New methods for the control of multiple stereocenters

Reactions which assemble multiple stereocenters in a highly convergent manner provide new avenues for the synthesis of complex natural products. Oxabicyclic compounds have been shown to be useful precursors to highly functionalized cyclic and acyclic compounds following reaction with a variety of nucleophiles including carbon, silicon and hydride. The regio-, stereo-, and enantioselectivity of the ring opening has been investigated. Syntheses of fragments of the natural products rifamycin and ionomycin illustrate the utility of this approach. INTRODUCTION The synthesis of naturally occurring macrocyclic compounds containing arrays of contiguous stereocenters provides a significant challenge to the organic chemist. The structural complexity of the macrolides, polyether antibiotics, and macrolactams have encouraged the development of new methodology as well as the design of novel synthetic strategies (ref. 1-3). One of the most commonly used strategies for their synthesis is based on the diastereoselective addition of a nucleophilic reagent to an electrophilic species such as a carbonyl group (ref. 43) . New approaches which set multiple stereocenters in a convergent manner would provide a useful alternative to these strategies. Our initial objective in the development of a convergent approach to these classes of target compounds was to explore the reactivity of an oxabicyclic compound toward a nucleophilic partner. There were several questions which needed to be answered at the outset of the project as illustrated in the equation below. With what types of nucleophiles does ring opening occur in E3.2.11 and [2.2.1] oxabicyclic compounds? Is the product derived from sN2 or sN2' attack? What is the stereochemistry of sN2' opening and can it be controlled (ref. 6)? Can control of the absolute stereochemistry be accomplished in the ring opening if the starting material is meso? Oxabicyclo[3.2. lloctenones 1 and 2 have been available since the 70's when Hoffmann and Noyori described novel routes for their preparation based on a cycloaddition between furan and a polyhalogenated ketone in the presence of a catalyst (ref. 7). Routes which are amenable to the large scale preparation of these materials are now available making these compounds attractive starting materials for our investigation (ref. 8). Diels-Alder cycloaddition between furan and a dienophile followed by reduction and protection of the resulting alcohol yields oxabicyclo[2.2. llheptenes 3. 0 iR 1 0 0 h 2 0 0