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.

Oxidative Transformations of Lignans

“…Laccases are copper-containing oxidases which have been used in, among others, wood, pulp, and paper industries [168]. They play a key role in the dimerization of 4-hydroxycinnamic acids in the biosyntheses of natural lignans [22,169]. Lignans have also been used as substrates in laccase activity studies [170,171].…”

“…Peroxidases are another group of oxidases which are also involved in the biosynthesis of lignans through β-β coupling of two phenylpropanoid units [22,169,176,177]. They typically use hydrogen peroxide as cofactor in the oxidation reactions.…”

“…As an example, (−)-dehydroxycubebin was oxidized by DDQ in AcOH, and reacted by either benzylic ring closure to an aryltetralin ( 1 ), or by O -acetylation through nucleophilic attack at the benzylic position ( 2 ) [18] (Scheme 1). When the solvent was changed to the more acidic and less nucleophilic trifluoroacetic acid (TFA), aryl-aryl coupling to a dibenzocyclooctadiene ( 3 ) was favored [19,20,21,22,23,24,25,26,27].…”

Antidepressant Potential of Cinnamic Acids: Mechanisms of Action and Perspectives in Drug Development

“…In this context, hydroxylated and/or methoxylated aromatic acids have shown promising results as neuroprotective agents [25]. Among these acids, there are phenolic acids, which are divided into hydroxybenzoic acids and hydroxycinnamic acids, based on C 6 -C 1 and C 6 -C 3 skeletons, respectively [26]. According to the literature, phenolic acids have potentially antioxidant properties due to the presence of a phenolic ring that promotes the electron donation and hydrogen atom transfer to free radicals, acting as free-radical scavengers, reducing agents, and quenchers of single oxygen formation [27,28].…”

In(III)-TMSBr-Catalyzed Cascade Reaction of Diarylalkynes with Acrylates for the Synthesis of Aryldihydronaphthalene Derivatives

“…In this regard, aryldihydronaphthalene derivatives are particularly attractive targets mainly due to their widespread occurrence in natural products and bioactive compounds ( Figure 1 ) [ 3 , 4 , 5 , 6 , 7 ]. They are also employed as fluorescent ligands in biochemistry studies or building blocks towards the synthesis of several biologically-active cyclic molecules [ 8 , 9 , 10 , 11 ]. Consequently, their significant roles have driven the establishment of several synthetic methodologies for their preparation.…”