Stereocontrolled Synthesis of α-Xylofuranosides Using a Conformationally Restricted Donor

Abstract

A number of biologically relevant glycoconjugates possess 1,2- cis-furanosidic linkages, a class of glycosidic bond that remains challenging to introduce with high stereoselectivity. In this paper, we report an approach to one family of such linkages, α-xylofuranosides, via the use of thioglycoside donors possessing a conformationally restricting xylylene protecting group. The method was shown to provide the desired targets in good to excellent yield and stereoselectivity. Computational investigations support the proposal that the protecting group locks the electrophilic intermediate in these reactions into a conformation that leads to the high selectivity. The power of the methodology was demonstrated through the synthesis of a complex hexasaccharide motif from lipoarabinomannan, an immunomodulatory polysaccharide from mycobacteria.

Figure 1

(A) Schematic representation of 1,2-cis-α-furanosides (1) and 1,2-cis-β-furanosides (2). (B) Examples of β-arabinofuranosides (3), β-fructofuranosides (4), and α-galactofuranosides (5).

Figure 2

(A) 2,3-O-Xylylene-protected donor (6) for the stereoselective synthesis of β-arabinofuranosides and 2,3-O-xylylene-protected donors (7 and 8) explored in this paper as reagents for synthesizing α-xylofuranosides. (B) Central hypothesis of this work: that 7 and 8 will lead to an intermediate (e.g., 9) that preferentially reacts with nucleophiles to produce α-glycosides. (C) 5-Thiomethyl-α-xylofuranoside (α-MTX) residue (10) present in mycobacterial LAM.

Scheme 1. Synthesis of 7 and 8

Figure 3

Structure of oxacarbenium ion 34 (left), its low-energy conformation as determined by DFT calculations (middle), and a 2,3,5-tri-O-methyl-xylofuranosyl oxacarbenium (35) studied earlier by Codée and co-workers (right).

Figure 4

Optimized geometries of the 1,2-cis (left) and 1,2-trans (right) glycoside products formed upon trapping of oxcarbenium ion 34 with methanol.

Figure 5

Coordinate scan of the C1–O1 bond from 1.5 to 2.4 Å in the 1,2-trans (open circles) and 1,2-cis (filled triangles) methyl glycoside products arising from trapping of 34 with methanol.

Scheme 2. Retrosynthetic Analysis of 36

Scheme 3. Synthesis of Thioglycosides 37 (A) and 38 (B)

Scheme 4. Synthesis of Hexasaccharide 36