Study of the Lactone Systems in Picrotoxin Chemistry: A Contribution to the Chemistry of Tutin

Abstract

Picrotoxin is the astringent and poisonous principle in the berries of East Indian plants of the cocculus species (Menisperum cocculus, Anamirta cocculus) and was first isolated by the French apothecary, P. Boullay (Bl. Pharm., 4, 367. (1812)), in 1812. When pure, it is a colourless crystalline material and acts in a toxic manner on the central portion of the autonomic nervous system (Grünwald, Arch. exp. Path. Pharm., 60, 249. (1909)). It has proved to be an efficient antidote to poisoning by barbituric acid hypnotics (Malony and Tatum, J. Pharm. exp. Ther., 44, 299. (1932)) and by virtue of its intensely bitter flavour it has been used as an adulterant in the manufacture of beer. It was at first thought to be an alkaloid, but analysis soon showed it to be a compound containing only carbon, hydrogen and oxygen. Tutin is the bitter principle in the three species of coriaria in New Zealand, the commonest example of which is referred to as "tree toot" or "tutu". Easterfield and Aston (J. Chem. Soc., T, 120. (1901)), 1901, were the first to report the isolation of tutin and they referred to it as being a non nitrogenous glucoside. Pharmacologically, tutin is closely allied to picrotoxin. Although picrotoxin and tutin contain no nitrogen, their toxicity is comparable to that of strychnine, and this fact, together with their high oxygen content, has lead to their being referred to as "oxygen alkaloids". There are many other naturally occuring, highly toxic compounds which also come under this classification. In many specific reactions there is an extremely close analogy between picrotoxin and tutin, but as more research is carried out on tutin, the overall analogy between the two compounds is becoming less marked. The task of ascertaining their molecular structures is made difficult by the extreme ease with which molecular rearrangements take place. It is often not possible to be sure of a simple direct relationship between the products of a reaction and the starting material. Although picrotoxin has been known since 1812, and many capable workers have spent much effort over the last seventy years, the molecular structure has not yet been conclusively determined; and indeed, it has been only in recent years that an advanced stage in the elucidation of the problems of picrotoxin chemistry has been reached. Research into the chemistry of picrotoxin and tutin and their derivatives may yield information concerning the relationship of molecular structure to biological action and also concerning the mechanism of molecular rearrangements.