (C 5 Me 5 )RhCl 2 ] 2 selectively provides3 -substituted products 3 only if styrenes, acrylic esters, [9,10] dimethylallylamine, or acrolein diethylacetal [3] are used as alkenes.…”

Rhodium(III)‐Catalyzed Enantio‐ and Diastereoselective C−H Cyclopropylation of N‐Phenoxylsulfonamides: Combined Experimental and Computational Studies

“…In particular, the 1,1-dimethylcyclopropane motif as ap rivileged structural unit has frequently appeared in FDA-approved drugs,s uch as boceprevir and cilastatin (Figure 1). [4c] Therefore,the development of efficient synthetic methods for rapid construction of the highly valuable cyclopropane core is an important research objective.C onsequently,n otable synthetic progress has been made, [6][7][8][9][10] including classical metal-catalyzed decomposition of diazoalkanes, [6] Simmons-Smith type cyclopropanations, [7] Michael addition initiated ring closure, [8] and enzymatic synthesis. [9] Cyclopropenes [11] are versatile and reactive electrophilic cyclopropylating reagents owing to ring strain (approximately 54 kcal mol À1 ).…”

Sustainable Knowledge‐Driven Approaches in Transition‐Metal‐Catalyzed Transformations

“…More recently, Rovis et al. performed a multivariate analysis to control the diastereoselectity of Rh III ‐catalyzed cyclopropanation of alkenes with N ‐enoxyphthalimides . Using ethyl acrylate as a coupling partner, they first evaluated the influence of 15 Cp x ‐ligated Rh III complexes and 8 N ‐enoxyphthalimide derivatives on the diastereoselectivity of a model cyclopropanation reaction (Scheme a).…”

“…More recently,R ovis et al performed am ultivariatea nalysis to controlt he diastereoselectity of Rh III -catalyzed cyclopropanation of alkenes with N-enoxyphthalimides. [22] Using ethyl acrylate as ac oupling partner,t hey first evaluated the influence of 15 Cp x -ligated Rh III complexes and 8 N-enoxyphthalimide derivatives on the diastereoselectivityo famodel cyclopropanation reaction( Scheme 16 a). Althought he trans-cyclopropane diastereomer was generallyf avored, sterically demanding Cp x ligands and electron-deficient phthalimide combinationss howed the highest cis selectivities.…”