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 (+)‐β‐caryophyllene, (−)‐raikovenal, (−)‐1β,9αH‐5‐linoleoyloxy‐4,5‐secocaryophyllen‐4‐one, and (−)‐rumphellanones A−C. A sequential enantioselective reduction/trapping/cross‐coupling reaction of cyclobutenones furnished an array of chiral trans‐2,3‐disubstituted‐4,4‐disubstituted cyclobutanones. The developed strategy was applied in the syntheses of several gem‐dimethylcyclobutane‐containing natural products, including (+)‐β‐caryophyllene, (−)‐rumphellanones A−C, (−)‐1β,9αH‐5‐linoleoyloxy‐4,5‐secocaryophyllen‐4‐one, and (−)‐raikovenal.