Construction of the Carbon Skeleton of Salvinorin A

The Mexican sage, Salvia divinorum, has been used for many years by the Mazatec Indians of Oaxaca, Mexico for medicinal purposes and in religious divination ceremonies. Due to its hallucinogenic properties, S. divinorum has recently become the focus of recreational drug users across the globe; therefore, numerous laws have been established to limit the use and availability of this psychedelic mint. In 1982, Ortega reported the first isolation of the neoclerodane diterpenoid, salvinorin A, from S. divinorum followed by a subsequent isolation by the Valdes group two years later. It has been determined that salvinorin A is responsible for the hallucinogenic effects experienced after either ingesting the leaves or inhaling the smoke of S. divinorum. Interestingly, salvinorin A has remained the only known non-nitrogenous hallucinogen as well as the first potent diterpenoid kappa-opioid receptor agonist. Its potential role in therapeutics has led to its worldwide recognition and piqued the interest of both medicinal and synthetic chemists.;Herein is reported our current progress toward the total synthesis of salvinorin A. We have developed an efficient synthesis of the Diels-Alder precursor to the decalin core of salvinorin A. Obstacles encountered in the original intramolecular Diels-Alder (IMDA) cycloaddition established by Burns led to several IMDA studies, which culminated in the discovery of several stereoconvergent transformations. These results furnished additional access to the decalin core of the salvinorin A. Implemented in tandem, the IMDA/Tsuji allylation sequence turned out to be an exceptional and very stereospecific method for the installation of the two quaternary stereocenters contained in the core structure of salvinorin A. Bistriflate formation followed by a palladium-catalyzed methoxy carbonylation provided the functional handles necessary to construct the skeletal framework of the natural product. Present strategies focused on the completion of salvinorin A will also be discussed.;The second portion of this manuscript will chronicle the preparation and relative stereochemical elucidation of 5-hydroxy-4a-methylperhydro-1 H-benzo[7]annulen-2(3H)-ones. Enolization regioselectivity studies based on these compounds will also be reviewed.