Thio Sugars: Stereochemical Questions and Synthesis of Antimetabolites

Dithioacetals of sugars provide useful starting materials for synthesis of various deoxy sugar derivatives by way of polythio intermediates, and also afford convenient access to acyclic aldose derivatives having two different substituents at C-i. The conformations of aldose diethyl and diphenyl dithioacetals in solution, as determined by p.m.r. spectroscopy with the aid of lanthanide salts, follow the general principle of avoidance of parallel 1,3interactions earlier advanced for peracylated derivatives. The introduction of additional alkylthio groups into the chain, as observed by Brigl, offers a useful route to thio sugars and deoxy sugars, but configurational assignment of the thio derivatives has proved difficult; the extreme readiness whereby 2-alkyl2-thioaldoses undergo epimerization is a contributing factor that has been studied by use of deuterium incorporation and other procedures. The diethyl dithioacetal of 2-S-ethyl-2-thio-D-mannose, a compound whose conformation has been studied comparatively by p.m.r. spectroscopy in solution and by x-ray crystallography in the solid state, is readily converted in high yield into ethyl 2-S-ethyl-2-thio-cx-D-mannofuranoside. The latter compound, also obtainable by nitrous acid deamination of the diethyl dithioacetal of 2-amino2-deoxy-D-glucose, constitutes a convenient starting material for synthesis of 2'-thio and 2'-deoxyfuranosyl nucleosides, certain of which display in vivo tumor-inhibitory activity. Other tumor-inhibitory nucleoside analogues, having an acyclic sugar chain, are obtained from protected aldose dithioacetals by halogenation and subsequent coupling with a derivative of a heterocyclic base, followed by removal of protecting groups. The biological activities of the products show variation according to the stereochemistry of the acyclic chain. These acyclic sugar nucleosides, which have the SR / —CH functionality at C-i, are frequently obtained as pairs of C-i Nbase epimers, and the assignment of stereochemistry at this position is discussed, together with determination of the favored conformation of the acyclic chain.