2384 J.Org. Chem., Vol. 40,No. 16, 1975
Aiyar and Chang
7244 (1971); (c) S. F. Brown, Senior Thesis, Princeton University, 1967; (d) W. G. Dauben, private communication; (e) G. W. Griffin and A. K. Price, J. Org. Chem., 29, 3192 (1964): (f) R. J. Stedman. L. D. Davis, and L. S. Miiier, IM., 33, 1280 (1968); (9) W. G. Dauben and D. L. Whalen, J. Am. Chem. SOC., 88, 4739 (1986); (h) G. L. Dunn. V. J. Dipasquo, and J. R. E. Hoover, J. Org. Chem., 33, 1454 (1968); (I) R. C. Cookson and D. C. Warrell, J. Chem. SOC. C, 1391 (1967); (i)0. A. Ungefug and K. V. Scherer, Jr., Tetrahedron Lett., 2923 (1970). (6) (a) S. Winstein, P. Carter, F. A. L. Anet. and A. J. R. Bourn, J. Am. Chem. SOC.,87, 5247 (1965); (b) M. A. Battiste and M. E. Brennan, retrahedron Lett., 5857 (1966); (c) reference 3c, p 71; (d) F. A. L. Anet and R. Anet, “Determination of Organic Structures by Physical Methods”, Vol. 3, F. C. Nachod and J. J. Zuckerman, Ed., Academic Press, New York, N.Y., 1971, pp 378-379; (e) A. J. H. Kiunder and B. Zwanenburg, Tetrahedron, 29, 1683 (1973).
(7) K. L. Williamson, Y.-F. L. Hsu. R. Lacko, and C. H. Youn, J. Am. Chem. SOC., 91, 6129 (1969). (8) For a review of this type of reaction see W. L. Diiiing, Chem. Rev., 66, 373 (1966). (9) K. Mackenzie and P. R. Young, J. Chem. SOC.C, 1242 (1970). (10) W. L. Diliing and R. A. Plepys, J. Org. Chem., 35, 2971 (1970); 37, 3753 (1972). (11) (a) M. Karplus, J. Chem. Phys., 30, 11 (1959); (b) H. Conroy, Adv. Org. Chem. 2,308 (1960). (12) E. S. Oould, “Mechanism and Structure in Organic Chemistry”. Hoit, Rinehart and Winston, New York. N.Y., 1959, p 295. (13) F. F. Caserio, 0. E. Dennis, R. H. DeWolfe, and W. G. Young, J. Am. Chem. SOC.,77, 4182 (1955). (14) G. Stork and W. N. White, J. Am. Chem. SOC.,78, 4609 (1956). ( 15) Reference 3c, p 129.
New Diastereomers of Podophyllotoxin. Related Hydroxy Acids V. Nambi Aiyar and Frederic C. Chang* Department of Biochemistry, University of Tennessee, Center for the Health Sciences, Memphis, Tennessee 38163 Received March 2 0 , 1 9 7 5 Two new diastereomers of podophyllotoxin, L-epiisopicropodophyllin (8) and L-epiisopodophyllotoxin (6), and two new related hydroxy acids, L-4-deoxyisopicropodophyllicacid (13) and L-epiisopodophyllic acid (17), are described. An unusual cleavage of a lactone under hydrogenolysis conditions was encountered. Compounds 6 and 8 were found to have cytotoxic activity against cells derived from human carcinoma of the nasopharynx in cell culture. Of the eight possible diastereomers in the L series1 rrpresented by podophyllotoxin, four members (1-4) are known,2 and two (5 and 6) are present as unresolved compo-nents in their racemic forms.3 In this paper we report one of the two remaining diastereomers, 8, in addition to 6 in optically active form: and two new derived hydroxy acids, 13 and 17 (Chart I).
the parent ketone, with orientation of the hydroxy group a t C-4 uncertain.
Chart I1 a R
Chart I OH (20,3a, R = 0 ) ( 2 q 30, R = 0) (2@,3P, R = 0) 12 DL-isopodophyllotoxone (20,&, R = 0 ) 14 4-deoxyisopicropodophyllin (20, h,R = H,H) 16 4-deoxyisopodophyllotoxin (2@,&,R = H,H) 9 isopicropodophyllone 10 podophyllotoxone 11 picropodophyllone
R OMe 1 podophyllotoxin 2 epipodophyllotoxin 3 picropodophyllin 4 pip i c* ro po do p hyI I i n 5 iso podo ph y1lo toxin 6 epiiHopodophyllotoxin 7 isopicropodophyllin 8 epiisopicropodophyllin
Ar
61
Isopicropodophyllone (9) (Chart 11) is a recently reported4 naturally occurring keto lignan from Podophyllum pleianthum, which had been prepared by isomerizations of podophyllotoxone6 (10).On reduction with NaBH4,9 yielded two lactone alcohols; the minor product’ (12%) is podophyllotoxin (l),and the major (66%) is an isomeric alcohol, 8. On the basis of previous work3t6 in which reduction of the ketones 10, 11, and 12 (DL form) with ZnBH4’ each yielded an alcohol with unchanged configuration a t the three asymmetric centers 1, 2, and 3, the major alcohol 8 would be expected to have the l a , 2 a , 3 a configuration of
13 4-deoxyisopicropodophyllic acid (20, h,R = H, H) 15 4-deoxyisopodophyllic acid (2p, 3a, R =H,H) 17 epiisopodophyllic acid (2P,&, R = H,aOH)
In this and subsequent charts partial formulas are used, and Ar at C-1 indicates the 3,4,5-trimethoxyphenyl group. Confirmation that 8 had retained the all-cis (a)configuration a t centers 1, 2, and 3 , and determination of configuration of the C-4 hydroxyl group, were accomplished by correlation with known compounds. Hydrogenolysis (Pd/C) yielded the expected known deoxylactone 14 as a minor product (24%), the major product being the hydroxy acid 13,which could be lactonized to 14. Product 13 was unexpected; hydrogenolyses under identical conditions have been r e p ~ r t e d ~ gfor ~ . podophyllotoxin ~ (1) and its other known diastereoisomers 2, 3, and 5, and in each instance
J. Org. Chem., Vol. 40, No. 16, 1975
New Diastereomers of Podophyllotoxin the corresponding deoxylactone was obtained in good yield; no cleavage to hydroxy acid was found. Additionally all four deoxylactones were found to be stable to similar treatment with palladium catalyst in acetic acid.1° We have carried out hydrogenations of 1,3,6, and 14 and encountered no cleavage products. Since deoxylactone 14 is unchanged under conditions that cause cleavage of 8 to 13, it follows that opening of the lactone ring (step a) takes place before the C-4 hydroxyl is replaced (step b), and dihydroxy acid A would be an intermediate in the overall reaction (Scheme I). However, at-
2385
*:* H
COMPOUND 6 Figure 1. Conformational formula (partial) of L-epiisopodophyllotoxin (6).
Scheme I gested a route for conversion of 8 to an optically active, 1a,2&3a diastereoisomer, either 5 or 6. When actually tried, the reaction proceeded as desired, with formation of dihydroxy acid 17, which consequently led to a hydroxylactone, 5 or 6 (Scheme 111).Since in an ex-
OH II
Scheme I11 OH
1 J A
Ar
8
tempts to show the presence of A by following the course of reaction by TLC have been unsuccessful even in decelerated reaction conditions of lowered proportions of catalyst and decreased hydrogen pressure. Apparently the cleavage step a is much slower than the hydrogenolysis step b, so that A does not accumulate. In support of this we have found that under hydrogenolysis conditions which produce 13 from 8 slowly, the hydrogenation of dihydroxy acid 17 to the corresponding monohydroxy acid 15 proceeds rapidly, the reaction being complete within minutes. The conversion of 8 to 13 and the knownll deoxylacetone 14 confirms its la,2a73aconfiguration. Neither the monohydroxy acid 13 (la,2a,3a) nor the dihydroxy acid 17 (la72/3,3a,4a,see below) has been reported previously. Both acids are lactonized readily when heated, or treated with acid or dicyclohexylcarbodiimide (DCC). At 70 eV the mass spectrum of 13 shows a very minor (2%) molecular ion, arid that of 17, 4%; their spectra are essentially those of the corresponding lactones. However, a t 70 eV mass spectra of their methyl esters (13a and 17a) do show normal molecular ions. Previous workT0showing that cleavage of 14 under even mild conditions was accompanied by epimerization a t (2-2 to yield the all-trans (la,2@,3a)hydroxy acid 15, which could be relactonized to deoxylactone 16 (Scheme 11), sug-
Scheme I1
I
14
OH
\
13 13a Meester
Al.
OH
Ar
0
17 17a Meester
6
ploratory experiment NaOH was found not to cause epimerization of hydroxy acid 13 a t (2-2, it is likely that 8 is first epimerized before the lactone ring is opened. Both 5 and 6 are known in their DL forms, 5a and 6a; the acetates of 6 and 6a11 were found to be identical in uv, ir, NMR, and mass spectral comparisons, but differed as expected with respect to optical rotation (6 has [ a ] D-37.5'). The identity of 6 and 6a establishes simultaneously the 4a-OH configuration of 8, as in both reaction steps involved in converting 8 to 6 retention of configuration at C-4 (as well as a t C-3) should be expected. Thus 8 is L-(+)-epiisopicropodophyllin,12 and 6 is L-( -)-epiisopodophyllotoxin. The stereochemistry of podophyllotoxin and several related compounds has been elucidated in publications appearing over a number of year^.^^^^,'^ Recently an X-ray crystallographic study15 of bromopodophyllotoxin confirmed the original absolute configurational assignment16 of podophyllotoxin in refutation of doubts17 cast on the correctness of the Schrecker and Hartwell assignment. The X-ray work also supports the conformational conclusions arrived a t previously. The main features of the conformations of podophyllotoxin (1) and picropodophyllin (3) can be applied in deducing the conformations of the two new toxins 6 and 8. Epiisopodophyllotoxin (6) is analogous to 1 in having a trans-fused lactone ring which imposes on the cyclohexene ring B a rigid half-chair conformation. Unlike the two halfchair forms of cyclohexene which normally invert readily,ls the two forms are distinct, each being held rigidly by the lactone fusions; 1 has the 2a,3/3 half chair while the isopodo 6 has the 2@,3a.Accordingly, in 1 the la aromatic substituent and the 4a hydroxyl are quasi-axial and quasi-equatorial, respectively, but in 6 the two groups are conformationally reversed (Figure 1). Picropodophyllin (3) and epiisopicropodophyllin (8) also constitute an analogous pair. Both have cis-fused lactone
2386 J. Org. Chem., Vol. 40, No. 16,1975
Aiyar and Chang H
Cytotoxic Activity. The two alcohols showed significant inhibitory activity against cells derived from human carcinoma of the nasopharynx carried in cell culture, in assays conducted under the auspices of the Drug Development Branch, National Cancer Institute. Compounds 6 and 8 had ED50 values (in pg/ml) of 6 X lov3 and 9 X lom1,respectively. Experimental Section22
CONFORMER A
CONFORMER
B
Figure 2. Conformationalformulas (partial) of the half-boat forms of L-epiisopicropodophyllin(8). rings which fix ring B in flexible half-boat forms, each of which can flip between two c o n f ~ r m e r s . ~The ~ J ~two isomers 3 and 8 differ in the cis fusion of the lactone ring, one being a and the other j3 configurated. Figure 2 illustrates the two conformers A and B of the 2a,3a isomer. It is seen that in conformer B the substituents at 1 and 4 are both equatorial, and in A they are both axial. In a previous NMR study,14 3, its acetate, and the corresponding ketone were shown to exist in the two conformations. The equilibrium proportions of the two conformers were deduced to be different in the three compounds, and the differences were attributed mainly to the increase in steric interaction between the substituent at C-4 and the remainder of the molecule in changing from oxygen (attached to trigonal carbon), to hydroxy, and, to acetoxyl. Cleavage of the lactone ring in the hydrogenolysis of 8 is intriguing; we are not aware of a similar opening of a lactone under hydrogenolysis conditions. Since under identicaj conditions only 8 among the several diastereomers undergoes the cleavage reaction, and since the deoxylactone 14, with the same configurations as compound 8 at positions l, 2, and 3, is not cleaved, it is clear that the special geometry of 8, particularly that of the hydroxy group at (2-4, is the key to the course of reaction. It may be more than coincidence that among the diastereomers, 8 has a conformation which brings the 4-OHclosest20 to the oxido oxygen of the lactone. The reaction appears to be complex and an explanation of the cleavage simply on the basis of a hydrogen bonding interaction is obviously inadequate. The roles of catalyst and hydrogen need to be considered,21 as preliminary studies of the hydrogenolytic cleavage show that no reaction takes place without the presence of all three components: acetic acid as solvent, Pd/C as catalyst, and a hydrogen atmosphere. The hydroxy group in D,L-epiisopodophyllotoxin(6a) was originally assigned the p configuration on the assumption that ZnBH4 reduction of the ketone 12 would yield an equatorial alcoho1,Z as was true of the trans lactone 10, but on the basis of NMR studies the assignment was reversed.13 The ZnBH4 reductions of isomeric ketones 10 and 11 (mentioned above) have also been reported3 to give 4a alcohols; thus all four diastereomeric ketones yield alcohols of CY configuration despite the difference in conformations of the structures. For ketone 9, which has two flexible conformers analogous to A and B of alcohol 8, it can be seen from a model that regardless of which conformer reacts in the reduction, the j3 side of the molecule is much more open for attack of the hydride reagent. For ketone 12 the situation is much less obvious; possibly the additional distortion of ring B caused by the lactone trans fused through the 26,3a equatorial bonds moves the quasi-equatorial aromatic group at C-1 more toward the underside of the average plane of the A, B, C rings.18
Epiisopicropodophyllin (8). To a solution of ketone 9 (1 g) in MeOH-dioxane (4:l vlv) was added NaBH4 (800 mg) at 0'. After the mixture had stood for 1 hr at O', it was poured on ice, treated with acetic acid dropwise until no more gas was evolved, diluted with water, and extracted with CHC13 (3 X 50 ml). Removal of solvent after drying gave a residue (920 mg) which was crystallized from CHC13-MeOH to give 580 mg of 8: mp 262-263'; [ a ] D +15O (c 1.03, pyridine);uv max (EtOH) 293 nm (e 3.51) and 250 (3.12);ir (KBr) 2.90 (OH) and 5.68 pm (lactone C=O); NMR (DMSO) T 6.37 ( 8 , 9 H, OMe), 3.90 ( 8 , 2 H, -OCH20-), 3.64 (s, 2 H, C-2',6'), 3.47 (s, H, C-8), 2.86 ( 8 , H, C-5), and 5.34 (perturbed d, H, C-l), other signals are merged with methoxy and DMSO-& resonances; IOO), 396 (2), 181 (52), 173 mass spectrum (70 eV) mle 414 (M+, 158). 169 (23).and 153 (67). Anal. Calcd for C22H220g%H20: C, 62.41; H, 5.43. Found: C, 62.40; H, 5.48. The mother liquor by preparative TLC (EtOAc-hexane 3:l) yielded 80 mg more of 8 (total yield 66%)and 120 mg (12%) of needles (from CHC13-MeOH) which was identified as podophyllotoxin by direct comparison with an authentic sample (TLC, ir, mixture melting point, and [ a ] D ) ; its acetate was also shown to be identical with podophyllotoxin acetate. Acetate of 8 was prepared with acetic anhydride in pyridine at 25' and crystallized from CCL as fine needles (92%):mp 97-98'; [ a ] D -29.5' ( c 0.91, CHC13); ir (CHC13) 5.65 (lactone C=O) and 5.78 pm (ester C=O); NMR (CDC13) T 7.88 (s, 3 H, -OCOMe), 7.07 (m, 2 H, C-2, 31, 6.17 (s, 6 H, OMe), 6.10 (s, 3 H, OMe), 5.69 (perturbed d, 2 H, -CH,O-), 5.52 (perturbed d, H, C-I), 3.98 ( 8 , 2 H, -OCH20-), 3.58 (s, 2 H, C-2',6'), 3.40 (s, H, C-81, and 3.15 (s, H, C-5); mass spectrum (70 eV) mle 456 (M+, 281, 396 (2), 185 (26), 168 (8), and 153 (8). Epiisopodophyllotoxin (6). To a CHC13 solution of 17 (150 mg) was added 100 mg of DCC, and the solution was left at 25' for 1hr. After removal of solvent and rinsing with warm MeOH (to remove excess DCC) the residue (98 mg) was crystallized (CHC13-MeOH) to give 6 as colorless needles: mp 248-250'; [a]D -37.5' (c 0.53, pyridine); uv max (EtOH) 291 nm (e 3.58) and 245 (3.20);ir (KBr) 2.85 (OH) and 5.64 pm (lactone C=O); NMR (DMSO) T 6.32 (s, 3 H, OMe), 6.37 (s, 6 H, OMe), 4.07 (s, 2 H, -OCHzO-), 3.80 ( 8 , H, C-8), 3.47 (s, 2 H, C-2',6'), 3.15 (s, H, C-51, other signals are merged with methoxy and DMSO-d5 resonances; mass spectrum (70 eV) m/e 414 (M+, loo), 399 (7), 396 (3), 185 (231, 181 (25), 168 (33), and 153 (42). Acetate of 6 was prepared as for the acetate of 8. The product crystallized as fine needles (MeOH): mp 238-240'; [ a ] D +24.0' (c 0.54, CHC13); ir (CHC13) 5.62 (lactone C=O) and 5.80 pm (ester C=O); NMR (CDC13) T 7.79 (s, 3 H, OCOMe) 6.06 ( 8 , 6 H, OMe), 6.04 (s,3 H, OMe),3.90 (s, 2 H, -OCH20-), 3.40 (s, H, C-81, 3.35 (a, 2 H, C-2',6'), 2.95 ( 8 , H, C-5); mass spectrum (70 eV) m/e 456 (M+, 35), 441 (2), 396 (5), 185 (22), 181 (18), 168 (loo),and 153 (50). Anal. Calcd for C24H240yCH30H: C, 61.47; H, 5.73. Found: C, 61.35; H, 5.54. The acetates of 6 and 6a11 were found to be identical by direct comparison of their ir, NMR, and mass spectra and by TLC. Hydrolysis of 8. A suspension of 8 (100 mg), 10%palladium on charcoal (100 mg), and 20 ml of acetic acid was shaken at 25' in a Parr apparatus under hydrogen pressure (40 psi) for 8 hr. Filtration of the catalyst and evaporation of solvent yielded a solid residue (78 mg) which by preparative TLC (ether) gave two compounds: one (Rf 0.78), obtained as colorless needles (24 mg, 24%) from CHC13-MeOH, was identified as 4-deoxyisopicropodophyllin (14) by direct comparison with an authentic sample1' (mixture melting point, ir, mass spectrum), mp 202-203', [ a ] D -131.6' (c 0.38, CHC13) (lit.2mp 202-203', [ a ] D -113' in pyridine). The second compound (Rf 0.42), 38 mg (38%),was obtained in amorphous form, mp 95-97', and characterized as 4-deoxyisopicropodophyllic acid (13): ir (CHC13) 2.95 (OH) and 5.85 gm (carboxy C=O); NMR (CDC13) T 6.25 (s, 6 H, OMe), 6.15 (s, 3 H, OMe), 4.12 (8, 2 H, -OCH20-), 3.54 (9, H, C-8), 3.50 (8, 2 H, C-2',6') 3.44 (8, H, C-5);
New Diastereomers of Podophyllotoxin mass spectrum (30 eV) m / e 416 (M+, lo), 398 (1001, 181 (601, 168 (30), a n d 153 (26). [At 70 eV, M+ (416) h a d relative intensity o f
2%.]
Methyl Ester 13a. An ethereal solution o f 13 (18 mg) was t r e a t e d w i t h diazomethane a n d processed t o y i e l d after preparative T L C a homogeneous powder: mp 99-101'; [ a ] D +46.4' (c 0.73, CHC13); ir (CHC13) 2.95 ( O H ) a n d 5.80 pm (ester C=O): NMR (CDCl3) T 6.59 (s, 3 H, COZMe), 6.21 (s, 6 H, OMe), 6.14 (s, 3 H, -OMe), 4.12 (s, 2 H,-OCH20-), 3.57 (s, 2 H, C-2',6'), a n d 3.42-3.27 (m, 2 H, C-5,8); mass spectrum m / e 430 ( M + , 331,398 (371,371 (6), 185 (78), 181 (781,169(55),a n d 153 (47). 197 4-Deoxyisopic1~opodophyllin (14). T o a solution o f 13 (10 mg) in 2 ml o f CHC13 was added DCC (6 mg). A f t e r 30 min t h e reaction p r o d u c t was p u r i f i e d by preparative TLC (EtOAc-hexane, 1:l) t o o b t a i n crystalline material, mp 201-202', i d e n t i f i e d as 14 by direct comparison w i t h a n authentic sample. Epiisopodophyllic Acid (17). Hydroxylactone 8 (300 m g ) was s t i r r e d in N a O H solution (4 g in 100 ml of 50%aqueous ethanol) a t 25' f o r 8 hr. T h e solution after d i l u t i o n w i t h water was extracted w i t h CHCla ( 2 X 20 m l ) t o remove n e u t r a l m a t e r i a l (30 mg). T h e aqueous p o r t i o n was neutralized w i t h 2 N H C l a n d extracted w i t h CHCla (4 X 20 ml). T h e organic layer was washed w i t h water, dried, a n d evaporated t o y i e l d 240 m g (80%) o f residue w h i c h crystallized f r o m CHC13-MeOH as needles o f 17: mp 126-128'; ir (CHC13) 2.90 ( O H ) a n d 5.88 pm (carboxy C=O); mass spectrum (70 eV) m/e 432 (M+, 4). T h e n e u t r a l nonsaponified m a t e r i a l was f o u n d t o be a m i x t u r e o f compounds 8 a n d 6 by TLC. Methyl Ester 17a. By t r e a t m e n t w i t h diazomethane, 17 (15 mg) after processing afforded colorless crystals: mp 166-168'; [a]D -257.5' (c 0.40, CHC13); ir (CHC13) 2.90 ( O H ) a n d 5.80 pm (ester C=O); NMR (CDC13) T 6.50 (s, 3 H, -COZMe), 6.27 (s, 3 H, OMe), 6.20 (s, 3 H, OMe), 4.15 (4.2H, -OCHzO-), 3.73 (8, H, C-81, 3.64 ( 8 , 2 H, C-2',6'), a n d 3.24 (9, H, C-5); mass spectrum (70 eV) m/e 446 (M+,141,414 (70),399 (16), 168 a n d 153 (38).
J . Org. Chem., Vol. 40, No. 16, 1975 2387 Registry No.-6, 55568-79-1; 6 acetate, 55515-05-4; 8, 5556880-4; 8 acetate, 55515-06-5; 9, 55515-07-6; 13, 55515-08-7; 13a, 55515-09-8; 14, 55568-81-5; 15, 55515-10-1; 15a, 55515-11-2; 16, 17187-81-4;17,518-48-9; 17a, 55515-12-3;diazomethane, 157-22-2.
References a n d Notes The absolute configuration at C-1 of most of the known compounds related to podophyllotoxin (I), whether natural or synthetic, is the same as that of the latter. We subscribe to a suggestion of Schreier (ref 13a,
(loo),
(loo),
Hydrogenolysis Experiments. 1. Attempted Hydrogenolysis or Cleavage of 8 and 14. A. A m i x t u r e o f 8 (20 mg), 20 m g of 10% Pd/C, a n d 10 ml of H O A c was shaken a t reduced pressure (no Hz) f o r 15 hr; 8 was recovered unchanged. B. A suspension o f 8 (20 mg) in 10 ml o f H O A c was shaken under 40 p s i pressure of hydrogen for 18 hr; 8 was recovered unchanged. C. A suspension o f 14 (15 mg), 10 m g o f 10%Pd/C, a n d 10 ml of H O A c was shaken a t 40 p s i hydrogen pressure f o r 18 hr; 14 was unchanged. 2. Comparison of Rates of Hydrogenolysis of 8 and 17. In parallel experiments w i t h 8 a n d 17, employing 20 m g o f compound, 25 m g o f 10% Pd/C, a n d 15 ml o f H O A c , shaken a t 5 p s i of h y d r o gen pressure, in w h i c h t h e reactions were m o n i t o r e d a t intervals by TLC, compound 17 was f o u n d t o b e completely consumed in 5 min, being converted t o a compound o f Rf 0.41. By preparative T L C t h e p r o d u c t was isolated a n d crystallized, mp 206-208', a n d characterized as 4-deoxyisopodophyllic acid (15) by conversion t o t h e m e t h y l ester 15a a n d t h e deoxylactone 16. Methyl ester 15a was prepared by treatment o f 15 w i t h diazomethane. T h e ester was obtained as needles (CHC13-MeOH): mp 198-200'; [a]D -20.8' (c 0.58, CHCl,); ir (CHC13) 2.95 ( O H ) a n d 5.80 pm (ester C=O) (lit.2 mp 200-201', [a]D -23.0'). 4-Deoxyisopodophyllotoxin (16) was prepared by cyclization of 15 w i t h DCC a n d obtained as needles, mp 250-252', [a]D +75.6O (c 0.68, pyridine). I d e n t i t y was established by comparison w i t h a n authentic sample ( T L C , ir, m i x t u r e m e l t i n g point, a n d [a]D). C o m p o u n d 8 (Rj0.39) showed l i t t l e change a t 5 min a n d underwent reaction slowly t o products w i t h Rf 0.78 ( m i n o r ) a n d 0.42 (major). T h e f o r m e r corresponds t o t h a t o f 14 a n d t h e l a t t e r t o 13. A considerable p r o p o r t i o n o f 8 remained even after 3 hr. In a separ a t e experiment a t 38 p s i hydrogen pressure reaction was complete (TLC) after 14 hr.
Acknowledgments. This work was supported in part by
USPHS Grant CIA-11507. We wish to thank Dr. A. von Wartburg and Sandoz, Ltd., and Dr. W. J. Gensler for lignan samples. Maris spectral determinations were performed by the Mass Spectrometry Laboratory, University of Tennessee.
OH (
W
O
Meodo:e OM?
1
footnote 31) to assign to these compounds the L absolute configuration. (An alternative convention based on the absolute configuration of C-1 by the RS system Cahn, Ingold, and Prelog, Angew. Chem., h f . M Engl., 5 , 385 (1966h would not be feasible: for where C-1 in podophyllotoxin is R, in 2'-bromopodophylloto~in~~ It is S). The only known close relatives of 1 of the D series are (+)-picrosikklmotoxin and (-kepipicrosikkimotoxin, both compounds obtained through reactions on an intermediate of the D series which had been derived by resolution of DLaapopicrosikkimotoxic acid. J. L. Hartwell and A. W. Schrecker, Prog. Chem. Org. Nat. Prod., 15, 83 (1958). W. J. Gensler and F. Johnson, J. Am. Chem. SOC.,85,3670 (1963). F. C. Chang, C. Chiang, and V. N. Aiyar, Phytochemistry, in press. A. von Wartburg, private communication. W. J. Gensler, F. Johnson, and A. D. Sloan. J. Am. Chem. SOC.,82, 6074 (1960). ZnBH4 was used in the previous reductions when it was found that NaBH4 on 10 and 11 in ethanol gave rise to an acid of uncertain structure.' Sodium borohydride in methanol used in the present reduction was unexceptional, the minor product 1 appears to result from the changes 9 10 1; supporting evidence for this will be presented in a future paper on the dlastereomeric ketones. W. J. Gensler, J. F. X. Judge, and M. V. Leldlng, J. Org. Chem., 37, 1062 (1972). A. W. Schrecker, M. M. Trail, and J. L. Hartwell, J. Org. Chem., 21, 292 (1956). A. W. Schrecker and J. L. Hartwell, J. Am. Chem. Soc., 75, 5916 ( 1953). We are indebted to Dr. A. von Wartburg and Sandoz, Ltd., for reference samples of many lignans, in particular for 14, the acetates of Sa and 6a, and for generous supplies of podophyllotoxin. The prefix "epi" used in the names of 6 and 8 to designate the 4 n configuration of the hydroxyl is admittedly confusing. It was originally used for 6 when the OH group was considered to be (3, but after revision of the configuration, the "epl" name was not changed. We have followed this usage In the naming of 8 to avoid compounding'the confusion. (a) E. Schreier, Helv. Chim. Acta, 46, 75 (1963); (b) ibid., 47, 1529 (1964). D. C. Ayres, J. A. Harris, P. N. Jenkins, and L. Phillips, J. Chem. SOC., Perkin Trans 1, 1343 (1972). T. J. Petcher, H. P. Weber, M. Kuhn, and A. von Wartburg, J. Chem. SOC.,Perkin Trans. 2, 288 (1973). A. W . Schrecker and J. L. Hartwell, J. Am. Chem. SOC.,79, 3827 (1957). R. B. Bates and J. B. Wood, 111, J. Org. Chem., 37, 562 (1972). E. L. Eliel, N. L. Allinger, S. J. Angyal, and G. A. Morrison, "Conformational Analysis", Interscience, New York. N.Y., 1965, pp 109-1 l l . C. M. Hanack, "Conformational Theory", Academic Press, New York, N.Y., 1965, pp 147-149. An interaction of the two groups, such as by hydrogen bonding, might promote a nucleophilic attack (of solvent) at the carbonyl carbon, resultino in hvdrolvsis of the lactone. Aobroximate OH-0 (4-OH-.oxido oxvggn of iactone) bond distances obtained by measurement of Dreidiig conformational models of the eight diastereomers, 1-8, show that conformer A of alcohol 8 has the shortest such distance by 0.4 A. (21) The palladlum on charcoal used in our reactions is a commercial product (Engelhard), and the possibility that Pd of several oxidation states may be present is not precluded. (22) Melting points were determined on an electrical hot stage and are uncorrected. infrared spectra were obtained using a Perkin lnfracord 137 Optical rotation measurements were obtained with a Carl Zeiss photoeiectrlc precision polarimeter. Ultraviolet spectra were measured on a Beckman Acta T. M. 111 spectrometer. Mass spectra were obtained on a Finnegan 1015 GC-MS spectrometer. Nuclear magnetic resonance spectra were done on a Varlan A-BOA spectrometer, with tetramethyisilane as Internal reference; chemical shifts are given on the T scale
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