The Stereodirecting Effect of the Glycosyl C5-Carboxylate Ester: Stereoselective Synthesis of β-Mannuronic Acid Alginates

Abstract

Glycosylations of mannuronate ester donors proceed highly selectively to produce the 1,2-cis-linked products. We here forward a mechanistic rationale for this counterintuitive selectivity, based on the remote stereodirecting effect of the C5-carboxylate ester, which has been demonstrated using pyranosyl uronate ester devoid of ring substituents other than the C5- carboxylate ester. It is postulated that the C5-carboxylate ester prefers to occupy an axial position in the oxacarbenium intermediate, thereby favoring the formation of the (3)H4 half-chair over the (4)H3 conformer. Nucleophilic attack on the (3)H4 half-chair intermediate occurs in a beta-fashion, providing the 1,2-cis-mannuronates with excellent stereoselectivity. The potential of the mannuronate ester donors in the formation of the beta-mannosidic linkage has been capitalized upon in the construction of a mannuronic acid alginate pentamer using a convergent orthogonal glycosylation strategy.

Structural and Functional Characterization of Pseudomonas aeruginosa AlgX

“…SeMet-incorporated protein was expressed, purified, and crystallized, and the structure was determined using the single-wavelength anomalous dispersion (SAD) method. The SAD model, in conjunction with the molecular replacement technique, was subsequently used to determine the structure of the native (sulfur-containing) protein that had been crystallized in the presence of a synthetic tetramer of polymannuronate (34,38) (Fig. 1).…”

“…In an attempt to determine an AlgX-alginate complex, the native sulfur-containing protein was co-crystallized in the presence of synthetic tetramannuronate (38). This tetramer has an acetylated ethylamine linker from the synthesis still attached at the reducing end.…”

Mannuronic Acids: Reactivity and Selectivity

“…The β-configured mannuronic acid donor 6 could also be used for the construction of the β-mannuronic acid linkage, indicating that direct displacement of the charged thiophenyl aglycon in an S N 2-type reaction was not at the basis of the observed selectivity (Table 1, entries 4 and 5). [15] In subsequent research other donor types, including carboxybenzyl [16] mannuronic acids and N-phenyltrifluoroimidates, [17] also proved to be useful for the stereoselective formation of β-mannuronic acid bonds. Furthermore, both O-and C-nucleophiles could be used (Table 1, entries 6 and 7).…”

“…Furthermore, both O-and C-nucleophiles could be used (Table 1, entries 6 and 7). [15] β-Configured S-phenyl mannuronic acid donors have been used as key synthons in the stereoselective assembly of alginate pentamer 26, as depicted in Scheme 1. [15] Reaction of donor 20 with azidopropanol under our standard preactivation conditions gave the reducing end mannuronate 21.…”

“…[15] β-Configured S-phenyl mannuronic acid donors have been used as key synthons in the stereoselective assembly of alginate pentamer 26, as depicted in Scheme 1. [15] Reaction of donor 20 with azidopropanol under our standard preactivation conditions gave the reducing end mannuronate 21. Treatment of the same donor with benzyl 2-(hydroxymethyl)benzoate under similar conditions and subsequent selective reduction of the formed benzyl ester led to carboxylbenzyl donor 7.…”