Cyclobutane is one of the Csp3-rich building-block in the medicinal chemist toolbox that can be used as a phenyl bioisostere to try to escape flatland. Numerous methodologies have been developed over the years to access cyclobutanes. However, current methods to access 1,1,3-trisubstituted cyclobutanes with high diastereoselectivity remain limited.

Using the high strain energy of bicyclo[1.1.0]butanes, Aggarwal and his team developed an elegant access to diversely functionalized 1,1,3-trisubstituted cyclobutanes with high diastereoselectivity via the intermediacy of bicyclo[1.1.0]butylboronate complexes. These complexes are prepared by the reaction of boronic esters with known bicyclo[1.1.0]butyl lithium and then reacted in situ with a wide variety of electrophiles to yield the 1,1,3-trisubstituted cyclobutanes after cleavage of the central C-C s-bond. The resulting cyclobutyl boronic esters can be engaged in various transformations such as Suzuki couplings, oxidations or protodeborylation as exemplified by the authors.

After DFT calculations, the high diastereoselectivity observed has been rationalized by separate concerted and stepwise reaction mechanisms operating depending on the boronic ester and electrophile used.

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