A Versatile Access to Calystegine Analogues as Potential Glycosidases Inhibitors

• Published in: Journal of organic chemistry Vol. 74; no. 16; pp. 6266 - 6274
• Main Authors: Kaliappan, Krishna P, Das, Prasanta, Chavan, Sanjay T, Sabharwal, Sushma G
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 21-08-2009
• Subjects: Carbohydrates with 4, 5, 6, ... C atoms, dissacharides and oligosaccharides; Carbohydrates. Nucleosides and nucleotides; Chemistry; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Exact sciences and technology; Glucosidases - antagonists & inhibitors; Glucosylceramidase - antagonists & inhibitors; Glycoside Hydrolases - antagonists & inhibitors; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Inhibitory Concentration 50; Nortropanes - chemical synthesis; Nortropanes - chemistry; Nortropanes - pharmacology; Organic chemistry; Preparations and properties; Aldose; Enzyme; Nitrone; Deprotection; Metathesis; β-N-Acetylhexosaminidase; Enzyme inhibitor; Oside; Mannose; Hydrogenation; Glycosylases; Stereoselectivity; Alkaloid; Grignard reagent; Alkene; Cyclization; Analog; Glycosidases; α-Mannosidase; Hydrolases; Inhibition; Chemical synthesis; Ethylenic compound; Nucleophilic addition
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo901342w

An efficient metathetic strategy and nitrone chemistry have been suitably tethered to construct 8-azabicyclo[3.2.1]octanes as versatile precursors for the synthesis of several calystegine analogues. This synthetic strategy relies on the ability of mannose-derived nitrone to undergo a highly stereoselective nucleophilic addition of various Grignard reagents to access syn orientation of alkenes, which then smoothly undergo ring-closing metathesis (RCM) to provide this framework. These RCM products 18 and 20 have been successfully used as advance precursors to synthesize many calystegine analogues (27, 36, 38, 40, 43, and 44) either by syn-dihydroxylation or by hydrogenation and followed by global deprotection. Interestingly, both compounds 36 and 40 exhibited significant noncompetitive inhibition against α-mannosidase and N-acetyl-β-d-glucosaminidase.