Stereoselective reduction of cyclopropylalkaones possessing a difluoromethylenephosphonate group at the ring: Application to stereoselective synthesis of novel cyclopropane nucleotide analogues

Difluoro{(1S*,2S*)-2-[(1S*)-1-(6-oxo-1,6-dihydro-9H-purin-9-yl)ethyl]cyclop ropyl}methylphosphonic acid 12a and the related analogues were prepared as 'multi-substrate analogue' inhibitors for purine nucleoside phosphorylase. Reduction of diethyl [(1S*,2S*)-2-acethylcyclopropyl](difluoro)methylphosph onate 8a with K-Selectride at a low temperature proceeded from the less-hin dered face of the carbonyl in the bisected s-cis conformation to give the c orresponding cyclopropylalkanol 9a in high diastereoselectivity (94% de). I n an analogous manner, several cyclopropylalkanols 8b-g possessing a difluo romethylene phosphonate functional group at the ring were stereoselectively synthesized. The cyclopropylalkanol 9a was manipulated to the nucleotide a nalogue 12a through a conventional method. The diastercomeric nucleotide an alogue 15 was prepared from 9a via the Mitsunobu inversion. Preliminary res ults on an assay of PNP inhibitory activity of 9a and 15 are presented. (C) 2000 Elsevier Science Ltd. All rights reserved.