Stereospecific synthesis and antiviral properties of different enantiomerically pure carbocyclic 2'-deoxyribonucleoside analogs derived from common chiral pools: (+)-(1R,5S)- and (-)-(1S,5R)-2-oxabicyclo[3.3.0]oct-6-en-3-one

Abstract

Enantiomerically pure (+)- and (-)-carbocyclic thymidine, (-)-carbocyclic 3'-epi-thymidine, (+)-carbocyclic 3'-deoxy-3'-azidothymidine, (+)-carbocyclic 2,3'-O-anhydrothymidine, (+)-carbocyclic 3'-O,6'-methylenethymidine, and (+)-(6'S)-carbocyclic 6'-methylthymidine were synthesized in a stereospecific manner from common chiral pools of (+)-(1R,5S)- and (-)-(1S,5R)-2-oxabicyclo[3.3.0]oct-6-en-3-one and evaluated for antiviral activity. (+)-Carbathymidine and, to a lesser extent, (+)-carbocyclic 2'-deoxyadenosine proved to be effective against HSV-1 [minimum inhibitory concentration (MIC): 0.2 and 2 micrograms/mL, respectively] and HSV-2 (MIC: 2 and 20 micrograms/mL, respectively), but virtually inactive against TK- HSV-1 (MIC: 40 and 100 micrograms/mL, respectively). (+)-Carbathymidine was also active against vaccinia virus (2 micrograms/mL). None of the compounds had a specific effect on the replication of HIV or other RNA viruses.

New and Efficient Synthesis of Racemic Cyclopent-3-en-1-yl Nucleoside Analogues and Their Derivatives

“…Bicyclic nucleosides attracted recently considerable interest because they are conformationally rigid or at least highly constrained analogues 4,20 . Thus, cyclopropanation of the cyclopentene ring was investigated.…”

“…The regioisomers were distinguished by their HMBC-NMR spectra. Both compounds will serve in the future as starting materials for the preparation of, e.g., adenine nucleoside analogues using known procedures 6,7,20 .…”

Influence of the N3‐Protection Group on N1‐ vs. O2‐Alkylation in the Mitsunobu Reaction

“…[4] Since the conformation of the five-membered ring is believed to play a critical role in modulating biological activity, the behaviour of nucleosides with a cyclopentane moiety sometimes differs significantly from that of their natural counterparts. [5] Nevertheless, carbocyclic nucleoside analogues like carbovir (1) [6] and the structurally related abacavir (2) [7] (Ziagen TM ) were found to be potent inhibitors of HIV reverse transcriptase. Moreover, the guanine derivative entecavir (3) [8] (Baraclude TM ) was approved by the FDA in early 2005 for the treatment of chronic HBV infections.…”

Synthesis of Carbocyclic Pyrimidine Nucleosides Using the Mitsunobu Reaction - Part I: Influence of the Alcohol on N1- versus O2-Alkylation

“…7 Since the conformation of the five-membered ring is believed to play a critical role in modulating biological activity, the behavior of nucleosides with a cyclopentane moiety sometimes differs significantly from that of their natural counterparts. 8 A number of strategies have been designed for the preparation of carbocyclic nucleosides. 9 The strategies can be subdivided into two categories: i) the linear approach involves initial synthesis of a functionalized cyclopentylamine and a step-wise synthesis of the heterocyclic base and ii) the convergent approach, here, the appropriate heterocycle is coupled directly to a functionalized carbocyclic moiety, leading to a variety of carbocyclic nucleosides starting from one common cyclopentane precursor.…”