Studies on stereospecific diketopiperazine oxidation and applications to the synthesis of complex epidithiodiketopiperazines

Abstract

I. Introduction and Background on Epidithiodiketopiperazines

A brief history and summary of methods for synthesis of epidithiodiketopiperazines (ETPs) are discussed. Three hypotheses for the mechanism of action of these biologically active natural products are reviewed, and the unified biosynthetic hypothesis that our group disclosed is summarized. The total syntheses of the natural product hyalodendrin are analyzed as a case study of the total synthesis of ETPs, and representative examples of our group’s entries into the synthesis of complex ETPs are examined.

II. Studies on Stereospecific Diketopiperazine C–H Hydroxylation

Mechanistic investigation of the permanganate-mediated hydroxylation reaction of 2,5-diketopiperazines (DKPs) is discussed. The course of the hydroxylation reaction with three permanganate oxidants examined in our total synthesis of naturally occurring epipolythiodiketopiperazines (ETPs) is investigated with respect to the activity of the different oxidants, as well as the stereochemical outcome and the configurational stability of the product diols. An example of a subsequent thiolation was then demonstrated to proceed under retention of stereochemistry, in contrast to the stereoinvertive thiolations previously observed in several total syntheses. The data is supported by computational analyses.

III. Progress Toward the Total Synthesis of (+)-Chetomin

We describe our work toward the total synthesis of ETP natural product (+)-chetomin. Key features of the synthetic progress include a method for construction of the key nitrogen¬–¬carbon bond with advanced reaction partners, including protected diols, sulfides, and ETPs, and stereocontrolled thiolation strategies. The challenges remaining to access (+)-chetomin are addressed on model systems.