UC San Diego

33The nocathiacins are a family of three thiopeptide antibiotics that posses remarkable biological activity and operate with a mechanism of action that involves binding to rRNA and disrupting the elongation step of bacterial protein synthesis. Chapter 1 details the retrosynthetic strategy and synthesis of advanced tetrasilylated nocathiacin III intermediate 1.45. The highlights of the synthesis include the efficient construction of the 3- hydroxypyridine core (1.9) via a hetero-Diels-Alder reaction and a novel transannular N-hydroxyindole/ macroetherification reaction which accomplishes bicycle and N-hydroxyindole formation in a one-pot cascade process. Chapter 2 outlines the development of a new synthetic method for the construction of 3-substituted N- hydroxyindoles via 1,5-nucleophilic addition to highly reactive nitrone species. The described chemistry provides a versatile entry into substituted N-hydroxyindoles carrying O-, S-, and carbon nucleophilic moieties, creating a diverse library of potentially biologically active and synthetically useful compounds. Furthermore, the method was applied to the successful synthesis of nocathiacin model systems through inter- and intramolecular etherification processes. Chapter 3 describes the discovery of a mild and selective method for the hydrolysis of esters employing trimethyltin hydroxide, which has found broad applicability in total synthesis since our publication. The overall scope and generality of the protocol is demonstrated as well as the remarkable sensitivity of this reagent upon exposure to highly epimerization sensitive substrates such as thiazolines and dichlorinated aryl glycine moieties. The propensity of Me3SnOH to selectively hydrolyze methyl esters over other esters is also shown. Chapter 4 reveals the significant contributions made towards the total synthesis of the thiopeptide antibiotic thiostrepton (4.1), which was completed in 2004. These include the concise, multi-gram scale synthesis of bis-dehydroalanine tail fragment 4.4, and the elucidation of the C5/C6 dehydropiperidine core stereochemistry