-267
Julv 1965 SCHEMEI I-T-chloroacet ylephedrine (erythro) -128"
I-S-ncetylephedrine (erythro) - 177""
i
&pseudoephedrine (threo) +87" d-S-( p-hydroxyethy1)-
pseudoephedrine (threo) 166.5'
+
2
1-ephedrine (erythzo) -22
E-S-(phydroxyethy1)ephedrine (erythro) -30.5'
J
tl-3,4-dimet hyl-2-phenylmorpholin e ( I ) threo) +132" 0
I-3,4-dimethyl-2-phenylmorpholin-&one (erythro) -320"
I-3,4-dimethy1-2-phenylmorpholine (11) (Prythr: 1 - 78
Molecular rotation; rf. P. XI. Jones and W. Klyne, J . Chem. SOC.,871 (1960).
applied to the K-(@-hydroxyethyl) derivative of dpseudoephedrine. Hence, the produced morpholine must have the threo configuration. This was corroborated by the n.ni.r. spectrum. The coupling constant of 8.8 c..p.s. between the benzylic and its vicinal hydrogens reflects the diaxial conformation expected in a threo configuration (I).lo
niatography, by examining the resulting mixture with respect to its optical rotation and by its effect on liver monoamine oxidase (NAO) in vitro, respectively. As shown in Table I, the optical rotation of a solution of the thermodynamically less stable erythro isomer (11) changed from levo- to dextrorotatory. As expected, the threo isomer (I)remained unchaiiged. TABLE I EFFECT OF CONCENTRATED H2S04ON THE OPTICAL ROTATIOX O F DIASTEREOISOMERS O F 3,4DIMETHYL-2-PHENYLMORPHOLINE
I ( 2 S : 38)"
I t is likely that cyclization proceeds v i a a carbonium ion generated in the benzylic position. Destabilizing nonbonded interaction between the phenyl and methyl groups leads to inversion at the benzylic carbon, giving rise to the strain-free cyclized threo configuration. If indeed cyclization proceeds v i a a benzyl carbonium ion, treatment with strong acid of the thermodynamically less stable erythro isomer should cause inversion to its threo diastereoisomer. To investigate this possibility Z-erythro-3,4-diniethyl2-phenylniorpholine was prepared from I-ephedrine v i a its I-K-chloroacetyl derivative which was cyclized and the resulting Z-3,4-diniethy1-2-phenylmorpholin-5-one reduced with lithium aluniiriuin hydride. The erythro configuration was reflected in the low coupling constant of 2.7 c.p.s. for the benzylic hydrogen as expected for an axial-equatorial conformation (I1).lo HI 4 G C G H 5
CH3
CH3
I1 ( 2 R : 3s)"
The inversion of I1 by concentrated sulfuric acid to its diastereoisomer I was detected by thin layer chro(10) (a) Cf. L. M. Jackman, "Bpplications of Nuclear Magnetic Resonance Spectrosoopy in Organic Chemistry," Pergamon Press, New York, N. Y.,1959, p. 86; (b) J . B. Hyne, Can. J . Chem., 99, 2536 (1961). and references cited therein. (11) Cf. R. S. Cahn, C. K. Ingold, and V. Prelog, Ezperzentza, 12, 81
(1956).
Diastereoisomer
--Optical 0 hr.6
rotation [ , Z . ] D , ~ deg.-16 hr.c 64 hr.c
d-threo ( I ) 32.6 31.6 32.3 l-erythro (11) -14.1 3.9 7.4d a c 0.5. * I n 10% aqueous HI SO^. c Solution of sample in concentrated HISO,, diluted to 10% aqueoiis H2SO1. d Ahoiit 46% inversion.
The inhibitory effect of dZ-3-methyl-2-phenylmorpholine on M A 0 was first mentioned by Thoma and Wick.3 Prompted by this observation, we have examined the effect of the corresponding IT-methyl analogs on guinea pig liver M A 0 in vitro. As shown in Table I1 erythro isoniers of ephedrine and of the corresponding morpholine (11) are distinctly more potent inhibitors of liver X 4 O than their threo diastereoisomers. I t thus appeared that the inhibitory effect on N A O reflected the configuration of the benzylic carbon. Since this carbon is involved in the acid-catalyzed inversion, it should be possible to detect the inversion by measuring the effect of the equilibrated mixture on liver NAO. ,4s expected (Table 111), treatment with strong acid significantly reduced the capacity to inhibit MAO, thus indicating about SOYo inversion. The detected changes in optical rotation and in the inhibitory effect on NAO, respectively, appear to be in accord with the postulated role of the benzyl carbonium ion as intermediate in the acid-catalyzed cyclization of K-(@-hydroxyethy1)derivatives of ephedrine. Biological Activity.l2-1n contrast to its d-threo diastereoisomer (I),in rats, an oral dose of 40 mg./kg. of (12) Unpublishedlresults of Drs. Jane Stewart and F. Herr from our Department of Biology.
AXALOGSOF THYROXINE
July 1965
Sulfuric Acid Treatment of Phendimetrazine Diastereoisomers. -Samples (50 mg.) of d-threo- ( I ) and l-erythro-3,4-dimethyl-2phenylmorpholine (11)were dissolved in concentrated HzS04 (0.5 ml. each) and left standing a t room temperature. After 15 and 64 hr., respectively, the samples were diluted with water to make a 10% solution, and the optical rotation was determined (Table I). The 6 4 h r . samples (in triplicate) were rendered alkaline, the free bases were extracted with ether, dried (NaZSO1), and treated with HC1, and the mixture was evaporated to dryness iinder reduced pressure. The residue1$was dissolved in water to make a final concentration of 1 X If, and the effect on guinea pig liver 11-40was determined in 0itr0.l~ The inhibition was 50 =I= 4%. Compared to the values listed in Table 111,such a degree
469
of inhibition corresponds to a mixture consisting of about the threo diastereoisomer.
SOYo of
Acknowledgment.-We wish to thank Dr. Frank A. L. hnet for the n.m.r. spectra and their interpretation and Jean Dubuc and his group, respectively, for the X 4 0 assays. (19) Thin layer chromatography [methanol-benzene, 1 : 10; sprayed with concentrated H2S04 followed by Draggendorf's reagent as modified by Rlunier and Nacheboeuf (cj. I(.Randerath, ' Dunnschichtchromatographie," Verlag Chemie, Weinheim, 1962, p. 128)l indicated a mixture consisting of the unchanged erythro ( R f 0.25) and the newly formed threo (Rf 0.33) isomers.
The Synthesis of Thyromimetic Substances and Potential Inhibitors of Thyroxine' CHARLES
:\I. BUESR,TULLIO GIUDICI,n'ORMAX I
