Synthesis of α-d-Glcp-(1→3)-α-d-Galf-(1→2)-α-l-Rhap constituent of the CPS of Streptococcus pneumoniae 22F. Effect of 3-O-substitution in 1,2-cis α-d-galactofuranosylation

Abstract

The synthesis of the trisaccharide a-D-Glcp-(1/3)-a-D-Galf-(1/2)-L-Rhap (3) constituent of Streptococcus pneumonia 22F was achieved with complete diastereoselectivity. This is the first example of a synthesis of an internal a-D-Galf containing oligosaccharide of a pathogen microorganism. Allyl a-Dgalactofuranoside, used as novel precursor of the internal Galf, allowed the introduction of an orthogonal group at O-3. The trichloroacetimidate method was used for the construction of 1,2-cis-a-D-galactofuranosyl linkage. The influence of the 3-O-substituent (PMB, Bz, PFBz, PMBz, TIPS) was evaluated in benzylated galactofuranosyl trichloroacetimidate donors in terms of yield and selectivity of a-D-Galf-(1/2)-a-L-Rhap product as well as donor rearrangement by-product. Complete stereoselectivity was observed with all protecting groups used in the Galf donor, but the 3-O-benzoyl substitution gave the best yield. Protective groups were also evaluated in the rhamnoside acceptor, benzyl substitution was a requirement for complete stereoselectivity.

Conformationally restricted 3,5-O-(di-tert-butylsilylene)-d-galactofuranosyl thioglycoside donor for 1,2-cis α-d-galactofuranosylation

“…35 More recently, a complete stereoselective formation of the a-D-Galf(1?2)Rha linkage in the synthesis of a trisaccharide constituent of Streptococcus pneumoniae 22F was carried out by the trichloroacetimidate method, after tuning the reactivity of the galactofuranosyl donor and the rhamnoside acceptor. 36 The less pronounced anomeric effect and the flexible ring of furanose increase the difficulty to obtain 1,2-cis linkages stereoselectively. Inspired by studies on C-glycosylation of five-membered ring oxacarbenium ions performed by Woerpel et al, 37 3,5-O-ditert-butylsilylene 21,22 and 3,5-O-tetra-isopropyldisiloxanyllidene 23 conformationally locked arabinofuranoside donors were developed to avoid the eclipsing interaction between the incoming nucleophile acceptor and H-2 of the oxacarbenium ion in the presumably E 3 conformation, 21 leading to 1,2-cis glycosides with high diastereoselectivity.…”

“…The less nucleophilicity of 6-OH of the benzoylated analogue 26 compared to 6-OH of benzylated analogue 28 could be rationalized due to a better selection to discriminate the a-face toward the oxacarbenium ion.Our study continued with rhamnosyl acceptor 30. Very recently, we demonstrated that complete stereoselective 1,2-cis linkage construction of a-D-Galf(1?2)Rha could be performed on glycosylation of 30 with flexible 3-O-benzoyl-2,5,6-tri-O-benzyl-b-D-galactofuranosyl trichloroacetimidate 36. On the other side, conformationally constrained trichloroacetimidate 9 gave disaccharide 31 with almost no selectivity in ethyl ether (1.1:1 a/b) whereas, surprisingly, only the b diastereomer was obtained in CH 2 Cl 2 45.…”

Regioselective 5-O-Opening of Conformationally Locked 3,5-O-Di-tert-butylsilylene-d-galactofuranosides. Synthesis of (1→5)-β-d-Galactofuranosyl Derivatives

“…The coupling constant value was in agreement with a flexible 1,2-cis α-galactofuranosyl derivative. 16,19,48,49 No significant changes in the chemical shifts of H-2 and H-6a,b were observed, indicating that no migration of the benzoyl groups took place, which was possible because of the basicity of the reagent. The furanose ring had lost the conformational restriction as indicated by J 2,3 and J 3,4 with lower values compared to those in the precursor 3 (J 2,3 and J 3,4 ∼ 9.5 Hz).…”

“…The synthesis of oligosaccharides containing internal Gal f requires a first choice of the galactofuranosyl template, which has to be functionalized or protected, , and this selection is deeply related to the method of glycosylation used. Several glycosylation methods have been essayed for this purpose; , the trichloroacetimidate method is the most widely employed according to the literature. − In contrast to pyranoses, the thioglycoside method has not been widely exploited as well , in spite of the success in oligosaccharide synthesis provided by the stability of the thio function toward a wide range of reaction conditions, which allows the manipulation of the protecting group prior to activation. The introduction of terminal Gal f has been described by this method, ,,,, however, examples of the synthesis of internal Gal f -oligosaccharides are more limited.…”