C2-Oxyanion Neighboring Group Participation: Transition State Structure for the Hydroxide-Promoted Hydrolysis of 4-Nitrophenyl α-d-Mannopyranoside

Abstract

The hydroxide-catalyzed hydrolysis of aryl 1,2-trans-glycosides proceeds through a mechanism involving neighboring group participation by a C2-oxyanion and rate-limiting formation of a 1,2-anhydro sugar (oxirane) intermediate. The transition state for the hydroxide-catalyzed hydrolysis of 4-nitrophenyl α-d-mannopyranoside in aqueous media has been studied by the use of multiple kinetic isotope effect (KIE) measurements in conjunction with ab initio theoretical methods. The experimental KIEs are C1-H (1.112 ± 0.004), C2-H (1.045 ± 0.005), anomeric 1-C (1.026 ± 0.006), C2-C (0.999 ± 0.005), leaving group oxygen 2-O (1.040 ± 0.012), and C2-O (1.044 ± 0.006). The transition state for the hydrolysis reaction was modeled computationally using the experimental KIE values as constraints. Taken together, the reported kinetic isotope effects and computational modeling are consistent with the reaction mechanism involving rate-limiting formation of a transient oxirane intermediate that opens in water to give α-d-mannopyranose. The transition state has significant nucleophilic participation by the C2-alkoxide, an essentially cleaved glycosidic bond, and a slight shortening of the endocyclic C1-O5 bond. The TS is late, consistent with the large, normal C2-O isotope effect.

Exploration of Strategies for Mechanism‐Based Inhibitor Design for Family GH99 endo‐α‐1,2‐Mannanases

“…This process has little biological precedent (for a related proposal see Ref. ), but occurs in the base‐promoted solvolysis of α‐mannosides …”

“…[11]), but occurs in the base-promoted solvolysis of a-mannosides. [12] Efforts to develop inhibitors of GH99 enzymes have relied upon appending 1,3-linked a-glucosyl (to target mammalian endo-a-1,2-mannosidases) or 1,3-linked a-mannosyl (to target bacterial endo-a-1,2-mannanases) groups to various sugarshapedh eterocycles. Spiro and co-workersr eportedt he discoveryo fa-glucosyl-1,3-deoxymannojirimycin (GlcDMJ) as an effective inhibitor of the mammalian enzyme, [13,14] and followon studies by Fleet and co-workersr evealed a-mannosyl-1,3deoxymannojirimycin (ManDMJ) to be as lightly weaker inhibitor for this enzyme ( Figure 1B).…”

“…Tri-O-benzyl-3-O-(2-naphthylmethyl)-d-mannonolactone(12):As olution of the hemiacetal 11 (742 mg, 1.26 mmol) in acetic anhydride (6.1 mL) and dry DMSO (6.6 mL) was stirred under N 2 for 22 h. The mixture was diluted with EtOAc (20 mL), quenched with ice and washed with water (3 20 mL) and brine (1 20 mL). The organic extracts were dried (MgSO 4 )a nd the solvent was evaporated.…”

Synthesis of Nucleosides through Direct Glycosylation of Nucleobases with 5‐O‐Monoprotected or 5‐Modified Ribose: Improved Protocol, Scope, and Mechanism

“…[25] Due to the noveltyo fo ur chemistry, am echanistic study was necessitated. [25] Due to the noveltyo fo ur chemistry, am echanistic study was necessitated.…”

First Detection of Unprotected 1,2-Anhydro Aldopyranoses

“…8 Bennet et al reported computational analysis of formation of unprotected 1,2-anhdyro sugars from p-nitrophenyl glycosides. 9 Quite recently, the participation of a partially protected 1,2-anhydrofuranose was confirmed in a nucleoside synthesis. 10 However, in spite of the fact that unprotected 1,2-anhydro sugars possess potential utilities as a new donor substrate in the synthetic field of glycoscience, the direct experimental observation of totally unprotected 1,2-anhydro sugars has not been achieved yet.…”