3080
SEYHAN h’. EGE, REVVEX~ ‘ O L O V S K Y AND WALTERJ. GENSLER [CONTRIBUTION FROM THE CHEMISTRY
Vol. 53
DEPARTXENT O F BOSTON UNIVERSITY, BOSTON15, MASS.]
Synthesis of Methyl 5,8,11,14-Eicosatetraenoate(Methyl Arachidonate) 1*2 BY
SEYHAN N. EGE, REUVENwOLOVSKY3 AND WALTERJ. GENSLER RECEIVED FEBRUARY 10, 1961
Arachidonic acid as its methyl ester has been synthesized v i a acetylenic intermediates. The Grignard derivative of 1heptyne was coupled with 4-chloro-2-butyn-1-01 t o give 2,5-undecadiyn-l-ol, which with phosphorus tribromide gave 1bromo-2,5-undecadiyne. 8-Chloro-1,4-octadiyne was obtained from the 5-chloro-1-pentynyl Grignard reagent and propargyl bromide. Coupling l-bromo-2,5-undecadiyne with 8-chloro-14-octadiyne yielded the tetraacetylene l-chloro-4,7,10,13nonadecatetrayne. Semi-hydrogenation followed by carbonation of the Grignard derivative offered arachidonic acid which upon esterification with diazomethane gave methyl arachidonate.
The group of essential fatty acids includes linoleic sharply increasing difficulty in handling sensitive acid (all cis-9,12-octadecadienoicacid), ?-linolenic skipped unsaturated compounds as the number of acid (all cis-6,9,12-octadecatrienoic acid) and unsaturations goes up. With this in mind, the arachidonic acid (all cis-5,8,l1,14-eicosatetraenoic scheme of synthesis outlined in Fig. 1was developed. acid). These acids have long been recognized4 The two fragments, l-bromo-2,5-undecadiyne (IV) as dietary factors in the normal growth of animals. and 8-chloro-1,4-octadiyne (VI), were synthesized I t has generally been a ~ c e p t e d ~that - ~ the all cis and coupled to give 1-chloro-4,7,10,13-nonadecaconfiguration atid the skipped’ arrangement of tetrayne (VII)” which is a key intermediate to double bonds are essential to the biological activity arachidonic acid. of these acids. More recently, through their acIn carrying out the coupling reactions of acetytion in depressing blood cholesterol levels, they have lenic Grignard reagents with propargylic halides, attracted attention as potential agents for the con- the use of tetrahydrofuran as a solvent was found trol of atherosclerosis. -4rachidonic acid, the most to be of great advantage. Preliminary experipotent of the group,8 seems to be, therefore of ments on the cuprous chloride-catalyzed coupling great importance as a nutritional factor. of 1-heptyne with propargyl bromide, as well Since arachidonic acid is not easily available in as of 5-chloro-1-pentyne with propargyl bromide in quantity from natural sources, it seemed desirable ether, in tetrahydrofuran a t 37”, and in tetrahydroto develop a practical route for its synthesis. When furan a t 6 5 O , indicated that the best results were we started our work, several syntheses of linoleic obtained when tetrahydrofuran was used as solvent acid had been described9 but none of arachidonic around room temperature. From these experiacid.l0 We are now reporting a practical synthesis ments two effects were apparent. First, reaction of arachidonic acid. times were cut from periods of several days to about Combination of two diunsaturated fragments to one to two hours when tetrahydrofuran was used form a tetraunsaturated skipped system such as in instead of ether a t 37”. Second, higher temperaarachidonic acid offers some advantage over com- tures in tetrahydrofuran were not of further adbination CJf a triunsaturated with a monounsatu- vantage since lower yields resulted as a consequence rated fragment. This is a consequence of the of decomposition or side reactions. l 2 2,5-Undecadiyn-l-ol (111), obtained in 87% (1) For the previous paper in t h e series nn t h e synthesis of unsaturated f a t t y acids, see n‘.J . Gensler and C. I3 Abrahdms, J . A m . Chem. yield from the reaction of 4-chloro-2-butyn-1-01 S O L . , so, 4593 (1958). (11)13with the Grignard derivative of 1-heptyne, (2) This iiivestigation was supported by a research grant (No. was converted in 70y0 yield t o the corresponding H3773) from the S a t i o n a l Hcart Institute, U.S. Public Health Service. (3) Visiting Scientist from t h e U’eizmann Institute of Science, bromide I V by treatment with phosphorus triRehovoth, Israel, 1969-1960. bromide. S-Chloro-1,4-octadiyne (VI) was ob( 4 ) For a comprehensive re\iew and leading references, see H. J. tained in 5370 yield by coupling the Grignard Deuel, Jr., “ T h e Lipids,” Vol. 111, Interscience Publishers, Inc., New reagent from 5-chloro-1-pentyne (V) with propargyl York, N. Y., 10.57, p. 783. ( 5 ) T. P.Hilditch, “The Chemical Constitution of Natural Pats,” bromide. The cuprous chloride-catalyzed cou195C, Third Edition, John \Xiley and Sons, lnc., New York, .\i. Y,, pling of the Grignard derivative of the chlorodiyne C h i p t e r 1X, pp. 4SB-JRO. V I with l-bromo-2,5-undecadiyne (IV) in cold (ii) R . T. Holman, Proll IIa,b
OH
I
/CH2-Y
a, R = -CHCHzCH 2 1 b,R = H 'CHz-CO
i""
The P-hydroxyketone system in streptimidone (Ia) and tetrahydrostreptimidone (IIa) easily undergoes the reverse aldol reaction in alkali to give (a) aldehyde derivatives from the P-ethylglu(1) R. P. Frohardt, H. W. Dion, Z . L. Jakubowski, A. Ryder, J. C. French and Q. R. Bartz, J . A m . Chcm. Soc., 81, 5500 (1959). (2) E. E. van Tamelen and V. Haarstad, ibid., 82, 2974 (1960).
tarimide moiety, the structure of which has been firmly established,' and (b) the corresponding C-9 methyl ketones (Ib, IIb). Available data supporting the formulation of the C-9 moiety as in I, which is a modification of the original proposal of Frohardt, et d . , l may be summarized as: ultraviolet and infrared data indicating the presence of a conjugated diene unit,3 facile base-catalyzed coiiversion of the existing ultraviolet chromophore to a 2,4-dienone system, and the n.n.r. spectrum of streptimidone acetate2 showing five hydrogens (four olefinic and one acetoxyl methine) in the olefinic hydrogen region and a doublet for the Cmethyl group. The present investigation, which was undertaken to provide definitive chemical data, has confirmed this formulation by (a) unequivocally establishing the carbon skeleton of the C-9 moiety through a degradation series, and (b) locating the diene unit on this skeleton by careful (3) The conjugated diene unit in streptimidone is shown by: (a) the ultraviolet spectrum, H::gk 232 mp, t 23,100; (b) two infrared absorption bands at 6.09(m) and 6.21(w) p : (c) the ultraviolet spec230 mp. trum of the sodium borohydride reduction product, k:&?" e 23,600,'
