Several hitherto unknown (E)-but-2-enyl nucleoside phosphonoamidate analogs (ANPs) were prepared directed with nitrogen reagents by cross-metathesis in water-under ultrasound irradiation. Two diastereoisomers were formally identified by X-ray diffraction. These compounds were evaluated against a large spectrum of DNA and RNA viruses. Among them, the phosphonoamidate thymine analogue 19 emerged as the best prodrug against varicella-zoster virus (VZV) with EC values of 0.33 and 0.39 μM for wild-type and thymidine kinase deficient strains, respectively, and a selectivity index ≥200 μM. This breakthrough approach paves the way for new purine and pyrimidine (E)-but-2-enyl phosphonoamidate analogs.

Several hitherto unknown acyclic 2‐methyl‐but‐2‐enyl nucleoside phosphonate analogs (ANPs) and their bis‐(pivaloyloxymethyl) prodrug forms were prepared by a challenging ultrasonic‐assisted olefin cross metathesis and further modifications under microwaves, giving rise to a small library of title compounds. These ANPs were evaluated against a wide spectrum of DNA/RNA viruses. Among them, the most active compound exhibited a micromolar anti‐HIV‐1 activity with an EC50 of 1.1 µM and an EC90 of 4.2 µM.

Nucleoside analogs are extremely useful for the development of therapeutic agents to control viral diseases and cancer. Among the numerous modifications on the nucleoside skeleton, replacement of the oxygen of the furanose ring by a CH2 group resulted in increased flexibility and higher resistance to phosphorylases and led to carbocyclic nucleoside analogs (or carbanucleosides). The broad spectrum of biological activities of carbocyclic nucleosides led to tremendous research interest in their syntheses. The article documents recent strategies for the synthesis of active carbocyclic nucleosides by presenting individual case studies, such as the neplanocins, entecavir and selected fluorinated carbocyclic nucleosides. Furthermore, it provides new insights into new directions for more potent and active carbocyclic nucleoside analogs.

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Protected pyrimidine nucleobases are of major importance as intermediates in the synthesis of nucleoside analogues and molecules with biological interests. We describe herein a novel practical microwaveassisted N-Boc protection of pyrimidine nucleobases under mild conditions using silica gel, avoiding treatment steps, and in increased yield.Pyrimidine systems are found in many drugs which interact with the synthesis and functions of nucleic acids such as the antitumor drug uorouridine 1 (1), the anti-HIV drug lamivudine 2 (2) or the anti-HBV drug telbivudine 3 (3), or the antimalarial drug pyrimethamine 4 (4), (Fig. 1), to only quote some of them.As chemical modications of nucleobases are of paramount importance in the development of new drugs, 5 their syntheses have been largely described. 6 Focusing on the base moiety, a key step is the choice of the appropriate protecting groups for the N1 and N3 atoms of pyrimidines which have to meet several requirements such as: a differential protection at N1 and N3, a selective deprotection, and a removal under mild reaction conditions. There is an abundant literature relating to the protection of amino groups, such as by 9-uorenyl-methoxycarbonyl (FMOC), 7 tert-butyl carbamates (Boc), benzyl carbamate, benzamide, acetamide, 8 phtalimides, 9 triphenyl methyl amide 10 and tosylamide. 11Among these groups, one of the most used is the Boc; it's stable towards most nucleophiles and bases 12 and it can be removed cleanly and selectively under neutral conditions. 13 This is of particular interest when working with biolabile groups such as found in nucleoside prodrugs. 14 Surprisingly, only two teams have reported the synthesis of N-Boc-protected pyrimidines under basic conditions and in two steps. Gothelf et al. 15 have prepared the N3-Boc-protected thymine (6) through the formation of N1,N3-di-Boc protected derivative and subsequent selective deprotection of N1-Boc group with K 2 CO 3 in dioxane, in only 31% overall yield (Fig. 2). Porcheddhu et al. 16 have described the synthesis of N4,N4-di-Boc cytosine (7) in two steps in moderate 60% yield, via the fully Boc protected cytosine which was then treated with aq. NaHCO 3 in MeOH at reux. However, in spite of their potential utility, these methods suffer from some drawbacks such (a) a long reaction time implied by the rst step, (b) unsatisfactory yields of the deprotection step and (c) cumbersome product isolation procedures. Thus, we present herein, a greener practical protocol to selectively synthesize N1-free, N3-Boc protected pyrimidine nucleobases (5-7, 8a-c) under milder conditions, shorter reaction time and in moderate to quantitatively yields.The general strategy involves two steps: (1) the use of microwave irradiation to reach quantitatively the fully protected pyrimidines (10a, b) and (2) the subsequent selective N1-deprotection by treatment with SiO 2 (ref. 17) in diethoxymethane/ethanol (9 : 1) as an eco-friendly surrogate to CH 2 Cl 2 /MeOH, to desired compounds 5 and 6, respectively Fig. 1 Chemotherapeutics c...

The detailed synthetic protocol for the straightforward, efficient synthesis of various alkenyl acyclonucleosides, including challenging trisubstituted alkenyl acyclonucleoside phosphonates, is described. The key step of those syntheses is an olefin cross-metathesis reaction between two olefins selected based on their reactivity using well-defined ruthenium alkylidene catalysts.

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