Enantioselective Hydrofunctionalization of Cyclobutenones: Total Synthesis of gem-Dimethylcyclobutane Natural Products

Cyclobutanes with a gem-dimethyl group are common motifs in natural products. However, strategies for constructing enantioenriched gem-dimethyl cyclobutanes are still underdeveloped. Herein, we report an enantioselective approach to synthesize a broad group of chiral 2,3-disubstituted cyclobutanones through sequential 1,4-conjugate addition/trapping/cross-coupling of readily available cyclobutenones. The intermediate 2-bromocyclobutanone provides a valuable synthetic handle for further coupling transformations. In addition, this strategy was successfully utilized to synthesize gem-dimethyl cyclobutane-containing natural products, including (+)-beta-caryophyllene, (-)-raikovenal, (-)-1 beta,9 alpha H-5-linoleoyloxy-4,5-secocaryophyllen-4-one, and (-)-rumphellanones A-C.