NEWPSEUDOGUAIANOLIDES FROM Hymenoxys SPECIES methosulfate was reacted with diethyl lithiophosphonate. Diwas obtained in 54% ethyl 3,5-dimethylpyridine-2-phosphonate yield by distillation: bp 107' (0.03 mm); nmr (neat) 6 1.33 (t, 6, J = 7 Hz, CHaCHZO), 2.32 (9, 3, CHaAr a t Cc), 2.63 (8, 3, CHIAr at CS),4.25 (quintet, 4, J = 7 Ha, CHaCHaO), 7.52 (d, 1, ArH a t C,), 8.45 (s, i, ArH at Ce). Anal. Calcd for CllH18NOaP: C, 54.32; H, 7.41; N, 5.76; P, 12.76. Found: C, 54.17: H, 7.35: N , 5.47: P. 12.88. 3,5-Dimethylpyridine-2-phosphonicAcid.-Hydrolysis of diethyl 3,5-dimethylpyridine-2-phosphonate (3 g) as described in previous examples yielded, after crystallization from aqueous ethanol, 3,5-dimathylpyridine-2-phosphonicacid, 1.2 g (54%), mp >300°. Anal. Calcd for CTHlONOaP: C, 44.92; H, 5.35; N, 7.49; P, 16.58; mol wt, 187. Found: C, 44.16; H, 5.62; N , 7.60; P, 16.62; mol wt, 186 (KOH titration). Diethyl 3,4-Dimethylpyridine-2-phosphonate(19) and diethyl 4,5-Dimethylpyridine-2-phosphonate (2O).-The procedure described for diethyl pyridine-2-phosphonate (12) was used. Distillation gave a mixture of 19 and 20 (47.5%): bp 125-126" 2.30 (0.05 mm); nmr (neat) 6 1.33 (t, 6, J = 7 Hz, CH~CHZO), (s, 15/4, CHsAr a t C, and CHaAr at C, in 20), 2.59 (9, 9/4, CHaAr at C3 in 19), 4.27 (quintet, 4, J = 7 He, CHSCHZO),7.30 (d, 3/4, ArH at Cg in 19), 7.76 (d, 1/4, ArH a t CSin 20), 8.50 (d, 1, ArH a t Ce). From both ArH and ArCHa ratio of 19 to 20 is 3: 1. AnaL28 Calccl for C11HlsNOaP.1/2Hz0 (mixture of 19 and 20): C, 52.38; FI,7.54; N,5.56; P, 12.30. Found: C,52.82, 52.75; H , 7.56, 7.86; N, 5.59; P, 12.69. Diethyl 2,6-Dimethylpyridine-4-phosphonate(24).--n-Butyllithium (23y0in hexane) (87 ml, 0.2 mol) was added dropwise during 1.25 hr at -5-0' to diethyl phosphonate (60 g, 0.45 mol). To the resulting diethyl lithiophosphonate was added solid Nmethoxy 2,6-dimethylpyridinium methosulfate [from 2,6-dimethylpyridine N-oxide (24.6 g, 0.2 mol) and dimethylsulfate (25.2 g, 0.2 mol)] portionwise during 2 hr at 5-15'. The mixture was stirred a t room temperature overnight and heated at 70" for 2 hr. After cooling, water (150 ml) was added and the organic portion extracted into chloroform (three 100-ml portions). The basic portion was obtained by extraction of the chloroform solution with 3 N hydrochloric acid, basification, reextraction with chloroform, and evaporation. Distillation of the residue gave 2,6-dimethylpyridine [ l o g (47%), bp 59-61' (70 mm)], and
J . Org. Chem., Vol. 36,No. 19, 197'0 4117 two further fractions [(a) bp 70-95" (0.2 mm) (0.7 g), and (b) bp 95-98' (0.2 mm) (13.5 g)]. Glc analysis indicated fraction a to consist of 2,6-dimethylpyridine (0.1 g), 2,6-dimethylpyridine N-oxide (0.5 g), and diethyl 2,6-dimethylpyridine-4-phosphonate (0.1 g) and fraction b to consist of 2,6-dimethylpyridine N-oxide (0.6 g) and diethyl 2,6-dimethylpyridine-4-phosphonate (12.6 9). The yield of phosphonate is 24% and the yield of Noxide is 6%. Redistillation of fraction b gave pure phosphonate (24): bp 105' (0.2 mm); nmr (neat) 6 1.32 (t, 6, J = 7 Hz, CHSCHZO),2.55 (8, 6, CHsAr), 4.20 (quintet, 4, J = 7 Hz, CHICKSO), 7.44 (d, 2, J = 13.5 Hn,ArH). A n a l . Calcd for CllHlsNOaP: C, 54.32; H , 7.41; N, 5.76; P, 12.76. Found: N,5.61; P, 12.88. 2,6-Dimethylpyridine-4-phosphonic Acid.-Diethyl 2,6-dimethylpyridine-4-phosphonate (24) (4 g) was heated under reflux with 18yo HC1 (50 ml) for 5 hr. Evaporation of the aqueous acid, trituration with ethanol, and recrystallization from aqueous ethanol yielded pure 2,6-dimethylpyridine-4-phosphonic acid, 2 - __ - g (65%); mp >300°. Anal. Calcd for CTH~ONOIP:C. 44.92: H . 5.35: N , 7.49: P, 16.58. Found: C, 44.48; H , 5.42; N,'7.33; P,'l6.40.
Registry No.--12, 23081-78-9; 12 (picrate), 2638480-5; 17,26384-81-6; 18, 26384-83-8; 19,26384-82-7; 20, 26384-84-9 ; 24, 26384-85-0; pyridine-2-phosphonic acid, 26384-86-1 ; diethyl 6-methylpyridine-2-phosphonate, 26384-87-2; 6-methyl-2-phosphonic acid, 26384-88-3; diethyl 4-methylpyridine-2-phosphonate, 26384-89-4; 4-methylpyridine-2-phosphonic acid, 26384-90-7 ; 3 -methylpyridine-2-phosphonic acid, 26384-91-8; diethyl-3,5-dimethylpyridine-2-phosphonate, 26384-92-9; 3,5-dimethylpyridine-2-phosphonic acid, 26384-93-0; 2,6-dimethylpyridine-4-phosphonic acid, 26394-19-4. Acknowledgments.-The author acknowledges the technical assistance of Mr. Gordon Jacobs and suggestions and criticisms of Dr. Frank E. Mange and Dr. C. David Gutsche.
New Pseudoguaianolides from Hymenoxys Species. A New Type of Lactone ClosurelJ WERNERHERZ,"K. AOTA,AND ALLENL. HALL Department of Chemistry, The Florida State University, Tallahassee, Florida 32306 Received April $0, 1970 Hymenoxys linearifolia Hook. afforded the flavone hymenoxin and two new pseudoguaianolides, linearifolin A and B, whose structure and stereochemistry has been inferred. Linearifolin B contains a 6-lactone ring closed to C-9 of the pseudoguaiane skeleton. H. acaulis (Pursh) K. F. Parker yielded 3,3'-dimethoxy-4',5,7-trihydroxyflavone and the previously known pseudoguaianolide fastigilin C whose stereochemistry is discussed. H . subintegra Cockll. gave the modified pseudoguaianolide psilotropin and H . rusbyi (Gray) Cockll. psilotropin, the pseu.doguaianolideglucoside paucin and the flavone pectolinarigenin.
I n an earlier paper3 we reported the isolation and structure determination of sesquiterpene dilactones and lactone glycosides from several Hymenoxys species. We now describe the results of our examinations of H . Zinearifolia Hook., H. acuulis (Pursh) R. F. Parker, H. subintegra Cockll., and H . rusbyi (Gray) Cockll. Extraction of H . linearifolia Hook. yielded the flavone hymenoxin (5,7-dihydroxy-3',4',6,8-tetramethoxyflavone) previously isolated4 from H . scaposa DC and two * To whom correspondence should be addressed.
new isomeric sesquiterpene lactones which we have named linearifolin A and B. Linearifolin A, CzoH2406, mp 187-188", [ a ]-90.0°, ~ exhibited uv absorption at 218 nm (E 22,500), the high intensity suggesting the presence of at least two chromophores. The ir spectrum indicated the presence of an a,p-unsaturated y-lactone (1765, 1649 cm-l), a hydroxyl group (3665, 3415 cm-l), an a#-unsaturated cyclopentenone (1711, 1580 cm-l) of the type found in helenalin6 and ambrosin,6 and an unsaturated conju-
(1) Supported in part by a grant from the U. 8. Public Health Service (GM-05814). (2) Previous paper on Sesquiterpene Lactones: H. Yoshioka, A. Higo, T. J. Mabry, W. €[era, and G. Anderson, Phytochem., in press. (3) W. Herz, K.. Aota, M. Holub, and 2. Samek, J. 07s. Chern., 85, 2611 (1970).
(4) M. B. ThomasandT. J. Mabry, ibid., 83, 3254 (1967). (6) W. Hem, A. Romo de Vivar, J. Romo, and N . Viswanathan, J. Amer. Chem. Soc., 8 6 , l Q (1963). (6) W. Herz, H. Watanabe, M. Miyaaeki, and Y. Kishida, ibid., 84, 2601
(1962).
4118 J. Org. Chem., VoZ. 36, No. 19, 1970
gated ester (1720, 1270 cm-l) which, because of the analytical values, was probably an angelate, tiglate or senecioate. The nmr spectrum of linearifolin A showed the low field doublets of doublets at 7.78 (J1= 5.9, Jz = 1.7 Hz) and 6.09 ppm (JI = 5.9, J2 = 3 Hz) characteristic of the unsubstituted a,P-unsaturated cyclopentenone found in helenalin6 and ambrosin,6 the usual narrowly split doublets at 6.25 (J = 2.5 Hz) and 6.44 ppm (J = 2.6 Hz) due to the conjugated methylene group of these compounds, and the signals of a tigloyl group7 (complex vinyl quartet at 6.61, vinyl methyl multiplets at 1.79 and 1.73 ppm). Because of the further presence in the nmr spectrum of a methyl singlet and a methyl doublet, it seemed reasonable to postulate for linearifolin A the pseudoguaianolide structure l a (devoid of stereochemistry) where attachment of the tigloyl side chain to C-6 (with H-6 being accounted for by a somewhat broadened
2
a
5
7
6
8
(!H20Ac
(7) R. R. Frazer, Can. J . Chem., 88,649 (1960).
HERZ,AOTA,AND HALL singlet at 5.29 ppm) and lactone ring closure to C-8 (with H-8 being tentatively identified as a doublet of doublets at 5.02 ppm) was based on analogy to the substitution patterns found in other pseudoguaianolides of Helenium, Gaillardia, and Hymenoxys specie^.^^^ Linearifolin A also contained a secondary hydroxyl group whose presence was indicated by the infrared spectrum and by a second nmr signal near 3.7 ppm superimposed on a resonance provisionally attributed to H-7. Attachment of the hydroxyl to C-9 of the provisional formula was necessitated by the multiplicity of the H-8 signal (doublet of doublets), a deduction which was corroborated by examination of the nmr spectrum of a substance 2 produced by oxidation of linearifolin A. I n the nmr spectrum of 2, the resonance attributed to H-8 of linearifolin A had undergone the expected downfield shift and simplification to a doublet; furthermore, the multiplet near 3.7 ppm had been reduced to oneproton intensity. Detailed analyses of the nmr spectra of la and 2, which are presented in Table I,9and are based on identification of every proton by double resonance techniques, confirmed the carbon skeleton and oxygenation pattern postulated for linearifolin A. Identification of the H-7 resonance in la and 2 was achieved in the usual10way by irradiating at frequencies corresponding to those of H-13a and H-13b. Conversely, in the case of 2, irradiation at 3.7 ppm collapsed not only the H-13a and H-13b doublets, but also the broad singlet at 5.66 ppm (clearly due to H-6 because it had not undergone simplification during the conversion of l a to 2) and the slightly broadened doublet of H-8 at 5.56. All other signals remained unaltered, thus leading to partial structure A for 2. I n the case of la, irradiation at 3.7 ppm (H-7 and H-9 superimposed) also affected a multiplet at 2.30, identifiable as H-10 because it was coupled to the methyl doublet at 1.41 ppm. Such mutual coupling could also be demonstrated in 2 between the methyl doublet and a multiplet at 2.7 ppm. H-10 was further coupled to a multiplet found at 3.09 in l a and at 3.43 ppm in 2. This multiplet was coupled vicinally to the P-hydrogen atom of the a,@-unsaturatedcyclopentenone system and allylically to the a hydrogen. The above observations allowed expansion of A to B which requires attachment of the quaternary methyl group to C-5, as in 1. We defer consideration of the direction of the lactone ring closure and the stereochemistry until we have dealt with linearifolin B. This neutral substance C20H2406, mp 214-215", [a]D -104", which was isolated only in small quantity, possessed the cyclopentenone chromophore of linearifolin A (nmr signals at 7.63 and 6.08 ppm, see Table I), its tigloyl side chain (nmr signals at 6.66, vinyl proton, 1.86 and 1.72, vinyl methyls), its secondary (doublet at 1.48 coupled to one-proton H-10 multiplet11 at 2.4 ppm) and tertiary methyl group (singlet a t 1.03 ppm), and a hydroxyl group (ir spectrum). However, except for the H-6 resonance, which was now a narrowly split doublet at 5.27 and was identified through its being coupled to H-7 at 3.53 ppm, the (8) See, for example, W. Herz, P. 8. Subramaniam, and N. Dennis, J . Org. Chem., 84,2916 (1969). (9) The 90-mHz Bruker nmr spectrometer used in this work was purchased with the aid of a grant from the National Science Foundation. (10) W. Herz, 8.Rajappa, 8.K. Roy, J. J. Sohmid, and R. N. Mirrington, Tetrahedron, 22, 1907 (1966). (11) The numbering system used here anticipates the structure which was deduced eventually.
J. Org. Chem., Vol. $5, No. 1.2, 1970
NEW PSEUDOQUAIANOLIDES FROM Hymenoxys SPECIES
4119
TABLE IQ NMRSPECTRA OF LINEARIFOLIN DERIVATIVES~ 7 -
H-1 H-2 H-3 H-6 H-7 H-8 H-9 H-10 H-13s. H-13b H-14 H-15 H-3' 2'-Me 3'-Me
3.09 ddd' 7.78 dd 6.09 dd 5.29 lord 3.68 oe 5.02 dd br 3.65 +I' 2.30~ 6.25 d 6.44d 1.41g 0.98' 6.68 1.75 .rnf 1.79 m'
la Ji,a = 1.7' Jz,a = 5 . 9 Ji,s = 3 .O Ja,7 1 . 3 zk 0 . 3 d J7,s = 6.0' Js,o = 2 . 1 Jo,io = 10.4 0.6h Ji,io = 10.7 J7,is8 = 2.4 h , u b = 2.6 JlO,l4 6.5
7
-
*
* -
= 7 0.5 J z , - M ~ , s J - M1 ~ .0 J v , z , : ~ e 1.5
Ja,,a,-Me
,
3.08 ddd 7.75 dd 6.08 dd 6 . 2 8 br 3.68 c 4.99 dd br 3.65 C 2.30 c 6.27 d 6.46 d 1.39$ 0.98' 5.52mi 1.87di 2.14 di
b lb-
6b-
c
J1,a = 2.0 Jz,s = 6 . 0 Ji,s 0 3 . 0 WljZ = 3 J7,s = 8 . 1 Js,s = 2.5
3.43 c 7.69 dd 6.28 dd 5.66 br 3.71 c 5.56 d br
Ji,a = 2.0 Jz,s = 6 . 0 Ji,a = 2 . 5 J B , T= 1.1 J7,s = 8 . 2 J S , I O= 0.8
J L I O 10.5 J7,lSa. 2 . 4 h,isb = 2.6 Jl0,V = 6 . 5
2.71 c 5.88 d 6.36 d 1.50$ 0.87' 6.66 c 1.74 m: 1.76 mD
Ji,io
-
3
J ~ , , s , - M=~ 1 . 4 J v , s * - ~ e= 1 , 2
-
= 13.2 J7,lSs = 3 . 3 J7,isb = 3.8 Jio,ir = 8 . 2 Ja,u < 0 . 5
r
3.15 ddd 7.63 dd 6.08 dd 5.27d 3.53 m 4.39 m 4.73 br 2.38 c 6.09 br 6.68 bf 1.48,d' 1.03' 6.66 c 1.72 mt 1.80 mo.
3Ji,z = 1.8 Jz,s = 5.8 Ji,s = 2.9 Jo,? = 3 . 7 Wiia = 8 . 7 Wiiz = 6 Wijz = 4 Ji,io = 12.6 Jr,isa < 0.5 J7,isb = 0 . 9 Jio,i4 ,= 7.2
--
Jat,at-~e= 7 f: 0 . 5 Ja,-Jle,s'-Me 1 .O Js*,zt-Me 1. 5
Run at 90 MH5 in CDCls solution on a Bruker nmr spectrometer, using tetramethylsilane as an internal standard. Multiplicities are indicated by the usual symbols: d, doublet; m, multiplet; c, complex multiplet whose center is given; br, broadened singlet. Unmarked signals are singlets, Coupling constants are accurate to within
