Total Synthesis of Proanthocyanidin A1, A2, and Their Stereoisomers

Abstract

The first novel stereoselective synthesis of naturally occurring A1 (1) and A2 proanthocyanidins (2) has been achieved. The key synthetic steps involved (a) the formation of a coupled product (13 or 14) between an open chain C-ring C-4 hydroxyethoxy analogue of either (+)-catechin or (-)-epicatechin with 5,7,3',3'-tetra-O-benzyl-(+)-catechin/-(-)-epicatechin in the presence of bentonite clay K-10, (b) removal of benzyl protecting groups under mild catalytic hydrogenation conditions to form the desired A-type compound in situ as a mixture of diastereomers via ketal/oxonium ion/carbonium ion formation, and (c) separation of the diasteromers via silica gel column chromatography. The structures of A1 and A2 proanthocyanidins were unequivocally established by analytical comparison to the natural products. Following this methodology, an additional six diastereomers of proanthocyanidins A1 and A2 have been synthesized. A plausible mechanism for the formation of the A-type linkage in proanthocyanidins has been proposed.

Proanthocyanidins and Where to Find Them: A Meta-Analytic Approach to Investigate Their Chemistry, Biosynthesis, Distribution, and Effect on Human Health

“…However, when the linkage between two units occurs, the hydroxyl group linked to the C-ring of each flavan-3-ol can be in either S or in R. Consequently, four different B-type PACs can be formed from C 4 –C 8 linkages (B1–B4), and another four from C 4 –C 6 (B1–B8) ( Figure 3 ). Moreover, C–O bounds between O 7 of one flavan-3-ol unit and C 2 of another one can be established [ 20 ]. In this case, the PAC is named A-type ( Figure 2 B).…”

Thermodynamic Stability of Flavylium Salts as a Valuable Tool To Design the Synthesis of A-Type Proanthocyanidin Analogues

“…Several attempts have been made in order to synthesize both A-type PACs , and their synthetic analogues (2,8-dioxabicyclo[3.3.1]­nonane derivatives). − Moreover, synthetic analogues afford the opportunity to prepare a large series of compounds with similar or improved biological activities when compared with natural ones . Although almost all methods reported to date synthesize these bicyclic derivatives using 2-hydroxychalcones as starting materials, − we consider that starting from flavylium salts could be a more interesting approach , (Scheme ).…”

“…1−3 As an example, cinnamtannin B-1 (1) is an A-type PAC (Figure 1) isolated from Laurus nobilis L. by the authors 4 that exhibits a large number of cellular actions such as antiaggregant and antiapoptotic effects in human platelets 5,6 and antimicrobial and antibiofilm activities, 7 among many others. 8 Several attempts have been made in order to synthesize both A-type PACs 9,10 and their synthetic analogues (2,8dioxabicyclo[3.3.1]nonane derivatives). 11−14 Moreover, synthetic analogues afford the opportunity to prepare a large series of compounds with similar or improved biological activities when compared with natural ones.…”

Rapid assembly of the procyanidin A skeleton

“…Syntheses of type A procyanidins included an innovative microwave-mediated route to diinsininone by Selenski and Pettus in 2006, 4 an elegant synthesis of procyanidin A2 by Ito, Ohmori and Suzuki via an alkoxyketal derivative of epicatechin in 2014, 5 and the successful synthesis of proanthocyanidins A1 and A2 by Sharma and coworkers in 2015. 6 Syntheses of closely related analogs were reported by Jurd in 1965, by Kondo in 2000 and by Kraus in 2009. 7 The structures of some type A procyanidins are depicted below in Figure 1.…”