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The Structure and Total Synthesis of Cassaic Acid’g2 Richard B. Turner, 0. Buchardt, E. Herzog, R. B. Morin, A. Riebel, and J. M. Sanders
Contributionf r o m the Department of Chemistry, Rice University, Houston, Texas. Received December 20,1965 Abstract: Evidence is presented which establishes the structure of cassaic acid and, hence, also the structures of the Er,vthrophleum alkaloids cassaine, cassaidine, and coumingine. The question of stereochemistry is discussed. The total synthesis of cassaic acid which was carried out as part of this investigation, coupled with conversions described in the literature, constitutes a formal synthesis of cassaine and cassaidine. Of special interest is the
method that was employed for establishing and maintaining a thermodynamically unfavorable configuration in an a-methyl ketone which served as a key intermediate.
T
he Erythrophleum alkaloid cassaine was first isocarbon was a trisubstituted phenanthrene d e r i ~ a t i v e , ~ lated in pure form by Dalma in 1935.3 The suband the product was ultimately identified as 1,8-distance possesses the molecular formula C24H3904N.On methyl-2-isobutylphenanthrene (1) by Humber and hydrolysis with dilute mineral acid, it affords P-dimethTaylor.lo Barring rearrangement in the steps leading ylaminoethanol and cassaic acid, C Z ~ H ~ from ~ O ~which , to 1, part structure 2 could, therefore, be assigned to cassaine may be regenerated by treatment of the sodium cassaic acid. This structure was then expanded to the salt with P-dimethylaminoethyl ch1oride.j Functional nonisoprenoid formulation 3 by Humber and Taylor group analysis indicated the presence of one hydroxyl and one keto group,* and ultraviolet absorption spectra AHCOOH of cassaic acid (X,, 215 mp (log E 4.3)) and of cassaine (A,, 223 mp (log E 4.26)) indicate that the carboxyl functions in these substances (acid and ester, respectively) are a,@-unsaturated.6 This conclusion was confirmed by the fact that on catalytic hydrogenation CK CH, cassaic acid and cassaine furnish dihydro derivatives, 1 2 which retain the keto group, but which show no discrete absorption in the 220-mp region of the uItravioIet. on the basis of considerations of the general behavior of On the basis of this evidence the substances were inthe keto group and of an assumed analogy to other ferred to be tricyclic. diterpenes. Information regarding nuclear structure was provided by selenium dehydrogenation of various derivatives of dihydrocassiac acid, from which reactions 1,2,&trimethylphenanthrene could be i ~ o l a t e d . ~ ~ ’ Further evidence was obtained by removal of the hydroxyl and keto functions in the dihydro acid and labeling of the carboxyl group in the latter compound by reaction of the corresponding methyl ester (cassanic acid methyl ester) with methylmagnesium bromide. Successive dehydration and dehydrogenation of the The work that has been carried out in this laboratory Grignard product afforded a crystalline hydrocarbon, had as its initial objective a rigorous demonstration of CnoHz2.8Detailed comparison of the ultraviolet specthe location of the keto group in cassaic acid. If the trum of the latter substance with spectra of various details of structure suggested by Humber and Taylor model compounds suggested that the CzoHzz hydrofor the ring A system are provisionally accepted as correct, the keto group in question can be located only (1) This investigation was supported by research grants furnished by the National Heart Institute, U. S. Public Health Service, and the Robert at C-9 or C-10, for cassaic acid is not an a- nor a pA. Welch Foundation. The provision by the Monsanto Co. of a predochydroxy ketone, it does not possess the properties of a toral fellowship for one of the authors (R. B. M.) is gratefully acknowledged. vinylogous @-ketoester, and does not exhibit conjugated ( 2 ) A preliminary account of a portion of this work appeared in ketonic absorption in the ultraviolet or infrared. The Tetrahedron Letters, No. 2, 7 (1959). argument receives additional support from the observa(3) G. Dalma, Ann. Chim. A p p l . , 25, 569 (1935). For reviews of earlier work see T. A. Henry, “The Plant Alkaloids,” 4th ed, J. and A. tion of Engel” that ozonolysis of the diketone dehydroChurchill, Ltd., London, 1949, p 725, and E. L. McCawley in “The Alkacassaic acid affords oxalic acid and a triketone in which loids,” Vol. V, R. H. F. Manske and H. L. Holmes, Ed., Academic the carbonyl groups are isolated and, hence, presumably Press Inc., New York, N. Y., 1955, Chapter 39. (4) G. Dalma, Helv. Chim. Acta, 22, 1497 (1939). situated in different rings. (5) F. Faltis and L. Holzinger, Ber., 72, 1443 (1939). Preliminary attempts to differentiate between the C-9 (6) L. Ruzicka and G. Dalma, Helv. Chim. Acta., 22, 1516 (1939). (7) L. Ruzicka, G. Dalma, and W. E. Scott, ibid., 24, 179E (194!); and C-10 alternatives by partial dehydrogenation of see also A. Ronco, “Zur Kenntnis der Erythrophleum-Alkaloide, Ueber die Konstitution der Cassainsaure,” Kommerzdruck und Verlags, A. G., Zurich, 1945. (8) L. Ruzicka, B. G. Engel, A. Ronco, and I
