Synthetic Routes to Three Novel Scaffolds for Potential Glycosidase Inhibitors

Abstract

Efficient syntheses of three novel scaffolds for potential β-glycosidase inhibitors were developed: The first consists of a 2,7-dioxabicyclo[2.2.1]heptane derivative, which was prepared by an intramolecular ketalisation. The second scaffold consists of a hydroxylated cyclopentylamine, which could be synthesised stereoselectively from 2-azabicyclo[2.2.1]hept-5-en-3-one. The third scaffold, a 4,5-dihydroxynicotinic acid,

Stereoselective Synthesis of Boat‐Locked Glycosides Designed as Glycosyl Hydrolase Conformational Probes

“…Vasella and co‐workers proposed the synthesis of isoquinuclidines 1 and 2 (Figure 1), which present inhibitory activity against α‐ and β‐mannosidases in agreement with the postulate that conformational change of the pyranose ring accompanies the enzymatic cleavage of β‐glycosides 12b. Another approach was developed by Rommel et al for the synthesis of a bicyclic aminogalactoside from D ‐galactose by a C1 homologation followed by an intramolecular ketalization of the open chain 20. In our laboratory, we developed the synthesis of galactosides 3 and 4 (Figure 1) locked in the 1,4 B boat conformation functionalized at the anomeric position with a phosphonyl group for UDP‐galactopyranose mutase (UGM) inhibition,21 a therapeutic target for the development of novel treatments of tuberculosis 22.…”

Structural Studies of the O‐Acetyl‐Containing O‐Antigen from a Shigella flexneri Serotype 6 Strain and Synthesis of Oligo­saccharide Fragments Thereof

“…Thus, taking advantage of the successful use of 2,3‐di‐ O ‐benzyl‐ D ‐galactopyranosiduronic acid esters as acceptors in α‐(1→4)‐ or β‐(1→4)‐glycosylation reactions involved in the synthesis of homogalacturonans31,32 or rhamnogalacturonans,32b,33 we selected benzyl (allyl 2,3‐di‐ O ‐benzyl‐β‐ D ‐galactopyranosid)uronate34 ( 9 ) as the precursor to residue A. This precursor was prepared from commercially available β‐ D ‐galactose pentaacetate via allyl glycoside 6 , obtained as a crystalline material in a non‐optimized 54 % yield over three steps (Scheme ) 35. Benzylation of acetal 6 and subsequent acidic hydrolysis of the benzylidene protecting group gave 4,6‐diol 7 (89 %) on a multigram scale 36.…”

The Construction of Anhydro Monosaccharides

“…In 2007, Koert et al. developed a facile route to compound 201 , which was believed to be critical to give β‐glycosidase inhibition by imitating the transition state of the β‐glycoside cleavage process . The 1,4‐anhydro pyranose structure of the target compound was established by the intramolecular ketalization of a subtly designed open‐chain dihydroxyketone ( 199 ) under acidic conditions, indicating that an open‐chain dihydroxy ketone would be an alternative precursor to synthesize anhydro sugars (Scheme ).…”