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 (+)-ß-caryophyllene, (-)-raikovenal, (-)-1ß,9αH-5-linoleoyloxy-4,5-secocaryophyllen-4-one, and (-)-rumphellanones A-C.

3-(Methoxycarbonyl)Cyclobutenone as a Reactive Dienophile in Enantioselective Diels-Alder Reactions Catalyzed by Chiral Oxazaborolidinium Ions.

Cyclobutenone has been used as a highly reactive dienophile in Diels-Alder reactions, however, no enantioselective example has been reported. We disclose herein a chiral oxazaborolidine-aluminum bromide catalyzed enantioselective Diels-Alder reaction of 3-alkoxycarbonyl cyclobutenone with a variety of dienes. Furthermore, a total synthesis of (-)-kingianin F was completed for the first time via enantioenriched cycloadduct bicyclo[4.2.0]octane derivative.

Enantioselective Synthesis of 3-Substituted Cyclobutenes by Catalytic Conjugate Addition/Trapping Strategies.

A copper-catalyzed tandem process to generate chiral cyclobutene derivatives has been developed. It is based on an enantioselective conjugate addition or reduction of a cyclobutenone and sequential trapping with a chlorophosphate in a one-pot process. These phosphates are stable under mildly acidic conditions and serve as good electrophiles in Negishi coupling reactions.

Enantioselective Desymmetrization of Cyclobutanones Enabled by Synergistic Palladium/Enamine Catalysis.

The enantioselective intramolecular α-arylation of cyclobutanones has been established by combining palladium and enamine catalyst systems. Two different enantioselective control strategies have been developed for cyclobutanone substrates bearing O- or N-tethered aryl bromides. Further synthetic applications are also reported.