Synthesis of 3,6-dideoxy-D-erythro-hexos-4-ulose (3,6-dideoxy-4-keto-D-glucose)

Abstract

The synthesis of 3,6-dideoxy-1,2-0-isopropylidene-a-~-xylo-hexopyranoside (14) starting from methyl 4,6-0-benzylidene-3-deoxy-a-D-ribo-hexopyranoside (2) and from methyl 4,6-0-benzylidene-3-deoxy-a-~-rylo-hexopyranoside (16) is described. An attempt to prepare 14 by the direct isopropylidation of the known 3,6-dideoxy-Drylo-hexose (29) was unsuccessful as the major product formed in this reaction was a furanose derivative, 30. Oxidation of 14 with ruthenium tetroxide in carbon tetrachloride gave the keto sugar derivative 32 which was hydrolyzed with Dowex-50 (H+) to give 3,6-dideoxy-D-erythro-hexos-4-ulose (3,6-dideoxy-4-keto-D-glucose, l), an important intermediate in the biosynthesis of several biologically important 3,6-dideoxy hexoses. The identification of the natural product with the synthetic material 1 has already been recorded.Elucidation of the biochemical pathways for the formation of the biologically important 3,6-dideoxy hexoses, which contribute to the serological specificity of many immunologically active lipopolysaccharides,2 has been the subject of several investigation^.^^^,^ Abequose, paratose, and ascarylose were shown to originate from cytidine 5'-diphosphate-6-deoxy-4-keto-D-glucose which in turn was formed from cytidine 5'-diphosphate-D-glucose. It was established recently that 3,6-dideoxy-D-erythro-hexos-4-~1-XH OH 1 ose (1) as its cytidine diphosphate nucleotide conjugate is the intermediate between cytidine 5'-diphosphate-6-deoxy-4-keto-D-glucose and the 3,G-dideoxy hexoses in Pasteurella pseudotuberculosis type V strain VO.la7 The biological importance of this keto sugar 1 has been increased by the finding that its L isomer (3,6-dideoxy-~-erythro-hexos-4-ulose) occurs in nature as part of the antibiotic cinerubine B.8 In this paper we describe the total synthesis of the free keto sugar 1. The preparation of the a-methyl glycoside of 1 by another route was recently reported by Paulsen and c o -w~r k e r s .~ Methyl 3-deoxy-4,6-0-benzylidene-a-D-ribo-hexopyranosidel0Jl (2) was prepared according to the method of Hedgley et a1.l1 Conversion of 2 to the benzyl ether 3 fol-OCH3 7, R = CH,CtiHj 8, R = H 9, R = Ac M M e s o d OR OR CHj CHj 10, R = AC 12 11, R = H RO CHJ CHJ 13, R = COGjH, 14, R = H 15, R = Tos lowed by removal of the benzylidene protection by acid hydrolysis provided methyl 2-0-benzyl-3-deoxy-a-~-ribohexopyranoside (4). Treatment of 4 with excess of methanesulfonyl chloride in pyridine gave the dimesylate 5.Selective displacement of the primary methanesulfonate group to obtain the 6-iodo derivative 6 was achieved by the treatment of 5 with 1.1 equiv of potassium iodide in refluxing 2-butanone for 90 hr. Hydrogenation of 6 in the presence of triethylamine and 10% Pd/C using ethanol as solvent provided the 3,6-dideoxy sugar derivative, 7.As a keto sugar is usually very sensitive toward acids, it was necessary to change the protection of the hydroxyl group a t position 1 from the methyl glycoside (which requires very strong acid conditions for hydrolysis) to a group that can be e...