Intramolecular Lithiation-Borylation for the Stereoselective Synthesis of Cyclopentyl and Cyclobutyl Bis-boronic Esters

Saturated carbocycles are common motifs in natural products and pharmaceuticals, and so methods for their construction, particularly with high diastereo- and enantiocontrol, are of high importance. Lithiation-borylation has emerged as powerful methodology for the stereocontrolled construction of acyclic carbon chains but has not previously been used for the stereocontrolled synthesis of carbocycles. Herein, we report that benzylic diethylcarbamates with a tethered vicinal bis-boronic ester moiety can be deprotonated with lithium amide bases, resulting in cyclization and 1,2-metallate rearrangement to give carbocycles. This intramolecular lithiation-borylation reaction is completely regioselective and, rather than being stereospecific like the acyclic variants, it is diastereoconvergent. The stereochemistry of the boronic ester is retained but the benzylic stereocenter undergoes epimerization, furnishing carbocycles with high diastereo- and enantiocontrol from easily accessible precursors. Site-selective transformations of the bis-boronic ester products are also demonstrated.