Mechanisms of the substitution reactions of phosphoramidites and their congeners

Abstract Mechanistic research on the nucleophilic substitution of trivalent phosphorus compounds is reviewed with emphasis on the reactions of phosphoramidites. The reactivity of these compounds towards hydroxyl groups is utilized, for instance, in the coupling step of the modern automated solid‐support synthesis of oligonucleotides. Growing interest in the large‐scale synthesis of oligonucleotides as antisense‐strategy drugs has increased the demand for relevant mechanistic research that has considerably improved our understanding of phosphoramidite alcoholysis reaction during the last few years. The review also covers phosphites that are formed as products of this reaction and also phosphorohalidites, azolyl phosphonites and P(III) azolidites that serve as its intermediates. Mechanisms of reactions of phosphoramidites with azoles and carbozylic acids are included together with those of halogenation and transamidation. Alternative reaction mechanisms published in the literature for substitution reactions of P(III) compounds range from dissociative to concerted and associative pathways while different types of activation have been suggested. Reactions of phosphoramidites with alcohols have been shown to be subject to both nucleophilic and acid catalysis and most likely proceed with a concerted mechanism of dissociative character. The consequences of these conclusions for the development of the phosphoramidite approach of oligonucleotide synthesis are also discussed. Copyright © 2003 John Wiley & Sons, Ltd.