1001
COMMUNICATIONS TO THE EDITOR
Feb. 20, 1958
THE STRUCTURE OF GLIOTOXIN
Sir : The formulas proposed earlier for gliotoxin and dethiogliotoxin (I, II)Ix2 are not compatible with CH20H
CH20H
YIII
VI1
S-CH-OH
I I1 several recent experimental observations. These include the transformation of gliotoxin on short contact with alkaline alumina a t 20" into the compound C13H10N202 (111),3and the lack of satisfactory correspondence in chemical and spectroscopic properties between the synthetic 10-hydroxypyrazinoindole derivative IV and a degradation product, anhydrodethiogliotoxin, which had been assigned this chemical c o n ~ t i t u t i o n . ~
violet absorption are consistent with formula VIII.6 Acetic anhydride a t 230" converts dehydrodethiogliotoxin to an alkali-insoluble, colorless, crystalline compound of the formula C15H14N204 [m.p. 185186", [0]"D 1.3 i 1.3'1. The chemical behavior and the absorption spectra in the ultraviolet and infrared regions support the formulation of the acetylated derivative as IX.
+
ACY0
N-CH3 CH2
N-CH3
0%' CH2
CH3
I11 IY We have now deduced the structure V for gliotoxin. This expression permits the unambiguous interpretation of the extensive transformations of gliotoxin and dethiogliotoxin (VI) into degradation
I
CHZOH
Y
CH20H
VI
products of known structure, and leads directly to satisfactory formulations for several derived substances of hitherto unknown or uncertain structure and genesis. For example, the long-known anhydrodethiogliotoxin is now given the structure VII, and a new series of transformations,6 described below, is uniquely formulable in terms of the new structures. Dehydrodethiogliotoxin, C13H14N204, [imp. 2522 5 4 O , [ a I z 5 D - 217 f 7", hxmax (log 6 ) 220 mp (4.19), 262 ink (3.82),292 m p (3.47)] is formed when dethiogliotoxin is heated over palladium-charcoal in boiling xylene. Its chemical behavior and ultra(1) J. R. Johnson and J. B. Buchanan, THIS JOURNAL,76, 2103 (1953). (2) J. R . Johnson, "The Structure of Gliotoxin." in "The Roger Adams Symposium," John Wiley and Sons, Inc., New York, N. Y., 1055. pp. 60-90. ( 3 ) John S. Warner, Doct.ora1 Thesis, Cornell Iiniversity. 1953. (4) L. R. Harper, Doctoral Thesis, Cornell University, 1954. ( 5 ) hlalcolm R . Bell. Doctoral Thesis, Cornell University, 1966.
IX Treatment of the acetylated compound with saturated methanolic ammonia a t 20" converts it slowly to a very sparingly soluble, colorless, crystalline compound, (C7H7N02),, which decomposes a t ca. 360°, without melting. This product exhibits a striking resemblance to the very insoluble dimeric substances produced by the action of ammonia and other bases on dipeptides or 2,5-piperazinediones containing a serine unit.7 Chemical and stereochemical considerations exclude attachment of a disulfide bridge in gliotoxin a t any positions other than 3 and 11. It is now clear that gliotoxin is an anhydrodipeptide related to the amino acids serine and phenylalanine, and it is particularly worthy of note that the 0-carbon atoms of the cooperating a-thio-a-amino acid units must have the same absolute configuration. (6) T h e late Professor E. A. Braude (Imperial College) informed one of us (R.B.W.) privately (23 March 1956) t h a t his associates R . L. Erskine and G. Lowe had effected t h e dehydrogenation of gliotoxin itself, using tetrachloro-o-benzoquinonein o-dichlorobenzene a t 100'. Professor Braude rightly regarded t h e preparation of dehydrogliotoxin 1m.p. 184-185O, AXmaa (log e) 214 mg ( 4 . 3 4 ) , 270 mp ( 3 . 7 2 ) , 298 m p ( 3 . 6 7 ) ] a s providing confirmatory evidence for the presence of t h e unusual cyclohexadiene moiety in gliotoxin, b u t otherwise formulated t h e change in terms of t h e old structure I. I t is now clear t h a t dehydrogliotoxin is t h e analog of the dehydrodethio compound VI11 which we had prepared prior t o receiving Professor Braude's communication. (7) M. Bergmann a n d collaborators, A n n . , 446, 17 ( 1 9 2 5 ) ; 448, 38 (1926); 458, 40 (1927). (8) W e wish t o acknowledge the generous support of the National Institutes of Health and t h e S a t i o n a l Science Foundation.
DEPARTMENT OF CHEMISTRY UNIVERSITY CORNELL ITHACA, NEWYORK DEPARTMEXT OF CHEMISTRY HARVARD UNIVERSITY* CAMBRIDGE, MASSACHUSETTS
MALCOLM R.BELL JOHN
R.JOHNSON
BERNARD S.n ' n n r R.B . \ ~ O O D \ V A R n
RECEIVED JANUARY 8, 1938
