J . Org. Chem., Vol. 44, No. 11, 1979 1831
Stereochemistry of the Tagitinins (16)J. J. Baldwin, A. W. Raab. and G. S. Ponticello, J. Org. Chem.. 43,2529 (1978). (17)E. Baer and H. 0.L. Fischer, J. Am. Chem. SOC.,67,2031 (1945). (18)W. E. Truce, E. M. Kreider, and W. W. Brand, Org. React. 18, 99 (1970). (19)The d in the structural label indicates that the compound bears a deuterium substituent, 2 = D. For the sake of clarity, the absolute configurations of these labeled species have been assigned without any consideration of the deuterium atom. Therefore, the structural labels for the deuterated and the corresponding protiated compounds differ only in the presence or absence of d following the number for that structure. Although the compounds bearing deuterium are mixtures of diastereomers, no evidence has been
observed which indicates a diastereomeric composition which is not equal to 1:l. (20)J. A. Edwards, 6. Berkoz, G. S.Lewis, 0. Halpern, J. H. Fried, A. M. Strosberg, K. M. Miller, S. Ulrich, F. Liu, and A. P. Roszkowski. J. Med. Chem., 17,200 (1974). (21)Thus, treatment of this presumed mixture of (S)-18 and (R)-21 with base would produce partially inverted oxirane 19 which would lead to partially racemized 20 upon treatment with isopropylamine. (22)G.G.Lyle and L. K. Keefer, J. Org. Chem., 31, 3921 (1966). (23)L. M. Weinstock and P. I. Pollack, Adv. Heterocycl. Chem., 9, 140-141 (1968).
Sesquiterpene Lactones of Tithonia diversifolia. Stereochemistry of the Tagitinins and Related Compounds' Nabin C. Baruah, Ram P. Sharma,* K. P. Madhusudanan, and Gopalakrishna Thyagarajan Department o f Organic Chemistry, Regional Research Laboratory, Jorhat-785006, Assam, India
Werner Hem* and Ramaswamy Murari Department of Chemistry, T h e Florida State Uniuersity, Tallahassee, Florida 32306 Received December 7, 1978 T h e sesquiterpene lactones tagitinins A, C, a n d F a n d t i r o t u n d i n a n d t h e flavone h i s p i d u l i n were isolated f r o m I n d i a n Tithonia diversifolia (Hemsl.) A. Gray. Complete stereochemical expressions are presented f o r these compounds as w e l l as for t a g i t i n i n B a n d E, a n d t h e configuration a t C-8 o f zexbrevin, zexbrevin B, orizabin, ciliarin, calaxin, t i f r u t i c i n , deoxytifruticin, viguiestin, a n d deacetylviguiestin is assigned.
Isolation of six sesquiterpene lactones, tagitinins A-F, from the antileukemic alcoholic extract of what was referred to as Tithonia tagitiflora Desf. [sic] has been reported re0 ~ e n t l y .We ~ ?have ~ isolated several of these compounds from - 1 HO 0 an Indian collection of Tithonia diversifolia (Hemsl.) A. Gray which we believe represents the actual source of the lactones 0 0 obtained by Pal and c o - ~ o r k e r sOur . ~ results which together with our previous work on tirotundin6p7 and w o o d h o u ~ i n ~ ~3a, ~ R = i - B u , H-80, t a g i t i n i n C 4a, R = i - B u , t a g i t i n i n F b, R = A n g , H-8a C'HIO..\c provide complete stereochemical expressions for the tagitinins c, R = A n g , H-80 and several related substances are described in the present b, R = H* ,liatrin report. 0 Tagitinin D was identical with tirotundin which we had same hexahydro derivative as hydrogenation of 3a, a result isolated earlier6 from T . rotundifolia; the name tagitinin D manifestly impossible if the stereochemistry at C-8 were dif.4' I ferent." 13C NMR spectra of tirotundin, woodhousin, and tagitinin C are listed in Table I for comparison.12Because of the close correspondence in chemical shifts and coupling constants between tagitinin C and dehydrodeoxytifruticin6J3 and for other reasons cited ear lie^-,^,^ we conclude that the C-8 stereochemistry of dehydrodesoxytifruticin,and therefore also that of its congeners tifruticin and deoxytifruticin from T . l a , H- CY, tirotundin 2a, R = H, H - ~ c tYa g, i t i n i n D fruticosa,fimust be inverted from 3c to 3b, 5b to 5a, and 6b b, H-80 b, R = A c , H - ~ c wYo,o d h o u s i n to 6a, respectively. C, R = Ac, H-80
+ p
should therefore be abandoned. The stereochemistry lb assigned originallyGto tirotundin was recently7 altered to l a as the result of an X-ray analysis. Tagitinin B had properties which suggested3 that it was a deacetyl derivative of woodhousin;a hence formulas 2 (R = H) and 3 (R = H, stereochemistry a t C-8 not specified) were assigned to it and to tagitinin C with which it had been correlated.3 Since the C-8 stereochemistry of woodhousin has recently been revised from 2c to 2b as the result of an X-ray a n a l y ~ i s tagitinin ,~ B and tagitinin C will have to be reformulated as 2a and 3a, respectively. This removes at least one element of confusion emanating from the work of Pal et al. who stated3 that hydrogenation of tagitinin F (assigned3 formula 4a because of its similarity to liatrin, 4b) furnished the 0022-3263/79/1944-1831$01.00/0
0 H-80, b, H-8P
5a,
tifruticin
0 H-80, d e o x y t i f r u t i c i n b, H-8P
6a,
Formula 7 with a trans-lactone function but without specification of stereochemistry at C-1, C-4, and C-8 was proposed3 for tagitinin A because of its similarity to tirotundin and its chemical behavior. We have established its stereochemistry at all centers in the following manner.
0 1979 American Chemical Society
1832 J . Org. Chem. Vol. 44, No. 11, 1979
Baruah e t al.
Table I. l3C NMR Svectra of Tithonia diversifolia Constituents and Related C o r n ~ o u n d s ~ ~~
~~~~~~
lbb
2b
3ac
7
14
c-1 c-2
38.9 t 42.2 t
C-3 C-4
108.8 43.4 d
42.72 t d 76.68 d 108.69 136.46 132.44 d 80.41 d 50.24 d 71.57 d 41.85 t d x:3.;i2 137.70 169.10 122.93 t 21.77 q d 21.61 q d 176.10 34.1 1 d 19.14 q d 18.75 q"
160.49 d 129.57 d 196.85 138.84 137.14 d 56.05 d d 47.05 d 74.11 d d 48.37 t 71.91 1:3t?. 11 169.76 124.43 t 28.88q 19.6,5q d 176.18 34.06 d 18.80 q d 18.64 q
78.46 d 46.94 t 105.69 44.38 d 37.81 t 81.86 d 47.84 d 69.90 d 34.65 t 81.69 137.01 169.75 121.73 t 24.96 q 19.18 q d 176.45 34.11 d 18.76 q d 18.12 q d
213.45 47.03 t 104.04 44.97 d 37.75 t 80.42 d
e-5 C -6 C-7
38.0 t d 81.3 d 47.9 d 69.8 d 38.4 t d
c-8 c-9 c-10 c-11 (2-12 (2-13 C-14 (2-15
80.0 137.2 169.4 121.4 t 26.9 q 19.19d 176.1 34.1 d 18.6 q d 18.7 q d
c-1' c-2' e-3' C-4'
17.80d 68.33 d 36.44 d 81.84 1:iCj.:37 169.12 122.04 t 22.21 q 18.95 q d 17,5.75 :1:3.91 d 18.60 qa' 18.32 q d
Some assignments revised from those given in ref 6.'" Assignment (1 Run in CDC13 at 67.9 MHz on a Bruker HX-270 instrument. of multiplets confirmed by single-frequency off-resonance decoupling except where indicated. Assignments may be interchanged.
7 , tagitinin A 8 An attempt t o remove the C-l'hydroxyl group of tagitinin A by heating with tosyl chloride-pyridine resulted in formation of 8. However, exposure of the dimethylamine adduct 9 t o acetic anhydride-pyridine produced a mixture of 10 and 1 I, possibly because the cyclic hemiacetal in this compound
tained by hydrogenation of tirotundin. This established the stereochemistry of tagitinin A a t C-3, C-4, (2-6, C-7, C-8. and C-10. The stereochemistry of 7 a t C - 1 was established by Horeau's method;I6Ji reaction with excess (f)-cy-phenylbutyric anhydride gave (-)-u-phenylbutyric acid in 41.8% optical yield. Hence the configuration a t C-1 is S; Le., the hydroxyl group is cy since the absolute stereochemistry of tirotundin is known (H-7 CY).^.^,^^
OH
OH
0 15
9
10
was in equilibrium with the open formula containing an unmasked &hydroxy ketone (IR spectrum). The major product 11 was hydrogenated to 12 which on consecutive treatment
I
17a, H-8a
b, H-8P
0 11
12
with methyl iodide and NaHC03I4 afforded tirotundin ( l a ) . Similarly hydrogenation of 10 (4,s-dihydrotagitinin F) yielded a substance, 13,15 identical in all respects with material ob-
13
14
v 16a, H-8a b, H-8P
!
0
18a. H - 8 a , zexbrevin b, H-83
Oxidation of tagitinin A (7)with Jones reagent furnished 14 which underwent dehydration (tosyl chloride-pyridine) to an u,P-unsaturated ketone, 15.The latter was hydrogenated to 16 and 17. To our surprise the properties of 16a and 17a (melting points, NMR signals, and IR bands) tallied exactly with those of the purported C-8 epimers tetrahydro- and hexahydrozexbrevin 16b and 17b.I9 Although we were unable to secure authentic samples of these substances for direct comparison, it would appear that the C-8 stereochemistry of zexbrevin must be inverted from 18b t o 18a.This also applies t o orizabin, calaxin, ciliarin, and zexbrevin BO ' which have been correlated with zexbrevin.22 In addition, we consider tagitinin E for which the structure of a l,lO-epoxy-cis-4,5-germacrenolide with the lactone ring closed to C - 8 and a n isobutyrate ester attached to C-6 was proposed." Although we did not isolate this substance, analysis o f t h e published data3 led to the deduction that tagitinin E
J . Org. Chem., Vol. 44, Ko. 11 1979 1833
Stereochemistry of' t h e Tagitinins T a b l e 11.270-MHz *HNMR Saectra"
~~~
.
6.94 d (17) 6.26 d (17)
H-1
H-2a H-2b H-4
5.88 d , hr (10)
H-,5a H-5b
H-6 H-7 H -8 H 9a
5.42 d. hr (10) :L55 m 5.:j3 m -2:4 -2 0.36 d ( 2 ) 5.81 d (2) 1.56
H-9b
H-13 H-l,?b H 14'' H 1Sh H-3'h
1.97tir 2.44 m 1.1u d (7)
H.41'~
1.08 d ( 7 )
H.21
14'
7
3a
4.23 m 2.44 m 2.1 md 2.1 m d 2.1 md 2.1 md 4 5 5 dddi' 3.99 m 5.59 ddd' 1.81 dd (13, 8)] 1.95 dd (13, 5) 6.25 d(X.5) 5.53 d ( 3 )
1.43br 1.11 d (6.5) 2.44 m 1.07 d (71 1.04 d (71
L'
i'
2.22 mh
4.55 m 4.13 m ,5.57 m
1.94 rn" 6.28 d (3.5) 5.57 d (3.5) 1.44 1.16 d ( 7 ) 2.43 m 1.07 d ( 7 ) 1.05 d ( 7 )
20a
-
2.81 d d (10, -5) 2.46 d t (15. - 5 ) 1.8 m (l
