Scalable Transannular Bromocyclization Approach to Function-alized Bis-Heterobicyclo[3.n.1]anes

Bicyclic, high fraction sp3 (Fsp3) building blocks have become prominent in drug discovery efforts due to the potential for improvement in physicochemical properties. As a result, methods to generate bicyclic rings have flourished in recent years, but there are limited robust and scalable approaches to access bicycles containing one or more heteroatoms. Such heterobicyclic compounds would be valuable to medicinal chemists due to the capability to engage in polar interactions, modulate physicochemical properties, and provide additional vectors for functionalization. Herein, we report a scalable, transannular bromocyclization route to prepare functionalized 2-oxa-4-azabicyclo[3.2.1]oct-3-ene and 2-oxa-4-azabicyclo[3.1.1]hept-3-ene scaffolds from readily accessible alkene building blocks. This method demonstrates broad functional group compatibility and introduces a bromide handle for further diversification of the core. X-ray crystal struc-tural analysis of these scaffolds illustrate the improved alignment of the exit vectors with those of meta-benzene and pyr-idine rings.