Asymmetric synthesis of (3S)-2,3,4,5-tetrahydropyridazine-3-carboxylic acid and its methyl ester†

Abstract

Methyl (2E,4E)-5-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)penta-2,4-dienoate 16a, assembled by a Wittig condensation of tributyl(methoxycarbonylmethylene)phosphorane 19a and (2E)-3-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)propenal 20, displays excellent Re-face reactivity towards diethyl azodicarboxylate 15a, bis(2,2,2-trichloroethyl) azodicarboxylate 15b, dibenzyl azodicarboxylate 15c, diisopropyl azodicarboxylate 15d and di-tert-butyl azodicarboxylate 15e in thermal hetero-Diels–Alder reactions to give the cycloadducts 17a–e. When subjected to the action of hydrogen over palladium–carbon, the cycloadducts 17a, 17b, 17d and 17e undergo hydrogenation of their olefinic bonds to give the dihydro derivatives 18a, 18b, 18d and 18e; in the case of the cycloadduct 17c, hydrogenolysis of the benzyloxycarbonyl group also occurs to give methyl (3S)-2,3,4,5-tetrahydropyridazine-3-carboxylate 1b with an ee of 98% and 2,3,4,6-tetra-O-acetyl-β-D-glucopyranose 22. Compound 1b, with an ee of 98%, is also available from the dihydro derivative 18e by the action of trifluoroacetic acid; however, under the acidic conditions, a condensation reaction between the aglycone 1b and the glycone 22 competes to give methyl (3S)-2,3,4,5-tetrahydro-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyl)pyridazine-3-carboxylate 25.

Sodium (3S)-2,3,4,5-tetrahydropyridazine-3-carboxylate 1c, with an ee of 99%, is available from the ester 1b by a saponification reaction. The trifluoroacetic acid salt 27, with an ee of 95%, is obtained from benzyl (3S,6S)-1,2-bis(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-6-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)pyridazine-3-carboxylate 17g by a hydrogenation–trifluoroacetolysis sequence. A hetero-Diels–Alder reaction involving the benzyl pentadienoate 16c and di-tert-butyl azodicarboxylate 15e provides the cycloadduct 17g.