Synthesis of Procyanidins C2 and C1 Using Lewis Acid Mediated Equimolar Condensation

Abstract

Synthesis of procyanidin C2 and C1 was achieved via a stereoselective intermolecular condensation of equimolar amount of dimeric catechin or epicatechin nucleophile and monomeric catechin or epicatechin electrophile using Lewis acid. In the case of synthesis of procyanidin C2, AgBF4 and AgOTf afforded condensed product in excellent yield. As to the synthesis of procyanidin C1, Yb(OTf)3 was effective for equimolar condensation. INTRODUCTION Proanthocyanidins are known as condensed or non-hydrolysable tannins. These tannins are widely found in the vegetables, fruits and the bark of trees. Proanthocyanidins have been reported to exhibit strong free-radical scavenging and antioxidative activities. Many biological activities such as antitumor, antiviral, anti-inflammatory, and inhibition of DNA polymerase were reported. Thus proanthocyanidins are increasingly recognized as possessing health beneficial effects for humans. Tannin extracts from the nature give various types of polyphenols. Because their identification as well as purification is extremely difficult, further investigation of biological activities, i. e. mechanism of action remains unsolved. In these days, in order to obtain procyanidin oligomers in pure state, synthetic efforts have been devoted. As to the synthesis of catechin and/or epicatechin trimers, several synthetic studies were reported. The typical synthetic methods are as follows. The first example is pioneering work of the synthesis of procyanidins reported by Saito et al. This method requires to use nucleophilic partner in large excess (3.0 to 4.5 eq.) for condensation to prevent further oligomerization. The disadvantage of this procedure is that excess nucleophilic partner needs to be removed after condensation. The next one is use of C-8 bromide derivative to prevent forming further oligomeration. Quite recent example is using C-8 bromide and C-8 metallated nucleophile for the selective synthesis of C-4 and C-8 bound catechin trimers. So far, little attention has been paid to the screening of Lewis acids for equimolar condensation to construct the skeleton of procyanidin trimers. We have already reported a stereoselective synthesis of catechin trimer derivative using equimolar condensation. However, synthesis of epicatechin trimer using equimolar condensation has not been reported yet. In this article, we wish to report total synthesis of procyanidin C2 (1) and the recent progress of the synthesis of procyanidin C1 (2) via equimolar condensation between dimeric catechin or epicatechin nucleophile and monomeric catechin or epicatechin electrophile (Figure 1). Figure 1. The structures of procyanidin C2 (1) and C1 (2). RESULTS AND DISCUSSION We have investigated various Lewis acids including Ag, Cu, and Yb for equimolar condensation between dimeric catechin nucleophile 3 and monomeric catechin electrophile 4. Among these Lewis acids, we found that silver Lewis acids such as AgBF4 and AgOTf gave condensed product in excellent yield Scheme 1). Scheme 1. Equimolar condensation between dimeric catechin nucleophile 3 and monomeric catechin electrophile 4. The condensed product 5 was obtained in high yield, we next pursued to establish total synthesis of procyanidin C2 (1). Hydrolysis of the acetate of 5 using NaOMe under reflux did not furnish 6 although this reaction worked well in the case of procyaidin B1-B4. Thus diol 5 was once acetylated using Ac2O to give triacetate and subsequent reduction with DIBALH afforded 6 in 45% yield through 2 steps. However, the yield of transformation from 5 to 6 was not high enough, we tried the Kozikowski’s method using n-Bu4NOH to afford 6 in 66% yield. The H and C NMR spectral data of 6 were identical with those of the reported values. The 3,4-cis trimer could not be detected. This result indicated that electrophile 4 reacted with nucleophile 3 at C-4 position in a stereoselective manner to afford 3,4-trans trimer 5. The benzyl ether 6 was deprotected to yield procyanidin C2 (1) by hydrogenolysis over Pearlman’s catalyst. As to the purification of 1, when the crude products were directly evaporated, partially insoluble materials remained. We met with some difficulty to purify 1 after debenzylation. We tried separation by ODS cartridge column chromatography and preparative HPLC, however, we could not obtain 1 in a satisfying yield. Kozikowski and colleagues reported that lyophilization is useful for purification of these type compounds. Thus we used this method to afford procyanidin C2 (1) in good yield. We confirmed that lyophilized procyanidin C2 (1) was pure by HPLC analysis. The optical rotation value and mass spectrum data of synthetic 1 were in good accordance with those of the reported values. With regard to the H and C NMR spectral data of 1, we could not find them in any reports to the best of our knowledge. In this article, we wish to supply these data in experimental section and supporting information for future reference. The H NMR spectral datum of peracetate 7 was in good agreement with that of the reported values (Scheme 2). 5 6 procyanidin C2 (1) 7 n-Bu4NOH H2, Pd(OH)2/C 66% O BnO