Graduation date: 2007Studies towards the total synthesis of (−)-kendomycin (1), a bacterial metabolite with a unique molecular architecture and pronounced biological activity, are described. These studies resulted in the synthesis of advanced intermediate 208, containing all of the carbon atoms of 1. A Dötz annulation between alkyne 122 and novel chromium carbenoid 123 was developed to construct the core aromatic subunit of (-)-kendomycin. The resulting phenol 121 was advanced to aldehyde 120, and the left-hand subunit of 1 was elaborated using asymmetric aldol and crotylation reactions as key steps. A first generation approach to the fully functionalized tetrahydropyran moiety involved stereoselective iodoetherification of alkene 173. Attempts at further functionalization of 177 and closure of the 16-membered macrocycle of kendomycin were unsuccessful. The second generation approach exploited a new cyclization strategy. Iodide 180, representing the C11-C14 fragment of kendomycin, was prepared using regio and stereoselective silylcupration of alkyne 181 as the key step. Linkage of iodide 197, prepared from aldehyde 120, with iodide 180 was accomplished through a Suzuki cross coupling and the resulting product 198 was advanced to aldehyde 200. An analogous sequence to that used with 120 led to alkene 204. Closure of the 18-membered macrocycle was accomplished through ring-closing metathesis to provide (Z)-olefin 206. Transannular selenoetherification was the method of choice for installing the fully substituted tetrahydropyran ring system of 1 and led to advanced intermediate 208.