Scale-Up Syntheses of Two Naturally Occurring Procyanidins:  (−)-Epicatechin-(4β,8)-(+)-catechin and (−)-Epicatechin-3-O-galloyl-(4β,8)-(−)-epicatechin-3-O-gallate

A scaleable process for the synthesis of two naturally occurring procyanidins, namely (−)-epicatechin-(4β,8)-(+)-catechin (1) and (−)-epicatechin-3-O-galloyl-(4β,8)-(−)-epicatechin-3-O-gallate (2), is described. The key steps were highlighted by improvements for the benzylation of (+)-catechin (3), stereoselective reduction of the C-3 keto group of (2R)-5,7,3‘,4‘-tetrakis(benzyloxy)flavan-3-one (10), and coupling between 4-hydroxyethoxy-5,7,3‘,4‘-tetra-O-benzyl-(−)-epicatechin (11) and 5,7,3‘,4‘-tetra-O-benzyl-(+)-catechin (4) or 5,7,3‘,4‘-tetra-O-benzyl-(-)-epicatechin (6), respectively. The debenzylation performed in a biphasic system resulted in an improved yield and purity of the target compounds. The chemistry was scaled-up to produce multigram quantities of the title compounds (1 and 2) for various in vitro, ex vivo, and in vivo studies. Moreover, the scale-up process provided a detailed description for the preparation of multihundred to kilogram scale quantities of intermediates used in the synthesis of these two titled procyanidins.