American Chemical Society
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Difunctional­ization of C–C σ‑Bonds Enabled by the Reaction of Bicyclo[1.1.0]butyl Boronate Complexes with Electrophiles: Reaction Development, Scope, and Stereochemical Origins

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posted on 2020-09-18, 16:35 authored by Steven H. Bennett, Alexander Fawcett, Elliott H. Denton, Tobias Biberger, Valerio Fasano, Nils Winter, Varinder K. Aggarwal
Difunctional­ization reactions of C–C σ-bonds have the potential to streamline access to molecules that would otherwise be difficult to prepare. However, the development of such reactions is challenging because C–C σ-bonds are typically unreactive. Exploiting the high ring-strain energy of polycyclic carbo­cycles is a common strategy to weaken and facilitate the reaction of C–C σ-bonds, but there are limited examples of highly strained C–C σ-bonds being used in difunctional­ization reactions. We demonstrate that highly strained bicyclo­[1.1.0]­butyl boronate complexes (strain energy ca. 65 kcal/mol), which were prepared by reacting boronic esters with bicyclo­[1.1.0]­butyl lithium, react with electro­philes to achieve the diastereo­selective difunctional­ization of the strained central C–C σ-bond of the bicyclo­[1.1.0]­butyl unit. The reaction shows broad substrate scope, with a range of different electro­philes and boronic esters being successfully employed to form a diverse set of 1,1,3-trisubstituted cyclo­butanes (>50 examples) with high diastereo­selectivity. The high diastereo­selectivity observed has been rationalized based on a combination of experimental data and DFT calculations, which suggests that separate concerted and stepwise reaction mechanisms are operating, depending upon the migrating substituent and electro­phile used.