The development of thiophosphoryl 'click' chemistry

Abstract

We have established novel, aqueous 'Click' chemistry that is based on the thiophosphoryl group. Two systems for the creation of thiophosphoryl derivatives were involved: Thiophosphoramidate I and Bromoacetyl II. The first step in the Thiophosphoramidate system is our aqueous thiophosphorylation of amines using thiophosphoryl chloride. Through careful control of reaction conditions we have devised a method that allows us to prepare and alkylate the thiophosphoramidate group in aqueous media with high conversions, and thus provide a fast, clean and straightforward route to a number of products. The thiophosphoramidate system was, then, successfully applied towards the production of nucleoside monothiophosphoramidates. In addition, a number of quinoline-based thiophosphoramidates were generated as potential antileishmanials and in vivo assays were performed against Leishmania mexicana. The bromoacetyl system uses thiophosphorylated alcohols that we alkylated with a range of activated bromoacetate esters. Hydrolysis and aminolysis kinetic studies were employed on this system for a better understanding of the conditions required for facile production of amides on these thiophosphoryl acetate esters in water. Finally, we have combined the achievements from these two systems into the thiophosphoramidate-romoacetyl strategy III, expanding the scope for generating thiophosphoryl derivatives.