Tryptophan strychnine

Much more complex are the thousands of alkaloids that include an indole (or 2,3-dihydroindole) sub-unit and in each of these one can discern the tryptamine nnit of the biosynthetic precursor tryptophan strychnine (33.3.2) (Strychnos nux vomica), vincristine (33.7) (Catharanthus roseus), and the antipsychotic and antihypertensive reserpine (Rauwolfia serpentina) are examples. A group of amides of lysergic acid, for example, ergotamine, occur in ergot fnngi (e.g. Claviceps purpurea), the remainder of the molecule comprising proline, phenylalanine and alanine nnits. Lysergic acid diethylamide is the notorious LSD. 

Important indole derivatives (see Scheme 2) include (i) indigo, a vat dye known and widely used since antiquity, and originally obtained from indican, a (3-glucoside of indoxyl which occurs in some plants. Indigo is now prepared synthetically. Tyrian purple, a natural dye used since classical times, is 6,6 -dibromoindigo (ii) the numerous indole alkaloids, with complex derivatives such as yohimbine and strychnine (iii) tryptophan, an essential amino acid found in most proteins. Its metabolites include skatole and tryptamine and (iv) 3-indoleacetic acid, which is important as a plant growth hormone. 

Indole is an important heterocyclic system because it is built into proteins in the form of the amino acid tryptophan (Chapter 49), because it is the basis of important drugs such as indomethacin, and because it provides the skeleton of the indole alkaloids—biologically active compounds from plants including strychnine and LSD (alkaloids are discussed in Chapter 51). 

Pseudoakuammicine is the first racemic base to be discovered in the strychnine-yohimbine series of alkaloids, and the question of its origin naturally arises. The only stage in the extraction of Picralima seeds during which racemization of akuammicine might have occurred involved prolonged percolation with hot methanol however, as already discussed, akuammicine is not racemized under these conditions but suffers a more extensive decomposition. In any event, such a racemization would necessarily involve fission of the 3,7 and 15,16 bonds, followed by a nonspecific resynthesis, which is considered to be a very unlikely possibility. It was therefore suggested that, in the plant, pseudoakuammicine is produced by a nonspecific biosynthesis this would accord with its formation from a tryptophan-phenylalanine precursor, but not from an optically pure prephenic acid derivative (40). 

Diagram 27. Woodward s hypothesis for biosynthesis of strychnine from, ultimately, tryptophan and dihydroxyphenylalanine. 

The poisonous principle of calabash curare is C-curarine, a dimeric alkaloid derived from tryptophan.This alkaloid was first reported in 1937 [l],and total synthesis was achieved in 1964 [2]. C-Toxiferine I, an alkaloid with a structure similar to that of C-curarine, and with hydroxy groups at the 18 and 18 -positions, was isolated and characterized from the same plant [3,4].These alkaloids possess two of the strychnine-like moieties described in the previous section. The C of these alkaloids indicates the origin from calabash. 

L-Tryptophan is an indole ring containing aromatic amino acid derived via the shikimate pathway. The tryptophan-derived alkaloids are found in eight families, of which, Apocynaceae, Loganiaceae, Rubiaceae, and Nyssaceae are the best sources. The alkaloids under discussion are the Catharanthus alkaloids, namely, ajmalicine, tabersonine, catharanthine, vindoline, vinblastine, vincristine and vincamine as well as terpenoid alkaloids derived from other families, namely, yohimbine, reserpine, strychnine, brucine, and ellipticine. The above-mentioned alkaloids are pharmacologically very important and hence extremely valuable. This chapter describes various aspects of the tryptophan-derived alkaloids like occurrence, biological activity, phytochemistry, and commercial and biotechnological aspects. 

Simple rearrangement of the Corynanthe skeleton [as [6.243)] affords the Strychnos type, exemplified by akuammicine [6.242), and strychnine [6.263). Like [6.242), strychnine has been found to have the expected origins in tryptophan and in mevalonate via geraniol the extra C2 unit (C-22 and C-23) arises from acetate. Late intermediates have been identified and the pathway deduced is shown in Scheme 6.47 [182]. 

Plant aromatic L-amino acid decarboxylases (AADCs) catalyze the initial reactions in the formation of terpenoid indole alkaloids (TIAs) such as quinine and strychnine, and benzyliso-quiuoline alkaloids (BIAs) such as morphine and codeine (Fig. 3). L-tryptophan decarboxylase (TDC) initiates TIA synthesis with the formation of tryptamine. TDC is encoded by two genes in Cola accuminata TDCl is expressed as part of a developmentally regulated chemical defense system, whereas TDC2 is induced after elicitation with yeast extract or methyl jas-monate (MI). 

AB ABCE ABCDE - ABCDEF W-G aldehyde (-)-Strychnine] (27) After his racemic synthesis of strychnine (26), Kuehne also achieved an enantioselective synthesis of (—)-strychnine (Scheme 9). To avoid the low yield conversion of isostrychnine to strychnine, the second approach was directed to the W-G aldehyde. Starting from L-tryptophan methyl ester (86), the cyclization precursor 87 was prepared in seven steps in a similar way as in the previous racemic synthesis. The domino condensation-electrocyclization reaction of 87 with dienal 88 proceeded with quite high diastereoselectivity (>95% de) [AB ABCE, C7 quaternary center] (85). After conversion of the tetracyclic compound 89 to tosylate 92, removal of the benzyl group resulted in the clean formation of the D ring [ABCE ABCDE ]. Unlike in the first synthesis, introduction of the hydroxyethylidene side chain by a Horner-Wadsworth-Emmons reaction of ketone 93 proceeded with high stereoselectivity (E Z = 17 1). Einally, the E isomer 94E was converted to (-)-strychnine via the W-G aldehyde (50). 

---