Synthesis of Polyphosphorylated Molecules Directly from Polyphosphates

Technology

In one step, this invention triphosphorylates nucleophilic substrates like alcohols, amines, and phosphates. Trimetaphosphate serves as the phosphate source and is combined with a coupling reagent to generate an activated species. The activated species can be reacted with nucleophilic substrates to produce functionalized trimetaphosphate derivatives that can be easily isolated and purified by crystallization. Rapid hydrolysis of trimetaphosphate derivatives in water is finally used to generate linear triphosphate products. The invention can also be applied to generate linear, branched, and cyclic polyphosphates (including mono, di, tri, tetra, and hexaphosphorylated molecules). 

Problem Addressed

Intense, and therefore costly synthesis is needed to generate many polyphosphorylated biomolecules relevant to biochemical and pharmacological research, due to the difficulty of obtaining these molecules from biological sources. Additionally, no single phosphorylation method is acceptable for all desired biological substrates. As a result, even relatively common polyphosphorylated substrates are extremely expensive from commercial sources. Known reactions to triphosphorylate substrates in one step are low yielding and require costly purification of products. These inventors have developed a high yielding method for the synthesis of triphosphorylated molecules directly from trimetaphosphate combined with a simple isolation and purification procedure for products. As a result, the generation of triphosphorylated molecules is much more cost efficient than current methods and can be extended to a variety of previously excluded substrates.

Advantages

• First of its kind activated species generated from trimetaphosphate
• High yielding, one step synthesis of triphosphates derivatives that is more cost effective and easier to purify than current methods
• Novel access to previously inaccessible substrates facilitates the generation and commercialization of highly desired polyphosphorylated entities

Publications

Shepard, Scott M., and Christopher C. Cummins. "Functionalization of Intact Trimetaphosphate: A Triphosphorylating Reagent for C, N, and O Nucleophiles." Journal of the American Chemical Society, 141 (2019): 1852-1856. doi: 10.1021/jacs.8b12204.