Studies on the relationship between optical activity and physiological activity: the synthesis of compounds relating to tropic acid

It has long been known that, when a physiologically active substance contains an asymmetric carbon atom, the pharmacological effects of the two enantiomorphs, while qualitatively identical, may differ considerably in magnitude. The best illustrations of this phenomenon are given by the substances hyoscyamine, hyoscine and adrenaline, all of which were investigated by Cushny, the pioneer worker in this field. Thus, according to this author, who has summarised his work in his monograph "Biological Relations of Optically Isomeric Substances", the activity of l-hyoscyamine is about twenty times that of its d-isomeride, l-hyoscine is 16-18 times as active as the d-form, while l- adrenaline possesses an activity which is 12-15 times as strong as that of d-adrenaline.The present investigation was commenced with the object of providing further evidence by which the theory discussed above could be judged, and in view of the marked differences between the pharmacological activities of d- and l-hyoscyaminè, this substance was chosen for study. Hyoscyamine(VIII) is the tropyl ester of tropic acid (IX), the optical activity of the alkaloid being due to the asymmetric carbon atom present in the tropic acid moiety of the molecule. Now, Cushny has produced convincing evidence to show that the presence of the alcoholic hydroxy group in the acidic portion of the protein is essential for marked physiological activity . In order to retain this group while destroying the asymmetry of the molecule it would be necessary to prepare phenyldihydroxymethyl acetic acid (X). Two general methods by which this object might be achieved appeared to be available:(1) By the introduction of cyano groups into the methylene group of phenylacetic acid, reducing these aminomethyl groups, and finally converting the amino groups into hydroxyls by the action of nitrous acid; (2) By the direct introduction of an hydroxymethyl group into the tropic acid molecule