Synthesis of modified proanthocyanidins: easy and general introduction of a hydroxy group at C-6 of catechin; efficient synthesis of elephantorrhizol Franc¸ois-Didier Boyer, a Nour-Eddine Es-Safi, a,c Josiane Beauhaire, a Christine Le Guerneve ´ b and Paul-Henri Ducrot a, * a Unite ´ de Phytopharmacie et Me ´diateurs Chimiques, Inra, Route de Saint-Cyr, 78026 Versailles Cedex, France b UMR Sciences pour l’Œnologie, Inra, 2, place Viala, 34060 Montpellier Cedex, France c Laboratoire de Chimie Organique et d’E ´ tudes Physico-chimiques, E ´ cole Normale Supe ´rieure, B.P. 5118, Takaddoum Rabat, Morocco Received 6 October 2004; revised 15 November 2004; accepted 18 November 2004 Available online 16 December 2004 Abstract—A general procedure for the oxidation of catechin derivatives is described, leading to the introduction of a new h group at C-6. This procedure has been applied for the synthesis of elephantorrhizol, a natural flavan-3-ol exhibiting a fully tuted cycle A. Ó 2004 Elsevier Ltd. All rights reserved. Proanthocyanidins are known ascondensed ornon- hydrolyzable tannins. 1–3 Many biological activities, par- ticularly a powerful free-radical scavenging 4–9 activity, have been reported for flavonoids, and their investiga- tion is now increasingly important. Most of the descri- bed procyanidins 1 involve oligomerization of catechin derivatives 2a–d ( Fig. 1). However,other flavan-3-ols have also been describedwith additional hydroxy groupson their aromaticrings.Gallocatechins2c,d, exhibiting three hydroxy groups on the B ring, are the most encountered. However,11 hydroxylation patterns have been reported in the literature involving in some cases the presence of up to four free phenolic groups on the A ring. Recently indeed, two new flavan-3-ols with new hydroxylation patterns on ring A have been described. (+)-3 0 ,4 0 , 5, 6, 7, 8-hexahydroxyflavan-3-ol 3 (elephantorrhizol) was identified in Elephantorrhiza goetzei 10,11 and 3-acetyl-5-methoxy-7,3 0 ,4 0 -trihydroxy- 8-O-glucoside-flavan-3-ol, barbatoflavan 4, from Cam- panula barbata (Fig. 1). 12 Due to the increasing interest devoted to this type of compounds, according to their potentialpharmacological properties, it is of interest to investigate structure–activity relationships and, there- fore, to have access to synthetically modified flavanols. Severalreports have been already published about the oxidation of flavanoidsusing various oxidizing re- agents 13–15 but, surprisingly, none of them was devoted 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.11.061 Keywords: Catechin; Procyanidin; Elephantorrhizol; Flavanol. * Corresponding author. Tel.: +33 1 30 83 36 41; fax: +33 1 30 83 31 19; e-mail: ducrot@versailles.inra.fr Figure 1. Bioorganic & Medicinal Chemistry Letters 15 (2005) 563–566