Bioinspired Syntheses of Dimeric Hydroxycinnamic Acids (Lignans) and Hybrids, Using Phenol Oxidative Coupling as Key Reaction, and Medicinal Significance Thereof

Abstract

Lignans are mainly dimers of 4-hydroxycinnamic acids (HCAs) and reduced analogs thereof which are produced in Nature through phenol oxidative coupling (POC) as the primary C-C or C-O bond-forming reaction under the action of the enzymes peroxidases and laccases. They present a large structural variety and particularly interesting biological activities, therefore, significant efforts has been devoted to the development of efficient methodologies for the synthesis of lignans isolated from natural sources, analogs and hybrids with other biologically interesting small molecules. We summarize in the present review those methods which mimic Nature for the assembly of the most common lignan skeleta by using either enzymes or one-electron inorganic oxidants to effect POC of HCAs and derivatives, such as esters and amides, or cross-POC of pairs of HCAs or HCAs with 4-hydrocycinnamyl alcohols. We, furthermore, provide outlines of mechanistic schemes accounting for the formation of the coupled products and, where applicable, indicate their potential application in medicine.

Keywords

• 4-hydroxycinnamic acids
• lignans
• biomimetic synthesis
• phenol oxidative coupling
• regioselective coupling
• stereoselective coupling
• dilactones
• dihydronaphthalenes
• dihydrobenzofurans
• hybrids