June 20, 1956
COMMUNICATIONS TO THE EDITOR
2907
has been suggested several time^.^!^,^ Among the All the solid products described are diamagnetic, post-transition metal-metal halide systems, the and give powder pattern lines different from those variations in metal solubility both within the obtained with any binary mixture of the comgroup and with change in halide ion are consistent ponents. with such an interpretation, and, moreover, there INSTITUTE FOR ATOMIC RESEARCH is a direct correspondence between appreciable DEPARTMENT J O H X D. CORBETT OF CHEMISTRY STATE COLLEGE RICHARD K MCMULLAN solubility in the molten halide and the existence of IOWA AMES, Ion-A a known gaseous subhalide.6 However, with the RECEIVED MAY3, 1956 possible exception of CaCl,6 the isolation of lower oxidation states from these melts apparently has not been achieved; the systems characteristically THE STRUCTURE OF THE ANTIBIOTIC METHYMYCIN revert to the original components on solidification. The effect of certain foreign salts on the metal Sir : solubility has been reported for the cadmium7 and Methymycin' belongs chemically to a class of bismuth8 systems. An interpretation of the results antibiotics2 which contains such therapeutically that appears more satisfactory than those pre- important representatives as erythromycin3 and viously presented3,' can be obtained from a consid- carbomycin (magnamycin) and partial structures eration of the possible acid-base or ''complexing" have been advanced for two of them (erythromyinteractions between the added salt and the two cin3 and pikromycin5). We should now like t o oxidation states present. Added base, ;.e., halide report certain degradation experiments which, ion, would be expected to reduce the amount of coupled with earlier results,6 lead us to propose subhalide formed through stabilization of the more structure I as a complete expression for methyacidic, higher oxidation state. Conversely, ad- mycin. dition of an acid capable of complexing halide ion Mild hydrolysis of methymycin with aqueous would increase the amount of subhalide formed. sulfuric acid led t o the desosamine free fragment I1 Use of the strongly acidic A1C13 in such systems (m.D. 163-165'. la1 -1- 79' (all rotations in chlorohas resulted in the preparation of stable Bi(I), form), 225 mp, log E 4.03, " : : :A 2.80, Cd(1) and Ga(1) compounds. 2.95, 5.76, 5.91 and 6.08 p ; Found: C, 65.17; The solubility of Bi in BiC13 a t 260' corresponds H, 9.11; C-CHS, 19.34) which was further to 46y0 conversion to BiC1; a black, asphalt-like characterized as the acetate I11 (m.p. 198-200', mixture is obtained on solidification. At the same [(Y]D 93'; Found: C, 64.39; H, 8.29; acetyl, temperature, addition of AlCl, results in the reac- 12.11) and as the ketone IV (m.p. 173-179', 2Bi 3A1C13 = 3BiAlC14 taking tion BiC13 224 mp, log e 3.96; Found: ~ place quantitatively [56.3, 55.7% Bi, 55.3% theor.]. [ a ] +177', C, 65.87; H, 8.47; C-CH3, 19.95). The ketone The product, m.p. ca. 253', is maroon in bulk and reddish-brown as a powder. I t disproportionates IV gave a negative Schiff test and yielded 58% of t o metal and trihalide essentially quantitatively in carbon dioxide upon treatment with alkali followed water, dioxaneor alcohol, and darkens rapidly in air. by acidification (a parallel experiment with I1 furnished no carbon dioxide). Similarly, the solubility of Cd in CdC1, a t 740' When methymycin or I1 was treated with corresponds to 17.6y0 conversion of Cd2C12; a methanolic sulfuric acid, there was produced the black mixture is obtained on quenching. With spiroketal V (m.p. 79-81', [ Q ] D - 68', no high 2AlC&/CdC12, the solubility of cadmium a t 330' " : : :A 5.77 F ; indicates 71.5y0 conversion to the Cd(1) oxidation selective ultraviolet absorption, state. The solid, very light gray in bulk, white as Found: C, 66.51; H, 9.25; OCH3, 9.81; active a powder, also readily disproportionates in con- hydrogen, O.OO), which upon lithium aluminum tact with the above solvents. Similar results have hydride reduction led to the corresponding diol (m.p. 159-161', [ Q ] D 118'; Found: c, 65.77; been obtained in the iodide system. The compound GazCh, which has been found t o H, 10.17; OCH3, 9.40). Permanganate oxidation of I1 in acetone solution be Ga(I)[Ga(III)C14],5 is an example of such an acid-stabilized lower oxidation state. Further re- furnished three products: VI (m.p. 164-172', duction of the Ga(II1) therein by metal gives a [(Y]D +52' (acetone), A"',: 2.90, 5.66 and 5.78 p ; solution containing 7.4y0 GaCl a t I n the Found: C, 58.35; H, 7.79; C-CHI, 21.01; neut. presence of sufficient A1C13 the amount of metal dis- equiv., 318), VI1 (m.p. 55-58', [ a ] ~ 69', solved a t 180' is within 0.1% of that for the reac-" : : :A 5.68-5.76 p (broad); Found: C, 63.40; tion Ga(GaCl4) 2Ga 4%1cl3 = 4GaA1C14. H, 8.39; C-CH,, 22.51) and VIIIa (m.p. 126-128', The white product, m.p. 175', is, as expected, (1) M. N. Donin, J. Pagano, J. D. Dutcher and C. M . McKee. physically very similar to Ga(GaC14). "Antibiotics Annual 1953-1954," Medical Encyclopedia, Inc., New \
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(2) G. von Hevesy and E. Lawenstein, 2 anorg. allgem Chem , 187, 266 (1930). (3) K. Grjotheim, F. Gronvold and J. Krogh-Moe, THTSJOURNAL, 77, 5824 (1955). (4) J. D. Corbett and S. von Winbush. ibid., 77, 3964 (1955). (5) S. von Winbush, R. K. McMullan and J. D. Corbett, to be published. (6) (a) P.Ehrlich and L. Gentsch, Nafurwiss., 40, 460 (1953); (b) The compound has been found t o be CaHC1, P. Ehrlich, B. Ait, and L. Gentsch, Z . anovg. allgem. Chcm.. 883, 58 (1956). (7) D.Cubicciotti, THISJOURNAL, 74, 1198 (1952). ( 8 ) G. Cleary and D. Cubicciotti, ibid., 74, 557 (1952).
York, p. 179. ( 2 ) For leading references see R. Corbaz, L. Ettlinger, E . Ggumann, W. Keller-Schierlein, F. Kradolfer, E. Kyburz, L. Neipp,V. Prelog, A. Wettstein and H. ZBhner, Helw. Chim. A d a , 89, 304 (1956). (3) Cf.P.F. Wiley, K. Gerzon, E. H. Flynn, M. V. Sigal and U. C. Quarck, THISJOURNAL, 77, 3677 (1955). (4) R.L.Wagner, F. A. Hochstein, K. Murai, N. Messina and P. P. Regna, ibid., 76, 4684 (1953). (5) H. Brockmann and R. Oster, Nafurwiss., 4 8 , 155 (1955). (6) (a) C. Djerassi, A. Bowers and H. N. Khastgir, THISJOURNAL. 78, 1729 (1956); (b) C. Djerassi, A. Bowers, R. Hodges and B. Riniker, ibid., 78, 1733 (1956).
COMMUNICATIONS TO THE EDITOR
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[ a ]+38', ~ : : :A 3.05 (broad), 5.68 and 5.76 p ; Found: C, 59.91; H, 8.05; neut. equiv., 199 (immediate titration), 100 (after standing for 2 hours in excess base)). Lead tetraacetate oxidation of the hydroxy acid VI gave the methyl ketone VI1 (positive iodoform test), which in turn upon alkaline saponification led to the lactone acid VIIIa and 3-hydroxy-2-pentanone (isolated and identified as the bis-2,4-dinitrophenylhydrazoneof pentane-2,3-dione).T CHI OCH, CH3 R CH3CHzCH&(OH) c H = c H c 11c H I c H z c IH - c cI/H c H I
I
I c=o
II,R = LOH H 111, R = L O A c IV, R = 0 CHs OCHa CH3 I
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CH3 I
I
I
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0
c=o
V
CHo
CHI
I CHaCHXHC=R
CHI
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O=C&HCHaCHCHCHCH3 L n a II
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I
0
OH VI, R = LC02H VII, R = 0 CHI CHa
c=o
I
I
O=CCHCHzCHCHCHCHa
IVIIIa, R bH LO& =
b, R = CHI CHa 0
I
II
CHaCHzCHC-(OH) CCH=CH-
Vol. 78
manner shown in I1 and this in turn would lead to formulation VIIIa for the lactone acid. This acid (as well as its methyl ester VIIIb, m.p. 79-81') proved to be identical with a specimen isolated by Prof. V. Prelog and colleaguesYfrom some related antibiotics. Since the Swiss investigatorsg have shown that decarboxylation of VIIIa followed by oxidation yields acetaldehyde and meso-a,cy'dimethylglutaric acid, this fully confirms structures VI and VI1 and consequently also 11. The placement of the desosamine fragment as shown in I rather than attaching it t o the tertiary hydroxyl function follows from three lines of evidence: (a) methymycin amideea is recovered unchanged under conditions where I1 is oxidized to the ketone IV in good yield; (b) since the lithium aluminum hydride reduction product of methymycinebI8was processed under non-acidic conditions prior to periodate oxidation, a glycosidic linkage involving desosamine and the tertiary hydroxyl group would almost certainly not have been cleaved and consequently no periodate would have been consumed ; (c) the alternative structure would not explain the resistance6b to periodate of the lithium aluminum hydride reduction product of tetrahydrodesoxymethymycin.6a Acknowledgment.-IVe are greatly indebted to the Squibb Institute for Medical Research for generous fellowship support and to Mr. Joseph F. Alicino (Squibb Institute) for his outstanding microanalytical contributions. (9) We are greatly indebted t o Prof. V. Prelog (E. T. H., Zurich) for carrying out the direct comparison and for informing us of his results prior t o publication. (IO) Squibb Postdoctorate Research Fellow a t Wayne University, 1955-1956.
DEPARTXENT OF CHEMISTRY WAYNEUNIVERSITY CARLDJERASSI DETROIT,MICHIGAN JOHN A. ZDERIC'~ RECEIVED APRIL 18, 1956 USE OF GAS PHASE CHROMATOGRAPHY FOR T H E SEPARATION OF MIXTURES OF CARRIER FREE RADIOACTIVE SUBSTANCES : PRODUCTS OF CHEMICAL REACTIONS ACTIVATE1 ESSES
Sir: When organic bromides are irradiated with It neutrons, the Brs2(36 hr.) formed with high 0 kinetic energy by the Brsl(n,y)Brs2 process rupIX tures the parent bond and reenters combination as a variety of compounds.' Such compounds are It is clear that 2,4,6-trimethylcyclohex-2-en-lone, isolated6b from the alkali fusion of methy- present a t mole fractions of the order of 10-l2. mycin (I), must have arisen by a cyclization proc- By gas-liquid partition chromatography we have ess involving a fragment containing the carbon separated over twenty different radioactive orsequence of VIIIa. Since methymycin cannot ganic compounds from a drop of neutron irradiated contain the partial structure IX8 (which would n-propyl bromide and detected their presence with also have led t o the oxidation products VI, VI1 and the aid of a scintillation counter (curve A, Fig. 1)) VIII), the trimethylcyclohexenone precursor can, thus demonstrating that: (1) the gas chromatofor all practical purposes, be attached only in the graphic technique is as effective for materials a t tracer concentrations as a t macro concentrations ; (7) Comparison with an authentic sample (P. F. Wiley, K. Gerzon, (2) the number of products from the ( n , r ) reaction E. H. Flynn, M. V. Sigal and U. C. Quarck, THISJOURNAL, 77, 3676 (1955)) was kindly carried out by Dr. K. Gerzon. in n-C3H,Br is a t least twice as great as formerly ( 8 ) Lithium aluminum hydride reduction of methymycin (ref. 6b) or suspected. Curve B, Fig. 1, shows a similar chroof I1 followed by periodate oxidation results in consumption of only matogram of the organic products containing Brsa one equivalent of reagent and formation of propionaldehyde which is
I o-c-
only compatible with structures I and 11. Furthermore, IX is also excluded by t h e formation of t h e spiroketal V.
( 1 ) For a discussion of chemical reactions activated b y nuclear processes see J E 'A'>llard, An?z Rer of X uc SCC, 3, 193 (1963)
