COMMUNICATIONS TO THE EDITOR
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Vol. 70
of such a compound would lead to compounds of the structure (111), which type of structure has recently been proposed for ketoyobyrine, on the basis of an exhaustive study of its chemistry% and likewise on the basis of a comparison of its absorption speetnun with that of rutaearpine.2b Pending more complete presentation of our various syntheses of the type of structure represented by (111),we wish to record our synthetic confirmation of this proposed structure for ketoyobyrine. 6-Methylhomophthalic acid, m. p. 1W0, was prepared from 0-tolylacetic acid* by conversion Via the Arndt-Eistert reaction into o-tolylpropiDIVISION OF CHE~~ICAL DEVELOPMENT LEONJ. HEUSER onic acid, which was then treated according to the method of Mercer and Robertson.' CondensaE. R. &UIBB AND SONS MORRISA. DOLLNEWBRUNSWICK, N. J. ERICT. STILLERtion with tryptamine yielded N-(@-indolrlethyl)6-methylhomophtfialimide, m. p. 228 ConRECEIVED JULY19, 1948 version of the latter into the corresponding homophthalamic acid,' m. p. of picrate 147O, THE SYNTHESIS OF KBTOYOBYRINE methylation of the acid with diazomethane, m. p. sir: of methyl ester 222O, dec., followed by ring For several years we have been investigating closure with phosphorus oxychloride, yielded the possibility of synthesizing the basic ring struc- ketoyobyrine, m. p. 3 1 6 - 3 1 8 O , dec. ture of yohimbine by ring closure of isoquinolylA d . Calcd. for C ~ ~ H ~ ( I OC,N ~79.98; : H, ethyl oxindoles of the type represented by formula 5.37; N, 9.32. Found: C, 79.43; H, 5.55; N, (I).l The introduction of the double bond in ring 9.24. Comparisons of the ultraviolet absorption D presented numerous f i c u l t i e s because of the spectrum of synthetic ketoyobyrine with that of ease with which compounds of the type (I) (as the product of natural origin showed the two to well as the yohimbine molecule itself) suffer be identical. Absorption maxima for synthetic cleavage at the nitrogen atom of ring D. More- material: at 385,366 and 340 mp, log z 4.40,4.51 over, we have pointed out* that 1,2-dihydroiso- and 4.52, respectively. quinolines like (I) are virtually unknown. (2) (a) Woodward and Witlcop, T a ~ JOURNAL, s TO, 2409 (1948); Accordingly, our efforts were later directed (b) Raymond-Hamet, Compt. r e d . , 116, 137 (1848). toward the preparation and ring closure of com(3) Julian, Karpel, Magnani and Meyer, Tms JOURNAL, TO, 180 pounds of the type represented by formula (11) (1948). (4) M u m and Robertson, J . Ckm. Soc., 288 (1938). H H
and gave analytical data: C, 38.25; H, 6.22; N, 11.31; C1, 12.52 (Calcd. for CorH&017*3HCl: C, 38.01; H, 6.14; N, 11.49; C1, 12.47). When assayed with K. preumoniae in a broth dilution test,' the anhydrous mannosidostreptomycin had a potency of circa 210 units/mg.* Additional information on the properties and activities of these crystalline hydrochlorides will be published a t a later date. We wish to express our appreciation to Dr. R. Donovick, Mr. R. Blue, and Mr. D. Lapedes for the bio-assays, Mr. F. Rum-Alesi for the countercurrent distributions, and Mr. J. Alicino for the micro-analysis.
.
(5)
Cf.Haworth, Perkin and Pink, J. Ckm. Soc., 1709 (1926).
'MEGLIDDEN COMPANY PERCY L. JULIAN RESEARCH LABORATORIES WILLIAM J. KARPBL SOYA PRODUCTS DIVISION ARTHUR MAGNANI CHICAGO,ILLINOIS EDWINW. MEYBR RECEIVED JULY 24,1948
YJ
R/' (I)
(11) (R = CHs or H)
(R = CHI or H)
N
R
(111) Ketoyobyrine (R
-
CHI)
where the appropriate double bond of ring D could be introduced without difficulty. Ring closure (1) Julian, Magnani, PiLl and Korpel, THISJOURNAL, TO, 174 (1948).
THE OZONIZATION OF THE MALEIC ANHYDRIDE ADDUCT OF DEHYDROERGOSTERYL ACETATE
sir: A recent publication of Bergmann and Stevens' describes the preparation of the maleic anhydride adduct of 3(~)-acetoxy-9,11-oxidobisnor-5,7choladienic acid (11) by the ozonization of 9,lloxidoergosteryl acetate-maleic anhydride adduct. For some time previous a study of analogous reactions has been under way in our laboratories and we now wish to report the preparation of the maleic anhydride adduct of 3(/3)-acetoxybisnor5,7,9-cholatrienic acid (I) by the selective ozonization of 9,ll-dehydroergosteryl acetate-maleic anhydride adduct (111). A solution of the dehydroadduct (111) in methylene chloride was treated with two equiva(1) Bergmann and Stevens, J . Org. C k m . , 18, 10 (1948).
Aug., 1948
COMMUNICATIONS TO THE EDITOR CHs
2835
Details of this work, together with further conversions of compound I, will be published a t a later date.
I
CHCOzII I
RESEARCH LABORATORIES ROBERT H. LEVIN THEUPJOHN COMPANY MILDRED M. WESNBR KALAMAZOO, MICHIGAN ELIZABETH M. MEINZER RECEIVED JUNE18, 1948 DEGRADATIVE STUDIES ON STREPTOMYCIN
Sir: CHI
Degradation of dihydrostreptomycin with barium hydroxide under conditions which convert streptidine to streptaminel yielded an amorphous, I antibiotically inactive product containing barium chloride. This substance was acetylated with pyridine and acetic anhydride to a crystalline compound (I), m. p. 261.5-262.5', [ a ] 2 8 ~ -84' (c 1, water). -CH-CO Anal. Calcd. for C1sH#OnN3(CH3C)MA=I (COCH8)io: C, 50.92; H, 6.25; N, 4.57; 0AcO -CH-CO acetyl, 7.61 cc. of 0.1 N NaOH per 100 mg. lents of ozone a t -30'. The methylene chloride CHs-C, 32.3: mol. wt., 919.9. Found: C, 50.64; was replaced with glacial acetic acid and the H, 6.17; N, 4.47; O-aketyl,* 7.37 cc.; CH1-C,a ozonide decomposed with zinc dust. After sepa- 32.3; mol. wt., 920 (Rast). ration of the zinc, the acetic acid solution was Methanolysis of I with subsequent reacetylatreated with chromic acid in acetic acid a t 20' tion yielded hexaacetylstreptamine, transition for three hours and the excess chromic acid was point' 250°, m. p. 341-345', N, 6.61% (calcd. decomposed with sodium bisulfite solution. The 6.50), and methyl pentaacetyldihydro-a-L-strepreaction mixture was poured into water and the tobiosamide,b-8 m. p. 194-195', unchanged on precipitate of the bisnor acid (I), m.p. 226-237', admixture with a specimen prepared from dihywas separated by filtration. For analysis, the drostreptomycin trihydrochloride, [ a I z a~ 120' acid (I) was crystallized from ether-hexane, (c 0.5, chloroform). I is designated decaacetyl240-243'. The yield of pure acid (I) was dideguanyldihydrostreptomycin. It was found to m% 55 of the theoretical. be readily soluble in methanol, water and hot Anal. Calcd, for C ~ ~ H ~ OC, T : 69.69; H, ethanol, sparingly so in chloroform, ethyl acetate 7.10; Found: C, 69.73; H, 7.10. and ethanol, and insoluble in benzene and ethyl Treatment of the acid (I) with diazomethane ether. in methylene chloride gave the maleic anhydride Aqueous solutions of N,N,N-tetraacetyldiadduct of methyl 3(8)-acetoxybisnor-5,7,9-chola- deguanyldihydrostreptomycin (11), N1,Ns-ditrienate (IV), m.p. 246-248'. AnaZ. Calcd. for acetylstreptamine (111) and N-acetyldihydro-aC&HmO,: C, 70.14; H, 7.31. Found: C, 69.98; L-streptobiosaminide (IV) were prepared by parH, 7.48. After saponification, methylation with tial deacetylation of the aforementioned acetyl diazomethane, and acetylation with acetic .an- derivatives wi$h 0.05 N sodium hydroxide in hydride, the trimethyl ester of the maleic acid water-dioxane. These N-acetates were subjected adduct of 3( p )-acetoxybisnor-5,7,9-cholatrienic to oxidation with a large excess of buffered perioacid (V) was obtained, m.p. 193-195'. Anal. date a t pH 4.9 and 20.0' and showed the following Calcd. for CaH4208: C, 68.61; H, 7.80. Found: (1) R. L. Peck, C. E. Holfhine, Jr., Elizabeth W. Peel, R. P. C, 68.66; H, 7.65. The trimethyl ester of the Graber, F. W. Holly, R. Mozingo and K.Folkers, T ~ x aJOURNAL, 68, maleic acid adduct of 3(@)-acetoxy-9,1 l-oxido- 776 (1946). (2) M. L. Wolfrom, M. Konigsberg and S. Soltzberg, ibid., 68, 490 bisnor-5,7-choladienic acid (VI) was prepared by treating the acetoxytrimethyl ester (V) with (1938). (3) R. U. Lemieux and C. B. Purves, Can. 3. Research, BII, 485 monoperphthalic acid. It was crystallized from (1947). (4) H. E. Carter, R. K. Clark, Jr., S . R. Dickman, Y. H. Loo, ether, m.p. 208-209.5'. Anal. Calcd. for C31HloOo: C, 66.64; H, 7.58. Found: C, 66.76; J. S . Meek, P. S. Skell, W. A. Strong, J. T.Alberi, Q. R. Bar-. S. B. Binkley, H. M. Crooks, I. R. Hooper and Mildred C. Rebstwk, H, 7.64. Scicncc, 108, 53 (1946). The 9,ll-oxido compound was also prepared (5) Q.R. Bartz, J. Controulis H. M. Crooks, Jr.,and Mildred C. from the methyl ester of I by perphthalic acid Rebstock, ibid., 2163 (1946). (6) N. G. Brink, F. A. Kuehl, Jr., E. H. Flynn and K. Folkerr, treatment and had a melting point of 263-265' THIS JOURNAL, 68, 2557 (1946). (block), which is in fair agreement with that re(7) I. R . Hooper, L. H. Klemm, W. J. Polglase and M. L. Wolfrom, ported for the methyl ester of I1 by Bergmann ibid., 68, 2120 (1946); 6@,1052 (1947). (8) J. Fried and 0. Wintersteiner. ibid., 6% 79 (1947). and Stevens.'
I
CHCO2H
>o
