Total synthesis of phorboxazole A / Kevin Patrick Minbiole.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Minbiole, Kevin Patrick.

Contributor:

Smith, Amos B., III, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Physical Description:

xviii, 348 pages : illustrations ; 29 cm

Production:

2001.

Summary:

This dissertation describes the total synthesis of the potent anticancer agent (+)-phorboxazole A (1), which was completed in the Smith laboratories in November, 2000. Our synthetic approach to this architecturally complex sponge metabolite exploited the Petasis-Ferrier rearrangement as a strategic cornerstone. Retrosynthetic disconnection of (+)-phorboxazole A (1) suggested three major subtargets: oxazole triflate 177, aldehyde 178, and Wittig salt 179.*

In the course of this synthetic venture several interesting discoveries were made with respect to the Petasis-Ferrier rearrangement. Experimental evidence offered insights into the rearrangement mechanism, leading to revised rearrangement substrates and, ultimately, successful cis-tetrahydropyran assembly. The inherent symmetry of the reaction, namely the ability to transpose the enol ether functionality within Petasis-Ferrier substrates, proved crucial in the use of this method.*

Our assembly of ethylidene acetal 216, substrate for the Petasis-Ferrier rearrangement, necessitated the extension of the Julia olefination protocol to enol ether synthesis. We were pleased to find that lithiation of (+)-239 and quench with ethyl carbenoid 240 furnished enol ether 216 in excellent yield.*

Because our synthetic plan called for coupling via an oxazole triflate moiety, an improve one-pot oxazole triflate assembly was developed. The incorporation of such substructures into the phorboxazole skeleton was examined and optimized.*

Assembly of our three major subtargets and final elaboration completed the total synthesis of (+)-phorboxazole A (1) in 27 linear steps, and in an overall yield of 3%. A total of 73 steps were required to prepared the natural product from commercially available materials.

*Please refer to dissertation for diagrams.

Notes:

Supervisor: Amos B. Smith, III.

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 2001.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3003666.

OCLC:

244971432