A Short and Convenient Synthesis of New 1,2-Disubstituted Carbocyclic Nucleoside Analogues of Pyrimidine Based on a Cyclopentene Ring

Abstract

The synthesis of a new series of 1,2-disubstituted carbonucleoside analogues, pyrimidines of general structure I, is reported. These compounds were prepared in good yield from (±)-6-azabicyclo[3.2.0]hept-3-en-7-one (1) via two synthetic routes that involve NaBH 4 -mediated C-N bond cleavage as the key step. The uracil derivative Ia was halogenated with Cl, Br, and I at position 5 by treatment with the corresponding N-halosuccinimide.Nucleoside analogues display a wide range of biological activities and have attracted particular attention as antiviral and antitumor agents. 1-4 The synthesis of new modified nucleosides represents an important and increasingly active area of interest for organic chemists in the search for compounds with improved biological properties. 5,6 Within this area, systems of particular interest include carbocyclic nucleosides and 2¢,3¢-dideoxynucleosides. Carbocyclic nucleosides are compounds in which the furanose oxygen atom of a classical nucleoside is replaced by a methylene group. These compounds possess greater metabolic stability toward the nucleoside phosphorylases and a higher lipophilicity, 7 two properties that are potentially beneficial in terms of increased in vivo half life, oral efficiency and cell wall penetration. 8 On the other hand, a number of 2¢,3¢-dideoxynucleosides are currently the drugs of choice for the treatment of certain viral infections (including AIDS). 9 Indeed, the potent HIV-1 inhibitor carbovir and its prodrug, abacavir, combine the two types of structural modification described above.On the basis of the factors outlined above, and as part of our study of the therapeutic potential of 1,2-disubstituted carbonucleosides (OTCs), 10-12 we describe now the synthesis of (±)-cis-1-(2-hydroxymethyl-4-cyclopentenyl)-2,4-pyrimidinediones of structure I (Schemes 1 and 3). We previously developed another series of pyrimidinebased OTCs in which the pseudosugar is a cyclopentane ring, 11 and in this present study unsaturation has now been incorporated into the 2¢,3¢-position of the carbocycle. 12 Such a structural modification also allows versatility in the functionalization of the ring. 5-Halopyrimidines (Ibd, Scheme 3) are not only of interest for their potential chemotherapeutic properties 13 but also as synthetic intermediates in the formation of new carbon-carbon or carbon-heteroatom bonds. 14 Our usual approach to the synthesis of uracil-based OTCs is to construct the heterocyclic base on an appropriate amino alcohol by reaction with a b-alkoxyacryloyl isocyanate followed by acid-catalyzed cyclization according to published procedures. 15,16 The preparation of the uracil derivative Ia, which is the precursor for the other compounds in the series, employed b-lactam 1 as the starting material. Compound 1 was obtained in 46% yield by a [2 + 2]-cycloaddition between cyclopentadiene and chlorosulfonyl isocyanate, 12 two commercially available compounds, and Ia was subsequently prepared following the two synthetic routes outlined in Scheme 1. The first route represents t...

Synthesis of novel N-cyclopentenyl-lactams using the Aubé reaction

“…2 and Supporting Information File 1 [46–47]. The synthesized trihydroxylated amides (±)- 11 –(±)- 15 can be considered as mimics of 1,2-carbocyclic nucleosides due to close structural resemblance with that of molecules documented in the literature [29–30]. …”

“…These cyclopentenoid–lactams, which look like carbocyclic nucleosides, were prepared using the Aubé reaction where it was planned to use an azido alcohol embedded in a cyclopentenoid system. It is well established in the literature that carbocyclic nucleosides and related compounds are important to pharmaceuticals and these compounds have been the focus of many studies and a number of reported syntheses [17–30]. Some selected compounds and their important associated activities are highlighted in Fig.…”