New methods in the design and synthesis of antitumor agents

This body of work is divided into three distinct sections. The first portion of this work is focused on the area of enediyne chemistry. Prodrugs which contain the enediyne pharmacophore have received attention in recent years for their ability to cleave the sugar phosphate backbone of DNA via the diyl radical species that result from Bergman cycloaromatization of the enediyne moiety. Prodrug designs covered in this work are based on the premise that potent prodrugs may be assembled in a logical fashion wherein biologically active "delivery vehicle" platforms are designed and constructed independently of the enediyne "warhead" and the two components connected via a short carbon tether. The emphasis of the enediyne research covered here has been the design of an efficient route to the enediyne "warhead" component of the prodrugs described. In the course of this work, a novel route to the enediyne pharmacophore has been discovered. This new reaction--a tandem carbenoid coupling-HX elimination procedure--was explored in detail and is described within.;The second portion of this work centers on the guainolide family of natural products. These compounds show pronounced anti-tumor activity. A new route to the AB ring system of the guainolides has been demonstrated, and offers to be applicable to the entire guainolide family. This new procedure--a microwave accelerated Claisen rearrangement--selenolactonization procedure--is described in detail and its application is demonstrated in the construction of a range of cis-fused bicyclic lactones.;The third and final portion of this work covers the first catalytic asymmetric total synthesis of methyl (R)-(+)-Lasiodiplodin. Lasiodiplodin is a member of a broad range of macrocyclic lactones known to exhibit specific biological activity. A series of chiral chromium carbonyl based catalysts were developed which allow for the asymmetric alkylation of aldehydes, affording the corresponding chiral secondary alcohols in high yield and with high enantiomeric excesses. One of these catalyst designs was utilized in the construction of the asymmetric center contained within Lasiodiplodin. The complete construction of this important molecule is described, with particular attention focused on the asymmetric step.