eprintid: 9516 rev_number: 4 userid: 6 dir: disk0/00/00/95/16 datestamp: 2011-11-10 20:03:32 lastmod: 2016-11-15 13:50:55 status_changed: 2011-11-10 20:03:32 type: thesis_degree metadata_visibility: show contact_email: calee@pitt.edu item_issues_count: 0 eprint_status: archive creators_name: Lee, Christopher Allen creators_email: calee@pitt.edu creators_id: CALEE title: Synthesis and Studies Directed Toward Multidrug Resistance-Modulating Natural Products ispublished: unpub divisions: sch_as_chemistry full_text_status: public keywords: Bryostatin; Dihydroagarofurans; MDR; Orbiculin A; P-gp; Celafolin A-1; tandem conjugate addition aldol abstract: Studies directed toward the enantioselective preparation of dihydroagarofuran natural products are presented. The purpose of this project is to synthesize dihydroagarofuran natural products in order to study what structural features are required for inhibition of Phospho-glycoprotein (P-gp) induced multidrug resistance in this family of molecules. Once an optimal synthetic route is established, analogs can be synthesized to probe P-gp function at the molecular level. Three synthetic routes to the dihydroagarofuran family of natural products were investigated. Each synthesis utilized (R)-(-)-carvone, an inexpensive terpene available in high enantiomeric purity, as the sole source of chirality. Our studies have shown that the dihydroagarofuran tricyclic skeleton can be prepared in as few as eight steps from (R)-(-)-carvone. Each synthesis is substantially shorter than previously published routes to similar ring systems.In conjunction with our studies toward interesting multidrug resistance modulating natural products, a short and enantioselective route to the tetrahydropyran (THP) bryostatin B ring was developed. This new method utilizes a cyclic acetal to generate a reactive oxocarbenium ion, which was subsequently trapped with a tethered silyl enol ether. The resulting diastereoselective reaction gives exclusively 2,6-cis-tetrahydropyranone rings in excellent yield. Unlike previous routes to create oxocarbenium ions from acetals, our approach uses Ce(NO3)3 an exceptionally mild Lewis acid. Ce(NO3)3 is inexpensive, non-toxic, and easy to separate from reaction mixtures. The use of acetals as oxocarbenium ion precursors is an attractive method for complex molecule synthesis, since acetals can be constructed under extemely mild conditions. This new method can be easily extended to the enantioselective preparation of other complex THP ring containing macrolide natural products, such as (+) Phorboxazole A or (+) Leucascandrolide A. date: 2005-01-31 date_type: completed institution: University of Pittsburgh refereed: TRUE etdcommittee_type: committee_chair etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_name: Floreancig, Paul etdcommittee_name: Schafmeister, Christian etdcommittee_name: Yalowich, Jack etdcommittee_name: Nelson, Scott etdcommittee_email: florean@pitt.edu etdcommittee_email: meister@pitt.edu etdcommittee_email: yalowich@pitt.edu etdcommittee_email: sgnelson@pitt.edu etdcommittee_id: FLOREAN etdcommittee_id: MEISTER etdcommittee_id: YALOWICH etdcommittee_id: SGNELSON etd_defense_date: 2004-10-25 etd_approval_date: 2005-01-31 etd_submission_date: 2004-10-26 etd_access_restriction: immediate etd_patent_pending: FALSE assigned_doi: doi:10.5195/pitt.etd.2011.9516 thesis_type: dissertation degree: PhD committee: Paul Floreancig (florean@pitt.edu) - Committee Chair committee: Christian Schafmeister (meister@pitt.edu) - Committee Member committee: Jack Yalowich (yalowich@pitt.edu) - Committee Member committee: Scott Nelson (sgnelson@pitt.edu) - Committee Member etdurn: etd-10262004-113523 other_id: http://etd.library.pitt.edu/ETD/available/etd-10262004-113523/ other_id: etd-10262004-113523 citation: Lee, Christopher Allen (2005) Synthesis and Studies Directed Toward Multidrug Resistance-Modulating Natural Products. Doctoral Dissertation, University of Pittsburgh. (Unpublished) document_url: http://d-scholarship-dev.library.pitt.edu/9516/1/Lee102504.pdf