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Davallic acid, a triterpene with a novel skeleton.
Tetrahedron
Letters
NO. 22,
pp.
1451-1457,
1963.
Pergamon Press Ltd.
Printed in Great Britain.
DAVALLIC ACID, A TRITBRPENE WITH A BOVRL SKELETON.
KojI Nakanlehlf Yong-Yeng Lln: Hlroshl Kakleawa Department of Chemistry, Tokyo Kyolku Unlverslty, Tokyo, Japan Hong-Yen Helland H.C. Helu Taiwan Provincial Hygienic Laboratory, TaIpel, Taiwan, China (Received 3 July 1963)
DAVALLIC acid, C30H4802, m.p. 283'. Is Ieolated from the rhizome of a Chinese fern, Davallla dlvarlcatg, which Is widely used as a tonic and diuretic in Taiwan. The present studies establish Its structure as I. Davalllc acid Is a pentacyclic compound containing one carboxyl group
and a trl-substituted double bond as revealed
by the spectroscopic data of Its derivatives; e.g., retwl davallate(II), C3lH5CO2, m.p. 234' , M+ 454 * vKBr 1740 cm-'t hzH
207 mp (a 5100), sChf 5.32 (one oleflnlc proton,
diffuse).
Reduction of the ester II with llthlum a.lumInum
hydride gave davallol (III), m.p. 169-170'; acetate (IV), m.p. 191°, Scc14 BB quartet at 3.9 and 4.2 ppm (J 11 cps) due to hindered -CH20Ac.
Treatment of davallol (III) with
chromic trloxlde In pyrldine afforded the aldehyde davallal (V), m.p. 149'.
The high-field region of Its 100 mc IIwR(l)
+ Present address: Department of Chemistry. Tohoku UnIversIty, Sendal. Japan.
1451
Davallic
1452
acid
No.22
spectrum was revealing In that it disclosed the presence of five methyl singlets (0.75. 0.77, 0.83, 0.94, and 1.00 ppm), and a triplet at 0.80, 0.86. and 0.92 ppm with peak height ratios of ca. 1:2:1 that could be assigned either to an isopropyl(2) or two secondary methyl groups. When davalllc acid was refluxed with hydrochloric acid in acetic acid, followed by nethylatlon. methyl lsodavallate -1 (VII), C31H5002, m.p. 230°, was obtained in good yield together with minute amount6 of two more Isomers, methyl lsodavallate-2 (VIII), m.p. 215*, and methyl leodavallate-3 (IX) m.p. 165O.
The NKR spectra of lsbmers-1 and -2 lacked
oleflnio protons, whereas the spectrum of Isomer-3 had a dlffuee band around ECDC13 5.20. Oxidation of Isomer-l with chromic trloxlde In acetic acid flrst gave the trans-enedlone(VIIa), m.p.
211°,
As; 1740, 1680, 1615 cml, hiiiH 2'71mp (e 7,500). '31H46'4 which upon further oxidation with selenium dioxide gave the dlenetrlone (VIIb), C3lH42C5, m.P. 231'. AE (e 7,500). 283 mp (e 7,900).
215 mp
Presence of the a-dlketone
group in the dlenetrlone wae confirmed by Its conversion with alkaline hydrogen peroxide into a seco-dicarboxyllc 1740, 1700. 1690, 1660, 1630 cm*; acid (VIIc). A",B,g hFiH
252 mp (e 8,8OC), 208 mp (e 7.000).
These series of
oxidations and dehydrogenatlons are well-known in the field of tetracycllc terpenoldst3) and establish
the C8-C9 location
of the double bond in Isomer-l (VII). Placement of the double bond at C9-Cl1 rather at C7-C8 follows
from the W
absorption of nordavallatrlene (XI) and
mass spectra of methyl davallate (II), davallol (III).
Davallic
No.22
acid
1453
I R:COOH R:COOHe III R:CH20H IV R:CH20Ac - _ _^^ II
COOHe
236 \ (IX)
“COOHe
(VII) \
‘&
SeO+
@
COOH
$42,
HE
(VIIb)
(VIIa)
(VIIC)
+
x
Pb(oAc)4
qJ
+
(Xl
q&
(XI)
1454
Davallic
acid
No.22
davall.al(V), davallene (VI) nnd methyl leodavallate-1 (VII)(4). They were all characterizedby a strong H"-15 peak due to cleavage of the C17-methy1(5),and base peaks at m/c 28i'(II),259(III).257(V), 243(VI) and 287(VII), namely at M+-167. Thls fragmentationconetltutesthe base peak of arborene(6)that carries a 9(U)-double bond, and has been assigned to cleavagesat bonds 12-13, 13-14, and 15-16(6). Oxldatlonof methyl lsodavallate-1(VII) with chromic trloxlde In acetic acid gave the A 7,9(11)-trane-dlene, c31H#02, m.p. 207-2oa",having a triplet in the UV at 233.
240, and 249 mp (In EtOH). The 240 mp meulum Is typical (71, for 13a, 140-methylcompoundssuch as multlflorenol
bauerencl('),and eupholt9);In contrast,the 138. 14a-compounds(lanostaneseries(9) and arborene(6))absorb at 236, 243, and 252 mp. The formationof methyl lsodavallate-2(VIII) Is similar to the euphenol-lsoeuphenol rearrangement,the baee peak at m/e 236 being tentatively asslgied to the cleavageshown. The structureof the third isomer IX follows from the NMR spectrumand the base peak at m/e 149. These transformationsrequire a 14~. 13a, 18~. and not a 14a, 130-configuration of the 17a-configuration, lanosterolseries, In which the rearrangementmerely glves Oxidationof methyl devallatewith CrOj-AcOH afforded12-ketomethyldavallate,m-p. 252'. vKBr 1740, 1680. 1605 cm*, hEtoH 246 mp (c 9,500).with a positiveCotton effect ORD curve (peak: WI;;;" +5430; trough: C+l!iz -9920) of molecularamplitude (a) +15350. (6) having This IS in contrastto the 136,14a-arboren-12-one
No.22
Davallicacid
1455
a negative Cotton effect curve. Decarboqlatlon of davalllcacid with lead tetraacetate yielded acetoxy nordavalladlene(X), m.p. 195'. vKBr 1740 cm*, sCDC13 1.54 (%-Me), 1.97 (OAc), 5.33 ppm (diffuse),together with some trlene XI, r.p. 165O. h:F
233, 241, 250 rnp
(e 2,000, 2,200, 1,400), SCDC13 1.54(=C-We),5.36(dlffuse). The trlene wae also producedby treatmentof X with dry HCl in chloroform. The low hm,, intensityof the trlene Is caused by contamination(V.P.C.)but euffloee to Indicate the preeenceof a conjugateddlene and not a triene system, and suggeststhat the originaldouble bond Is A9(11) rather than 67. Evidence for rlng E Ia as follow. In conjunctionwith structuralstudies on arborlnol(6), the Wolff-Klshnerreduction of davallal (V) to davallene (VI), m.p. 167O was carried out at Stanford,and It was found that davalleneand fernene(12) were ldentlcal (m.p.,IR,V.P.C.)(13).Fernene hae been related to hopene-2(14) and this alao correlatesdavalllc acid (I) with the hopane series(15). The stereochemistryat C-8, 14, 13, 18 and 17 required for the formationof leomere-1, -2 and -3 from davalllc acid ie in agreementwith this
correlation. Apparently,fernene and davalllcacid belong to a new group of trlterpeneederived blogenetlcallyfrom hopane (the precursorcould be somethingllke hopene-a with an exocycllcC21-C22 double bond). We suggest the name "fernane"for thie rearrangedhopane skeleton. Dreldlng models show that ring B of davalllcacid (I) 18 fixed in a boat form. The carboxylgroup 16 assigneda B-arlal conflguratlon in view of the pscS of leodavalllcacid (A' leomer) at
Davallic acid
lk56
No.22
8.60* (calcd. for a- and e-COOH, respectively, 8.41 and 7.91)'16), the IR doublet of methyl davallate at 1147 and 1160 cm1 (CC14+17).
and the chemical shift of the -CH20Ac
quartet centered at scc14 4.05(18) In the NMR spectrum of davallol acetate (IV). The mass spectra were measured at Stanford University and some at Hitachi Co., Naka Laboratories.
The authors are
grateful to Professor C. Djerassl and Dr. H. Vorbrfiggenfor discussions and Identification of davallene.
The studies were
carried out In close contact with fernene(14), and we acknowledge this close cooperation.
' The 100 mc measurement were kindly carried out by Dr. N. S. Bhacca, VarIan Associates. 2 J. M. Lehn and G. Ourisson, m.
&.
m.
Q..
1137 (1962).
3 D, H. R. Barton, J. S. Fawcett and B. R. Thomas, J. e. e., 3147 (1951); W. Voser, M. Montavon. H. H. Gflnthard, 0. Jeger and L. RusIcka, Helv. 2, 1893 (1950); J. F. Cavalla and J. F. McChIe, J. m. z., 744 (1951). 4 The mass spectra of methyl davallate (II) and methyl Isodavallate-1 (VII) were Identical. 5 C. Djerassl, H. BudzIkIei?IczandJ.M. Wilson, Tetrahedron Letters, 263 (1962). 6 H. V#srbrfiggen, S. C. PakrashI and C. Djerassl, m.,
In press.
7 P. Sengupta and H. N. Khastglr. Tetrahedron Q, 123 (1963). 8 F. N. Lahey and M. V. Leedlng, Proc. Chem. Sot. (London), 342 (1958). g G. Ourlsson and P. Crabbh. "Les trIterp&es p. 154, Hermann, Paris (1961).
t&.racyclIques",
"D . H . R . Barton , J. F. McGhIe. M. K. Pradham and S. A. Knight, J. m. x.. 876 (1955). "Measured with an automatic JASCO ORD/UV-5 spectropolarlmeter. 12H. Ageta, K. Iwata and K. Yonesawa. -Chem. Pharm. E&&. (Tokyo) a, 408 (1963). * Davalllc acid Itself was not soluble enough for pK measurements
No.22
Davallic
acid
1457
13Dr. H . Vorbr@en . private communication. 14H. Ageta, K. Iwata and S. Batorl, thl6 journal, previous paper. 15G. V. Baddeley,T. G. Haleall and X. B. H. JOneB, 1. Q&& a., 3891 (1961). 16P. P. Sommer. V. P. Arya and N. Simon, TetrahedronLetter6 18 (1960);P. P. Someer, C. Paecual,V. P . Arya and U. Siron, Helv. Ch&m. Acta. In Preee. 17Equatorialand axial COOMe groups of terpenee absorb at 1245 and 1155 cm1 (eometlneedoublet),reepectlvely: Dr. M. Fetlzon, private comunication. 18E. Wenkert and P. Beak, TetrahedronLetters, 358 (1961).
Letters
NO. 22,
pp.
1451-1457,
1963.
Pergamon Press Ltd.
Printed in Great Britain.
DAVALLIC ACID, A TRITBRPENE WITH A BOVRL SKELETON.
KojI Nakanlehlf Yong-Yeng Lln: Hlroshl Kakleawa Department of Chemistry, Tokyo Kyolku Unlverslty, Tokyo, Japan Hong-Yen Helland H.C. Helu Taiwan Provincial Hygienic Laboratory, TaIpel, Taiwan, China (Received 3 July 1963)
DAVALLIC acid, C30H4802, m.p. 283'. Is Ieolated from the rhizome of a Chinese fern, Davallla dlvarlcatg, which Is widely used as a tonic and diuretic in Taiwan. The present studies establish Its structure as I. Davalllc acid Is a pentacyclic compound containing one carboxyl group
and a trl-substituted double bond as revealed
by the spectroscopic data of Its derivatives; e.g., retwl davallate(II), C3lH5CO2, m.p. 234' , M+ 454 * vKBr 1740 cm-'t hzH
207 mp (a 5100), sChf 5.32 (one oleflnlc proton,
diffuse).
Reduction of the ester II with llthlum a.lumInum
hydride gave davallol (III), m.p. 169-170'; acetate (IV), m.p. 191°, Scc14 BB quartet at 3.9 and 4.2 ppm (J 11 cps) due to hindered -CH20Ac.
Treatment of davallol (III) with
chromic trloxlde In pyrldine afforded the aldehyde davallal (V), m.p. 149'.
The high-field region of Its 100 mc IIwR(l)
+ Present address: Department of Chemistry. Tohoku UnIversIty, Sendal. Japan.
1451
Davallic
1452
acid
No.22
spectrum was revealing In that it disclosed the presence of five methyl singlets (0.75. 0.77, 0.83, 0.94, and 1.00 ppm), and a triplet at 0.80, 0.86. and 0.92 ppm with peak height ratios of ca. 1:2:1 that could be assigned either to an isopropyl(2) or two secondary methyl groups. When davalllc acid was refluxed with hydrochloric acid in acetic acid, followed by nethylatlon. methyl lsodavallate -1 (VII), C31H5002, m.p. 230°, was obtained in good yield together with minute amount6 of two more Isomers, methyl lsodavallate-2 (VIII), m.p. 215*, and methyl leodavallate-3 (IX) m.p. 165O.
The NKR spectra of lsbmers-1 and -2 lacked
oleflnio protons, whereas the spectrum of Isomer-3 had a dlffuee band around ECDC13 5.20. Oxidation of Isomer-l with chromic trloxlde In acetic acid flrst gave the trans-enedlone(VIIa), m.p.
211°,
As; 1740, 1680, 1615 cml, hiiiH 2'71mp (e 7,500). '31H46'4 which upon further oxidation with selenium dioxide gave the dlenetrlone (VIIb), C3lH42C5, m.P. 231'. AE (e 7,500). 283 mp (e 7,900).
215 mp
Presence of the a-dlketone
group in the dlenetrlone wae confirmed by Its conversion with alkaline hydrogen peroxide into a seco-dicarboxyllc 1740, 1700. 1690, 1660, 1630 cm*; acid (VIIc). A",B,g hFiH
252 mp (e 8,8OC), 208 mp (e 7.000).
These series of
oxidations and dehydrogenatlons are well-known in the field of tetracycllc terpenoldst3) and establish
the C8-C9 location
of the double bond in Isomer-l (VII). Placement of the double bond at C9-Cl1 rather at C7-C8 follows
from the W
absorption of nordavallatrlene (XI) and
mass spectra of methyl davallate (II), davallol (III).
Davallic
No.22
acid
1453
I R:COOH R:COOHe III R:CH20H IV R:CH20Ac - _ _^^ II
COOHe
236 \ (IX)
“COOHe
(VII) \
‘&
SeO+
@
COOH
$42,
HE
(VIIb)
(VIIa)
(VIIC)
+
x
Pb(oAc)4
qJ
+
(Xl
q&
(XI)
1454
Davallic
acid
No.22
davall.al(V), davallene (VI) nnd methyl leodavallate-1 (VII)(4). They were all characterizedby a strong H"-15 peak due to cleavage of the C17-methy1(5),and base peaks at m/c 28i'(II),259(III).257(V), 243(VI) and 287(VII), namely at M+-167. Thls fragmentationconetltutesthe base peak of arborene(6)that carries a 9(U)-double bond, and has been assigned to cleavagesat bonds 12-13, 13-14, and 15-16(6). Oxldatlonof methyl lsodavallate-1(VII) with chromic trloxlde In acetic acid gave the A 7,9(11)-trane-dlene, c31H#02, m.p. 207-2oa",having a triplet in the UV at 233.
240, and 249 mp (In EtOH). The 240 mp meulum Is typical (71, for 13a, 140-methylcompoundssuch as multlflorenol
bauerencl('),and eupholt9);In contrast,the 138. 14a-compounds(lanostaneseries(9) and arborene(6))absorb at 236, 243, and 252 mp. The formationof methyl lsodavallate-2(VIII) Is similar to the euphenol-lsoeuphenol rearrangement,the baee peak at m/e 236 being tentatively asslgied to the cleavageshown. The structureof the third isomer IX follows from the NMR spectrumand the base peak at m/e 149. These transformationsrequire a 14~. 13a, 18~. and not a 14a, 130-configuration of the 17a-configuration, lanosterolseries, In which the rearrangementmerely glves Oxidationof methyl devallatewith CrOj-AcOH afforded12-ketomethyldavallate,m-p. 252'. vKBr 1740, 1680. 1605 cm*, hEtoH 246 mp (c 9,500).with a positiveCotton effect ORD curve (peak: WI;;;" +5430; trough: C+l!iz -9920) of molecularamplitude (a) +15350. (6) having This IS in contrastto the 136,14a-arboren-12-one
No.22
Davallicacid
1455
a negative Cotton effect curve. Decarboqlatlon of davalllcacid with lead tetraacetate yielded acetoxy nordavalladlene(X), m.p. 195'. vKBr 1740 cm*, sCDC13 1.54 (%-Me), 1.97 (OAc), 5.33 ppm (diffuse),together with some trlene XI, r.p. 165O. h:F
233, 241, 250 rnp
(e 2,000, 2,200, 1,400), SCDC13 1.54(=C-We),5.36(dlffuse). The trlene wae also producedby treatmentof X with dry HCl in chloroform. The low hm,, intensityof the trlene Is caused by contamination(V.P.C.)but euffloee to Indicate the preeenceof a conjugateddlene and not a triene system, and suggeststhat the originaldouble bond Is A9(11) rather than 67. Evidence for rlng E Ia as follow. In conjunctionwith structuralstudies on arborlnol(6), the Wolff-Klshnerreduction of davallal (V) to davallene (VI), m.p. 167O was carried out at Stanford,and It was found that davalleneand fernene(12) were ldentlcal (m.p.,IR,V.P.C.)(13).Fernene hae been related to hopene-2(14) and this alao correlatesdavalllc acid (I) with the hopane series(15). The stereochemistryat C-8, 14, 13, 18 and 17 required for the formationof leomere-1, -2 and -3 from davalllc acid ie in agreementwith this
correlation. Apparently,fernene and davalllcacid belong to a new group of trlterpeneederived blogenetlcallyfrom hopane (the precursorcould be somethingllke hopene-a with an exocycllcC21-C22 double bond). We suggest the name "fernane"for thie rearrangedhopane skeleton. Dreldlng models show that ring B of davalllcacid (I) 18 fixed in a boat form. The carboxylgroup 16 assigneda B-arlal conflguratlon in view of the pscS of leodavalllcacid (A' leomer) at
Davallic acid
lk56
No.22
8.60* (calcd. for a- and e-COOH, respectively, 8.41 and 7.91)'16), the IR doublet of methyl davallate at 1147 and 1160 cm1 (CC14+17).
and the chemical shift of the -CH20Ac
quartet centered at scc14 4.05(18) In the NMR spectrum of davallol acetate (IV). The mass spectra were measured at Stanford University and some at Hitachi Co., Naka Laboratories.
The authors are
grateful to Professor C. Djerassl and Dr. H. Vorbrfiggenfor discussions and Identification of davallene.
The studies were
carried out In close contact with fernene(14), and we acknowledge this close cooperation.
' The 100 mc measurement were kindly carried out by Dr. N. S. Bhacca, VarIan Associates. 2 J. M. Lehn and G. Ourisson, m.
&.
m.
Q..
1137 (1962).
3 D, H. R. Barton, J. S. Fawcett and B. R. Thomas, J. e. e., 3147 (1951); W. Voser, M. Montavon. H. H. Gflnthard, 0. Jeger and L. RusIcka, Helv. 2, 1893 (1950); J. F. Cavalla and J. F. McChIe, J. m. z., 744 (1951). 4 The mass spectra of methyl davallate (II) and methyl Isodavallate-1 (VII) were Identical. 5 C. Djerassl, H. BudzIkIei?IczandJ.M. Wilson, Tetrahedron Letters, 263 (1962). 6 H. V#srbrfiggen, S. C. PakrashI and C. Djerassl, m.,
In press.
7 P. Sengupta and H. N. Khastglr. Tetrahedron Q, 123 (1963). 8 F. N. Lahey and M. V. Leedlng, Proc. Chem. Sot. (London), 342 (1958). g G. Ourlsson and P. Crabbh. "Les trIterp&es p. 154, Hermann, Paris (1961).
t&.racyclIques",
"D . H . R . Barton , J. F. McGhIe. M. K. Pradham and S. A. Knight, J. m. x.. 876 (1955). "Measured with an automatic JASCO ORD/UV-5 spectropolarlmeter. 12H. Ageta, K. Iwata and K. Yonesawa. -Chem. Pharm. E&&. (Tokyo) a, 408 (1963). * Davalllc acid Itself was not soluble enough for pK measurements
No.22
Davallic
acid
1457
13Dr. H . Vorbr@en . private communication. 14H. Ageta, K. Iwata and S. Batorl, thl6 journal, previous paper. 15G. V. Baddeley,T. G. Haleall and X. B. H. JOneB, 1. Q&& a., 3891 (1961). 16P. P. Sommer. V. P. Arya and N. Simon, TetrahedronLetter6 18 (1960);P. P. Someer, C. Paecual,V. P . Arya and U. Siron, Helv. Ch&m. Acta. In Preee. 17Equatorialand axial COOMe groups of terpenee absorb at 1245 and 1155 cm1 (eometlneedoublet),reepectlvely: Dr. M. Fetlzon, private comunication. 18E. Wenkert and P. Beak, TetrahedronLetters, 358 (1961).