Recent Advances in the Mitsunobu Reaction: Modifications and Applications to Biologically Active Molecules

Abstract

The Mitsunobu reaction involves the “redox” condensation of an acidic pronucleophile with a primary or secondary alcohol promoted by a reactive phosphonium salt derived from an alkyl or aryl phosphine and an azo compound. The synthetic utility of the reaction is demonstrated by the wide range of acidic pronucleophiles that are tolerated including carboxylic acids, phenols, imides, hydroxamates, thiols, thioamides, fluorinated alcohols, oximes, pyridinium and imidazolium salts, pyrimidine bases, β-ketoesters and trimethylmethane tricarboxylate (TMET) thereby generating a variety of functionally diverse molecules. The focus of this review is to highlight the recent development of new or alternative reagents and purification strategies for the Mitsunobu reaction with a discussion of their suitability for modern drug design supported by selected examples from the literature.