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Naturally occurring oxygen heterocyclics V. Mammein
WATURALLYOCCURRIWG
OXYGENRETEROCYCLICSV. MUmEm
Carl Djewaa_81, E. J. Elrenbraun,R. A. FInnwan and B. Gilbert
Departmentof Chomietry,
Ww
StateUniversity,Detroit 2, Miohlgan
(Retoeived 5 February 1959)
RECENT paper0 have been oonoernedwith the isolation
2
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 lsopropylidenedouble bond 3 of mameln (I) has been reduoed, upon heating with yk aqueous alkali led to
1
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,Progreet3In 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
Baturally ocourring oxygen heterocyclicaV. maeuaein
11
(V).7 methyl ;-propyl ketone,6 isovalericacid and iaovalerylphloroglucinol Theee three oleavage products account for 21 out of the 22 carbon atoms of mammein an&together with the earlier reported 3 spectral results, suggest strongly that mammein is a substitutedcoumarln.Methylationof the residual material, after removal of the above cleavage products, furnished a crystalline,fluorescentdimethyl ether, m.p, 109-109,5°,of the oompositionC19H2604, whose ultravioletabsorption spectrumwas virtually superimposableupon that S of 5,7-dimethoxyooumarin, 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-dlhydroq-6leovaleroylooumarln(IX) ' (m.p. 228-229'r found:C, 67.308 H, 7.32; 0,
26.23. 5$2o 05 requires C, 67.09; H, 6.62; 0, 26.29), which was tranaformed by Clemmensenreduction into 4-;-propyl-5,7-dihydroxy-6ieovalerylcoumarln(X) (m.p. 183.5-186';found: C, 66.45; H, 7.98. C17H2204,H20requires C, 66.21; H, 7.85.) Methylationwith dimethyl sulfate and potassium carbonate provided the non-fluorescent4-E-propyl-5,7dimethoxy-6-isovalerylcoumarln (XI) (m.p. 51-53'r found: C, 71.52~
6
Thio subetanoewas first isolated in this laboratoryby Dr.
S.P. Marfey. 7 T.S. Kenny, A. Robertson and S.W. George, J. Chem. Soa, 1601 (1939). ' 8. F&me and T. Severin, Arch. Pharm* SE, 486 (1957). 9 We believe that ring oloeure in the direction of IX (rather than yielding the isomerlc S-ieovaleroylcoumarin) Is favored by sterio considerationsas well aa by hydrogen bonding between the oarbonyl group and the two ortho-hydroxylgroups.
12
rJsturally
ooourrlng
oxygen heterooyollos
V. mameln
H /
(CH~ZCH(CH~)~
OH
HO \ d
R
Rl
I
R=(CH3j2C=CHCH
U
R=(CH3)2CHCH2C
III IV
; Rl=(CH ) CHCH k 2, Rl=(C&HCk,CO
CO
l
V VI
R=H R=(GH3)2CHCH2CH2
R=(CH3)2CHCH2CO; R =(GH )2CICHCH2 R=Rl=(CH3)2CHCH2Cd2; OI4OCOCH,
R=O
IX X
R=H2
t o=
3H7 < 2 t?02 C2H5
Naturally occurring oxygen heterocyclioeV. mammein
. H, 8.05; 20.40;
0,
13
19.91; 0CH3, 20.08. C Ii 0 requires C, 71.67; H, 8.23; 0, 19 26 4
2 0cH
19.49), while alkaline opening of X followed by 3’ acidificationand methylationwith dimethyl sulfate afforded XI as well as the fluorescentisomer 4-E-propyl-5,7-dimethoxy-8-isavalerylooumarin (XII) (m.p. lOY-110').The latter proved to be identicalwith the alkali cleavage product ClyH2604 (Found: C, 71.59; H, 8.35; 0, 29.41; OCH3, 19.93) of dihydromammein(II), thus establishingthe presence of a oaunarin skeleton and the nature of the eubstituentaat positions 4,5 and 7 of mammein. The identificationof-the cleavage product with the eynthetic 4-z-propyl-5,7-dimethoxy-8-isovalerylcoumarin (XII) does not necessarilyimply that the ieovalerylgroup in dihydromammein(II) was also situated in the same position, since the ooumarinioacid generated in the alkaline cleavage reaction could have cyclized in two directions as was found to be the case with syntheticX. In order to demonstratethat both the isovaleroyland the iaopentenyl groups of mammein (I) were located in the aromatic ring, dihydromammein (II) was subjected to Clemmensenreduction followed by acetylation and the resulting 4-;-propyl-5,7-diacetoxy-6,8-di-isovalerylooumarin (IV) m.p. 103-107'; found: C, 70.59; R,'8.10; 0, 21.51. C26R36C6 requires C, 70.24; H, 8.16; 0, 21.59) was heated with alkali. Acetylationof the phenolic componentof this cleavage led to the triacetateof di-iaovalerylphloroglucinol (VI), which wae ayntheeizedby 10 Clemmensenreduction of isovaleryl-isovaleroylphloroglucinol followed by acetylation(m.p. 104.5-105°;found: C, 67.44; H, 8.44; 0, 24.0@ CH3C0, 31.61. C22R3406 requiree C, 66.98; R, 8.69; 0, 24.34~ 3 CR3C0, 32.73). The above reactions require that memmein be representedeither lo 1. Riedl, s
02, 692 (1952).
14
Naturally occurring oxygen heterooyoliosV. mammain
struoture I or III, We have already reported 3 that treatmentof mammein at room temperaturewith base followed by acidificationfurnisheda yellow isomer, isomammeln,which ia clearly the product arising from alternate 11 ring closure of the intermediatecoumarinioacid. 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 4,8-dimethyl-5,7-dimethog-6-acetylcoumarin,12we assign structureIII to laomammeln,from whiah it followa that mammein is 4-g-propyl-5,7-dihydroxy-6-isopentenyl-&ieavaleroylco-in
(I). Work on other constituentsof Mammea americana L. ia in pro-
gress.13
11
M. Crawford and J. 8. Raaburn, J. Chem. 300, 2155 (1956); R. M. Naik and V. M. Thakor, J. 0%
12
Chem, 22, 1240 (1957).
F. M. Dean, E. Evans and A. Robertson,J. Chem. Soo.4565 (1954).We are
Indebted to Dr. Dean of the University of
Liverpool for this apeaimen. 13 Mnanoial aesiatanaeby the National Science Foundationand the Natioaal Heart Institute (grant No. R-2574) of the National Institutesof Health, U.S. Fublio Health Servioe, la gratefully aoknowledged.
OXYGENRETEROCYCLICSV. MUmEm
Carl Djewaa_81, E. J. Elrenbraun,R. A. FInnwan and B. Gilbert
Departmentof Chomietry,
Ww
StateUniversity,Detroit 2, Miohlgan
(Retoeived 5 February 1959)
RECENT paper0 have been oonoernedwith the isolation
2
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 lsopropylidenedouble bond 3 of mameln (I) has been reduoed, upon heating with yk aqueous alkali led to
1
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,Progreet3In 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
Baturally ocourring oxygen heterocyclicaV. maeuaein
11
(V).7 methyl ;-propyl ketone,6 isovalericacid and iaovalerylphloroglucinol Theee three oleavage products account for 21 out of the 22 carbon atoms of mammein an&together with the earlier reported 3 spectral results, suggest strongly that mammein is a substitutedcoumarln.Methylationof the residual material, after removal of the above cleavage products, furnished a crystalline,fluorescentdimethyl ether, m.p, 109-109,5°,of the oompositionC19H2604, whose ultravioletabsorption spectrumwas virtually superimposableupon that S of 5,7-dimethoxyooumarin, 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-dlhydroq-6leovaleroylooumarln(IX) ' (m.p. 228-229'r found:C, 67.308 H, 7.32; 0,
26.23. 5$2o 05 requires C, 67.09; H, 6.62; 0, 26.29), which was tranaformed by Clemmensenreduction into 4-;-propyl-5,7-dihydroxy-6ieovalerylcoumarln(X) (m.p. 183.5-186';found: C, 66.45; H, 7.98. C17H2204,H20requires C, 66.21; H, 7.85.) Methylationwith dimethyl sulfate and potassium carbonate provided the non-fluorescent4-E-propyl-5,7dimethoxy-6-isovalerylcoumarln (XI) (m.p. 51-53'r found: C, 71.52~
6
Thio subetanoewas first isolated in this laboratoryby Dr.
S.P. Marfey. 7 T.S. Kenny, A. Robertson and S.W. George, J. Chem. Soa, 1601 (1939). ' 8. F&me and T. Severin, Arch. Pharm* SE, 486 (1957). 9 We believe that ring oloeure in the direction of IX (rather than yielding the isomerlc S-ieovaleroylcoumarin) Is favored by sterio considerationsas well aa by hydrogen bonding between the oarbonyl group and the two ortho-hydroxylgroups.
12
rJsturally
ooourrlng
oxygen heterooyollos
V. mameln
H /
(CH~ZCH(CH~)~
OH
HO \ d
R
Rl
I
R=(CH3j2C=CHCH
U
R=(CH3)2CHCH2C
III IV
; Rl=(CH ) CHCH k 2, Rl=(C&HCk,CO
CO
l
V VI
R=H R=(GH3)2CHCH2CH2
R=(CH3)2CHCH2CO; R =(GH )2CICHCH2 R=Rl=(CH3)2CHCH2Cd2; OI4OCOCH,
R=O
IX X
R=H2
t o=
3H7 < 2 t?02 C2H5
Naturally occurring oxygen heterocyclioeV. mammein
. H, 8.05; 20.40;
0,
13
19.91; 0CH3, 20.08. C Ii 0 requires C, 71.67; H, 8.23; 0, 19 26 4
2 0cH
19.49), while alkaline opening of X followed by 3’ acidificationand methylationwith dimethyl sulfate afforded XI as well as the fluorescentisomer 4-E-propyl-5,7-dimethoxy-8-isavalerylooumarin (XII) (m.p. lOY-110').The latter proved to be identicalwith the alkali cleavage product ClyH2604 (Found: C, 71.59; H, 8.35; 0, 29.41; OCH3, 19.93) of dihydromammein(II), thus establishingthe presence of a oaunarin skeleton and the nature of the eubstituentaat positions 4,5 and 7 of mammein. The identificationof-the cleavage product with the eynthetic 4-z-propyl-5,7-dimethoxy-8-isovalerylcoumarin (XII) does not necessarilyimply that the ieovalerylgroup in dihydromammein(II) was also situated in the same position, since the ooumarinioacid generated in the alkaline cleavage reaction could have cyclized in two directions as was found to be the case with syntheticX. In order to demonstratethat both the isovaleroyland the iaopentenyl groups of mammein (I) were located in the aromatic ring, dihydromammein (II) was subjected to Clemmensenreduction followed by acetylation and the resulting 4-;-propyl-5,7-diacetoxy-6,8-di-isovalerylooumarin (IV) m.p. 103-107'; found: C, 70.59; R,'8.10; 0, 21.51. C26R36C6 requires C, 70.24; H, 8.16; 0, 21.59) was heated with alkali. Acetylationof the phenolic componentof this cleavage led to the triacetateof di-iaovalerylphloroglucinol (VI), which wae ayntheeizedby 10 Clemmensenreduction of isovaleryl-isovaleroylphloroglucinol followed by acetylation(m.p. 104.5-105°;found: C, 67.44; H, 8.44; 0, 24.0@ CH3C0, 31.61. C22R3406 requiree C, 66.98; R, 8.69; 0, 24.34~ 3 CR3C0, 32.73). The above reactions require that memmein be representedeither lo 1. Riedl, s
02, 692 (1952).
14
Naturally occurring oxygen heterooyoliosV. mammain
struoture I or III, We have already reported 3 that treatmentof mammein at room temperaturewith base followed by acidificationfurnisheda yellow isomer, isomammeln,which ia clearly the product arising from alternate 11 ring closure of the intermediatecoumarinioacid. 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 4,8-dimethyl-5,7-dimethog-6-acetylcoumarin,12we assign structureIII to laomammeln,from whiah it followa that mammein is 4-g-propyl-5,7-dihydroxy-6-isopentenyl-&ieavaleroylco-in
(I). Work on other constituentsof Mammea americana L. ia in pro-
gress.13
11
M. Crawford and J. 8. Raaburn, J. Chem. 300, 2155 (1956); R. M. Naik and V. M. Thakor, J. 0%
12
Chem, 22, 1240 (1957).
F. M. Dean, E. Evans and A. Robertson,J. Chem. Soo.4565 (1954).We are
Indebted to Dr. Dean of the University of
Liverpool for this apeaimen. 13 Mnanoial aesiatanaeby the National Science Foundationand the Natioaal Heart Institute (grant No. R-2574) of the National Institutesof Health, U.S. Fublio Health Servioe, la gratefully aoknowledged.