Catalytic, Asymmetric Michael-Aldol Annulations via a Stereodivergent/Stereoconvergent Path Operating under Curtin-Hammett Control

A bifunctional iminophosphorane (BIMP)-catalyzedmethodfor thesynthesis of densely functionalized cyclohexanols establishes fivecontiguous stereocenters (diastereoselection up to >20:1, enantioselectivityup to >99:1) in a Michael/aldol domino reaction between trisubstitutedelectrophilic alkenes and gamma-nitroketones. Mechanistic studiessuggest a scenario in which stereoconvergency is achieved by kineticallycontrolled cyclization after the initial diastereodivergent Michaeladdition. Diastereoconvergency during cyclization is shown to resultfrom Curtin-Hammett kinetics, a finding that contrasts thecrystallization-driven stereoconvergency previously reported in similarsystems. Despite the change in the stereocontrol mechanism, the operationalattributes remain attractive, with the crystalline products typicallyisolated in analytically pure form upon filtration of the reactionmixture.

Automated summary

A bifunctional iminophosphorane (BIMP)-catalyzed method was developed for the synthesis of densely functionalized cyclohexanols via a Michael/aldol domino reaction. The reaction establishes five contiguous stereocenters with high diastereoselection and enantioselectivity. Mechanistic studies revealed the achievement of stereoconvergency through kinetically controlled cyclization after initial diastereodivergent Michael addition. The findings contrast the previously reported crystallization-driven stereoconvergency in similar systems, but the operational attributes remain attractive.