title: Concise and scalable synthesis of aspalathin, a powerful plasma sugar-lowering natural product.
abstract: Aspalathin (1), a dihydrochalcone C-glucoside, exhibits powerful plasma sugar-lowering properties and thus potentially could be used to treat diabetes. Small quantities occur in rooibos tea, manufactured via fermentation of the leaves of Aspalathus linearis, hence necessitating the need for an efficient and concise synthesis. Efforts to synthesize aspalathin (1) via coupling of a glucose donor to the nucleophilic phloroglucinol ring of the dihydrochalcone moiety have invariably failed, presumably because of ring deactivation by the electron-withdrawing carbonyl group. Reduction of the carbonyl group of a chalcone (15) and coupling of the resulting 1,3-diarylpropane (16) to tetra-O-benzyl-β-D-glucopyranose afforded the C-glucosyl-1,3-diarylpropane (17). Regiospecific benzylic oxidation regenerated the carbonyl group and afforded the per-O-methylaspalathin (1a) quantitatively. This method was not successful with the per-O-benzyl-protected dihydrochalcone. However, the nucleophilicity of the phenolic hydroxy groups of the dihydrochalcone or its acetophenone precursor is not diminished by the carbonyl group. Thus, glucosylation of the di-O-benzylacetophenone (5c) at -40 °C afforded the α-O-glucoside (19) in 86% yield. Raising the temperature allowed facile BF3-catalyzed rearrangement to the β-C-glucoside (6b), which upon hydrogenation, afforded aspalathin (1) in 80% overall yield [based on the usage of di-O-benzylphloroacetophenone (5c) and tetra-O-benzyl-1α-fluoro-β-D-glucose (2e)].
authors.affiliation: Department of Chemistry, University of the Free State , Nelson Mandela Avenue, Bloemfontein, 9301, South Africa.
authors.forename: Ze
authors.initials: Z
authors.lastname: Han
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Achilonu
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Kendrekar
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Joubert
authors.forename: Daneel
authors.initials: D
authors.lastname: Ferreira
authors.forename: Susan L
authors.initials: SL
authors.lastname: Bonnet
authors.forename: Jan H
authors.initials: JH
authors.lastname: van der Westhuizen
mesh_terms: D036903:Aspalathus / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D018515:Plant Leaves / Q000737:chemistry
chemical_list: D001688:Biological Products; D001786:Blood Glucose; D047188:Chalcones; D007004:Hypoglycemic Agents; C517016:aspalathin