Synthetic approaches to an indole alkaloid precursor
Date
1973
Authors
Elmes, Alfred Roy
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Abstract
In Part 1 of this thesis, synthetic endeavours leading to the acrylic ester [56] are presented o This compound, resembling the precursor secodine [52] is postulated as having a resemblance to the dihydropyridine or dihydropyridinium intermediates implicated as being involved in the later stages in biosynthesis of the major indole alkaloid families. A suggestion is made that the new compound [56] would be a more appropriate precursor than secodine for experimental bio-evaluation.
Synthesis was specifically directed at obtaining the alcohol [86], from which the expectedly unstable acrylic ester [56] could be generated in one step under carefully controlled conditions.
N-[β{3(2-Carbomethoxylmethylindolyl)}ethyl]-3-acetyl-l,4,5,6-tetrahydropyridine [70] was prepared by condensation of 3-acetylpyridine with the appropriate tryptophyl derivative, followed by reduction. All attempts to alkylate in the ester side chain of [70] using methyl formate and subsequent reduction were without success.
Two basic alternative routes leading to [86] were followed. One involved prior elaboration of the ester side chain, to the alcohol [88]. The alcohol group was then protected by benzylation before attempting to introduce the ethyl bridge at C-3 of the indole nucleus, condense with 3-acetylpyridine, and catalytically reduce the pyridinium salt yielding [86]. In the other method, the alcohol group of methyl 3(S-hydroxyethyl)indole-2-acetate was 3uitably protected, either as the tetrahydropyranyl or benzyl ether, and attempts made to alkylate in the ester side chain as with [70].
The second investigation concerns the generation of 1,4-dihydropyridines from the corresponding pyridinium compounds having the stabilising 3-acetyl function. This research is related in another direction again, to the implicated biointermediate(s).
Reduction of N-[β-(3-indolyl)ethyl]-3-acetylpyridinium bromide [102] with sodium hydrosulphite, gave the rather unstable N-[β(3-indolyl)ethyl]-3-acetyl-1,4-dihydropyridine [103]. Reaction of the bromide salt [102] with potassium cyanide in alcohol gave the relatively more stable cyano adduct [104]. These dihydropyridines were stable to base, but very labile to dilute acid, undergoing transformation to a mixture of products. The nature of these products in the case of the indole substituted compounds is not known with certainty.