Electrochemically enabled total synthesis of anti-cancer natural products: the total synthesis of (±)-pauciflorol F and (±)-isopauciflorol F, electrooxidative methods development, and efforts toward a versatile total synthesis of 12-deoxyphorbol
Date
2021
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Chapter 1 outlines electrosynthetic chemistry and its applications in natural product total synthesis. As early as 1950, electrosynthetic methods were recognized as a powerful, but underutilized, tool that chemists could apply to natural product synthesis. Historically these methods have found little use until recent years due to the esoteric nature of electrosynthetic methods. While these methods are oftentimes not well understood, they are a powerfully enabling tool for synthetic chemists. These methods allow for non-traditional bond disconnections which are otherwise impossible under conventional chemical means. Widespread adoption of electrochemical methods was initially slow, but in recent years, thanks in no small part to the Baran, Shono, Stahl, Stephenson, and Moeller groups, the application of electrochemical methods to total synthesis has experienced a revitalization with new researchers entering the arena each day. ☐ Chapter 2, the first project herein, describes the synthesis of TFNHPI, its application to the oxidation of benzyl propargyl alcohols, and the expedient total synthesis of (±)-pauciflorol F and (±)-isopauciflorol F. The oxidation of benzyl propargyl alcohols to the corresponding ketones is a known blind spot in oxidative chemistry. Although these substrates appear trivial, their proclivity to ionize, rearrange, or otherwise decompose when exposed to traditional acidic oxidation conditions makes these oxidations surprisingly challenging. By utilizing TFNHPI as an electrochemical mediator, we were able to oxidize numerous benzyl propargyl alcohols, some of which do not oxidize under traditional conditions. We were then able to apply this electrochemical methodology to the total syntheses of (±)-pauciflorol F and (±)-isopauciflorol F, two resveratrol derived phytoalexins commonly believed to have anti-cancer properties. Upon subjecting (±)-pauciflorol F and (±)-isopauciflorol F to the NCI-60 cell line assay, we found that, unfortunately, the racemic formats of these compounds held no appreciable biological activity. ☐ Chapter 3 describes the efforts toward a versatile and expedient total synthesis of 12-deoxyphorbol esters. 12-deoxyphorbol esters, such as prostratin, are of great medicinal importance in the context of both cancer chemotherapeutics and HIV/AIDS adjuvant therapies. The impediment to many of the biological studies of these natural products is this very low natural availability of these compounds from the producing organisms. Numerous groups have endeavored to develop concise and practical syntheses of 12-deoxyphorbol esters and phorbol esters over the last 50 years. The oxidation at C13 is commonly believed to be the crux of any phorbol synthesis. Here, we describe the discovery of an electrochemical method utilizing TFNHPI as a mediator to affect the C—H oxidation and install the desired C13 oxygen protected as a tert-butyl peroxide in a single, simple operation. This method will ultimately allow for rapid and facile assembly of numerous 12-deoxyphorbol analogues. We also describe a concise route to the tetracyclic tigliane core of 12-deoxyphorbol utilizing carbonyl chemistry and nickel(0) carbonyl-alkyne cyclization chemistry.
Description
Keywords
Electrochemistry, Natural products, Total synthesis