Bifunctional acyclic nucleoside phosphonates: synthesis of chiral 9-{3-hydroxy[1,4-bis(phosphonomethoxy)]butan-2-yl} derivatives of purines

We report herein a general method for the synthesis of new types of chiral acyclic nucleoside four-carbon bisphosphonates. The alkylation of 2-amino-6-chloropurine and adenine was performed with (2S,3S)- or (2R,3R)-1,4-[bis(diisopropoxyphosphoryl)methoxy]]-3-[(methylsulfonyl)oxy]butan-2-yl benzoate. Alkylations provided (2R,3R) or (2S,3S) N9-substituted nucleobases, which were further converted to other derivatives. These conversions included either a modification of the nucleobase or transformation of the bisphosphonate chain. Subsequent deprotection of the diisopropyl esters with bromotrimethylsilane provided the resulting (2R,3R)- or (2S,3S)-bisphosphonic acids.

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(2R,3R)-2-Amino-6-(cyclopropyl)amino-9-{3-(hydroxy)-1,4-[bis(phosphono)methoxy]butan-2-yl}purineC14H24N6O9P2Ee >99.8%[α]D20=+12.9 (c 0.25, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R)

(2R,3R)-9-{3-(Hydroxy)-1,4-[bis(phosphonomethoxy)]butan-2-yl}guanineC11H19N5O10P2Ee >99.8%[α]D20=+10.9 (c 0.23, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R)

(2R,3R)-2,6-Diamino-9-{3-(hydroxy)-1,4-[bis(phosphonomethoxy)]butan-2-yl}purineC11H20N6O9P2Ee >99.8%[α]D20=+19.2 (c 0.34, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R)

(2R,3R)-9-{3-(Hydroxy)-1,4-[bis(phosphonomethoxy)]butan-2-yl}adenineC11H19N5O9P2Ee >99.8%[α]D20=+12.2 (c 0.26, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R)