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

Abstract

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 scaledup to produce multigram quantities of the title compounds (1 and 2) for various in Witro, ex WiWo, and in WiWo 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.

Structure–Activity Relationship of Oligomeric Flavan-3-ols: Importance of the Upper-Unit B-ring Hydroxyl Groups in the Dimeric Structure for Strong Activities

“…We synthesized four dimeric compounds: (9), and (+)-catechin- [4,8]-(−)-epigallocatechin (10) to determine which part is the most important for biological activities and if the total number of phenolic hydroxyl groups in the entire molecule correlates with biological properties. The synthesized compounds 7-10 are natural products that can be isolated from beverages, e.g., green tea [24] and beer [25], and are known as strongly bioactive polyphenols.…”

“…We expected that comparison between 7 and 8 would show the effect on biological activities induced by the difference in the number of hydroxyl groups on the lower-unit B-ring and that the galloyl modified 9 could demonstrate whether the galloyl moiety of the lower-unit is effective to improve activity. Synthesis of (+)-catechin- [4,8]-(−)-epigallocatechin (10), a reference compound of 7, is shown in Scheme 3. The electrophile 18 [27] was condensed with a nucleophile 12 in the presence of TMSOTf as the Lewis acid at −78 °C in CH2Cl2 and gave dimeric compound 19 in 84% yield.…”

“…Therefore, synthesis is considered the most suitable method for clarifying the SAR of proanthocyanidins. Following contribution by Kozukowski et al [3][4][5], many studies on proanthocyanidin synthesis and their biological properties were demonstrated [6][7][8][9][10][11][12][13][14].…”

Catechin‐Modified Polylactide Stereocomplex at Chain End Improved Antibiobacterial Property

“…The combined organic layer was dried over sodium sulfonates. After filtration and evaporation, the resulting white powder was recrystallized using trichloroethylene (40 mL) . The white powder benzyl cathechin (BnCT) was obtained.…”

Hydrogen

“…136 Diastereoselective and enantioselective hydroformylations have also been reported. 131,142 For example, asymmetric hydroformylation of vinylarenes provides intermediates to nonsteroidal anti-inflammatory drugs such as (S)-ibuprofen, 143 (S)naproxen, 143 and (S)-tiaprofenic acid (eq 57), 144 the macrocyclic natural product (+)-patulolide (eq 58), 145 (59) Alkynes also undergo hydroformylation, giving acrolein derivatives (eq 60). 138,147 With β-aminoalkynes, hydroformylation provides pyrrole derivatives, presumably via the unsaturated aldehyde (eq 61).…”