2380 J . Org. Chem., Vol. 40,No. 16, 1975
Dilling
Pentacyclodecane Chemistry. XII. Proton Nuclear Magnetic Resonance Spectral Correlations of 6- and 5-Substituted Pentacyclo[5.3.0.02~5.03~9.04~8]and -[5.3.0.02*6.03~9.04*8]decane (1,3- and 1,4-Bishomocubyl) Derivatives' Wendell L. Dilling Environmental Sciences Research, The Dow Chemical Company, Midland, Michigan 48640 Received November 11,1974
The proton magnetic resonance spectra of 30 derivatives (secondary and tertiary alcohols, formates, acetates, tosylates, chlorides, and hydrocarbons) of 1,3- (1) and 1,4-bishomocubane(33)have been measured. For a given isomeric pair of 1,3-bishomocubylderivatives, the signals produced by an anti proton or by protons on an anti substituent always appear at fields higher than those produced by the corresponding syn protons. The corresponding signals due to the 1,4-bishomocubylderivatives appear at intermediate fields. The chemical shift differences A6 (&, - &,ti) for a given pair of 1,3-bishomocubylisomers increase slightly and then decrease with an increase in the number ( n ) of intervening atoms between the proton in question and the methylene bridge carbon atom ( n , Ali: 0, 0.23-0.29; 1, 0.29-0.32; 2, 0.11-0.14; 3, 0.10-0.11; 4,0.03-0.09 ppm). The stereochemistries of the Diels-Alder dimerization of 1,2,3,4,5-pentachlorocyclopentadiene(45) and the reaction of endo-anti-tricyclo[5.2.1.02~6]deca-4,8-dien-3-ol(51) with thionyl chloride were determined with the aid of these correlations. Some aspects of the NMR spectra of 1,3- and 1,4-bishomocuby12 derivatives have been discussed b r i e f l ~ .The ~ shielded a protons of certain ketones (24,3e 26$ 4 0 p and others3e), ketals (29,3e 3 9 p and other@), a ketone hydrate,3e and the brominated hydrocarbon 253e have been
Table I NMR Chemical Shift Differences between Syn and Anti Protons of 1,3-Bishomocubyl Derivatives as a Function of Distance from the Methylene Group
Tn-Hd
y,
X = C, 0, or S Y = H or functional group n
1
2,Y=OH 3,X=OH 4, Y = OCHO 5 , X = OCHO 6, Y = OAc 7, X = OAc 8, Y = OTs 9, X = OTs 10, x = c1 11, X = Me; Y = OH 12 X = OH; Y = M e 13, X = Me, Y = OCHO 14, X = OCHO; Y = Me 15, X = Me; Y = OAc 16, X = OAc; Y = Me 17, X = Me; Y = OTs 18, X = OTs; Y = Me
33 34, Y = OH
35, Y = OCHO 36, Y = OAc 37, Y = OTs 38, X = Y = OMe
X = Me; Y = OPNB X = Ph; Y = OH X = Ph; Y = OPNB X = Y = OMe X, Y = CH, X, Y = 0 R' = R3 = Br R' = Br; X, Y = 0 27, R' = R2 = C1; X, Y = 0 28, R' = R2 = Ph; X, Y = 0 29, R' = R3 = Br; X = Y=Z=OMe 30, R' = R2 = R3 = R' = C1 31, R' = R2 = R3 = R' = c1; X = Y = Z = OMe 32, R' = R2 = R3 = R4 = C1; X = Y = OMe; Z = Br 19, 20, 21, 22, 23, 24, 25, 26,
39, 40, 41, 42, 43,
X, Y = OCHzCH,O X, Y = 0 Z = C1 X = Y = OMe; Z = C1 X, Y = OCH,CH,O; Z = C1
(unspecified substituents are H)
A 6 (6Hs
-6
~ ~ Ppm ) ,
0 0.23-0.29 1 0.29-0.32 2 0.11-0.14 3 0.10-0).11 4 0.03-0.09 5 0.00-0.04 7 0.01-0.03 pointed out, but there appears to be no simple explanation to account for this shielding.3e The effects of various substituents on the chemical shifts of protons on other tertiary carbon atoms of some 1,3-bishomocubyl derivatives also have been discussed.3e The effects of a bromine atom on the chemical shifts of various protons on the ethylene ketal of the ketone 24 have been calculated and compared with the experimental values.3f The low absolute magnitude of the geminal coupling constant of the 1,3 hydrocarbon 1 was suggested to be due to the small C-CH2-C angle.3b
Results and Discussion We have determined the NMR spectra of a large number of 1,3- and 1,4-bishomocubyl derivatives (1-21, 23, 24, 3337, 40, 41) over the past several yeam2v4 In particular we have accumulated data on a number of syn- and anti-substituted isomer pairs of 1,3-bishomocubane 1. Spectra typical of the series, those of the syn and anti alcohols 2 and 3, are shown in Figures 1 and 2. The data for protons on the methylene bridges or protons on functional groups attached to the methylene bridges are given in Tables 111-XI which will appear in the microfilm edition of this journal. (See paragraph at end of paper regarding supplementary material.) Some data reported by other workers5 also have been included.
J. Org. Chem., Vol. 40, No. 16, 1975 2381
lH NMR of 1,3- and 1,4-Bishomocubyl Derivatives
I
40
I
1
I
I
30
20
10
0
8 (ppml
Figure 2. NMR spectrum of anti-pentacyclo[5.3.0.0z~5.03~g.0~~~]~ decan-6-01(3) in deuteriochloroform (60 MHz). In all isomers examined, the anti protons (Ha) always appeared a t higher field than the syn protons (H".The magnitude of the chemical shift difference A6 (SHS - ~ H B is) dependent on the distance of the proton from the methylene carbon atom. In general the shift difference decreases with increasing distance. An exception is the case where the proton is separated by one atom from the methylene carbon atom. A summary of these data is given in Table I. Steric compression by the proton on C-1 may explain the downfield shift of the syn protons compared with the anti protons. Crude measurements made with ball and spring models of the hydrocarbon 1 indicated that the syn protonC-1 proton distance is the shortest of the four proton-proton distances (relative) shown in the figure.
1
A number of examples of this type of steric deshielding have been reported;6 an outstanding example is the halfcage alcohol 446a(chemicals shifts shown).
H I
44
It is also possible that the syn proton deshielding of 1 and its derivatives is due to some anisotropic factor caused by the twisted rings. The rather sharp decrease in the chemical shift differences for protons on syn and anti substituents as the number of interposed atoms increases (Table I) (except, n = 1) is a natural consequence of the greater distance between the C-1 proton and the proton in question. Models of the C-6 methyl derivatives ( n = 1) indicate that in some conformations the methyl protons are considerably closer to the four protons on the tertiary carbon atoms C-1, -2, -4,and -8 than are the syn and anti pro-
tons which are bonded directly to the methylene bridge carbon atoms. The protons on the methylene group which bear a functional group or on functional groups attached to the methylene carbon atom of the 1,4-bishomocubyl derivatives always had chemical shifts intermediate between those of the corresponding protons of the syn and anti 1,3-bishomocubyl derivatives where the differences in shifts were outside of the experimental error (f-0.02 ppm). In general the shift of the 1,4 derivative was closer to that of the anti 1,3 derivative than to that of the syn 1,3 derivative. The chemical shifts of the methylene groups (-CHaHS-) were assigned on the basis that the anti proton always occurred at the higher field as was observed for the protons on the methylene bridge which bears a functional group. Interestingly, the chemical shift difference between the methylene protons was always greater for the anti isomers (Table 11). The data in Table I1 are for both CC14 and CDC13 solutions; very little difference in chemical shifts was noted for the two solvents. For the secondary derivatives (first two entries in Table 11) it will be noted that the syn methylene proton (Ha) signals occur over a relatively narrow chemical shift range while the anti methylene proton (Ha) signals occur over a wider range. Thus the change in chemical shift differences (As) is due almost entirely to an upfield shift of the anti methylene proton signal of the anti-X isomer compared with the anti methylene proton signal of the syn-X isomer. The reason for this phenomenon is not readily apparent; it may be due to some conformational change which occurs on substituting the syn-X group for an anti-X group. The same general trend is also observed in the methyl derivatives (last two entries in Table 11), but the effect is not so pronounced. Chemical shift differences larger than those shown in Table I1 are observed when the tertiary ring carbon atoms are unsymmetrically substituted, e.g., 27 and 28. The geminal coupling are all in the range 10.5-11.9 Hz,except constants, JHBH~, for the highly chlorinated derivatives 27 and 30. The chemical shifts of the secondary methylene protons of the 1,4bishomocubyl derivatives are all in the range of 1.33-1.45 ppm, except for those derivatives with chlorine atoms on the tertiary ring carbon atoms. The chemical shifts of the protons on the methylene group which bears the functional group and the chemical shifts of the protons on the functional groups show a regular dependence on the solvent. The solvent shift ( ~ C D C I~ 6cci4)for the former protons ranges from 0.06 to 0.12 ppm; most of the values are near 0.10 ppm. For protons on atoms
2382 J. Org. Chem., Vol. 40, No. 16,1975
Dilling
Table I1 NMR Chemical Shift Differences of Methylene Protons of Syn and Anti 1,3-Bishomocubyl Derivatives Chemical shift Chemical shift ranges, ppm
Ha
Compd type
HS
Q$
m t i X'
1.27 -1.3 9
X
0.36-0.39
H, OH, OCHO, OAc, OTs, C1
0.18-O.20
OH, OCHO, OAc, OTs
0.3 1-0.33
OH, OCHO, OAc, OTs
0.22-0.27
OH, OCHO, OAc, OTs, OPNB
1.58-1.67
1.58-1.66
-
CY t to the ring methylene group, the solvent shift is -0.03-0.11 ppm. The above correlations are useful for the structure elucidation of bishomocubyl derivatives. For example, Williamson and coworkers7 have shown that pentachlorocyclopentadiene 45 dimerized thermally to give a dimer which had
H
-
A 6 ( 6 ~ s 6Ha)
n
1.21-1.45
C1
difference range,
C1
\/
H
ther structure 48 or 49. The NMR spectrum of the caged compound 48 or 49 exhibited a sharp singlet a t 4.56 ppm (solvent not reported). Ungefug and Scherer5j also reported the same product, 6 4.61 ppm (CDCl3), which they prepared in the same manner as Williamson and coworkers. The anti,anti isomer 48 reasonably can be assigned as the correct structure based on a comparison of the chemical shifts of the protons on 48 and the 1,4-bishomocubyl derivative 504b(6 4.28 ppm in CCld, 4.31 in CDC13). The syn pro-
H
h c 1 8 o r
\
47
46
50
1
hv Me,CO
or
48
49
either structure 46 or 47. Irradiation of the dimer in acetone solution gave a 1,3-bishomocubyl derivative6 with ei-
ton signal of 48 is expected to appear downfield from that of the 1,4-bishomocuby150 proton. The anti proton chemical shift for the syn,syn derivative 49 is expected to be slightly upfield from 4.3 ppm. For two reasons the undecachloro derivative 50 is a satisfactory model for comparison with the decachloro compounds 48 and 49 even though the second methylene groups of 48 and 49 bear only one chlorine atom while the second methylene group of 50 bears two chlorine atoms. First, the chemical shifts of the 1,4bishomocubyl derivatives' methylene protons are not very sensitive to substituents on the other methylene group. Second, the chemical shift of the methylene protons of the
J. Org. Chem., Vol. 40, No. 16, 1975 2383
lH NMR of 1,3- and l,4-Bishomocubyl Derivatives decachloro 1,4-bishomocubyl derivative 41 (2.57 ppm) is intermediate between those of the syn and anti protons of the octachloro 1,4-bishomocubyl derivative 30 (2.84, 2.54 ppm) (the second methylene group of 30 is replaced with a dichloromethylene group in 41). The same comparison can be made for the methoxy protons of compounds 31 (3.60, 3.47 ppm), 32 (3.66, 3.51 pprn), and 42 (3.55 pprn). The chemical shift difference between compounds 48 and 50 is 0.30 ppm; that between the syn proton of 30 and the protons of 41 is 0.27 ppm. Thus the Diels-Alder dimer of the diene 45 has structure 46, the one predicted on the basis of the less severe nonbonded interactions in the Diels-Alder transition state.7 Mackenzie and Youngg also concluded that 46 was the correct structure of the diene 45 dimer on the basis of other NMR data. Another example of the utility of these NMR correlations involves the stereochemistry of the reaction of the endo-anti dienol 51 with thionyl chloride and pyridine to
+-dQ H--
I
H--
52
sh &
CI
and/or
pyridine
H - - Y
c1
w
52
52
atom 1 e a ~ e s .In l ~pyridine where chloride ion is present, the stereochemical result would likely be the same, since sN2' reactions occur with the nucleophile entering on the same side as that from which the leaving group departs.14
Experimental Section The proton NMR spectra were obtained by Mr. F. L. Beman and coworkers with a Varian A-60 analytical spectrometer operating at 60 MHz or by Dr. J. P. Heeschen and coworkers with a Varian HA-100high-resolution spectrometer operating a t 100 MHz. The NMR solution concentrations were 10-20%. All proton chemical shifts (6) are relative to internal tetramethylsilane (positive when downfield from the reference) and are accurate to -&0.02 ppm; coupling constants are accurate to -0.2 Hz. Chemical shifts (in hertz) of protons which produced AB quartet patterns were calculated from the expression 6 = midpoint i UAB& where VAB = [ V I - Y 4 ) ( V Z - v ~ ) ] ~and ' ~ v i , u2, vg, and v 4 are t,he resonance frequencies of the four lines of the AB quartet.15 References for the syntheses and characterizations of the compounds are given in the tables in the microfilm edition of this journal.
--$' Me.CO
c1
OH 51
51
10
give an allylic chloride, presumably the anti isomer 52.1a Irradiation of the chloride 52 in acetone gave a monochloro1,3-bishomocubane,8 presumably the anti isomer The chemical shift difference of the methylene protons of the caged chloride 10 is 0.38 ppm, consistent only with the chlorine atom being a t the anti position (Table 11). The NMR spectrum of the diene 52 also was consistent with the anti chlorine stereochemistry. In particular the signal for the proton on the carbon atom which bears the chlorine atom appeared as a narrow multiplet (-11 Hz base width). The signal for the proton on the carbon atom which bears the hydroxyl group of the anti dienol 51 also was a narrow multiplet (-11 Hz base width).1° In contrast the corresponding proton of the syn dienol 53 was a doublet, 5 2 3 =
Registry No.-1, 6707-86-4; 2, 13351-15-0; 3, 15776-05-3; 4, 39522-31-1; 5, 39522-32-2; 6, 55399-44-5; 7, 55399-45-6; 8, 1687236-9; 9, 16966-85-1; 10, 51965-71-0; 11,51965-68-5; 12,52021-57-5; 13, 51965-72-1; 14, 52021-58-6; 15, 52916-90-2; 16, 52949-82-3; 17, 33823-77-7; 18, 33823-78-8; 19, 51965-75-4; 20, 51965-73-2; 21, 51965-74-3; 23, 33744-62-6; 24, 15584-52-8; 33, 6707-88-6; 34, 13351-14-9; 35, 39522-33-3; 36, 55319-54-5; 37, 55319-55-6; 40, 15745-99-0; 41,15443-23-9. Supplementary Material Available. NMR chemical shifts of protons on the methylene bridges or protons on functional groups attached to the methylene bridges of compounds 1-43 (Tables IIIXI) will appear following these pages in the microfilm edition of this volume of the journal. Photocopies of the supplementary material from this paper only or microfiche (105 X 148 mm, 24X reduction, negatives) containing all of the supplementary material for the papers in this issue may be obtained from the Journals Department, American Chemical Society, 1155 16th St., N.W., Washington, D.C. 20036. Remit check or money order for $4.50 for photocopy or $2.50 for microfiche, referring to code number JOC-752380.
References and Notes (a) Pari XI: W. L. Dilling, R . A. Plepys, and J. A. Alford, J. Org. Chem., 39, 2656 (1974). (b) Presented at the 6th Great Lakes Regional Meeting of the American Chemical Society, Houghton, Mich., June 22-23, 1972, Abstracts of Papers, p 44, No. 49. (2) For the bishomocubane system of nomenclature see W. L. Dilling, C. E. Reineke, and R. A. Plepys, J. Org. Chem., 34, 2605 (1969); 37, 3753 (1)
53
54
8.5 Hz, with further smaller splitting evident (-16 Hz base width).1° The NMR spectrum of the syn chloride 54 is expected to show a similar pattern for the proton on the carbon atom which bears the chlorine atom. The larger coupling, 5 2 3 , in the syn hydroxy isomer 53 probably is due to the H-2-H-3 dihedral angle being nearly 0' as determined from molecular models.ll The H-2-H-3 dihedral angle in the anti isomers 51 and 52 is about 120°, and therefore 523 is expected to be small.11 Thus the reaction of the anti alcohol 51 with thionyl chloride in pyridine either occurs with retention (SNi) 52 and/or retention with allylic rearrangement (SNi' or sN2') 52'. The reaction of alcohols with thionyl chloride in pyridine usually results in inversion of configuration12 while allylic alcohols react with thionyl chloride in ether to give rearranged chlorides in which the chlorine atom attacks the allylic system on the same side from which the oxygen
(1972). (3) (a)R. J. Stedman and L. D. Davis, Tetrahedron Lett., 1671 (1968); (b) R . Cahill, R. C. Cookson, and T. A. Crabb, Tetrahedron, 25, 4711 (1969); (c) L. M. Jackman and S. Sternhell, "Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry", 2nd ed, Pergamon Press, Oxford, 1969, p 221; (d) J. W. ApSlmon, P. V. Demarco, D. W. Mathieson, W. G. Craig, A. Karlm, L. Saunders, and W. B. Whalley, Tetrahedron, 26, 119 (1970); (e) N. 6. Chapman. J. M. Key, and K. J. Toyne, J. Org. Chem., 35, 3860 (1970); (f) A. K. Davis, D. W. Mathieson, P. D. Nicklin, J. R. Bell, and K. J. Toyne, Tetrahedron Lett., 413 (1973). (4) (a) E. T. McBee, W. L. Dilling, and ti. P. Braendlin, J. Org. Chem., 27, 2704 (1962); (b) W. L. Dilling. H. P. Braendlin. and E. T. McBee, Tetrahedron, 23, 1211 (1967); 24, 3517 (1966); 25, 2047 (1969): (c) W. L. Dilling and M.L. Dilling. ibid., 23, 1225 (1967); (d) W. L. Dilling and C. E. Reineke, Tetrahedron Lett., 2547 (1967); (e) W. L. Dilling. R. A. Plepys, and R . D. Kroening, J. Am. Chem. Soc., 91, 3404 (1969); 92, 3522 (1970); (f) W. L. Dilling and J. A. Alford, Tetrahedron Lett., 761 (1971); (9) W. L. Dilling, R. A. Plepys, and R . D. Kroening, J. Am. Chem. SOC.,94, 8133 (1972); (h) W. L. Dilling and J. A. Alford, i6M.. 96, 3615 (1974). (5) (a)R. C. Cookson, J. Hudec, and R. 0. Wllllams, J. Chem. SOC.C, 1382 (1967); (b) W. G. Dauben and D. L. Whalen, J. Am. Chem. Soc., 93,
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 20,1975 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 9 isopicropodophyllone 10 podophyllotoxone 11 picropodophyllone 12 DL-isopodophyllotoxone 14 4-deoxyisopicropodophyllin 16 4-deoxyisopodophyllotoxin
(20,3a, R = 0 ) ( 2 q 30, R = 0) (2@,3P, R = 0) (20,&, R = 0 ) (20, h,R = H,H) (2@,&,R = H,H)
R OMe
1 podophyllotoxin 2 epipodophyllotoxin 3 picropodophyllin 4 61 pip i c* ro po d o p hy I I i n 5 iso podo p h y 1lo toxin 6 epiiHopodophyllotoxin 7 isopicropodophyllin 8 epiisopicropodophyllin
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 at 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
Ar 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 a t C-1 indicates the 3,4,5-trimethoxyphenyl group.
Confirmation that 8 had retained the all-cis (a)configuration at 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
