Synthetic Approaches To Thiazine Nucleoside Analogs And A Facile Preparation Of 6-thioxanthosine (sulfoximine, Sulfilimine, Pummerer).

Abstract

The reaction of the ammonium salt of 4-mercapto-5-nitroimidazole with bromacetaldehyde diethylacetal afforded 4-(2-diethoxyethyl) mercapto-5-nitroimidazole(32) which upon heating in methanolic HCl afforded 3-ethoxy-7-nitroimidazo 5,1-b thiazole. Benzylation of 32 afforded a single compound which by an NOE difference spectrum was established to be 1-benzyl-5-(2-diethoxyethyl)mercapto-4-nitroimidazole (35). Reductive cyclization of 35 was not successful under the reaction conditions used in this study. Compounds 32 and 35 were oxidized to the sulfoxides 38 and 39 with m-CPBA. Compound 32 was aminated at the sulfur selectively to yield 2-diethoxyethyl-4'-(5'-nitro)imidazolyl sulfilimine (44) which upon catalytic hydrogenation in methanolic HCl afforded 3-methoxy-7-nitroimidazo 5, 1-b thiazole. Neither the animation of sulfoxides 38 and 39 nor the oxidation of sulfilimine 44 to afford the desired sulfoximine derivatives was successful under the reaction conditions used in this study. The reaction of ethyl-2,3-dibromopropionate with sodium azide afforded ethyl-2-azido-2-propenoate which upon reaction with an ethanolic sodium ethoxide solution of ethyl-2-mercaptoacetate afforded 2,3-dihydro- 1,4 thiazin-5-carboxyethyl-3-one (66). Upon reaction with CH(,3)I/(nBu)(,4)NF in benzene, the TMS derivative of 66 yielded 2,3-dihydro- 1,4 thiazin-5-carboxyethyl-4-methyl-3-one. On the other hand, the ribosylation of compound 66 was not successful under the reaction conditions used in this study. Oxidation of compound 66 with m-CPBA afforded a compound which underwent a Pummerer-type rearrangement. A facile synthesis of 6-thioxanthosine was accomplished which involved the ring closure of a cyclic o-aminonitrile precursor by using carbonyl sulfide. A study involving the generality of this reagent for the annulation of cyclic o-aminonitriles under different reaction conditions is also discussed.