Synthesis of isomeric and enantiomeric O-phosphonylmethyl derivatives of 9-(2,3-dihydroxypropyl)adenine

Abstract

Reaction of 9-(S)-(2,3-dihydroxypropyl)adenine (I) with chloromethanephosphonyl chloride (VII) in pyridine or triethyl phosphate, or with chloromethyl(pyridinio)phosphonate (IX) in pyridine, afforded a mixture of 2'-(IV) and 3'-O-chloromethanephosphonate (V) which were separated on anion exchange resin or alkylsilica gel. Treatment of compounds IV and V with aqueous alkaline hydroxide, followed by deionization, gave 9-(S)-(2-hydroxy-3-phosphonylmethoxypropyl)adenine (VI) and 9-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (III) (HPMPA), respectively. The (R)- and (RS)-forms of III and VI were prepared analogously from the respective (R)-enantiomer and racemate of I. 9-(S)-(2,3-Dihydroxypropyl)-N6-benzoyladenine (XIV) was converted into 3'-O-(dimethoxytrityl) derivative XVII and further into 2',N6-dibenzoyl derivative XIX. Reaction of compound XVII with IX, followed by acid hydrolysis and alkaline cyclization, afforded pure isomer VI whereas pure III was prepared from XIX by reaction with VII in triethyl phosphate and subsequent alkaline cyclization.