A Unified Synthetic Approach to the Transtaganolide and Basiliolide Natural Products

Citation

Nelson, Hosea Martin (2013) A Unified Synthetic Approach to the Transtaganolide and Basiliolide Natural Products. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/09DW-P586. https://resolver.caltech.edu/CaltechTHESIS:09282012-144447840

Abstract

Herein are described the first total syntheses of several members of the transtaganolide and basiliolide natural product family. A general strategy, hinging upon the use of a biomimetic Ireland–Claisen rearrangement/Diels–Alder cycloaddition cascade, was developed. It allowed for the rapid assembly of the most structurally complex, and biologically active members of the family.

A brief introduction that surveys the use of the pyrone Diels–Alder cycloaddition in total synthesis precedes details of our synthetic efforts. The diversity of structural motifs accessible through this reaction manifold is described through literature examples.

The account of our experimental work begins with details of extensive model studies. First, a simple system was prepared which probed the ability to construct basiliolide B via an intramolecular pyrone Diels–Alder reaction. It was demonstrated that the sterically congested core could be constructed in a highly diastereoselective fashion using this technology. Second, a simple prenylated pyrone was constructed, and shown to undergo a facile Ireland–Claisen rearrangement under a variety of conditions. Subsequently, the utilization of these two methods within a cascade allowed for the rapid construction of racemic transtaganolide C, transtaganolide D, basiliolide B, and epi-8-basiliolide B. Furthermore, a novel Pd-catalyzed [5+2] annulation technology is utilized to construct the venerable, carboxy-ketene-acetal containing C-ring present in most of the metabolites.

Integration of asymmetry into our general strategy is also described. Utilization of a chiral silane directing group allowed for the successful and rare application of an enantioselective Ireland–Claisen rearrangement, culminating in the total syntheses of (+)- transtaganolide C, (–)-transtaganolide D, (+)-transtaganolide B, and (–)-transtaganolide A. Furthermore, the impact of this work on existing biosynthetic hypotheses is discussed.

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