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Expedient Method for Direct Mono-amidation of Phosphonic and Phosphoric Acids

preprint
submitted on 03.04.2020 and posted on 06.04.2020 by Victoria Yan, Cong-Dat Pham, Florian Muller
Mono-amidated P(V) pro-drugs predominately contribute to the vastly improved delivery of phosphate and phosphonate-containing anti-viral/cancer nucleotide analogues. However, synthetic approaches towards their formation are often harsh and unreliable, which may hamper the identification of novel, more effective amine pro-drugs. Here, we show that direct mono-amidation of structurally complex phosphonic and phosphoric acids may be accomplished in as quickly as seconds by re-purposing the PPh3/DIAD redox pair. Where the triphenylphosphine oxide byproduct is often cited as a vulnerability, we use its formation as an asset. Juxtaposing the anionic nature of the generated mono-amidated product, the desired product may be isolated with a single water extraction. Compared to state-of-the-art strategies towards phosphoramidates, our approach is mild, reliable, and enables access to a variety of aliphatic and benzylic amines for pro-drug attachment.

Funding

American Cancer Society

National Comprehensive Cancer Network

History

Email Address of Submitting Author

victoriacyanide@gmail.com

Institution

University of Texas MD Anderson Cancer Center

Country

USA

ORCID For Submitting Author

0000-0003-0837-5184

Declaration of Conflict of Interest

V.C.Y., C.D.P., and F.L.M. are inventors on a patent application describing a novel method for the mono-amidation of phosphate- and phosphonate-containing drugs.

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