We present an improved synthesis of (S)-HPMPA (1) from an easily accessible and commercially available compound, (S)-3-(benzyloxy)propane-1,2-diol (10). Tritylation of primary alcohol 10 was highly selective, and pure product was isolated in good yield. Alkylation of (R)-1-(benzyloxy)-3-(trityloxy)propan-2-ol (11) with diethyl p-toluenesulfonyloxymethyl phosphonate (6) using sodium hydride in tetrahydrofuran followed by detritylation afforded the desired chiral synthon 12. Tosylation of the primary alcohol and subsequent reaction with sodium adeninate afforded protected S-HPMPA (14). Global deprotection using concentrated hydrochloric acid in a sealed tube afforded S-HPMA (1), and the deprotected 1 was crystallized from water and acetone to obtain a 99% pure product. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Preparation of (R)-1-(benzyloxy)-3-(trityloxy)propan-2-ol (11) Basic Protocol 2: Preparation of diethyl (S)-(((1-(benzyloxy)-3-hydroxypropan-2-yl)oxy)methyl)phosphonate (12) Basic Protocol 3: Preparation of (R)-3-(benzyloxy)-2-((diethoxyphosphoryl)methoxy)propyl-4-methylbenzenesulfonate (13) Basic Protocol 4: Preparation of diethyl (S)-(((1-(6-amino-9H-purin-9-yl)-3-(benzyloxy)propan-2-yl)oxy)methyl)phosphonate (14) Support Protocol 1: Preparation of sodium adeninate Basic Protocol 5: Preparation of (S)-(((1-(6-amino-9H-purin-9-yl)-3-hydroxypropan-2-yl)oxy)methyl)phosphonic acid (1).
Keywords: nucleosides; nucleotides; oligonucleotides.
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