Clarifying Stereochemical Outcomes in Radical-Initiated Vinyl Cyclopropane Cycloadditions within the Beckwith-Houk Framework

Abstract

The (3+2) cycloaddition reaction is a widely utilized strategy in organic synthesis for constructing cyclopentane frameworks, a structural motif prevalent in many bioactive compounds and pharmaceutical applications. Over the past decades, numerous catalytic radical cascade reactions orchestrated by various types of open-shell catalysts have been reported. However, discrepancies in the relative configurations of cyclopentanes obtained using closely related methodologies suggest that some stereochemical misassignments may have occurred. In this work, discrepancies in some of the originally assigned trans configurations were uncovered through detailed stereochemical analyses employing Density Functional Theory (DFT) calculations of chemical shifts and coupling constants combined with 1D quantitative Nuclear Overhauser Effect (qNOE) NMR experiments. Notably, DFT predictions or the detection of NOESY correlations alone were insufficient in confidently assigning the relative configuration, accentuating the integration of experimental qNOE data with computational methods for accurate structural assignments. The data provided here demonstrates a general and robust approach for configurational verification of complex organic molecules with broader applicability beyond the radical (3+2) cycloaddition products discussed here.