Elsevier

Tetrahedron

Volume 64, Issue 33, 11 August 2008, Pages 7828-7836
Tetrahedron

Synthesis and structure of novel cyclonucleoside analogues of uridine

https://doi.org/10.1016/j.tet.2008.05.112Get rights and content

Abstract

Novel cyclonucleoside analogues of uridine having pentylene and hexylene linker between the 5′-O and 3-N positions (thereby generating a 13- and 14-membered ring, respectively) were synthesized from uridine via ring-closing metathesis. An example of cyclic dinucleosides having two butylene linkers between the 5′-O and 3-N positions (24-membered ring) was synthesized from uridine via tandem cross-metathesis and ring-closing metathesis.

Introduction

Nucleoside analogues display a large range of biological activities as antiviral agent analogues1 and as antitumoral agents.2 Such nucleoside analogues normally are prodrug forms of active pharmaceutical agents. They must undergo interactions with proteins in cellular and compartmental membranes, nucleoside kinases, and mono- and/or dinucleotide kinases and then bind with target proteins (e.g., DNA polymerases, reverse transcriptases, and/or other nucleoside triphosphate metabolizing enzymes). In solution, nucleos(t)ide analogues can adopt a number of conformations, which can be determined with four parameters:3 (i) the glycosyl torsion angle χ, which determines the syn or anti disposition of the base relative to the sugar moiety; (ii) the torsion angle γ, which determines the orientation of 5′-OH with respect to C3′ as represented by the three main rotamers +sc, ap, −sc; (iii) the puckering of the furanose ring described by the phase angle of pseudorotation P;4, 5 and (iv) the degree of deviation from planarity of the furanose ring indicated by the maximum out-of-plane pucker νmax.4, 5 The conformations of nucleoside described by these three-state models (χ, γ, P) are in interdependent equilibria and the energy barrier between the preferred conformational state is usually low. The majority of nucleos(t)ide target enzymes appears to have strict conformational requirements for substrate binding. Moreover, the nucleotides adopt distinctive conformations when they are in DNA/DNA and DNA/RNA duplexes (South conformation in B-DNA and North conformation in A-RNA).3 These properties have motivated the synthesis of conformationally restricted nucleos(t)ides for the search of novel nucleoside analogues in the area of antitumoral and antiviral agents,6, 6(a), 6(b), 6(c), 6(d), 6(e), 6(f), 6(g), 6(h), 6(i), 6(j), 6(k), 6(l) and novel oligomers in the antisense technology.7, 7(a), 7(b), 7(c), 7(d), 7(e), 7(f), 7(g) Four families of constrained nucleoside and/or nucleotide analogues have been developed: bicyclonucleosides8, 8(a), 8(b), 8(c), 8(d), 8(e), 8(f), 8(g) (e.g., 1) obtained by bridging two atoms of the furanose moiety with an alkyl chain or analogous ether; cyclic phosphorus esters9, 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h) (e.g., 2) in which a similar bridge is formed between the phosphate group and the furanose moiety or the nucleobase; cyclonucleosides10, 10(a), 10(b), 10(c), 10(d), 10(e) (e.g., 3) in which the bridge is formed between the furanose moiety and the nucleobase; and nucleotide di(tri)mers11, 11(a), 11(b), 11(c), 11(d), 11(e), 11(f), 11(g), 11(h), 11(i), 11(j) (e.g., 4) (Fig. 1).

Metathesis12, 12(a), 12(b), 12(c), 12(d), 12(e), 12(f), 12(g) is an extremely useful method in organic chemistry due to the development of efficient and selective catalysts such as the ruthenium carbenes 5 (first generation Grubbs catalyst)13, 13(a), 13(b), 13(c) and 6 (second generation Grubbs catalyst),14, 14(a), 14(b) which offer a good compromise between efficiency and tolerance to functional groups (Fig. 2). The use of metathesis reactions such as Ring-Closing Metathesis (RCM) and Cross-Metathesis (CM) in the nucleoside field15 has been developed over the last decade for the synthesis of: (i) known antiviral agents such as Stavudine;16, 16(a), 16(b), 16(c) (ii) carbocyclic nucleosides;17, 17(a), 17(b), 17(c), 17(d), 17(e) (iii) acyclonucleosides;18 and (iv) polycyclic nucleosides.11(c), 11(d), 11(i), 19, 19(a), 19(b), 19(c), 19(d)

Recent papers described the synthesis of cyclonucleosides 79 having anti-hepatitis C virus activity in the HCV subgenomic RNA replicon.10(c), 10(d), 10(e) The mode of action of these novel compounds 79 was the subject of studies because the lack of 5′-OH does not permit the phosphorylation to furnish the corresponding nucleotide as required in the classical metabolism pathway. In this paper, we describe the synthesis of cyclonucleoside analogues of 79 via RCM reaction; the target nucleosides 10 having a saturated alkylidene bridge between the O5′-oxygen atom and the N3-nitrogen atom (Fig. 3).

Section snippets

Results and discussion

The strategy developed for the synthesis of 5′,3-cyclonucleosides 10 required to start from the readily available nucleoside acetonide 11.20 3-N and 5′-O bisallylation was realized with KOH, allyl bromide, and 18-crown-6, in THF at rt, to give the key diene 12 in 88% yield. The diene 12 was subjected to a metathesis reaction using catalyst 5 in dichloromethane at 40 °C. Under these conditions only the presence of dimers and starting material was observed.21 The crude product was separated by

Conclusion

In summary, we have demonstrated a concise method using RCM reaction for the synthesis of the 3,5′-O-pentano- and 3,5′-O-hexanouridine. The practicality of using LC/ESI-MS for the stepwise control of RCM and CM reactions in the nucleoside field was also demonstrated. Unfortunately, this strategy did not permit the synthesis of the cyclonucleoside having a butyl linker. In this case, the formation of cyclic dinucleosides having two butylene linkers between the 5′-O and N-3 positions was observed.

General

Melting points were determined on a digital melting-point apparatus (Electrothermal) and were uncorrected. Optical rotations were recorded in CHCl3 or MeOH solutions with a digital polarimeter DIP-370 (JASCO) using a 1 dm cell. 1H and 13C NMR spectra were recorded in CDCl3 or acetone-d6 (internal Me4Si) at 300.13 MHz and at 75.47 MHz, respectively (Bruker Advance-300). TLC was performed on Silica F254 (Merck) and detection was by UV light at 254 nm or by charring with phosphomolybdic-H2SO4 reagent.

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