Contributions to the synthesis of "mirror" cord factors, cyclodextrin analogs, and 3-deoxy-D-manno-2-octulosonic acid.
Creators: name: Shen, Yaping.
Publisher: name: Université d'Ottawa / University of Ottawa
Year: 1993
Subjects: subject: Chemistry, Organic.

description: Section I. The new disaccharide, crystalline (6-deoxy-$\alpha$-D-gluco-heptopyranosyluronic acid) 6-deoxy-$\alpha$-D-gluco-heptopyranosiduronic acid 5 was synthesized from $\alpha, \alpha$-trehalose 1. Reaction of 2,3,4,2$\sp\prime$,3$\sp\prime$,4$\sp\prime$-hexa-O-acetyl-6,6$\sp\prime$-di-O-tosyl-$\alpha, \alpha$-trehalose 7 with sodium dicarbonylcyclopentadienyliron, followed by oxidative carbonyl insertion and hydrolysis with bromine and water, gave the 2,3,4,2$\sp\prime$,3$\sp\prime$,4$\sp\prime$-hexa-acetate 16 of 5, which was then O-deacetylated (Zemplen). The protected bis-heptosiduronic acid, (2,3,4-tri-O-benzyl-6-deoxy-$\alpha$-D-gluco-heptopyranosyluronic acid) 2,3,4-tri-O-benzyl-6-deoxy-$\alpha$-D-gluco-heptopyranosiduronic acid 26, was similarly synthesized by the ironcarbonyl method of chain elongation, starting from 2,3,4,2$\sp\prime$,3$\sp\prime$,4$\sp \prime$-hexa-O-benzyl-6,6$\sp\prime$-di-O-tosyl-$\alpha, \alpha$-trehalose 24. In this case, oxidative carbonyl insertion was effected with iodine in the presence of methanol, and the dimethyl ester 25 obtained was subsequently saponified to 26. The dimethyl ester 25 was also prepared by acid-catalyzed methanolysis of the corresponding diamide 29, which can be obtained from the ditosylate 24 by cyanide displacement and alkaline hydrolysis of the resulting dinitrile 28. Mitsunobu esterification of the diacid 26 with (racemic) diastereomeric 3-O-benzylcorynomycolyl alcohols, obtained by reduction of synthetic, 3-O-benzylated methyl C$\sb{32}$-corynomycolates with lithium aluminum hydride, furnished the corresponding diesters in high yields. Hydrogenolytic debenzylation of the products led to "mirror" coryno-cord factors 47a and 47b. Section II. Approaches to chain extension at the C-6 positions in cyclomaltoheptaose (2) were examined with the aim of producing novel beta-cyclodextrin analogs composed of heptose or hepturonic acid units. Ironcarbonyl-mediated methoxycarbonylation, and nucleophilic displacement by cyanide, in the fully acetylated heptakis(6-deoxy-6-iodo) and heptakis(6-O-mesyl) derivatives of 2 respectively were unsuccessful, as were similar reactions attempted with the newly synthesized, analogous allyl-protected derivatives of 2. However, reaction of unprotected heptakis(6-deoxy-6-iodo)cyclomaltoheptaose with lithium cyanide in N,N-dimethylformamide afforded a high yield of the corresponding heptakis(6-cyano-6-deoxy) compound, i.e., cyclohepta-($1\to 4)$-(6-deoxy-$\alpha$-D-gluco-heptopyranosid)urononitrile 26, catalytic hydrogenation of which gave the title compound, cyclo-$( 1\to 4)$-(7-amino-6,7-dideoxy-$\alpha$-D-gluco-heptopyrano)heptaose 6, isolated as its peracetyl derivative 29. Section III. An approach to the synthesis of 3-deoxy-D-manno-2-octulosonic acid (KDO) 1 by the ironcarbonyl method of chain-elongation starting from methyl $\alpha$-D-mannopyranoside 2 was attempted. Reaction of methyl 2,3,4-tri-O-acetyl-6-O-p-tolylsulfonyl-$\alpha$-D-mannopyranoside 3 with sodium dicarbonylcyclopentadienyliron, followed by oxidative carbonyl insertion and hydrolysis with bromine and water, gave the methyl 2,3,4-tri-O-acetyl-6-deoxy-$\alpha$-D-manno-heptopyranosiduronic acid 5. O-Deacetylation then afforded methyl 6-deoxy-$\alpha$-D-manno-heptopyranosiduronic acid 6 in high yield. Compound 6 can also be obtained from methyl (methyl 2,3,4-tri-O-benzoyl-6-deoxy-$\alpha$-D-manno-heptopyranosid)uronate 8 by O-debenzoylation and alkaline hydrolysis of the resulting methylester 9. Acid hydrolysis of 6 gave the free hepturonic acid 10 and an unknown product. Treatment of this mixture with sodium borohydride, followed by acetylation, provided the corresponding penta-O-acetyl-2-deoxy-D-manno-heptonic acid 11.