Development of a Modular Strategy Towards the Total Synthesis of (+)-Pleuromutilin and Progress Towards the Synthesis of (–)-Merrilactone A

Citation

Feng, Sean S. L. (2020) Development of a Modular Strategy Towards the Total Synthesis of (+)-Pleuromutilin and Progress Towards the Synthesis of (–)-Merrilactone A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/chfe-0q83. https://resolver.caltech.edu/CaltechTHESIS:05052020-172131873

Abstract

Natural products have long stood as a rich source of biologically relevant molecules bearing highly functionalized and complex architectures. On one hand, they are a focal point for the development of new therapeutic agents owing to their inherent biological activities. On the other, they serve as an exciting testing ground for existing synthetic methodologies and provide opportunities for the development of new reactions.

Herein, we describe a modular strategy that was employed for the total synthesis of the antibiotic (+)-pleuromutilin. Key features of our synthesis include (1) the development of a highly stereoselective SmI₂-mediated ketyl radical cyclization to establish the central eight-membered ring and (2) a modular crotylation reaction to install the eight-membered ring’s backbone that permits full control over the stereochemistry at C12 as desired. During our synthetic studies, a transannular [1,5]-hydrogen atom transfer reaction that affects a stereospecific redox relay to set the C10 stereocenter was serendipitously uncovered. This strategy enabled the completion of a concise total synthesis of (+)-pleuromutilin, proceeding in 18 steps. To demonstrate the modularity of our synthetic approach, the same strategy was readily applied to the synthesis of (+)-12-epi-pleuromutilin with no reoptimization, providing a new platform for the preparation of fully synthetic derivatives that may hold promise as broad-spectrum antibiotics.

This report also highlights the work we have conducted in the development of a synthetic strategy towards (–)-merrilactone A. We detail our investigation of a Pd-catalyzed asymmetric allylic alkylation reaction that rapidly constructs the D-ring bearing the C5 and C6 vicinal quaternary centers. Potential paths forward to complete the synthesis of this neurotropic natural product leveraging this advanced intermediate will also be discussed.

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