Total Synthesis of Punctaporonin C by a Regio- and Stereoselective [2+2]-Photocycloaddition

The unique sesquiterpene punctaporonin C was synthesized starting from commercially available 7‐tert‐butoxynorbornadiene in a linear sequence of 29 steps and with an overall yield of 0.65 %. Key step of the synthesis was an intramolecular [2+2]‐photocycloaddition, in which the two vinylic double bonds in a 1,3‐divinyl‐2‐cyclopentyl tetronate were differentiated by reaction with the photoexcited tetronate. The reaction gave regio‐ and diastereoselective access to the tricyclic core skeleton of punctaporonin C in 63 % yield. Additional studies related to the tetronate [2+2]‐photocycloaddition revealed that even diastereotopic vinylic double bonds in a 1,3‐divinyl‐2‐cyclopentyl tetronate can be differentiated (d.r. up to 78:22). In the further course of the total synthesis the complete tetracyclic oxatetracyclo[6.3.2.01, 4.05, 12]tridecane skeleton of punctaporonin C was established by an intramolecular aldol reaction, closing a seven‐membered oxepane ring. The nucleophilic methyl ketone employed in this step was generated by Wacker oxidation of the vinylic double bond, which was not involved in the [2+2]‐photocycloaddition. Several reactions employed in the synthetic sequence required adaptation to the rigid skeleton of punctaporonin C, for example, the reduction of a mesylate, the alkylation of a cyclobutane carboxylate, or the methyl addition to a prostereogenic carbonyl group. Both vinyl groups of tetronate 2 were incorporated into the structure of the unusual sesquiterpene natural product punctaporonin C (1). One double bond was involved in a regio‐ and diastereoselective tetronate [2+2]‐photocycloaddition, the other double bond served as precursor for a methyl ketone, which underwent aldol ring‐closure to the bridging oxepane.