Chemical Approaches to Carbocyclic Nucleosides

Abstract

Nucleoside analogues are at the forefront of antiviral therapy for last decades. To circumvent some of their limitations, based on their metabolism, and in order to improve their anti‐viral potency and selectivity, several families of nucleoside analogues have been described through structural modifications at the sugar and heterocycles. The replacement of the oxygen of the nucleoside by a methylene has led to the family of carbocyclic (or cyclopentane) nucleoside analogues. Various potent anti‐HIV and anti‐HBV drugs belong to this family. Main syntheses of carbocyclic analogues of nucleosides used Diels‐Alder reactions (in racemic or asymmetric series), but also started from carbohydrates (ribose, glucose), as a source of optically active compounds, which then had to be transformed into carbacycles under various conditions. The growing interest in carbocyclic nucleosides has led several groups, including ours, to develop new analogues and to explore novel routes. This article will review some of the recent chemistry developed on selected five‐membered ring carbocyclic nucleosides.

Synthesis of fluorinated carbocyclic pyrimidine nucleoside analogues

“…9,10 The templating of additional ribose ring modifications, ontop of furanose oxygen replacement, enables further divergence to explore new modalities. 11,12 A third and perhaps more extensively interrogated class of ethereal replacement harnesses carbon; 13 carbanucleosides (a cyclopentane core with oxygen replaced by CH 2 ) exist naturally as highly cytotoxic agents aristeromycin and neplanocin A. Carbocyclic nucleosides are resistant to enzymatic degradation, as the hemi-aminal linkage targeted by nucleoside phosphorylases is absent, and adopt alternative ring conformations compared to classical (C3' or C2' endo) systems. 14,15 The carbocylic structural motif has successfully underpinned development of the therapeutics abacavir and entecavir and has recently been included within synthetic RNA oligonucleotides.…”

Conformationally Locked Carbocyclic Nucleosides Built on a 4′-Hydroxymethyl-3′-hydroxybicyclo[4.1.0]heptane Template. Stereoselective Synthesis and Antiviral Activity

“…Carbocyclic NAs (CNAs) are structurally related to ribonucleosides in which a carbocycle is in the place of the sugar moiety. , CNAs are recognized by the same enzymes as natural nucleosides and are more stable toward hydrolysis by phosphorylases displaying enhanced biostability. This family of CNAs includes, among others, the cyclopentene derivatives abacavir and entecavir and the six-membered counterpart cyclohexenyl G (DCG, Figure ).…”

A Highly Stereospecific Claisen–Sakurai Approach to Densely Functionalized Cyclopentenols

“…Densely functionalized five-membered ring systems are prevalent in many natural products and have become increasingly sought after by the pharmaceutical industry (Figure 1). 1 These types of compounds are ideal scaffolds for drug discovery due their rigid nature while retaining a high sp 3 :sp 2 atom ratio which can provide enhanced pharmacokinetic properties. 2 This motif is especially prevalent in virology with compounds with carbocyclic nucleoside analogue reverse transcriptase inhibitors, such as abacavir, licensed to combat HIV and HBV.…”

“…2 This motif is especially prevalent in virology with compounds with carbocyclic nucleoside analogue reverse transcriptase inhibitors, such as abacavir, licensed to combat HIV and HBV. 3 The neuraminidase inhibitor peramivir also contains a stereochemically dense cyclopentane core. 4 Complex cyclopentanes are found in numerous natural products, including terpenes, 5 polyketides, 6 and alkaloids, 7 such as palau'amine.…”

“… These types of compounds are ideal scaffolds for drug discovery due their rigid nature while retaining a high sp 3 :sp 2 atom ratio which can provide enhanced pharmacokinetic properties . This motif is especially prevalent in virology with compounds with carbocyclic nucleoside analogue reverse transcriptase inhibitors, such as abacavir, licensed to combat HIV and HBV . The neuraminidase inhibitor peramivir also contains a stereochemically dense cyclopentane core .…”