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)].

Aspalathin Protects Insulin‐Producing β Cells against Glucotoxicity and Oxidative Stress‐Induced Cell Death

“…3‐(3,4‐Dihydroxyphenyl)‐1‐(3‐β‐D‐glucopyranosyl‐2,4,6‐trihydroxyphenyl)‐1‐propanone (Aspalathin), a water‐soluble dihydrochalcone C‐glucoside, was synthesized by High Force Research Ltd (Durham, UK) with a purity of ≈98% based on HPLC (batch SZ1‐356‐54). [ 40 ] It was kindly provided by Prof. Christo Müller of the South African Medical Research Council (Cape Town, South Africa).…”

Aspalathin improves glucose and lipid metabolism in 3T3‐L1 adipocytes exposed to palmitate

“…Pure ASP (ca. 98%, batch SZ1‐356‐54) was synthesized by High Force Research LTD (Durham, UK) using a patented method of synthesis . GRE, previously characterized in terms of phenolic profile and containing 18.4% aspalathin was obtained from the Post‐Harvest and Wine Technology Division, Agricultural Research Council (ARC), Infruitec‐Nietvoorbij (Stellenbosch, RSA).…”

“…Pure ASP (ca. 98%, batch SZ1-356-54) was synthesized by High Force Research LTD (Durham, UK) using a patented method of synthesis [15]. GRE, previously characterized in terms of phenolic profile and containing 18.4% aspalathin [8] (Ser 473 ), AMPK, p-AMPK (Thr 172 ), GLUT4, peroxisome proliferator-activated receptor alpha (PPAR␣), peroxisome proliferator-activated receptor gamma (PPAR␥), and carnitine palmitoyltransferase one (CPT1), as well as the IRS1 (Ser 307 ) ELISA kit.…”

Recent Advances in C-Glycoside Chemistry: Application, Synthesis and Reactions

“…Esta unidade estrutural está presente em muitos produtos naturais biologicamente ativos, 39,40 tais como, a Aspalatina (Figura 3) um Cglicopiranosídeo que possui propriedades antioxidante, antimutagênica e efeitos benéficos sobre a homeostase da glicose em Diabetes tipo 2. 41 De acordo com Han e colaboradores 41 esforços para sintetizar a Aspalatina, através de um processo que envolve o intermediário de chalcona, falharam. Além disso, ainda segundo os autores, a C-glicosilação de acetofenona proporcionou o intermediário aril C-glcosil cetona como traços.…”