Model Synthetic Study of Tutin, a Picrotoxane-Type Sesquiterpene: Stereoselective Construction of a cis-Fused 5,6-Ring Skeleton.

Abstract

Picrotoxinin, coriamyrtin, and tutin are representative natural products classified as picrotoxane-type sesquiterpenes and they function as strong neurotoxins. Because they possess a cis-fused 5,6-ring skeleton with a highly congested functionalization, organic chemistry researchers have pursued the development of a stereoselective synthesis method for such skeleton. This study aims to stereoselectively synthesize the cis-fused 5,6-ring skeleton with two tetrasubstituted carbons at both angular positions using a model compound. The results revealed that the desymmetrization of the 2-methyl-1,3-cyclopentanedione moiety via the DL-proline-mediated intramolecular aldol reaction of a pentanal derivative bearing an isopropenyl group and the five-membered ring at the 3- and 5-position, respectively, provided the desired cis-fused skeleton. This reaction can construct four contiguous stereogenic centers of the bicyclic skeleton with the two angular positions in good yield with high stereoselectivity. Further, this reaction was applied to the kinetic resolution of the racemate using L-proline, providing the enantiomeric pure aldol product with the desired skeleton. This method can be utilized for total synthesis of picrotoxane-type sesquiterpenes.