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Total Synthesis of Salvinorin A via an IMDA-Tsuji Allylation Strategy

Line, Nathan

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Chemistry.
Salvia divinorum, a Mexican sage, was used for hundreds of years by the Mazatec Indians for both medicinal and religious purposes. These hallucinogenic properties have caused a recent interest in the recreational drug world and therefore, resulted in a multitude of laws/restrictions banning Salvia from the United States as well as many other countries around the world. In 1982, Ortega reported the first isolation of the neoclerodane diterpenoid, salvinorin A, from Salvia divinorum. Valdes later confirmed this finding independently two years later. It was determined that salvinorin A was the compound responsible for the hallucinogenic effects experienced through ingestion or inhalation of Salvia. Interestingly, salvinorin A was and has remained the only nonalkaloid hallucinogen as well as the first highly potent and selective ¿-opioid receptor agonist. These properties have not only piqued the interest of synthetic chemists but also medicinal chemists towards its potential role as a therapeutic agent. Herein is a summary of my total synthesis of salvinorin A with the goals to innovate a flexible and reliable total synthesis of salvinorin A and analogs to pursue SAR studies. I have developed an efficient synthesis of the decalin core that overcame obstacles and scale-up issues in the routes established by previous members. Utilizing the linear dithiane Diels-Alder precursor, I was able to implement an intramolecular Diels-Alders (IMDA)/Tsuji allylation combination to stereoselectively install the decalin core with both quaternary centers. Bistriflate formation followed by a palladium-mediated methoxy carbonylation provided the functional group handles needed to construct the skeletal framework. The furan moiety was installed selectively using a BINOL-titanium catalyst with a furyltitanim nucleophile. Conjugate reduction of both the methyl ester and furyl-lactone functional groups using SmI2 followed by diol manipulation provided targeted natural product salvinorin A.
Craig Forsyth, Prof. (Advisor)
Anita Mattson, Prof. (Committee Member)
David Nagib, Prof. (Committee Member)
192 p.

Recommended Citations

Citations

  • Line, N. (2016). Total Synthesis of Salvinorin A via an IMDA-Tsuji Allylation Strategy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461161309

    APA Style (7th edition)

  • Line, Nathan. Total Synthesis of Salvinorin A via an IMDA-Tsuji Allylation Strategy. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1461161309.

    MLA Style (8th edition)

  • Line, Nathan. "Total Synthesis of Salvinorin A via an IMDA-Tsuji Allylation Strategy." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461161309

    Chicago Manual of Style (17th edition)