Multigram Synthesis of Advanced 6,6-Difluorospiro[3.3]heptane-derived Building Blocks

A convenient methodology for constructing 6,6‐difluorospiro[3.3]heptane scaffold – a conformationally restricted isostere of gem ‐difluorocycloalkanes – is developed. Alarge array of novel 2‐mono‐ and 2,2‐bifunctionalized difluorospiro[3.3]heptane building blocks was obtained through the convergent synthesis strategy using a common synthetic precursor – 1,1‐bis(bromomethyl)‐3,3‐difluorocyclobutane. The target compounds and intermediates were prepared by short reaction sequences (6–10 steps) on multigram scale (up to 0.47 kg).