A Study of Picrotin and Picrotoxinin and Their Derivatives

Abstract

Picrotoxin was one of the first bitter principles to be isolated, but the riddle of its structure still remains unsolved. Its history is therefore similar to that of morphine, which was one of the first alkaloids to be isolated, and whose structure is still not settled with certainty. Picrotoxin finds limited application in medicine having been used successfully as an antidote for barbiturate poisoning as it antagonises the soporific action of these substances. It would seem important therefore from a medical point of view to ascertain the structure of picrotoxin, as the knowledge so gained might lead to the synthesis of similar but perhaps less dangerous drugs, just as the determination of the constitution of cocaine made possible the synthesis of more powerful but less toxic local anaesthetics. Around the two compounds picrotin and picrotoxinin, there has been built up an immense mass of confusing information. A multitude of reactions involving the use of nearly every common laboratory reagent has been carried out on both compounds by various workers, and today nearly one hundred aromatic and hydro-aromatic derivatives are known. Unfortunately, however, it has not been possible to establish with certainty, the structures of more than a few of these compounds, so the work has shown but small reward. Moreover it appears that picrotin and picrotoxinin are very prone to undergo complex and puzzling molecular rearrangements. This is a characteristic of many other natural products, notably the terpenes including the so called oxygen-alkaloid santonin which seems somewhat similar in its general chemistry to picrotoxinin and picrotin. The degradation products therefore are probably far removed in structure from their parent compounds, with the result that no simple relationships can be traced between the two. Thus the real root of the difficulty in discovering a clue to the structure of picrotin and picrotoxinin is this lack of direct unambiguous relationships between the reactants and products. In attempting to establish such relationships two main lines of research appear to offer fruitful possibilities. The first involves the preparation and investigation of yet further derivatives, and the second involves a thorough investigation of the inter-relationships of those compounds already known. In this thesis the compounds chosen for study were picrotin and its alkaline degradation products. Thus both lines of investigation were carried out on picrotin simultaneously. Later picrotoxinin and its alkaline degradation products were also included in the scheme of investigations.