108 JournalofMedzcinal Chemistry, 1975, Vol. 18, N o I
Aspergillus nzger (ATCC 168881, and Trichophyton rnentagrophytes (ATCC 9129). The primary screening plates were prepared using Eugon agar (BBL) for bacteria and Mycophil agar (BBL) for fungi as complete media and Davis minimal agar (Difco) for bacteria and Czapek agar (Difco) for fungi as the minimal media. The agar culture media were autoclaved, cooled to 45". inoculated with bacterial or fungal suspensions, mixed thoroughly, and poured into Petri plates (100 X 15 mm) so that each plate contained 15 ml of agar culture media seeded with the test microorganism. Agar wells 10 mm in diameter were prepared in the plates and the samples (0.1 ml) were pipeted into the well. The solutions used were: o-cycloserine. 0.2 mg/ml; 3, 20 mglml: 1, 20 mgjml. The plates were incubated at 37" for bacteria or 25' for fungi and read for activity at 24-hr intervals. The results were expressed as the distance from the edge of the well t o the outer edge of the clear zone of inhibition.
References
Acknowledgment. This work was supported by the Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi. We wish to acknowledge Dr. Stephen Billets for aid in mass spectral interpretations and Mrs. Sheida White for assistance in biological evaluations.
K.D. Berlin. N. I3. Joseph G. Cannon,* Plaston R. Khonje, Diuision o f Medicinal C h e m i s t r y and Natural Products, College ojPharmac?
and John Paul Long D e p a r t m e n t of Pharmacology, College of M e d i c i n e , T h e Lhiuersity of I o u a . Iowa C i t y , Iowa 57242.K w c i i ~ t ~Au,qust d 5, 1973
A prior communication2 from this laboratory described procedures by which the direction of Hofmann elimination of a quaternary apomorphine derivative 1 could be controlled so as to obtain predominantly 2 or 3 (Scheme I). It was also demonstrated that Emde degradation of 1 gave a Scheme I . Degradation of Quaternary Apomorphine Derivatives
single product, 4. Cooke and Haynesj stated that the t i i rection of Hofmann elimination of quaternary aporphines appears to depend on the distribution of substituents and that small changes in reaction conditions may affect the course of the reaction. It was of interest to determine whether the selectivitb of eliminations demonstrated tor 1 was operative in other aporphine systems. and the .L' methyl quaternary derivative 5 of nuciterine (1.2-ci2 methoxyaporphine) was selected for study.
('H0
5
3
'
\
T;i HC
4 iThis investigation was supported by Grant
KS04349, Kational Institute
ot' Neurological Diseases and Stroke. Abstracted in part from a thesis suhmitted hy P.R.K. in partial fulfillment of the requirements for the Ph.D.
degree. Cniversity of Iowa, 1974.
Neumeyer, et U L , have ~ reported that the ether cleavage product 6 of (R)-nuciferine (which possesses the same absolute configuration as the biologically active enantiomer of apomorphine5) exhibits no emetic activity in the d o g . Like apomorphine, 6 contains the elements of' the dopamine structure, which is concluded to be the biologically significant portion of the apomorphine molecule.* We rationalize the emetic inactivity of 6 on the basis that the dopamine portion of the molecule is held rigidly with the catechol ring and the amino group in a gauche disposition (7). In apomorphine, the dopamine moiety exists in an anti arrangement (8) which we conclude is necessary for maximal emetic effect. In the present work, it was specu lated that Hofmann cleavage of 5 between the nitrogen and carbon 6a would permit preparation of 12b, in which
