Chapter 9 The ring-closing metathesis approach to fumagillol

Abstract

Ring-closing metathesis (RCM) reaction is a useful means for preparing several classes of biologically active molecules. One of the most successful applications of RCM has been the synthesis of fumagillol and fumagillin analogs. The naturally occurring fumagillin was discovered and synthesized in the racemic form. It has long been known for its antibiotic and antiparasitic properties. It has benefits in the antitumor and anti-inflammation areas. It has emerged as a promising candidate for the treatment of cancer. This potential is currently being examined both in preclinical and clinical studies. This chapter discusses the synthesis of fumigillol. There is only one reported example of successful RCM involving an α,β-unsaturated ketone. RCM of α,β-unsaturated esters has been known to be difficult unless special conditions, possibly not applicable to ketones (the addition of Lewis-acids), are used. With the advent of very active and chemoselective, well-defined catalysts derived from ruthenium or molybdenum, things have changed dramatically and, in the past years, the RCM reaction has become widely accepted as one of the major tools available to the synthetic organic chemist.