Efficient Synthesis of α‐P‐Modified Nucleoside Triphosphates and Dinucleoside Tetraphosphates via Linear PVPVPIII‐Nucleoside Intermediates

Abstract As an important class of nucleoside triphosphate analogues, α‐ P ‐modified nucleoside triphosphates (NTPαXs) have long been recognized as versatile tools in molecular biology and medicinal chemistry. However, the available synthetic methods based on modified nucleoside monophosphate and cyclic P V P V P III ‐nucleoside intermediates are only low to moderate‐yielding. Inspired by recent progress on P V ‐P III coupling reactions, we attempted to access NTPαXs via the putative linear P V P V P III ‐nucleoside intermediates. The current research found that a specific type of nucleoside phosphoramidites, fluorenylmethyl (Fm) nucleosidyl‐phosphoromorpholidites, are highly reactive in coupling with n Bu 4 NH 3 P 2 O 7 even without acidic activators. In situ oxidation of linear P V P V P III ‐nucleosides with specific sulfurizing, boranylating, and selenylating reagents followed by deprotection of α‐ P and nucleoside moieties afforded NTPαXs (X=S, Se, and BH 3 ) in excellent isolated yields. By exploiting dicyanoimidazole (DCI)’s promoting effect on P V ‐P III coupling, the current linear P V P V P III ‐nucleoside‐based method was further developed into an efficient route to α‐ P ‐modified dinucleoside tetraphosphates.