## 3 Coumarins in the Context of Phenolic Composition
Shikimic acid is also the source of furanocoumarins and pyranocoumarins, which have a wide range of biological activity and are present in many natural products and synthetic drugs [98]. Furanocoumarins consist of a furan (or dihydrofuran) ring fused with the coumarin skeleton and can be classified as linear or angular; a good example can be seen in the structure of psoralen [99]. These structures are derived from umbelliferone by the addition of a prenyl group [100]. In general, furanocoumarins are biosynthesized, involving two pathways, the phenylpropanol and the mexulonic acid ones, by a coupling of dimethylallyl pyrophosphate (DMAPP) with umbelliferone, as well as through the formation of a prenylated simple coumarin intermediate [99]. Figure 10: Phenylpropanoloids’ general biosynthetic route. PAL: l-phenylalanine ammonia-lyase; TAL: tyrosine ammonia lyase. Pyranocumarins typically consist of a pyran (or dihydropyran) ring that is usually fused with the aromatic ring of the coumarin skeleton, as in xanthyletin [99]. Based on where the isopentenyl pyrophosphate is condensed to further cyclize and produce the heterocyclic, these coumarins can be classified as linear or angular. The synthesis of these complex coumarins might possibly be the outcome of the cyclization of a prenylated simple coumarin [101]. Phenylalanine, a compound generated by the shikimate biosynthetic pathway, undergoes conversion by phenylalanine ammonia lyase (PAL) into _trans_-cinnamic acid, which gives rise to the core metabolite 4'-coumaroyl-S-CoA. This intermediate can subsequently be converted into a variety of phenylpropanoids via 6'-hydroxylation, _trans_ > _cis_ isomerization of the exocyclic double bond, and the final lactonization/cyclization step (Figure 11). The initial and crucial step in biosynthesis is 6'_ortho_-hydroxylation, which is carried out by the 2-oxoglutate-dependent dioxygenase F6'H1. Some works have been devoted to clarifying the biosynthesis pathways of scopoletin at a molecular level. Scopoletin, like umbelliferone, undergoes benzene ring alterations, and studies conducted on _Arabidopsis thaliana_ demonstrated that scopoletin is produced through the phenylpropanol pathway via _ortho_-hydroxylation of cinnamate, _p_-coumarate, caffeine, and ferulate [102; 103]. Similarly, these coumarins, as well as aesculetin, can be produced via the phenylpropanol route (Figure 12), specifically generated from _trans_-cinnamic acid, but instead of undergoing the lactonization process of the caffeic acid derivative, 2'-hydroxy-caffeic acid, they can be synthesised via umbelliferone [104]. Cinnamic acid also plays a role in the synthesis of scopoletin, as an intermediate, but this time through caffeic acid ester derivatives. Besides the synthesis of coumarins, the phenylpropanol route is responsible for the synthesis of other phenolic compounds, such as flavonoids and phenolic acids. Figure 11: Proposed radical mechanism for 7-hydroxycoumarin (umbelliferone) biosynthesis from 4’-coumaroyl-S-CoA (adapted from [PERSON] et al. [102]). F6’H1, a 2-oxoglutate-dependent dioxygenase, comprises the first step. Furthermore, bicoumarins deserve attention as they are a category of great interest for pharmaceutical applications, particularly as anticoagulants. Bicoumarin connects two coumarin moieties by an orthoester structure, with the dicoumarol being the first isolated compound [105]. Dicoumarol, in particular, consists of two cyclic \(\beta\)-ketoesters linked by a methylene bridge, and was isolated from plant sources, in which the two coumarin units are linked at C3-C3\({}^{\prime}\) via the methylene group [106] (Figure 13). One possible route for the biogenesis of this compound might be the hydroxylation of the carbon atom at 4-position of coumarin framework, which then captures a molecule of formaldehyde, is condensed with another molecule of 4-hydroxycoumarin, and finally enolises the keto group that forms dicoumarol [107; 108].