Tetrazole: phosphoramidite coupling catalyst

However, even the pre-synthesized tetrazolides were still too reactive to be routinely used in the automated solid phase synthesis. The major advance that solved the problem was made in 1981, when Beaucage and Caruthers, who were experimenting with the nucleoside 3 -phosphoramidite derivatives [83] following some previous Russian work on the phosphorus(III)-amino compounds [84], discovered that these otherwise pretty stable compounds can be rapidly and very efficiently coupled to a solid-supported nucleoside in the presence of a mildly acidic nucleophilic catalyst, tetrazole [85]. This discovery combined with the already existing solid-phase assembly layout [68, 69, 82] paved the way for the very rapid expansion of the polymer-supported oligonucleotide synthesis, which has been summarized in the timely book edited by Gait [12a]. 

With the first nucleoside in place, we are ready to attach to it the second. For this purpose, the point of attachment, the 5 -OH, is deprotected with acid. Subsequent addition of a 3 -OH activated nucleoside effects coupling. The activating group is an unusual phosphoramidite [containing P(III)], which, as we shall see shortly, also serves as a masked phosphate [P(V)] for the final dinucleotide and is subject to nucleophilic substitution, not unlike PBrs (recall Sections 9-4 and 19-8). The displacement reaction is catalyzed and furnishes a phosphite derivative the catalyst is the, again unusual, aromatic heterocycle tetrazole, a tetrazacyclopentadiene related to pyrrole (Section 25-3) and imidazole (Section 26-1). Finally, the phosphorus is oxidized with iodine to the phosphate oxidation state. 

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