Synthesis of a model phyllobilin bearing an optical marker

Abstract

Phyllobilins, derived from the breakdown of chlorophyll in plants, are acyclic tetrapyrroles that bear the signature ring E of the parent macrocycle. Few synthetic studies have concerned members of this emergent class of natural products, which now number >70. A prior synthesis of southern rim structures relied on Knoevenagel and Nazarov reactions to construct a dipyrromethane bearing the annulated ring E. Here, the synthesis has been extended to linear tetrapyrroles containing ring E as well as an appended dicyanovinyl unit. The latter serves as an optical marker with clearly observable absorption near 400 nm, rendering all compounds yellow, orange or red, thereby facilitating isolation and reaction monitoring. Knoevenagel condensation was carried out with a DC half (gem-dimethyl-substituted dihydrodipyrrin-1-carboxaldehyde bearing a 9-carboethoxy group) and an AB half (dipyrromethane equipped with a β-ketoester at the 8-position and the dicyanovinyl group at the 1-position). The resulting propenone is blocked by the ester and dicyanovinyl groups from reactions at the respective pyrrolic termini. Subsequent Yb(OTf)₃-catalyzed Nazarov reaction accompanied by unexpected prototropic rearrangement afforded the isolated phyllobilin (8) wherein conjugation shifted from the DC dihydrodipyrrin moiety to the CB southern rim, thereby resembling the conjugation of a native phyllolumibilin. The expected direct products of Nazarov cyclization, the cis and trans products (pre-8-cis, pre-8-trans) due to the configuration of substituents in ring E, were not observed. Calculations by density functional theory showed the stability order as 8 > pre-8-trans > pre-8-cis. Access to phyllobilin analogues may open opportunities for fundamental studies pertaining to the native constituents, which are germane to plant sciences, nutrition, and ecology.