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
posted on 2020-09-18, 16:35authored bySteven
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.