Combined Phosphoramidite-Phosphodiester Reagents for the Synthesis of Methylene Bisphosphonates

Sander B Engelsma; Nico J Meeuwenoord; Hermen S Overkleeft; Gijsbert A van der Marel; Dmitri V Filippov

doi:10.1002/anie.201611878

Combined Phosphoramidite-Phosphodiester Reagents for the Synthesis of Methylene Bisphosphonates

Angew Chem Int Ed Engl. 2017 Mar 6;56(11):2955-2959. doi: 10.1002/anie.201611878. Epub 2017 Feb 7.

Authors

Sander B Engelsma¹, Nico J Meeuwenoord¹, Hermen S Overkleeft¹, Gijsbert A van der Marel¹, Dmitri V Filippov¹

Affiliation

¹ Leiden Institute of Chemistry, Department of Bioorganic Synthesis, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.

PMID: 28170152
DOI: 10.1002/anie.201611878

Abstract

A new class of phosphanylmethylphosphonate reagents has been developed to enable the controlled synthesis of methylene bisphosphonate mono- and diesters. Condensation of such reagents with an alcohol of choice through azole-mediated phosphoramidite chemistry followed by in situ oxidation provides orthogonally protected methylene bisphosphonate tetraesters. Global deprotection of the tetraester leads to terminal methylene bisphosphonates. Alternatively, selective deprotection at the terminal phosphonate followed by a condensation between the acquired methylene bisphosphonate triester and a second alcohol leads to methylene bisphosphonates diesters.

Keywords: methylene bisphosphonates; phosphanylmethylphosphonate; phosphorylation; pyrophosphate bioisosteres; solid-phase synthesis.

Publication types

Research Support, Non-U.S. Gov't