Studies Toward the Synthesis of Salvinorin A and Synthesis of Broad-Spectrum DENV/WNV NS3 Protease Inhibitors

Part I: Salvinorin A is the main active component of the plant Salvia divinorum. Salvia divinorum is native to the Mazatec region in Northern Oaxaca, Mexico. It has been used by local Mazatec Indians for its hallucinogenic properties in ritual divination and healing ceremonies. It is the first non-alkaloid hallucinogen and the first that is not an agonist of the 5-HT2A receptor. It is a potent, selective agonist of the Kappa opioid receptor (KOR). The aim of our current research is to complete the total synthesis of Salvinorin A, then to synthesize novel analogs not attainable by semi-synthetic methods. The region of the molecule we wish to focus on is the furan ring. Our routes to Salvinorin A were designed to allow for changes to be made to the section of the molecule where the furan is ring late in the synthesis. Part II: West-Nile Virus (WNV) and Dengue Virus (DENV), both members of the Flavivirirus genus, are transmitted to humans by mosquito vectors and are significant causes of human illness worldwide. The majority of people infected with either virus remain asymptomatic, however some of those infected will develop critical and life-threatening diseases West Nile encephalitis or Dengue hemorrhagic fever. As members of the same genus, they share many important biological features including a highly homologous NS3 protease. NS3 is essential for virion replication, making it an ideal target for a broad-spectrum inhibitor of the related viral proteases.