Concise Total Syntheses of Aspalathin and Nothofagin

Abstract

Syntheses of the C-glycosyl flavone natural products aspalathin and nothofagin have been accomplished in eight steps from tribenzyl glucal, tribenzyl phloroglucinol, and either 4-benzyloxy phenylacetylene or 3,4-dibenzyloxy phenylacetylene. The key step of the syntheses involves a highly stereoselective Lewis-acid promoted coupling of 1,2-di-O-acyl-3,4,6-tribenzylglucose with tribenzyl phloroglucinol, which gives rise to the corresponding β-C-aryl glycoside in 30-65% yields.Naturally occurring C-aryl glycosides exhibit a range of interesting biological properties. CGlycosyl flavonoids, in particular, have been shown to possess antiviral, cytotoxic, and DNA binding activities. 1 The natural product aspalathin, isolated from the leaves of aspalathus linearis and used in the manufacture of rooibos tea, 2 displays potent antioxidant and radical scavenging activity, 3 and has recently been found to inhibit proliferation and infiltration of liver cancer cells. 4 The structurally related flavonoid nothofagin, typically coisolated with aspalathin, 2 also displays antioxidant properties, but to a lesser extent than aspalathin. Both of these compounds can be considered as direct precursors of a variety of other biologically interesting C-aryl flavonoid natural products, such as orientin/isoorientin, 5 vitexin/isovitexin, 5 and aspalalinin 6 (Figure 1). In view of their impressive biological profile, we decided to undertake total syntheses of both aspalathin and nothofagin.Structurally, both natural products consist of a glucopyranosyl unit carbon-linked to a dihydrochalcone moiety, with β-stereochemistry observed at the anomeric carbon atom. 2 We envisioned that the crucial linkage between the carbohydrate and aromatic subunits could be fashioned by a Lewis-acid promoted Friedel-Crafts-type glycosylation reaction; this process is well-precedented in the literature when highly electron-rich aromatics are employed as nucleophiles, 7,8 and thus this method seemed a logical starting point for our investigations.Addition of TESOTf (1 equiv) to a solution of tribenzylphloroglucinol (2a, 9a 2 equiv) and 2,3,4,6-tetra-O-benzyl glucose-1-O-acetate 9b (1) in CH 2 Cl 2 at 0°C resulted in a clean conversion to the corresponding C-aryl glycoside as a ~3:1 mixture of β:α diastereomers in 89% yield (3a and 3b , Scheme 1). Indeed, Schmidt also previously obtained 3:1 diastereoselectivity in the ZnCl 2 -promoted coupling of 2,3,4,6-tetrabenzyl glucose-1-O-* thomas.minehan@csun.edu . Supporting Information Available Detailed experimental procedures, spectroscopic data, and 1 H and 13 C NMR spectra for compounds in Table 1 and Schemes 1-4. This material is available free of charge on the Internet at http://pubs.acs.org. 10 However, attempted coupling of 2,4,6-trisbenzyloxy acetophenone (2b ,9c 2 equiv) and 1 in the presence of TESOTf (1-5 equivalents) gave only trace quantities (<5%) of the desired C-aryl glycoside product, and unreacted starting materials were recovered in high yield. NIH Public AccessTo circumvent the low diaster...

Aspalathin from Rooibos (Aspalathus linearis): A Bioactive C-glucosyl Dihydrochalcone with Potential to Target the Metabolic Syndrome

“…Synthesis of aspalathin would represent a sustainable option if economically feasible. An eightstep process using tri-O-benzylglucal, tri-O-benzylphloroglucinol, and 3,4-bis(benzyloxy)phenylacetylene as starting materials was reported by Yepremyan et al [60]. This process involved a stereoselective Lewis acid-promoted coupling of 1,2-di-O-acyl-3,4,6-tri-O-benzylglucose with tri-O-benzylphloroglucinol, leading to the ▶ Fig.…”

The concise synthesis and biological evaluation of C-glycosyl chalcone analogues inspired by the natural product aspalathin

“…However, due to the high steric hindrance of the substrate, the product yields are relatively low. 17 Therefore, we designed and synthesized three types of chalcone analogues comprised of a glycosyl unit and dihydrochalcone-like moiety via aldol reaction. In addition, the C-pyranoside chalcones were also synthesized in order to compare their antioxidant activity with C-furanosides.…”

“…Currently, aspalathin has been pursued as a target for total synthesis, with two successful syntheses being reported. 17,18 However, these accomplishments call for the number of steps to be reduced and the reaction materials used are of high cost, which dene a rather substantial barrier to the use of chemical synthesis for the discovery of novel aspalathin analogues. Moreover, there are almost no reports on the analogues of aspalathin.…”

Production of <i>C</i>-glucosides of flavonoids and related compounds by <i>Escherichia coli</i> expressing buckwheat <i>C</i>-glucosyltransferase

“…The compounds were eluted with a linear gradient of 20-60% methanol (300 ml), and the fraction containing the product was concentrated and crystallized. NMR spectra were recorded on a Bruker Avance400 spectrometer (Bruker Biospin, Yokohama, Japan), and compared with reported NMR spectra of related compounds (Ogawa et al 2001;Yepremyan et al 2010 …”