Stereoselective Reduction of Cyclopropylalkaones Possessing a Difluoromethylenephosphonate Group at the Ring: Application to Stereoselective Synthesis of Novel Cyclopropane Nucleotide Analogues

Abstract Difluoro{(1 S ∗ ,2 S ∗ )-2-[(1 S ∗ )-1-(6-oxo-1,6-dihydro-9 H -purin-9-yl)ethyl]cyclopropyl}methylphosphonic acid 12a and the related analogues were prepared as ‘multi-substrate analogue’ inhibitors for purine nucleoside phosphorylase. Reduction of diethyl [(1 S ∗ ,2 S ∗ )-2-acethylcyclopropyl](difluoro)methylphosphonate 8a with K-Selectride at a low temperature proceeded from the less-hindered face of the carbonyl in the bisected s - cis conformation to give the corresponding cyclopropylalkanol 9a in high diastereoselectivity (94% de). In an analogous manner, several cyclopropylalkanols 8b – g possessing a difluoromethylene phosphonate functional group at the ring were stereoselectively synthesized. The cyclopropylalkanol 9a was manipulated to the nucleotide analogue 12a through a conventional method. The diastereomeric nucleotide analogue 15 was prepared from 9a via the Mitsunobu inversion. Preliminary results on an assay of PNP inhibitory activity of 9a and 15 are presented.