1 Department of Organic Chemistry, Technical University of Denmark2 Department of Chemistry, Technical University of Denmark
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.