Synthesis and stereochemical characterization of a series of five-carbon, acyclic-sugar derivatives of 1,6-dihydro-6-thioxopurine (6-mercaptopurine)

Abstract

The four acetylated d-aldose diethyl dithioacetals ( 1a-d) were treated with bromine to give the corresponding, unstable 1-bromides ( 2a-d), which were immediately condensed with 6-chloro-9-(chloromercuri)purine ( 3) to furnish the respective, protected nucleosides ( 4a-d). Subsequent treatment with thiourea gave the crystalline 6-mercaptopurine analogs ( 5a-d) which, upon deacetylation in butylamine-tetrahydrofuran, gave the free, acyclic-sugar nucleosides ( 6a-d)- With the exception of the arabino derivative 4b, the 6-chloropurine derivatives were mixtures of 1′-epimers. Crystallization of the acylated 6-mercaptopurine derivatives afforded single 1′-epimers for 5a-c; 5d remained an epimeric mixture. A positive Cotton effect for both the ribo and arabino analogs 5a and 5b, and a negative Cotton effect for the xylo derivative 5c, suggested the (1′ R) configuration for 5a and 5b, and the (1′ S) configuration for 5c. Proof of the stereochemistry at C-1 (as well as proof of derivatization at N-9 of the purine ring) was afforded by X-ray crystallographic analysis of the arabino derivative 5b, which was demonstrated to have the (1′ R) configuration. Use of the Generalized Heterocycle Rule also supported the stereochemical attributions at C-1′ for the remaining compounds. The arabino derivative 5b adopts an extended, planar, zigzag conformation of the side chain in solution, as well as in the crystalline state, whereas the ribo ( 5a) and xylo ( 5c) derivatives exist in solution as non-extended, sickle conformations; the lyxo analog ( 5a) was found to be a mixture of 1′-epimers, both of which adopt in solution an extended, planar, zigzag arrangement of the sugar chain.