Degradative and synthetic studies on tubocurarine and some related compounds

Murray, John B (1965) Degradative and synthetic studies on tubocurarine and some related compounds. PhD thesis, University of Glasgow.

Abstract

The history of curare, its production, the botanical sources and biologically-active constituents of the various curares are reviewed. The derivation of the structure of curine and tubocurarine is discussed together with the total synthesis of (+)-tuboourarine by Tolkachev, Voronin and Preobrazhenskii, The pharmacological role of acetylcholine related to nerve impulse transmission at the neuromuscular junction, and the action of depolarizing neuromuscular blocking agents are briefly reviewed. The use of neuromuscular blocking agents in surgery and the compounds employed in practice are discussed. Structure-action relationships between tubocurarine, its isomers and certain of their derivatives are examined and the marked differences in potency noted. An experimental approach to the determination of the absolute configuration of (+)-tubocurarine has been examined. The method, based on the measurement of optical rotations of benzyltetrahydroisoquinoline compounds in solvents of increasing polarity, required the cleavage of the bisbenzyltetrahydroisoquinoline molecule of (+)-tubocurarine into its constituent benzyltetrahydroisoquinoline moieties. Attempts to convert (+)-0,0-dlmethyltubocurarlne iodide, required for this purpose, to (+)-0,0-dimethyltubocurine with lithium aluminium hydride were unsuccessful, N-Dealkylation of the quaternary iodide with ethanolamine, however, yielded the required product in 58% yield, N-Dealkylation of (+)-tubocurarine chloride with ethanolamine similarly yielded the tertiary base (+)-tubocurine in high yield. Successful conversion of the resulting (+)- tubocurine to (+)-0,0-dimethyltubocurine by treatment with excess diazomethane and subsequent methylation to the corresponding tubocuraine derivatives provided evidence that dealkylation proceeds without racemisation. Esamination of methods for the cleavage of (+)-0,0-dimethyltubocurine with soditun ajad liquid ammonia, which in the closelyrelated (-)-0,0-dimethyl -curine is reported to yield (-)-O-methylarmepavine and (-)-N-methylcoclaurine in benzene-toluene and (-)-0-methylarmepavine,(-)-N-methylcoclaurine and (-) -laudanidine in dioxan, led to the isolation of two non-phenolic and three phenolic compounds. Separation of the reaction products on altimina columns resulted in the identification of starting material from the non- phenolic fraction, and (-)-laudanidine and (+)-N-methylcoclau3:lne from the phenolic fraction, implying that the course of the reaction is not influenced by solvent, but merely facilitated by the presence of methoxyl substituents ortho to the phenolic ether undergoing cleavage, in accordance -with the observations of Tomita. Sodium and liquid ammonia fission of phaeanthine revealed e-vidence of fission on both sides of the phenolic ether linkage in further support of these conclusions. Optical rotation measurements on (of)-N-methylcoclaurine and (-)-laudanidine in different solvents confirmed the hypothesis of Tomita who in 1962 deduced the absolute configuration at both optical centres of the tubocuraii.ne molecule. (-)-0,0-Dimethylcurine was similarly produced by the action of diazomethane on curine. The four tertiary bases, (-1-)-tubocurine, (+)-0,0-dimethyltubocurine, (-)-curine and (-)-0,0-dimethylcurine were treated with a series of alkyl halides to produce their respective series of quaternary halides.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: J B Stenlake
• Keywords: Organic chemistry
• Date of Award: 1965
• Depositing User: Enlighten Team
• Unique ID: glathesis:1965-73805
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jun 2019 08:56
• Last Modified: 14 Jun 2019 08:56
• URI: https://theses.gla.ac.uk/id/eprint/73805