Simple β-Carboline Alkaloids

Alkaloids based on a β-carboline system (Figure 73) exemplify the formation of a new sixmembered heterocyclic ring using the ethylamine side-chain of tryptamine in a process analogous to generation of tetrahydroisoquinoline alkaloids. Position 2 of the indole system is nucleophilic due to the adjacent nitrogen, and can participate in a Mannich/Pictet–Spengler type reaction, attacking a Schiff base generated from tryptamine and an aldehyde (or keto acid) (Figure 73). Aromaticity is restored by subsequent loss of the C-2 proton. (It should be noted that the analogous chemical reaction actually involves nucleophilic attack from C-3, and then a subsequent rearrangement occurs to give bonding at C-2; there is no evidence yet for this type of process in biosynthetic pathways.) Extra carbons are supplied by aldehyes or keto acids, according to the complexity of the substrate (compare tetrahydroisoquinoline alkaloids, page 321).

Figure 73

Figure 74

Thus, complex β-carbolines, e.g. the terpenoid indole alkaloid ajmalicine, are produced by a pathway using an aldehyde such as secologanin. Simpler structures employ keto acids, e.g. harmine (Figure 74) incorporates two extra carbons from pyruvate. In such a case, an acid is an intermediate, and oxidative decarboxylation gives the dihydro-β-carboline, from which reduced tetrahydro-β-carboline structures, e.g. elaeagninefrom Elaeagnus angustifolia (Elaeagnaceae), or fully aromatic β-carboline structures, e.g. harman and harmine from Peganum harmala (Zygophyllaceae) are derived (Figure 74). The methoxy substitution in the indole system of harmine is introduced at some stage in the pathway by successive hydroxylation and methylation reactions. A sequence from 6-hydroxytryptamine is also feasible. The reported psychoactive properties of the plants Peganum harmala and Banisteriopsis caapi(Malpighiaceae) is due to the β-carboline alkaloids such as harmine, harmaline, and tetrahydroharmine (Figure 74).