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Carl Djewaa_81, E. J. Elrenbraun,R. A. FInnwan and B. Gilbert

Department of Chomietry,


StateUniversity,Detroit 2, Miohlgan

(Retoeived 5 February 1959)

RECENT paper0 have been oonoernedwith the isolation


and oharaoterlza-

tion 3 of memaein, a orystallineineeotioidaloonatituentof the see& of Mamma amerloana L. We should nor like to record oertain observations whioh lead to the aaaignmentof structure I to thie rubstanoe.Mammein represents the first naturally oocurring oowin 4 with a n-propyl aub-

stituent at C-4 and It is aleo interestingto note that a number of aynthetlo ooumarlnshave been shorn to exhibit ineeotioidalactivitye5 Dlhydromammein(II), In whloh the lsopropylidene double bond 3 of mameln (I) has been reduoed, upon heating with yk aqueous alkali led to


Paper IV: D. Herb&, W. B. More, O.R. Gottlleb and C. Djerarsl, J. Amer. Chem. Soo,& in press (1959).

2 M. P. Morris and C. Pagan, J. Amer. Chew SOO, 12, 1489 (1953). ' C. Djerami, E. J. Eiaenbraun,B. Gilbert, A. J. Lemln, S. P. Marfey and M. P. Morris, J. Amer. Chem. SOOT 80, 3686 (1956). 4 For pertinentreviews lee: F. Y. Dean In L. Zeohmeister'e, Progreet3 In the Chemistry of Ormnio Natural Produote Vol. IX, pp. 225-291. Springer,Vienna (1952); L. Reppel, (1954); W. Karrer, Kormtitutlonund Vorkomnen der omanlsohen Pflamenstoffe,pp. 532-562 Birlch&eer,Baael (1958). 5 P. L&gem, B. Martin and P. H&r, (1944). 10 Eelv. Chim. dote 21, 892

Chem. suggest strongly that mammein is a substitutedcoumarln. which was tranaformed by Clemmensenreduction into 4-. whose ultravioletabsorption spectrumwas virtually superimposable upon that S of 5.52~ 6 Thio subetanoewas first isolated in this laboratoryby Dr. 183.found: C.of the oompositionC19H2604.5-186'.S. 26. 66.) Methylationwith dimethyl sulfate and potassium carbonate provided the non-fluorescent 4-E-propyl-5. 9 We believe that ring oloeure in the direction of IX (rather than yielding the isomerlc S-ieovaleroylcoumarin) Is favored by sterio considerations as well aa by hydrogen bonding between the oarbonyl group and the two ortho-hydroxyl groups. F&me and T. 51-53'r found: C. 66. Kenny. 228-229'r found:C.p.fluorescentdimethyl ether. S.Methylationof the residual material. maeuaein 11 6 isovalericacid and iaovalerylphloroglucinol (V). A.-propyl ketone. J. 67. H. 109-109. 7 T. H.21. Robertson and S.32. C17H2204. Pharm* SE.308 H. furnished a crystalline.09. 6. 0.85. m. George.W. after removal of the above cleavage products.p.Baturally ocourring oxygen heterocyclicaV.5°. 1601 (1939). 7.23. 67. . (XI) (m. Marfey.7 methyl . Arch.p. 7.-propyl-5. Severin.H20requires C. The structure (XII) of this crucial degradationproduct was establishedby the following synthetio sequenoer Peahmann condensationof ieovaleroylphlorogluainol (VII)7 with ethyl butyroaaetate(VIII) furnished4-n-propyl-5.7-dimethoxyooumarin. 71. 26.29). Soa.7-dlhydroq-6leovaleroylooumarln (IX) ' (m. Theee three oleavage products account for 21 out of the 22 carbon atoms of mammein an&together with the earlier reported 3 spectral results. 5$2o 05 requires C.7-dihydroxy-6ieovalerylcoumarln (X) (m.P. H. 486 (1957). 0.p. ' 8.62.

12 rJsturally ooourrlng oxygen heterooyollos V. IX X R=O R=H2 t o= 3H7 < 2 t?02 C2H5 . Rl=(CH ) CHCH k 2. OI4OCOCH. R =(GH )2CICHCH2 R=Rl=(CH3)2CHCH2Cd2. mameln H (CH~ZCH(CH~)~ / HO \ d Rl OH R I R=(CH3j2C=CHCH U III IV R=(CH3)2CHCH2C .CO l CO V VI R=H R=(GH3)2CHCH2CH2 R=(CH3)2CHCH2CO. Rl=(C&HCk.

61. since the ooumarinioacid generated in the alkaline cleavage reaction could have cyclized in two directions as was found to be the case with syntheticX.69.59. 0. 20.24. 0. H.7-dimethoxy-8-isavalerylooumarin (XII) (m.98. 71.93) of dihydromammein(II).16. dihydromammein (II) was subjected to Clemmensenreduction followed by acetylation and the resulting 4-. 104. C Ii 0 requires C. C22R3406 requiree C. 66. 103-107'. 29.7-diacetoxy-6. 8. thus establishingthe presence of a oaunarin skeleton and the nature of the eubstituentaat positions 4. 21. 71.44.p. 2 0cH . 31. 8. mammein 13 19.p.40. H. 8.found: C. 24. H. 0. 32.'8. R.35. 8.59. lOY-110').41. 70.. Riedl. 19 26 4 19. Naturally occurring oxygen heterocyclioe V. found: C. 0CH3.73).5-105°. H.-propyl-5. while alkaline opening of X followed by 3’ acidificationand methylationwith dimethyl sulfate afforded XI as well as the fluorescentisomer 4-E-propyl-5. In order to demonstratethat both the isovaleroyland the iaopentenyl groups of mammein (I) were located in the aromatic ring. which wae ayntheeizedby 10 Clemmensenreduction of isovaleryl-isovaleroylphloroglucinol followed by acetylation(m.05.49). 70.34~ 3 CR3C0.7-dimethoxy-8-isovalerylcoumarin (XII) does not necessarilyimply that the ieovalerylgroup in dihydromammein(II) was also situated in the same position. 24. OCH3. 0.23. Acetylationof the phenolic componentof this cleavage led to the triacetateof di-iaovalerylphloroglucinol (VI).08.0@ CH3C0. s 02. R. 0. 67. 20. 8-di-isovalerylooumarin (IV) m.51. The identification of-the cleavage product with the eynthetic 4-z-propyl-5.p.67.59) was heated with alkali. 0. H. 19.10.The latter proved to be identicalwith the alkali cleavage product ClyH2604 (Found: C.91. 21.5 and 7 of mammein. The above reactions require that memmein be representedeither lo 1. C26R36C6 requires C. 0. 692 (1952). 8.44. 8.

mammain struoture I or III. M. 300. 0% Chem.J. Fublio Health Servioe. 22. U. 1240 (1957). la gratefully aoknowledged. 12 F. isomammeln. ia in progress. M.7-dihydroxy-6-isopentenyl-&ieavaleroylco-in (I). . Work on other constituentsof Mammea americana L. R. Raaburn. E. Crawford and J. 2155 (1956).12we assign structureIII to laomammeln. 8. Dean of the University of Liverpool for this apeaimen. Soo. Dean.4565 (1954). M.14 Naturally occurring oxygen heterooyoliosV. Evans and A. Thakor. For mechanisticreasons (hydrogenbonding of the hydroxyl groups ortho to the ieovaleroylgroup in the coumarinicacid favoring ring closure in the alternate dlreotion) and becauee of the similarityof the ultravioletabsorption epectra of isomammeindimethyl ether 3 and 4. Chem.which ia clearly the product arising from alternate 11 ring closure of the intermediatecoumarinioacid.8-dimethyl-5. Chem. R-2574) of the National Institutesof Health. Robertson. 7-dimethog-6-acetylcoumarin.S.13 11 M.We are Indebted to Dr. J. J. Naik and V.from whiah it followa that mammein is 4-g-propyl-5. We have already reported 3 that treatmentof mammein at room temperaturewith base followed by acidificationfurnisheda yellow isomer. 13 Mnanoial aesiatanaeby the National Science Foundationand the Natioaal Heart Institute (grant No.