Approaches to the synthesis of histrionicotoxin

Tyrrell, Elizabeth (1988) Approaches to the synthesis of histrionicotoxin. University of Southampton, Doctoral Thesis.

Abstract

This thesis describes two approaches to the synthesis of histrionicotoxin. Histrionicotoxin, [2R,6S,7S,8S]-7-(cis-1-buten-3-ynyl)-8-hydroxy-2--(cis-2-penten-4-ynyl)-1-azaspiro[5,5]undecane, derived from the skin secretions of the Colombian frog Dendrobates histrionicus, is a potent and selective inhibitor of cholinergic receptors. Chapter One commences with an historical overview into the isolation, characterisation and pharmacology of histrionicotoxin and concludes with a survey of the synthetic approaches to histrionicotoxin and its congeners. Chapter Two describes briefly the approaches to histrionicotoxin that have featured nitrone mediated [3+ 2] cycloaddition reactions in the key step and concludes with a discussion of the chemistry of [3+ 2] cycloaddition reactions. Chapter Three details the first of our two approaches to histrionicotoxin. This involved an intermolecular [3+ 2] cycloaddition reaction between cyclohexenone oxime (as the source of dipole) and methyl acrylate as the dipolarophile. Chapter Four describes the second of our approaches to histrionicotoxin. This involves one of two intramolecular [3+ 2] cycloaddition reactions. 1-Hydroxyimini-2-cyclohexen-2-yl-methyl acrylate was chosen as the target molecule. Unfortunately this key compound was resistant to cyclisation to form the azaspiro[5,5]undecane framework. In the second intramolecular [3+ 2] cycloaddition approach, 11-hydroxy-7-oxo-14-tri methylsilyl-2-12-tetradecadienoic acid ethyl ester was synthesised. This compound readily cyclised, in the presence of hydroxylamine hydrochloride to afford ethyl 1,8-dihydroxy-7-vinyl-1-azaspiro[5,5]undecan-2-yl acetate.

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