Efficient synthesis of H-phosphonates by transesterification of diphenyl H-phosphonate with lipid alcohols in the absence of a solvent or catalyst.

We report a solvent-, acid-, base- and metal-free method to prepare dialkyl phosphites (H-phosphonates) based on the double transesterification reaction of diphenyl phosphite with lipid primary or secondary alcohols or functionalized alcohols or phenols. We report that diphenyl phosphite, used as a substrate, is much more reactive than dimethyl phosphite or diethyl phosphite. This method is applied to prepare a series of dialkyl and functionalized dialkyl H-phosphonates in high yields, allowing the incorporation of various functionalities in the structure of the phosphites, including bromo alkyl, ester, carbamate, phosphonate, phosphoramidate, amide, thioether, azide and azobenzene. This methodology was applied to the synthesis, on a multigram scale, of the branched ionizable phospholipid BiP-20, which was recently identified as a very promising ionizable lipid for in vivo gene editing.