Synthetic and Mechanistic Studies in Alkaloid Chemistry

Leckie, Robert Harvey (1973) Synthetic and Mechanistic Studies in Alkaloid Chemistry. PhD thesis, University of Glasgow.

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The opening section of this thesis describes the first reported preparation of potentially biologically-interesting alkoxy 1-benzyl-3(2H)-isoquinolone derivatives incorporating dissimilarly-substituted aryl rings. Treatment of alkyl 2-arylacetylarylacetates ("keto-esters") with strongly basic amines gave only 2-aryl-3-hydroxy-1,4-naphthaquinones. Reaction with hydrazine hydrate however afforded colourless labile intermediates which were readily converted into N-ainino-1-benzyl-3(2H)-isoquinolones. Similarly reaction with hydroxylamine hydrochloride in pyridine gave derivatives of N-hydroxy-1-benzyl-3(2H)-isoquinolone. Members of the series which could not be obtained from the keto-ester by these methods were available following selective reduction of the ketone function, conversion to the corresponding hydroxy-dimethylamide and re-oxidation to the keto-amide. Treatment of the latter with amines or amine acetates in hot acetic acid gave good yields of 3(2H)-isoquinolone derivatives. A somewhat unstable N-methyl 3(2H)-isoquinolone prepared in this way was also available via an alternative method, namely reaction of the keto-amide with methylamine hydrochloride in pyridine. The chemical and spectroscopic properties of the 1-benzyl derivatives appear closely to parallel those of 1-H analogues. In particular the o-quinonoid lactam tautomer appears to predominate over hypothetical stilbenoid-lactam, lactim and acyl-imine tautomers (where appropriate). An application of an earlier synthesis of alkoxy 1-H 3(2H)-isoquinolones to the preparation of the tetrahydroprotoberberine alkaloid (+/-)-norcoralydine has been completed in the present work. The second major part of the thesis constitutes an investigation into the influence of variously - oriented hydroxyl and methoxyl groupings in the Hof- mann degradation of the tetrahydrobenzylisoquinoline alkaloids, following reports that certain combinations of these substituents appeared to facilitate the elimination process. Examination of the relative rates of stilbene formation from quaternary hydroxides derived from a series of 1-N,N-dimethylaraino-1,2-diarylethanes suggested that methoxyl substituents in the 1-aryl ring did not appear to have a significant effect (at least under the conditions used). This was in sharp contrast to the effect of hydroxyl groups in positions 2 or 4 of the 1-aryl ring, decomposition of even the quaternary methiodides proceeding rapidly to stilbenes. Evidence is presented that 3-hydroxy substituents in the 1-aryl ring of 1-N,N-dimethylamino-1,2-diarylethanes and 5- or 7-hydroxy substituents in tetrahydro-benzylisoquinoline derivatives retard Hofmann elimination in the derived quaternary hydroxides by removal of hydroxide ion with formation of relatively stable phenolate zwitterions (hydroxide ion being normally responsible for initiating the decomposition of quater-nised non-phenolic amines via removal of a methylene proton to the amino moiety). In contrast, quaternised phenolic amines with hydroxyl groups in the 2 or 4 positions (aminodiarylethanes) and 6 or 8 positions (benzyl-isoquinolines) are themselves capable of facile decomposition, presumably via uncharged "quinone-methide" intermediates. The structure of an orange-red crystalline by-product formed in the course of the above work during the preparation of 1-(3,4-dimethoxy)-1-keto-2-phenylethane from veratrole and phenylacetyl chloride is shown by spectroscopic and other evidence to be 1-benzylidene-5,6-dimethoxy-2-phenyl-3-veratryl indene. The final section of the thesis deals with synthetic approaches to the pentacyclic antineoplastic alkaloid camptothecin, a constituent of the Chinese tree Camptotheca acuminata. A study of the reduction of quinoline-2,3-dicarboxylic acid derivatives as a source of potential synthetic intermediates gave mixtures of hydroxy-amides and lactones in which the heterocyclic ring was partly or wholly reduced. No 2H-pyrrolo (3,4-b) quinoline was detected and the low yields of individual products obtained made this approach less attractive than recently published syntheses.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1973
Depositing User: Enlighten Team
Unique ID: glathesis:1973-78620
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 28 Feb 2020 12:09
Last Modified: 28 Feb 2020 12:09

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