STEREOSELECTIVE SYNTHESIS OF FURO[2,3-C]PYRIDINE PYRIMIDINE THIOETHERS, A NEW CLASS OF POTENT HIV-1 NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS

An efficient stereoselective total synthesis of the furo[2,3-c]pyridin e thiopyrimidine HIV-1 reverse transcriptase inhibitors, PNU-142721 an d PNU-109886, has been developed. A convergent approach was utilized, providing direct access to the desired (S)-configuration of the molecu le by making use of the alkylation of 4-amino-6-chloro-2-thiopyrimidin e with the appropriate (R)-1-chloroethyl furo[2,3-c]pyridine intermedi ates. The successful preparation makes use of an efficient enzymatic k inetic resolution of the key 1-hydroxyethyl furo[2,3-c]pyridine interm ediates to establish stereochemical control of the respective stereoge nic centers. In addition, a workable asymmetric reduction strategy was developed for the synthesis of PNU-109886. Prudent reagent selection for the chlorination required for the final coupling reactions allowed for maintenance of the stereochemical integrity of the target compoun ds. Structural assignment of the absolute configuration of PNU-142721 and PNU-109886 as the (S)-enantiomer was confirmed by X-ray crystallog raphic analysis.