Gram-scale production and applications of optically pure ¹³C-labelled (+)-catechin and (-)-epicatechin

In this paper gram-scale asymmetric total syntheses of pure (+)-4-[¹³C]catechin (1) and (-)-4-[¹³C]epicatechin (2) are described. Labelling was introduced through acylation of a phloroglucinol derivative 4 by 1-[¹³C]acetic acid, after activation by TFAA. Condensation of the resulting C₆-C₂ acetophenone building block 6 with a C₁-C6 benzaldehyde unit 9 provided the C₆-C₃-C₆ flavonoid skeleton, with benzyl ethers as phenol protecting groups. Asymmetry was introduced by an inexpensive and very efficient resolution process, performed at the penultimate step towards naturally occurring flavan-3-ols, by using tartaric acid derivatives. Both enantiomers of 4-[¹³C]catechin were obtained with a high level of enantiomeric purity, especially (+)-1 of the natural series. The other enantiomer (-)-1 was a valuable precursor of natural (-)-4-[¹³C]epicatechin by epimerisation at C-2. These two natural flavanols are thus obtained for the first time in large quantities in optically pure form as labelled compounds and will be useful tools for biological studies using NMR or isotopic mass spectrometry in forthcoming experiments.