Total Synthesis of Parameritannin A2, a Branched Epicatechin Tetramer with Two Double Linkages

Abstract

The first total synthesis of parameritannin A2 (1), a branched epicatechin (EC) tetramer is reported. The “phloroglucinol trick” was used to circumvent two synthetic issues encountered when assembling four EC units, namely, the steric constraint and the formation of the C4−C6 interflavan linkage. As a substructure of the middle EC unit, phloroglucinol enabled the single-step assembly of two EC units (top and side) through A-type linkages. The middle EC unit was constructed by conducting a newly developed three-carbon flavan annulation via a Pummerer/Friedel–Crafts cascade reaction to furnish a trimeric intermediate bearing a thio-leaving group at C4 position, which allowed the final installation of the bottom EC unit.