July 20, 1952
COMMUNICATIONS TO THE EDITOR
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acidity of boric acid to the marked degree charac- 55.17; H, 4.84; N, 5.85; C1, 7.40. Found: C, 54.85; H, 5.13; N, 5.97; C1, 7.19. P-Apoterrateristic of 1,8-naphthalenediols. Lithium aluminum hydride reduction of penta- mycin hydrochloride (I)2, [a]'% -28" (c, 1% in methyldecarboxamidoterrinolide consumes 0.5 mole ethanol), PKa, = 3.6, P K a , = 5.2, P K a , = 7.8 of hydride and yields no hydrogen; the reaction (dimethylfonnamide-water). Anal. Calcd. for CZZproduct is a dialcohol (IV), m.p. 114-115', anal. H22Nz08.HCl.H20: C, 53.17; H, 5.07; N, 5.64; Calcd. for C24H2a07:C, 67.27; H, 6.59. Found: C1, 7.14. Found: C, 52.90; H, 4.76; N, 5.65; C, 67.09; H, 6.69, which is readily dehydrated in C1, 6.90. We consider a-and P-apoterramycin to be stereodilute mineral acid to an ether, m.p. 141-142'. Anal. Calcd. for C24H2608: C, 70.23; H, 6.38. isomers of structure I. The two compounds are Found: C, 70.06; H, 6.06. That the lactone interconvertible in acid and alkaline solution, and structure shown by this reduction is a phthalide is their ultraviolet spectra are virtually identical. indicated by the extreme resistance of decarbqxCHI amidoterrinolide to hydrolysis, This assignment is in agreement with the carbonyl band at 5.73 p (dioxane) in the infrared absorption spectra of I and 11. The marked similarity of the ultraviolet spectra of I, I1 and 1,8-dihydroxynaphthalene-2carboxylic acid8 determines the orientation of the 11 OH OH 0 phthalide ring on the naphthalenediol system. I Further, the acidity of terrinolide, @ K a , = 4.5, is in good agreement with the acidity of 1,8-dihydroxy-2Alkali fusion of the apoterramycins yields 1,8naphthaldehyde, pKa = 4.5 (dimethylformamide- dihydroxy-4-methylnaphthalene-3-carboxylicacida water). and 2,5-dihydroxybenzoquinone. Both isomers The presence of five phenolic hydroxyl groups in lose carbon dioxide, ammonia and dimethylamine I and I1 is shown by the formation of pentamethyl in hot concentrated hydrochloric acid, and are and pentaacetyl derivatives. The stability of I1 converted to decarboxamidoterrinolide (11).4 in strong acid, and the marked susceptibility of I Pentamethylterrinolide is formed by treatment of and I1 to air oxidation suggest that the C8H6Oa a-apoterramycin with methyl iodide and potassium moiety not accounted for by the dihydroxybenzo- carbonate in acetone. The presence of the diphthalide system is a trihydroxybenzene. ComOH parison of the ultraviolet spectrum of the dialcohol (IV) to the composite curves derived from 3hydroxymethyl-4-methyl-1,8-naphthalenedi01~ and the three isomeric trihydroxybenzenes indicates that the C6H608 group is hydroxyhydroquinone. The presence in terrinolide of a carboxltmide OH OH OH 0 group which is lost by hydrolysis in sulfuric acid is supported by the infrared absorption spectra of 11, R = H 111, R = CONHZ I, I1 and their derivatives. The second acid constant of I, p K a 2 = 7.5 (compare p K a l = 10.2 for hydroxybenzophthalide system in the apoterra11) requires that the carboxamide group in terrino- mycins and texrinolide (111) is evident since the lide (I) be attached to the hydroxyhydroquinone absorption spectra of these compounds are pracring between two phenolic groups. tically superimposablein the 330-420 mp region of (4) J. Btieseken, J. de Bruin and W.van Rijswijk de Jong, Rec. frau. the ultraviolet spectrum, and all three compounds chim., 68, 3 (1939). show the strong enhancement of the acidity of RESEARCH LABORATORIES F. A. HOCHSTEINboric acid characteristic of 1,8-naphthaIenediol~.~ CHAS.PFIZERAND Co., INC. P. P. REGNA Thus, the apoterramycins differ from terrinolide BROOKLYN 6, N. Y. K. J. BRUNINGS (111) only in the structure of the isolated sixCONVERSE LABORATORY HARVARD UNIVERSITY R. B. WOODWARDmembered ring. CAMBRIDGE, MASSACHUSETTS The isolation of 2,5-dihydroxybenzoquinonefrom RECEIVED JUNE25, 1952 a-apoterramycin suggests the relative positions of two carbonyl groups, a hydroxyl and a dimethylamine group in the isolated ring. The stability of TERRAMYCIN. VI. THE STRUCTURE OF 4- AND the apoterramycins under the conditions of their 6-APOTERRAMYCIN, ACID REARRANGEMENT formation from terramycin excludes a- or yPRODUCTS OF TERRAMYCIN diketone structures within the carbocyclic ring since Sir : (2) This compound was described by R. Pasternack, P. P. Regna, In 1.5 N aqueous hydrochloric acid a t 60°, terramycinl loses a molecule of water and re- R. L. Wagnu. A. Barley, P. A. Hochstein, P. N. Gordon and K. J. Brunings, ibid.. 71,2400 (1951). as CaHuNxOrHCL It has since been arranges to form two closely related optically active found that Karl Fisher reagent shows the presence of one molecule compounds: a-Apoterramycin hydrochloride (I), of water, and that recrystallization from methanol displaces the water [ c Y ] ~ ~ +123O D (c 1% in ethanol), PKa, = 4.0, with a molecule of methanol. (8) F. A. Hochstein, e1 at.,to be published. pKa* = 5.1, *pKa, = 8.4 (dimethylfonnamide(4) F. A. Hochstdn, P.P.Regna, K. J. Bruninga and R. B..Woodwater). Anal. Calcd. for CaHttNnO,.HCl: C, ward, T E J ~O ~ A L 74, , 8706 (1952).
x;
@&$pCO..; ' I/
r [ n
(1) P. P.Regna, I. A. Solomons, K. Mud,A. E. Timreck, P.J, Bcuninga and W. A. L d a , T E I ~ J o w u .TS, 4211 (1061),
(6) J. B(LcKLen,J, do Bruin and W.van Rijswiik de Jour, ILc. taw. shim., I, I (1989).
ComrtmIc.\ rmxs
3708
such systems necessitate the attachment of either a hydroxylic or a dimethylamino function i? to the carbonyl group. The @-&ketone structure (I) expresses the stability of the hydroaromatic ring except under conditions which bring about enolization of both carbonyl functions, thus permitting ready elimination of the dimethylamino group and the formation of a hydroxyhydroquinone ring, as, for example in 11' i V 3 VI. S(CH,)?
Y(CH3)r
TO THE
Vol. 74
EDITOR
The naphthacene carbon skeleton is demonstrated by the reaction sequence I -+ IV. Terramycin is reduced with zinc and acetic acid a t room temperature to form desoxydesdimethylaminoterramycin (11)2: Anal. Calcd. for CzoHleNOs. '/zCHaCOCH3: C, 59.99; H, 5.15; N, 3.26. Found: C, 59.99; H, 5.17; N, 3.29. In methanolic hydrochloric acid, I1 is readily converted to the orange-red crystalline compound (111) or a tautoiner : Aizal. Calcd. for CzoHlsNOs: C, 65.75; H, 4-14; K, 3.83. Found: C, 65.74; H, 4.29; N, 4.15. Zinc dust distillation of I11 yields naphtbcene. Structure I is consistent with the dehydration and rearrangement of terramycin in acid media to form the dihydroxybenzophthalide structure known to be present in a- and P-apoterramycin,3 to which we now assign structure V.
I
R-iHO'?,
OH I
011
VI F', A. HOCHSTEIN C. R. STEPHENS P. N. GORDON P. P. REGNA F. J. PILGRIM K. J. BRUNINGS
RESEARCH LABORATORIES Cms. PFIZER AND Co., INC. RROOKLYN 6, N. p.
L.
VI
The phthalide carbonyl in the apoterramycins CONVERSE LABORATORY HARVARD UNIVERSITY R . B. ~ ~ ' O O D W A R D must be derived from a highly conjugated or CAMBRIDGE, MASSACHUSETTS enolized carbonyl group, since the infrared absorpRECEIVED JUNE 25, 1952 tion spectrum of terramycin shows no absorption TERRAMYCIN. VII. THE STRUCTURE OF TERRAMYCIN
Sir : 'I'erramycin' has been assigned the structure I.
211
----+-
H0.4~
HrC HO OH H'
--+ OH 0
OH 0
oyaoH I1
CH 3
-+ Zn Naphthaceue
\if OHI
I OHOHO IrI I
Dust
Co"s
IV
(1) P. P. Regna. I. A. Solomons, K . Murai, A. E. Timreck, K . J .%uninps and W A . L a ~ i a r ,T m s JOVENAI., 75, 4211 (1961).
between 5 and 6 p. I n order to permit ready cleavage to form the apoterramycins, this carbonyl must be incorporated in an actual or potential pdicarbonyl system. With this limitation, only two formulas (I and VI) can be written for terramycin. The alternative VI is excluded, inter alia, by the acidity relationships of terramycin and its transformation products. For example, the pKa (8.0 in dimethylformamide-water) of the dimethylamino group in terramycin does not change markedly in the conversion to the apoterramycins. Structure I is also consistent with the formation of terracinoic acid147-hydroxy-3-methylindanone%acetic acid,j 7-hydro~y-3-methylphthalide,~ 6acetylsalicylicacid,'and 3-hydroxymethyl-4-methyl1,8-naphthalenedi01,~in the alkaline degradation of terramycin, which involves cleavages at the 3-4, 5-6, and 11-12 positions. The indanone ring of terracinoic acid is presumed to form through the intermediate VI1 by aldehyde condensation in the position para to the phenolic group, while 7-hydroxy-3-methylindanone-2-acetic acid is formed through condensation in the ortho position with loss of the carboxyl group. (2) R. Pasternack, P. P. Regaa, R . L. Wagner, A Bavley, F. A. Hochstein, P. N. Gordon and R. J. Brunings, ;bid., 73, 2400 (1951). In this paper I1 was assigned the formula CnHnNOs. (3) F. A. Hochstein, C . R. Stephens, P. N. Gordon, P. P. Regna, F. J. Pilgrim, K. J. Brunings and R. B. Woodward, ibid., 74, 3707 (1952). (4) R. Pasternack, L. H. Conover, A. Bavley, F. A. Hochstein, G . B. Hws and K. J. Brunings, ibid., 74, 1928 (1952). (5) F. A. Hochstcin, to be published. (6) F. A. Hochstein and R. Pasternack, THISJOURNAL, 78, 5008 (1951). ( 7 ) R. Kirhn and I.Dury, Bar., R4, $48 (19611.
