- Main
Strained Intermediates in Total Synthesis: Total Synthesis of 14- and 15-Hydroxypatchoulol and Synthetic Studies Toward Plumisclerin A
- Kang, Suh Hyun
- Advisor(s): Sarpong, Richmond
Abstract
Herein, I describe the development of a Pd-catalyzed C–C bond cleavage/vinylation/Mizoroki–Heck cyclization cascade reaction and its application to total syntheses of 14- and 15-hydroxypatchoulol, alongside our synthetic studies toward plumisclerin A.Chapter 1 reviews Pd-catalyzed Mizoroki–Heck reactions in total synthesis. In addition, it highlights recent contributions from the Sarpong group on Pd-catalyzed C–C bond cleavage/C–C bond forming strategies in synthetic methods development and total synthesis of natural products.Chapter 2 details our work on employing gem-dichloroalkene electrophiles as cross- coupling partners in palladium catalysis. Through the use of various phosphine-based ligands and careful substrate design, we achieved high selectivity among four possible products of the envisioned Pd-catalyzed cascade reaction: the vinylation product, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, and tricyclo[3.2.1.0]octane. Our mechanistic proposals regarding the observed product selectivity are supported by data science and computational studies conducted in collaboration with the Sigman group and the Coley group.Chapter 3 reviews the isolation, biosynthesis, biological activity, and previous syntheses of patchouli alcohol, as well as our proposal to synthesize the newly isolated natural products, 14- and 15-hydroxypatchoulol, using the developed Pd-catalyzed cascade reaction.Chapter 4 describes the total syntheses of 14- and 15-hydroxypatchoulol. It features two completed syntheses of 14-hydroxypatchoulol, each employing different gem-dichloroalkene electrophiles, completed in 9 and 12 overall steps, respectively. In addition to the completed syntheses, we report structural misassignment of 15-hydroxypatchoulol from the original isolation report.Chapter 5 reviews the isolation, biosynthesis, biological activity, and previous syntheses of plumisclerin A, along with other structurally related xenicane marine terpenoid natural products.Chapter 6 describes our synthetic studies toward plumisclerin A, in which we employ a titanocene-mediated reductive cyclization approach to construct the bicyclo[3.1.1]heptane moiety and introduce the side chain of the dihydropyran moiety through a Claisen rearrangement.