D. STANLEY TARBELL, H. RICHARD FRANK AND PAUL E. FANTA
502
[COXTRIBETION FROM THE
DEPARTMENT O F CHEMISTRY
Vol. 68
O F THE UXIVERSITY OF ROCHESTER]
Studies on the Structure of Colchicine BY D.
STANLEY TARBELL, H. RICHARD FRANK’ AND PAUL E. FANT.k2
Interest in the compound colchicine, obtained from the seeds of the autumn crocus, has been markedly increased in recent years by the discovery that it. arrests the process of cell division (mitosis) in plant or animal cells,3but its structure is still not definitely known in all details. The present paper reports some observations in this field, in which we have been interested for some time. Fundamental work on the structure of colchicine was done by Windaus,4 who proposed formula I.4d85 €12
c: I
I CHOCH~
I
111, R = H , R’ = I IV, R = CH3, R‘ = I V, R = CH3, R’ = H
I:[ One of the key degradation products obtained by Windaus was deaminocolchinol methyl ether, obtained by the following series of reactions. Hydrolysis of colchicine with very dilute acid yielded colchiceine (11), with loss of the methyl group, the rest of the molecule being unchanged. Treatment of I1 with alkaline hypoiodite replaced the hydroxymethylene group with iodine, yielding N-acetyliodocolchinol (111), which, in contrast to 11, behaved like a phenol and could be methylated by the ordinary methods, yielding IV. Removal of the iodine from IV gave Nacetylcolchinol methyl ether (V), and this on acid hydrolysis lost the N-acetyl group to form the corresponding amino compound, colchinol methyl ether. Hofinann exhaustive methylation of this amine led to the nitrogen-free compound, deaininocolchiiiol methyl ether, which Windaus (1) Abbott Laboratories Fellow, 1944-1946. (2) Abbott Laboratories Fellow, 1943-1944. (3) For references to the effect of colchicinc as n mitotic poison, which has had important applications in botany and in the study of cancer, see ( a i Lettr6 and Fernholz, Z. phssiol. Chem., 278, 175 (1943); (b) Henry, “The Pldnt Alkaloids.” 3rd ed., Blakiston, Philadelphia, 1939, p p . 577-578. (4) (a) IVindaus, Sitzber. Heidelberg. A k n d . TYiss., Math. natiww. tilasse, 2. abh (1911); (b) ibid., 18. abh (1914); (c) ibid., 16. dbh (1919); id) A ~ i s .439, , 59 (11124); this paper summarizes his earlier work. ( 5 ) Grewe, Ber., 71, 907 (1939).
regarded as a 9-methyltetramethoxyphenanthrene, because on cleavage of the methoxyl groups with hydriodic acid followed by zinc dust distillation, 9-methylphenanthrene was obtained. Windaus’ conclusion that in colchicine itself ring B was &membered was questioned by Cohen, Cook and Roe,6 who suggested that ring B might be seven-membered.’ The structure of deaminocolchinol methyl ether was not established by Windaus, but on his formulation it should be 2,3,4,6(or 7)-tetramethoxy-9-methylphenanthrene. In recent studiesS J. W. Cook has shown that i t is not a phenanthrene derivative, since i t forms no picrate and is reduced catalytically by palladium to a dihydride, in contrast to the synthetic 2,3,Z,Gand 2,3,4,7-tetramethoxy-9-methylphenanthrenes. The seven-membered ring structure VI postulated for deaminocolchinol methyl ether was supported by oxidation to a glycol with osmium tetroxide, which, on cleavage with lead tetraacetate, yielded a gummy product believed to be the dialdehyde
VI, R = H VII, R = I
IX
VIII. The gum gradually formed a crystalline monoaldehyde by an aldol condensation. This was shown to be 2,3,4,7-tetramethoxy-lO-phenanthraldehyde by oxidation to the corresponding acid IX which was synthesized; this result incidentally establishes the position of the methoxyl group in ring C of the colchicine derivatives IV and V. (6) Cohen, Cook and Roe, J . Chem. SN.,19-L (1940). (7) The interesting suggestion IDewar, .\’atitre, 168, 1 4 1 (1945)j t h a t ring C of colchicine and colchiceine is 7-membered, and is isomerizcd to an aromatic ring on treatment with hypoiodite, may account for the peculiar properties of these compounds. In this connection, attention may be called t o the fact t h a t colchicine is an indicator and is colored in dilute alkali c.[! Davies and Grier, P h a r m . J . , 109, 210 (1922)J. Absorption curves for colchicine in neutral and basic solution are given in Fig. 1. The curve in dilute acid (pH 2) is almost identical with the one in neutral solution. (8) (a) Buchanan, Cook and Loudon, J . Chem. S O L ,325 (1914); (b) Barton, Cook and Loudon, i b i d . , 176 (1945).
STUDIES ON THE STRUCTURE OF COLCHICINE
March, 1946
We have been able to provide independent evidence for the presence of a seven-membered ring9 in deaminoiodocolchinol methyl ether (VII) ; the iodine-containing compound was studied since the members of this series crystallize better than the iodine-free analogs. Oxidation of VI1 with permanganate in acetone a t room temperature gave a dibasic acid in yields up t o 25%, whose
503
I
I
I
CHzCOOH COOH C H I -O ~ - ~ OC H I CHIO 0 R CH3
X,R = I XI, R = H
07
/c-c\
-
CHO , -OCHs CHIO-0
I
0.0
CHa
200
300 400 500 Wave length in mH. Fig. 1.--Molar extinction curves in aqueous solution: colchicine __ in water, PH 7; - - - - in 0.01 iV sodium hvdroxide, pH 12.
XI1
composition and neutral equivalent agreed with structure X. The iodine atom was removed by reduction with hydrogen and nickel, yielding X I . Accompanying the dibasic acid was a very small amount (one or two mg. per run) of a red compound, which must be the phenanthrenequinone XI1 analogous to an iodine-free quinone obtained by Cook. It was converted into the quinoxaline XIII.
talline product formed by loss of methanol. This product can only be the phenanthrol XVI; it is insoluble in aqueous alkali, but can be dissolved in methanolic alkali. CH~COOCHa
a '"
COOCHI
N
)-=
c,
+
T;llniarin reaction , l ! l i I r r l t i n a n , P m c . Riiv. .So
