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The aim of this project has been to design and synthesise transitionstate analogues for the preparation of catalytic antibodies. As model reaction the formation/hydrolysis of 2'-deoxy-isomaltose was chosen.A 2'-deoxy-isomaltose analogue, methyl 6,7-dideoxy-7-[(3'R,4'R,5'R)-3',4'-dihydroxy-5'-hydroxymethylpiper idinyl]-alfa-D-glucohepto-pyranoside (1), where the ring oxygen and the exocyclic oxygen in the aglucone are replaced by carbons and the anomeric carbon is replaced by a nitrogen, was designed and synthesised.The starting material was 1,6:2,3-dianhydro-4-O-benzyl-beta-D-glucopyranose (4). The epoxide was opened regioselective with vinylmagnesium bromide followed by ozonolysis with reductive work-up, which resulted in the introduction of a hydroxymethyl group at C-2, whereby 1,6-anhydro-4-O-benzyl-2-C-deoxy-2-hydroxymethyl-beta-D-glucopyran ose was synthesised. Hydrolysis of the anhydro bond and periodate cleavage of the carbon chain gave 4-O-benzyl-2-C-deoxy-hydroxymethyl-D-xylo-pentodialdose. Reductive amination with ammonia resulted in (3R,4R,5R)-4-benzyloxy-3-hydroxy-5-hydroxymethyl-piperidine (9). By catalytic hydrogenation under acidic conditions the hydrochloride of (3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-piperidine was synthesised. Swern oxidation of methyl 2,3,4-tri-O-benzyl-6-deoxy-alfa-D-glucoheptopyranoside gave methyl 2,3,4-tri-O-benzyl-6-deoxy-alfa-D-glucoheptodialdo-1,5-pyranoside which was coupled with the piperidine 9 by reductive amination. This gave methyl 2,3,4-tri-O-benzyl-6,7-dideoxy-7-[3'R,4'R,5'R)-4'-benzyloxy-3'-hyd roxy-5'-hydroxymethylpiperidinyl]-alfa-D-glucoheptopyranoside. Debenzylation by catalytic hydrogenation under acidic conditions resulted in the hydrochloride of 1, which was synthesised in 31% overall yield from 4. Treatment of 1 with hydrogen-peroxide resulted in stereoselective formation of the methyl 6,7-dideoxy-7-[(1'S,3'R,4'R,5'R)-3',4'-dihydroxy-5'-hydroxymethylp iperidinyl]-alfa-D-glucoheptopyranoside N-oxide a 2'-deoxy-gentiobiose analogue. N-Alkylation of 1 with methyliodide resulted in two isomers of methyl 6,7-dideoxy-7-[3'R,4'R,5'R)-N-methyl-3',4'-dihydroxy-5'-hydroxymet hylpiperidinyl]-alfa-D-glucoheptopyranoside, that respectively are a 2'-deoxy-gentiobiose analogue and a 2'-deoxy-isomaltose analogue, in a ratio of 3:1.
|Place of Publication||Kgs. Lyngby, Denmark|
|Publisher||Technical University of Denmark|
|Number of pages||153|
|Publication status||Published - Dec 1996|