Structure activity relationships in the muscarine and the quaternary 1,3-dioxolane (Fourneau series) series are briefly discussed. The most active member of the latter series (2-methyl-4-dimethylaminomethyl-1,3-dioxolane methiodide, (IX), F2268) was shown to consist of a mixture of 60% cis and 40% trans isomers. The same was found to apply to all synthetic intermediates in that series. Unequivocal assignments of configuration were made by relating various intermediates leading to (IX) and its analogs to D-cis-1,3-dimethyl-1,3-dioxolane itself, obtained by degradation of 1,6-anhydrogalactose. Attempted separation of cis–trans isomers in the 1,3-dioxolane series was not successful. However, a mixture of cis, trans-2-trichloromethyl-4-hydroxymethyl-1,3-dioxolane (XVI) could be fractionated by crystallization of the corresponding tosylates. Catalytic hydrogenolysis converted the pure cis- and trans-trichloromethyl derivatives (XVII) and (XVIII) to pure cis- and trans-2-methyl-4-hydroxymethyl-1,3-dioxolane tosylates (XIX) and (XX), which eventually afforded for the first time pure cis-F2268 and trans-F2268 (XXII) and (XXIII).Optically active members in the 1,3-dioxolane series were prepared. Members of the D(−)-series were conveniently obtained from D-isopropylidene glycerol. Members of the L(+)-series could be obtained in optically impure forms by resolution of dl-tertiary bases such as (XXXVI) with D- and L-dibenzoyltartaric acid. The best preparations had an optical purity not exceeding 32%. The resolution of the cis base (X) was unsuccessful.The synthesis of an oxazoline analog, (XLIV), of F2268 was accomplished. The reaction sequence involves solvolysis of N-acetyl-2,3-dibromo-n-propylamine (XLI) to give the 5-bromomethyl-2-methyloxazoline (XLII). This unstable intermediate was reacted with dimethylamine to give the tertiary base (XLIII), which was quaternized with methyl iodide whereupon the quaternary base (XLIV) was formed in good yield. The structure of the latter was established by an independent synthesis of the hydrolysis product (XLV).Preliminary pharmacological data are reported for the various new quaternary salts. The compounds were assayed for cholinomimetic activity. It is concluded from these studies that quaternary 1,3-dioxolanes display structure-activity relationships analogous to the muscarones. The use of triethylammonium analogs has revealed a large degree of preference of cholinergic receptors for the presence of a cis configuration in 2,4-disubstituted-1,3-dioxolanes. It was also noted that the oxazoline derivative (XLIV) ranks amongst the most active cholinomimetics thus far reported. Relationships between configuration and activity are briefly discussed.
Antimicrobial Properties of Volatile Phenylpropanes
