The Staudinger/aza-Wittig/Grignard reaction as key step for the concise synthesis of 1-C-Alkyl-iminoalditol glycomimetics

• Published in: Carbohydrate research Vol. 429; pp. 62 - 70
• Main Authors: Zoidl, Manuel, Gonzalez Santana, Andres, Torvisco, Ana, Tysoe, Christina, Siriwardena, Aloysius, Withers, Stephen G., Wrodnigg, Tanja M.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 24.06.2016; Elsevier
• Subjects: Alkanes - chemistry; beta-Glucosidase - antagonists & inhibitors; beta-Glucosidase - chemistry; Biochemistry & Molecular Biology; C-glycoside iminosugars; Chemical Sciences; Chemistry; Chemistry, Applied; Chemistry, Organic; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Glycomimetics; Glycoside Hydrolases - antagonists & inhibitors; Glycoside Hydrolases - chemistry; Life Sciences & Biomedicine; Molecular Mimicry; Physical Sciences; Polysaccharides - chemistry; Science & Technology; Staudinger/aza Wittig/Grignard reaction cascade; Stereoisomerism; Structure-Activity Relationship; Sugar Alcohols - chemical synthesis; Sugar Alcohols - chemistry; β-glucosidase inhibitors; Glycomimetics; C-glycoside iminosugars; β-glucosidase inhibitors; Staudinger/aza Wittig/Grignard reaction cascade; IMINOSUGAR C-GLYCOSIDES; ONE-POT SYNTHESIS; PHARMACOLOGICAL CHAPERONES; L-ARABINITOL; GLUCOCEREBROSIDASE INHIBITORS; GAUCHER-DISEASE; SELECTIVE INHIBITORS; beta-glucosidase inhibitors; NATURAL OCCURRENCE; BETA-GLUCOSIDASE; D-XYLITOL
• ISSN: 0008-6215; 1873-426X; 0008-6215
• DOI: 10.1016/j.carres.2016.04.006

•The Staudinger/aza-Wittig Grignard reaction cascade is a concise synthetic method for the synthesis of biologically active 1-C-alkyl iminoalditol glycomimetics.•A concise synthetic approach to biologically active 1-C-alkyl iminoalditol glycomimetics: The Staudinger/aza-Wittig Grignard reaction cascade.•The stereoselective control of C-1 alkyl substitution can be controlled by the choice of protecting groups at the sugar substrate as well as the nature of the nucleophilic Grignard reagent in the Staudinger/aza-Wittig Grignard reaction cascade.•Compounds exhibit selective b-glucosidase inhibition. The scope of a one-pot tandem approach for the synthesis of C-1 alkyl iminoalditol derivatives with a Staudinger/aza-Wittig/Grignard cascade has been evaluated. The reaction conditions have been optimized for two azidodeoxy aldose substrates and a range of Grignard reagents. The nature of both, substrate as well as nucleophile, was found to control the stereoselectivity of the alkyl addition to the cyclic iminium intermediate at position C-1. This approach enabled the synthesis of a collection of C-alkyl iminoalditols, which were biologically evaluated as inhibitors against a set of standard glycoside hydrolases. All compounds were found to exhibit highly selective inhibition of β-glucosidase activity.