Total Synthesis of the Trisaccharide Antigen of the Campylobacter jejuni RM1221 Capsular Polysaccharide via de Novo Synthesis of the 6-Deoxy-d-manno-heptose Building Blocks

Abstract

A de novo approach utilizing the d-proline-catalyzed and LDA-promoted aldol reactions as key steps for the preparation of differentiated-protected 6-deoxy-d-manno-heptose building blocks was developed. PPh3AuBAr4 F-catalyzed glycosylation with the 6-deoxy-d-manno-heptosyl o-hexynylbenzoate as donor was demonstrated as a direct and practical method for the stereoselective synthesis of the β-linked 6-deoxy-d-manno-heptoside as the major product. Coupling of the 6-deoxy-α-d-manno-heptosyl H-phosphonate with the 3-hydroxyl disaccharide acceptor based on H-phosphonate chemistry was described for the construction of the trisaccharide skeleton with the acid-labile phosphodiester linkage. Finally, first total synthesis of the unique trisaccharide antigen of the capsular polysaccharide of Campylobacter jejuni RM1221 that belongs to HS:53 serotype complex was accomplished for further evaluation as vaccine candidate against C. jejuni RM1221 infection.

Promoter-Assisted Stereoselective Synthesis of the 6-Deoxy-β-d-manno-heptopyranose Oligosaccharides

“…The most widely used approach for stereoselective construction of 1,2- cis -mannosidic linkages is the Crich-type β-mannosylation that relies on the recruitment of 4,6-benzylidene-protected mannosyl donors. − Nevertheless, the structural feature of the 6-deoxy- d - manno -heptose unit renders introduction of the 4,6-benzylidene-type groups inconvenient . Gauthier et al utilized the 2-naphthylmethyl (NAP)-mediated intramolecular aglycone delivery (IAD) strategy for the stereocontrolled synthesis of the 6-deoxy-β- d - manno -heptosides of B. pseudomallei and B. mallei . , Scott and co-workers described a postcoupling C-2 inversion approach to synthesize 2- O -acetyl-6-deoxy- d - manno -heptopyranose hexasaccharide of B. pseudomallei and B. mallei . , Gu and co-workers employed the hydrogen-bond-mediated aglycone delivery (HAD) strategy for the stereoselective synthesis of the β-1,3-linked 6-deoxy- d - manno -heptopyranose oligosaccharides of B. pseudomallei and B. mallei . , Our group reported the first total synthesis of the 6-deoxy-β- d - manno -heptose-containing trisaccharide antigen of C. jejuni HS53-type strain RM1221 via the PPh 3 AuBAr 4 F -catalyzed glycosidation with glycosyl o -hexynylbenzoate as the donor. − Although these elegant approaches have proven to be effective in the construction of 1,2- cis -mannosidic linkages of 6-deoxy-β- d - manno -heptosides, they still suffered from limited substrate scope, lengthy synthetic routes, and poor overall yields.…”

“…Considerable efforts have been devoted to the synthesis of 6-deoxy- d - manno -heptose building blocks, in which one-carbon or two-carbon chain elongation was often used to obtain the unique seven-carbon sugars. , Notably, de novo synthesis via two aldol reactions served as an alternative approach for the preparation of 6-deoxy- d - manno -heptose building blocks. ,, Here, we report a promoter-assisted glycosidation approach for the stereoselective construction of 1,2- cis -β-mannosidic linkages of 6-deoxy- d - manno -heptosides based on gram-scale de novo synthesis of 6-deoxy- d - manno -heptose building blocks. Under the assistance of SphosAuNTf 2 , the β-selective mannosylation of glycosyl o -hexynylbenzoate was then applied to the stereocontrolled synthesis of 6-deoxy-β- d - manno -heptopyranose tri- and tetrasaccharides relevant to B. pseudomallei and B. mallei .…”

“…Starting from the known alcohol 1 , we set out to develop a modified and practical de novo synthetic route to obtain gram-scale 6-deoxy- d - manno -heptose building blocks (Scheme ). Benzylation of the 2-hydroxyl group of 1 (>20 g) with benzyl bromide in the presence of sodium hydride and dimethylformamide followed by chemoselective cleavage of the isopropylidene acetal group using aqueous HCl in dichloromethane gave β-hydroxyl ketone 2 in 72% yield over two steps.…”

“…The glycosidation of o -hexynylbenzoate 7 with N -benzyl- N -benzyloxycarbonyl pentyl linker , 8 was then investigated under the promotion of various gold­(I) complexes in dichloromethane at −40 °C (Table ). Under the activation of PPh 3 AuBAr 4 F (0.35 equiv) adopted by the previous reports, , glycosidation of donor 7 (1:1.1 α:β) with linker 8 gave glycoside 9 in 88% yield with poor selectivity (1.4:1 β:α, entry 1). When 0.1 equiv of Ph 3 PAuOTf was used, the glycosidation proceeded smoothly to afford glycoside 9 in an excellent 98% yield, but almost no selectivity was observed (entry 2).…”

Total Synthesis and Immunological Evaluation of the Tri-d-glycero-d-manno-heptose Antigen of the Lipopolysaccharide as a Vaccine Candidate against Helicobacter pylori

“…Compared with the traditional preparation of d - glycero - d - manno -heptose building blocks using the homologation strategy that often employed highly toxic osmium salt for dihydroxylation of the double bond, , de novo synthesis represents an appealing alternative strategy for producing rare heptose building blocks. , Here, we report the total synthesis of the α-(1→3)-linked tri- d - glycero - d - manno -heptose antigen based on de novo synthesis of the differentially protected d - glycero - d - manno -heptosyl building blocks. Immunization of mice with the resulting semisynthetic glycoconjugate generates IgG antibodies that bound strongly to the intact H. pylori bacteria, indicating that the α-(1→3)-linked tri- d - glycero - d - manno -heptose is a highly promising antigen for vaccine development against H. pylori infections.…”