Stereoretentive Formation of Cyclobutanes from Pyrrolidines: Lessons Learned from DFT Studies of the Reaction Mechanism

The stereoselective synthesis of cyclobutanes that possess an array of stereocenters in a contiguous fashion has attracted the wide interest of the synthetic community. Cyclo-butanes can be generated from the contraction of pyrrolidines through the formation of 1,4-biradical intermediates. Little else is known about the reaction mechanism of this reaction. Here, we unveil the mechanism for this stereospecific synthesis of cyclo-butanes by means of density functional theory (DFT) calculations. The rate-determining step of this transformation corresponds to the release of N2 from the 1,1-diazene intermediate to form an open-shell singlet 1,4-biradical. The formation of the stereo-retentive product is explained by the barrierless collapse of this open-shell singlet 1,4-biradical. The knowledge of the reaction mechanism is used to predict that the methodology could be amenable to the synthesis of [2]-ladderanes and bicyclic cyclobutanes.

Automated summary

The mechanism for the stereospecific synthesis of cyclobutanes is revealed using density functional theory (DFT) calculations. The rate-determining step involves the release of N2 from the 1,1-diazene intermediate to form an open-shell singlet 1,4-biradical. The formation of the stereo-retentive product is explained by the barrierless collapse of this open-shell singlet 1,4-biradical. The methodology could potentially be used for the synthesis of [2]-ladderanes and bicyclic cyclobutanes.