Synthesis of (R)- and (S)-β-hydroxyphosphonate acyclonucleosides: structural analogues of Adefovir (PMEA)

A synthetic pathway to new acyclonucleoside phosphonates, as analogues of Adefovir, is described. The reduction of an acyclonucleoside β-ketophosphonate, readily available from the nucleobase and benzylacrylate, afforded a mixture of (R)- and (S)-β-hydroxyphosphonate derivatives which was resolved. The assignment of the absolute configuration was proposed on the basis of NMR studies and was supported by molecular modelling studies.

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(R,S)-[N-6-Monomethoxytrityl-N-9-(3-methoxyphenylacetoxy-4-dimethyl-phosphonobutyl)]adenineC40H41N5O7P[α]D2=+53.3 (c 0.89, MeOH)Absolute configuration: (R,S)Source of Chirality: (S)-methoxyphenylacetic acid

(S,S)-[N-6-Monomethoxytrityl-N-9-(3-methoxyphenylacetoxy-4-dimethyl-phosphonobutyl)]adenineC40H41N5O7P[α]D20=+48.6 (c 0.74, MeOH)Absolute configuration: (S,S)Source of Chirality: (S)-methoxyphenylacetic acid

(S)-[N-6-Monomethoxytrityl-N-9-(3-hydroxy-4-dimethyl-phosphonobutyl)]adenineC31H33N5O5P[α]D20=-30.4 (c 0.6, MeOH)Absolute configuration: (S)Source of Chirality: (S)-methoxyphenylacetic acid

(S)-N-9-(3-Hydroxy-4-phosphonobutyl)adenineC9H11N5O4Na2P[α]D20=-10.6 (c 0.47, H2O)Absolute configuration: (S)Source of Chirality: (S)-methoxyphenylacetic acid