Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Synthesis and Studies Directed Toward Multidrug Resistance-Modulating Natural Products

Lee, Christopher Allen (2005) Synthesis and Studies Directed Toward Multidrug Resistance-Modulating Natural Products. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (1MB) | Preview


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.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Lee, Christopher Allencalee@pitt.eduCALEE
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFloreancig, Paulflorean@pitt.eduFLOREAN
Committee MemberSchafmeister, Christianmeister@pitt.eduMEISTER
Committee MemberYalowich, Jackyalowich@pitt.eduYALOWICH
Committee MemberNelson, Scottsgnelson@pitt.eduSGNELSON
Date: 31 January 2005
Date Type: Completion
Defense Date: 25 October 2004
Approval Date: 31 January 2005
Submission Date: 26 October 2004
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Bryostatin; Dihydroagarofurans; MDR; Orbiculin A; P-gp; Celafolin A-1; tandem conjugate addition aldol
Other ID:, etd-10262004-113523
Date Deposited: 10 Nov 2011 20:03
Last Modified: 15 Nov 2016 13:50


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item