Stereoselective Synthesis of Furo[2,3-c]pyridine Pyrimidine Thioethers, A New Class of Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

Abstract

An efficient stereoselective total synthesis of the furo[2,3-c]pyridine thiopyrimidine HIV-1 reverse transcriptase inhibitors, PNU-142721 and PNU-109886, has been developed. A convergent approach was utilized, providing direct access to the desired (S)-configuration of the molecule by making use of the alkylation of 4-amino-6-chloro-2-thiopyrimidine with the appropriate (R)-1-chloroethyl furo[2,3-c]pyridine intermediates. The successful preparation makes use of an efficient enzymatic kinetic resolution of the key 1-hydroxyethyl furo[2,3-c]pyridine intermediates to establish stereochemical control of the respective stereogenic 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 compounds. Structural assignment of the absolute configuration of PNU-142721 and PNU-109886 as the (S)-enantiomer was confirmed by X-ray crystallographic analysis.

Purification and Characterization of an NADH-Dependent Alcohol Dehydrogenase fromCandida marisfor the Synthesis of Optically Active 1-(Pyridyl)ethanol Derivatives

“…8,13) To synthesize these derivatives, enzymatic enantioselective reduction of their corresponding carbonyl compounds, acetylpyridine derivatives, is one of the most practical and economical strategies. To obtain 1-(pyridyl)ethanol derivatives at high optical purity, a reductase showing high enantioselectivity is necessary.…”

“…5-Acetylfuro [2,3-c]pyridine (AFP) and 5-acetyl-7-chlorofuro [2,3-c]pyridine were prepared following previous reports. 8,9) Racemic alcohols were prepared by NaBH 4 reduction. Glucose dehydrogenase was purchased from Amano Enzyme (Aichi, Japan).…”

Non-Nucleoside Reverse Transcriptase Inhibitors: The NNRTI Boom

“…However, it is characterized by a less favourable pharmacokinetic profile than PNU-142721 (Wishka et al, 1998b). PNU-142721 possess high antiviral activity against a broad spectrum of HIV-1 variants and a favourable pharmacokinetic profile, including penetration of the blood-brain barrier in the rat.…”

Simple Biocatalytic Access to Enantiopure (S)‐1‐Heteroarylethanols Employing a Microbial Hydrogen Transfer Reaction

“…[2a, 18] Optically pure 1-(3-pyridyl)-ethanol 2b was used as starting material for the synthesis of allo-heteroyohimbine alkaloids. [19] For both strains, an increase in reaction rate was observed from the o-(3a) via the m-(2a) to the Scheme 1.…”