458 zyxwvutsrqponm Journal of Medicinal Chemistry, zyxwvutsr 1979, zyxwvutsrq Vol. 22, No. zyxwvuts 4 Notes zyxwvutsrqp Resolution and Absolute Configuration of trans-2-( 2,5-Dimet zyxwvu hoxy-4-methylphenyl)cyclopropylamine, a Potent Hallucinogen Analogue David E. Nichols,* Ronald Woodard, Bruce A. Hathaway, Department of Medicinal Chemistry and Pharmacognosy Martin T. Lowy, and George K. W. Yim Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907. Received April 17, 1978 An hallucinogen analogue, trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine (DMCPA), was resolved into its two enantiomers by fractional crystallization of salts with d- or l-0,O-dibenzoyltartaric acid. A comparison of the ORD and CD curves of the N-5-bromosalicylidene derivatives of trans-2-phenylcyclopropylamine of known absolute configuration and of the title compound established the stereochemistry of the latter to be (lR,2S)-(-) and (1S,2R)-(+). We have earlier shown that the zyxwvuts (-) isomer shows selective behavioral effects in cats and mice. In the present study it was found that the (-) isomer selectively elicits rabbit hyperthermia when compared with the (+) isomer. In view of the stereoselective ability of the (-) isomer to elicit hallucinogen-like behavioral profiles in these animal models, the proof of absolute configuration lends further support to a new model which interrelates the active binding conformation of phenethylamine hallucinogens to that of serotonin and tryptamines. Recently, Nichols et al.' proposed a new model for the receptor which interrelates the structures of phenethyl- amine hallucinogens, LSD, and serotonin. Fundamental to the validity of this new model was the prediction that the 1R,2S isomer of trans-2-(2,5-dimethoxy-4-methyi- pheny1)cyclopropylamine (la, DMCPA) would show OCH3 la OCH3 lb 2 stereoselective activity when compared with the 1S,2R enantiomer lb. This compound has previously been re- ported as the racemic material by Aldous et aL2 These workers characterized the compound as LSD-like in action and about one-third the potency of the known hallucinogen DOM (2). Subsequently, Nichols, Pfister, and Yim3 re- ported that behavioral studies in both mice and cats showed the (-) isomer of DMCPA to be selectively active when compared with the (+) isomer. Pharmacological comparison with the optical isomers of DOM indicated DMCPA to be of the same order of potency as DOM, consistent with the report of Aldous et aL2 This paper describes in detail the synthesis, resolution, and determination of absolute configuration which are essential to the further development of this new receptor model. In addition, we present data for the rabbit hy- perthermia model which further support stereoselectivity of action for the (-) isomer of DMCPA. Chemistry. Racemic 1 was prepared by a modification of the method of Kaiser et al.4 utilizing a reaction between dimethylsulfoxonium methylide and tert-butyl 2,5-di- methoxy-4-methylcinnamate (3) (Scheme I). Although it is unclear in their report, Aldous and co-workers2ap- parently used the corresponding ethyl ester for this re- action. We found the tert-butyl ester to give more sat- isfactory results, consistent with the original work by 0022-2623/79/ 1822-0458$01.00/0 Scheme I OCHJ OCH3 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONM 0 C H3O 3 C H3O I OCH3 4 C H3O HZ/Pd-C ATW "CooCH2Ph -1 CH3O 5 Kaiser et al.4 Hydrolysis of the resulting cyclopropane ester gave the corresponding cyclopropanecarboxylic acid 4. The acid was subjected to the Weinstock modification of the Curtius rearrangement.5 Treatment of the resulting isocyanate with benzyl alcohol gave the carbobenzoxamide derivative zyxwv 5 in excellent yield. Hydrogenolysis of 5 over palladium on carbon led to the desired racemic amine 1. Chemical resolution was accomplished by recrystalli- zation to constant rotation of the diastereomeric salts formed with either d- or l-0,O-dibenzoyltartaric acid. The resolved amines were liberated from the resolving agents and converted into their hydrochloride salts. Attempts to obtain crystals suitable for X-ray crstal- lography using a variety of heavy atom containing salts or derivatives have so far proven fruitless. Since N-sali- cylidene derivatives have been reported to give excellent C 1979 American Chemical Society