Synthesis and Reactivity of Halogenated 1,2,4-Triazole Nucleoside Analogues with High Potential for Chemical Modifications

Abstract

1,2,4-Triazole nucleoside analogues bonded at N-1 of the base were synthesized by addition of N-halo-3,5-dibromo-1,2,4-triazoles to 1,2-unsaturated carbohydrate derivatives (glycals). Examples are given for 1,5-anhydro-3,4,6-tri-O-acetyl-2-deoxy-D-arabino-hex-1-enitol (tri-O-acetyl-D-glucal), and 1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-D-arabino-hex-1-enitol (tri-O-benzyl-D-glucal), respectively. The graduated reactivity of the three halogens [C-5 (triazole) > C-2 (sugar) > C-3 (triazole)] in the addition products allows subsequent regioselective replacement and deprotection reactions like hydrodehalogenations, nucleophilic substitutions (by methoxide, hydrazine, benzylamine, thiophenolate), deacetylations, and debenzylations, respectively. Thus, the paper opens a new synthetic approach to triazole nucleoside analogues of 2-deoxy-sugars. X-ray analyses support the structures of nine products. 1,3,5-Tribromo-1,2,4-triazole (1), synthesized by a very simple procedure in 1967, 1 attracted interest as a bromination reagent shortly after publication. 2 Addition products of 1 to suitable unsaturated compounds offer valuable synthetic potential due to the graduated reactivities of the halogens in nucleophilic addition-elimination reactions. Thus, investigations on 3,5-dibromo-1-methyl-1,2,4-triazole have shown that the halogen atom located on C-5 is significantly more reactive than that on C-3. 3,4 This observation was convincingly confirmed by recent studies on various 1-alkyl-3,5-dibromo-1,2,4-triazoles 5 and on 1-(2,3,5-tri-O-acetyl-b-D-ribofuranosyl)-3(5)-bromo-5(3)-carbamido-1,2,4-triazole 6 as well as reactions with 1-phenyl-5-bromo-1,2,4-triazole. 7,8 It is assumed that the mesomeric discrimination of intermediate A relative to B is the reason for the difference in reactivity of the halogens (Scheme 1).Various methods for regiospecific and stereoselective electrophilic addition reactions of azole and azine derivatives to pyranoid and furanoid glycals were reported in the literature as key steps in nucleoside syntheses. 9-12 Herdewijn et al. 13,14 and Eschenmoser et al. 15 synthesized pyranose nucleosides and investigated their incorporation into oligonucleotides, respectively. The biological activity of 1,2,4-triazole nucleoside analogues has been widely demonstrated, 16-19 thus our efforts were focused on providing a new synthetic strategy towards 2-deoxy-sugar derivatives. The strategy presented in this paper allows the design of triazole nucleoside analogues with a variable pattern of groups on the C-5 of the triazole ring. This was achieved by regioselective additions of 1,3,5-trihalogeno-1,2,4-triazoles to 1,2-unsaturated sugars (glycals) combined with subsequent regioselective replacement of the halogens by nucleophiles or by hydrogen. Indeed, the enol ether unit of a glycal ensures, above all, the addition step is highly regioselective but rarely diastereoselective. [20][21][22] However, the loss of stereochemistry becomes less important because the halogen atom, introduced into C-2 of the sugar moiety, is...

Development of a Scalable Route toward an Alkylated 1,2,4-Triazol, a Key Starting Material for CXCR3 Antagonist ACT-777991

“…By using 7 , only two different regioisomers can be formed ( N 1 / N 2 vs N 4 ) in the alkylation step. Literature reference suggested that the following debromination could be performed selectively on the bromo substituent vicinal to the alkylated nitrogen, leaving the other bromide substituent behind as a functional handle for the methylation …”

“…3,5-Dibromo-1H-1,2,4-triazole (7) caught our attention as a starting material for the desymmetrization approach as it is inexpensive and readily available on large scale. 4 By using 7, only two different regioisomers can be formed (N 1 /N 2 vs N 4 ) in the alkylation step. Literature reference suggested that the following debromination could be performed selectively on the bromo substituent vicinal to the alkylated nitrogen, leaving the other bromide substituent behind as a functional handle for the methylation.…”

“…LC/MS purity: 99% a/a (210 nm); NMR Assay: 77% w/w (contains ∼18% MeCN); m.p. 101 °C (DSC); 1 (4). A 5 L double-jacketed glass reactor was charged with Me-acetimidate HCl (144 g, 1.09 mol, 1.5 equiv) and MeCN (2.5 L, 12 vol).…”

“…Unfortunately, the desired N 1 -product 4 of the alkylation step could only be isolated in 17% yield, as the reaction was unselective with regard to N 1 -, N 2 -, and N 4alkylation. The N 4 -isomer 6 had to be separated by chromatography before the N 2 -isomer 5 was then removed by recrystallization from MTBE.…”