1916
Journal of the American Chemical Society
(52) Wolf, R. A. Unpublished results. (53) Scheppele, S. E.; Grizzle, P. L.; Miller, D. W. J. Am. Chem. SOC. 1975, 97, 6165. (54) Hildebrand, J. H.; Prausnitz, J. M.; Scott, R. L. "Regular and Related Solutions", Van Nostrand-Reinhold: Princeton, N.J., 1970; pp 207-215. (55) Sanderson, J. R.; Story, P. R. J. Org. Chem. 1974, 39, 3463. (56) Giese, B. Angew. Chem., h t . Ed. Engl. 1977, 16, 125. (57) Pryor, W. A.; Smith, K. J. Am. Chem. SOC. 1970, 92, 2731. (58) Trachtman, M.; Miller, J. G. J. Am. Chem. SOC.1962, 84, 4928. (59) Bartlett, P. D.: Lorand, J. P. J. Am. Chem. SOC.1966, 88,3294. (60) Thornton, E. R. J. Am. Chem. SOC.1967, 89, 2915. (61) More O'Ferrall, R. A. J. Chem. SOC.6 1970, 274. (62) Jencks, D. A.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 7948. (63) (a) Koenig, T.; Wielesek. R. A.; Huntington, J. G. Tetrahedron Lett. 1974, 2283. (b) Koenig, T. Personal communication. (64) Shelton, J. R.; Uzelmeier, C. W. J. Am. Chem. SOC. 1966, 88, 5222. (65) McDonald, R. N.; Reitz, R. R. J. Am. Chem. SOC. 1976, 98, 8144. (66) Shono, T.; Nishiguchi, I. Tetrahedron 1974, 30, 2183. (67) Stefani, A. P.; Chuang, L.-Y.; Todd, H. E. J. Am. Chem. SOC. 1970, 92, 4168. (68) Fort, R. C., Jr.; Hiti, J. J. Org. Chem. 1977, 42, 3968. (69) Ernst, J. A.; Thankachan, C.; Tidwell, T. T. J. Org. Chem. 1974, 39, 3614. (70) Timberlake, J. W.; Garner, A. W. J. Org. Chem. 1976, 41. 1666. (71) Friedman, R. L.; Lewis, R. N.;Pastorino, R. L. Mod. Plast. 1971, 66. (72) Garner, A. W.; Timberlake. T. W.; Engel, P. S.; Melaugh, R. A. J. Am. Chem. SOC.1975, 97, 7377. (73) (a) Duismann. W.; Ruchardt, C. Tetrahedron Lett. 1974, 4517. (b) Chem. Ber. 1973, 106, 1083. (74) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1976, 9, 13. (75) Porter, N. A.; Dubay, G. R.; Green, J. G. J. Am. Cbem. Soc. 1978, 100, 920,
(76) (77) (78) (79) (80) (81) (82) (83) (84)
(85) (86) (87) (88) (89) (90) (91) (92) (93) (94) (95) (96) (97) (98)
/ 100.25 / December 6, 1978
and references cited therein. Engle, P. S.; Bishop. D. J. J. Am. Chem. SOC. 1975,97, 6754. Nozaki, K.; Bartlett, P. D. J. Am. Chem. SOC. 1946, 68, 1686. Tang, F.;Huyser, E. S. J. Org. Chem. 1978, 43, 1016. Russell, G. A. in ref 12, p 312. (a) Kozuka, S.; Lewis, E. S. J. Am. Chem. SOC. 1976, 98, 2254. (b) Lewis, E. S.; Ogino, D. ibid. 1976, 98, 2264. Milas, N. A.; Golubovic, A. J. Am. Chem. SOC. 1958, 80, 5994. Ruchardt, C.; Schwarzer, H. Chem. Ber. 1966, 99, 1861. Pryor, W. A.; Kneipp, K. G. J. Am. Chem. SOC.1971, 93, 5584. We thank Dr. Sal Rand of the Texaco Research Center, Beacon, N.Y., for taking the 100-MHz spectra for us. Koenig, T.; Wolf, R. J. Am. Chem. SOC.1967, 89, 2948. "The Aldrich Catalog-Handbook of Organic and Biochemicals". Aldrich Chemical Co., Inc.: Milwaukee, Wis.. 197771978, Gassman, P. G.; Heckert, D. C. Tetrahedron 1965, 21, 2725. Pratt, D. G.; Rothstein, E. J. Chem. SOC.C 1968, 2548. Atkinson, J. G.; Csakvary, J. J.; Herbert, G. T.; Stuart, R. S. J. Am. Chem. SOC.1968, 90, 498. Vogel, A. I. " A Textbook of Practical Orgenic Chemistry", Longman: London, 1956; p 859. Abell, P. I.; Tien, R . J. Org. Chem. 6965, 30, 4212. Haworth, E.; Perkin, W. H. J. Chem. SOC.1894, 65, 86. Walker. H. G.; Hauser. C. R. J. Am. Chem. SOC. 1946, 68, 1386. Simmons, H. E . ; Blanchard, E. P.; Smith, R. D. J. Am. Chem. SOC.1964, 86, 134. Cox, E. F.; Caserio, M. C.; Silver, M. S.; Roberts, J. D. J. Am. Chem. SOC. 1961, 83, 2719. Reference 86, p 211. Reference 86, p 222. Reference 86, p 215.
Epimerization and Isomerization in C20 Diterpenoid Alkaloids. Crystal and Molecular Structures of Atisinium Chloride, Dihydroatisine, Isoatisine, and Veatchinel S. William Pelletier,* Wilson H. De Camp, and Naresh V. Mody Contribution from the Institute f o r Natural Products Research and Department of Chemistry, Unicersity of Georgia, Athens, Georgia 30602. Received April 17, 1978
Abstract: The solid-state conformation of four C20 diterpenoid alkaloids has been determined by X-ray crystallography. Atisinium chloride (orthorhombic, P212121, a = 14.340, b = 18.180, e = 7.709 A, R = 0.038 for 2007 observed reflections) is shown to have restricted access to both sides of the iminium double bond. Dihydroatisine (orthorhombic, P212121. a = 13.004, b = 18.939, e = 7.840 A, R = 0.055 for 1651 observed reflections) is shown to have a chair conformation for ring E, thus giving a basis for assignment of all ' H and I3C N M R resonances, and showing that boat-chair conformational isomerism of ring E is unlikely. Isoatisine (orthorhombic, P 2 1 2 ~ 2 a, , = 13.212, b = 13.661, c = 10.403 A, R = 0.048 for 1945 observed reflections) shows that the oxazolidine ring F closes exclusively in the endo configuration when closure is in the is0 form. This result confirms a I3C N M R study that isoatisine does not exist as a pair of epimers. Furthermore, it indicates that the doubled signal of the C(4) methyl group in isoatisine is attributable neither to a mixture of C ( 19) epimers, as was suggested in the case of atisine, nor to a mixture of the chair and boat conformers of the piperidine ring E. Veatchine (orthorhombic, P212121,a = 9.934, b = 21.581, c = 8.674 A, R = 0.050 for 1614 observed reflections) reveals a crystal structure which is disordered between C(20) epimers, showing that the normal closure of the oxazolidine ring can take place on either side of the iminium double bond, in agreement with the observed '3C N M R data. The absolute configuration of atisinium chloride is shown to be 4S,5S,8R, IOR, 12R, 15s by the R-ratio test. By analogy, the absolute configuration of dihydroatisine must be 4S,5S,8R,lOR,12R,I5S, and that of isoatisinemust be4S,5S,8R, IOR,12R, 15S,19S. Theabsoluteconfigurationofveatchine must be 4S,5S,8R, 10R, 13R, 15R,20SR, with the S R indicating a predominance of the 20s epimer. A similar configuration a t C(20) is postulated for atisine on the basis of spectral data. The S:R ratio in veatchine is approximately 60:40, based on measurements of the diffracted intensity for sensitive reflections, which is in substantial agreement with the ratio found by integrating the C(4) methyl resonance in the IH N M R spectra of the two different sets of I3C chemical shifts for the carbon atoms of the oxazolidine ring, piperidine ring, and C(4) methyl group.
Introduction The C20 diterpenoid alkaloids isolated from various Aconitum and Garrya species (principally A. heterophyllum Wall. G. ueatchii Kellogg, and G. lauifolia Hartw.) have been the subjects of extensive chemical i n ~ e s t i g a t i o n . The ~ - ~ molecular structure and stereochemistry of atisine (1) and several related alkaloids were initially established by classical degradative and synthetic method^.^-^ Atisine ( l ) ,an amorphous base (pK, = OO02-7863/18 J 1500-7976$01 .OO/O
12.8), undergoes a facile isomerization of the oxazolidine ring F (see Experimental Section for ring definitions) from its "normal" position (closed on C(20)) to the "iso" position (closed on C( 19)) of isoatisine ( 2 ) by treatment with methanolic alkali or even by simple refluxing in hydroxylic solvent^.^ The path of this isomerization presumably goes through the ternary iminium form (3), which tautomerizes to the isoiminium form (4). The isomerization can be reversed by refluxing 0 1978 American Chemical Society
/ C ~ Diterpenoid Q Alkaloids
Pelletier, De Camp, M o d y
@a
1977
I151
c 63 c 1171
ill71
C
c I211 c 221
0 I221
RTISINIUM ION
ATiSINIUM ION Figure 1. A stereoscopic drawing of the atisinium ion.
-1
methyl singlets and the C(20)-proton signals in the NMR spectra of atisine, veatchine, and related alkaloids by comparison with their 13CN M R spectra.I2 We undertook the resolution of these various findings by means of the series of crystal structures reported here. First, the absolute configuration of the atisane skeleton was confirmed by the structure determination of atisinium chloride ( 5 ) . Based on the solid-state conformation of ring E in dihydroatisine (7), the correct assignments of the I3C N M R resonances were established for this conformationally mobile part of the molecule.12The hypothesis of chair-boat conformational equilibrium can therefore be rejected. Finally, we sought to establish the favored closures for both the normal and isooxazolidine rings. The structure of isoatisine (2) showed clearly that closure to C ( 19) in an endo configuration is favored. On the other hand, the crystal structure of veatchine (8) surpris-
ATlSlNE
" 2 -
-4
ISOATISINE
isoatisinium chloride ( 6 ) in such solvents as DMA, DMF, DEF, Me2S0, and high-boiling alcohols.6 Since the procedure
ATlSlNE
,c;r"" ,SH
'-.
t_
Rase
1 DIHYDROATISINE
c,-
OH
tC
.N+
-5
CC
OHHCI
----N+
Base
'OH
-
ISOATISINE
6
for the isolation of atisine involves its purification as atisinium chloride, the stereochemistry of atisine a t the iminium carbon, C(20), must therefore be ambiguous. Early work assumed, without experimental evidence, a p configuration for the hydrogen attached to C(2O).' The present work shows that this assumption is, a t best, only partially true. The inconclusive knowledge of the stereochemistry of atisine a t C(20) has led to differing viewpoints concerning the interpretation of the doubling of certain peaks in t h e l H N M R spectra. An early hypothesis involved an equilibrium between conformers of atisine in which ring E existed in either a chair or boat form.8 Pradhan and Girijavallabhan reported that the doubled C(4) methyl resonance coalesced to a broadened singlet in certain deuterated solvents, concluding that deuterium exchange occurred a t C(20) in atisine. They explained these observations by postulating a facile interconversion of This epimers in solution t5rough a zwitterionic ir~termediate.~ interpretation is inconsistent with the later observation that deuterium exchange does not occur.IQWhen the I3C N M R spectrum of atisine was taken in nonionic solvents such as toluene, chloroform, and acetone, the ratio of C(20) epimers remained constant.' I Consequently we concluded that these epimers do not exist in equilibrium with each other in nonionic solvents." Recently we have explained the doubling of the C(4)
8 -
VEATCHINE
9
ingly showed that both epimers existed in the unit cell in a disordered relationship. Closure of the oxazolidine ring to C(20) in an exo configuration is slightly, but significantly, favored. This result agrees with the I3C N M R data reported for veatchine. The C(4) methyl resonance appears, as noted above, as an unequal doublet in the ' H N M R spectra of both veatchine and isoatisine. The doubling persists in the I3C N M R spectrum only in the case of ceatchine. In combination with our crystal structure results, these observations show that veatchine exists in solution as a mixture of epimers. The same cannot be said for isoatisine, for which the doubling of the C(4) methyl singlet must be attributed to the conformational flexibility of the oxazolidine ring. This conclusion is supported by comparing the IH N M R spectrum of a-oxoisoatisine, in which the amide >C=O group is a t C(21), with that of isoatisine. The IH N M R spectrum of a-oxoisoatisine shows only one sharp singlet for the C(4)-CH3 group.* Molecular Structure and Conformation Except for the question of the conformation of rings E and F, the chemical connectivity has been previously established for atisinium chloride ( 5 ) , dihydroatisine (7), veatchine (8),
1918
Journal of the American Chemical Society
Table 1. Interatomic Distances
atoms
atisinium chloride
/
100.25
/ December 6, 1978
(A) (Estimated Standard Deviations in Parentheses) interatomic distance dihydroatisine isoatisine
veatchine
atoms
atisinium chloride
1.528 (3) 1.533 (5) C(15)-H(15b) 1.533 (4) 1.523 (6) C(1 )-C(2) C(I)-C(I0) 1.563 (3) 1.551 (5) 1.544 (3) 1.545 ( 5 ) C(16)-C(17) C( I)-H( l a ) 0.99 (3) 0.98 (3) 0.99 (2) 1.06 (4) C(17)-H(171) C(I)-H(lb) 0.99 (2) 1.02 (3) 1.03 (3) 0.89 (4) C(17)-H(172) 1.513 (4) 1.526 (6) 1.526 (4) 1.527 (6) C(18)-H(181) C(2)-C(3) C( 2)-H (2a) 1.00 (3) 1.00 (4) 1.06 (3) 1.00 ( 5 ) C(18)-H(182) C( 2) -H (2 b) 0.98 (3) 0.93 (4) 1.16 (3) 0.93 (4) C( 18)-H( 183) 1.543 (3) 1.534 ( 5 ) 1.546 (4) 1.535 (5) C( 19)-N C(3)-C(4) C ( 3)-H( 3a) 1.07 (4) 0.89 (4) 1.06 (3) 1.03 (3) C(19)-O(22) C( 3) -H (3 b) 1.01 (3) 0.98 (4) 1.01 (3) 1.09 (4) C(19)-H(191) 1.544 (3) 1.537 ( 5 ) 1.552 (3) 1.555 (5) C(19)-H(192) C(4)-C(5) C(4)-C( 18) 1.536 (4) 1.537 (6) 1.532 (4) 1.540 (6) C(20)-N C(4)-C( 19) C(20)-0(22ma) 1.530 (2) 1.543 ( 5 ) 1.525 (4) 1.523 (5) C( 20)-O( 22mi) 1.530 (3) 1.533 ( 5 ) 1.529 (3) 1.520 (5) C(5)-C(6) C(S)-C(lO) 1.541 (3) 1.547 (4) C(20)-H(20) 1.546 (3) 1.558 (5) C ( 5) -H (5b) 0.99 (2) 1.02 (4) 0.95 (3) 1.01 (4) C ( 20)- H( 20 1) 1.521 (3) 1.529 (5) 1.522 (4) 1.514 ( 5 ) C( 20)-H( 202) C(6)-C(7) C( 6) - H (6a) 0.98 (2) 1.09 (4) 0.94 (2) 1.01 (4) C(21)-N C (6)- H (6b) C(21)-C(22) 0.98 (2) 0.99 (4) 1.02 (3) 0.91 (4) C ( 2 1 )-C(22ma) 1.521 (3) 1.530 ( 5 ) 1.533 (3) 1.528 ( 5 ) C(7)-C(8) C(7)-H(7a) C(2 1)-C(22mi) 1.03 (3) 0.97 (3) 1.00 (2) 0.97 (3) C ( 7) - H (7 b) C(21)-H(211) 1.00 (3) 1.04 (3) 0.98 (3) 0.92 (4) C(21)-H(212) 1.541 (3) 1.550 (4) 1.550 (3) 1.551 (5) C(8)-C(9) C(8)-C( 14) C(21)-H(2ld) 1.551 (2) 1.539 (5) 1.543 (3) 1.568 ( 5 ) C(8)-C( 15) C(22)-0(22) 1.552 (3) 1.548 (5) 1.561 (3) 1.556 ( 5 ) C(9)-C( I O ) C( 22)-O(22a) 1.551 (3) 1.553 (4) 1.559 (3) 1.563 (5) C (22) -0(2 2 b) C(9)-C(I I ) 1.557 (3) 1.563 ( 5 ) 1.557 (3) 1.555 (5) C( 9) -H(9 b) C( 22)-O( 22c) 1.02 (2) 0.91 (3) 0.99 (2) 0.98 (3) C( IO)-C(20) C(22)-H(221) 1.495 (2) 1.539 (4) 1.547 (3) 1.515 (5) C(Il)-C(12) C(22)-H(222) 1.532 (3) 1.541 (5) 1.534 (3) 1.523 (6) C(l I)-H(l l a ) 1.05 (3) 1.01 (4) 1.02 (3) 1.16 (5) C(22ma)C(l I)-H(l Ib) 1.05 (3) 1.08 (4) 1.02 (2) 1 .oo (5) O(22ma) C( 12)-C( 13) 1.53 1 (4) I S 3 0 (6) 1.530 (4) 1.530 (6) C( 22ma)C(12)-C(16) 1.501 (3) 1.496 ( 5 ) 1 ,509 (3) H(22 Id) C( 12)-H( 12a) C(22ma)1.04 ( 5 ) C( 12)-H( 12b) 0.94 (3) 1.08 (4) 0.98 (3) 0.98 (4) H(222d) C( 13)-C( 14) 1.535 (4) 1.529 (6) 1.541 (3) 1.523 (6) C(22ma)C ( l3)-C( 16) C(22mi) 1.508 (5) C ( 13)-H( 13a) 0.96 (3) 0.97 (4) 0.93 (3) C(22mi)-0(22mi) C(13)-H(13b) 1.07 (3) 0.93 (4) 1.07 (3) 1.02 ( 5 ) C(22mi)-H(221d) C ( 14)- H( 14a) 0.94 (3) 0.94 (3) 1.07 (2) 0.98 (4) C( 22mi)- H( 223d) C( 1 4) -H ( 14b) 0.92 (3) 1.05 (4) 0.88 (3) 1.04 (4) O( 15)-H( 1 5 0 H ) C( l5)-C( 16) 1.517 (3) 1.521 (6) 1.523 (4) 1.507 (5) 0(22)-H(220H) C ( I 5 ) - 0 ( 15) 1.425 (3) 1.446 (4) 1.421 (3) 1.421 (5) O(22ma)C(15)-H(15a) 1.04(3) 1 0 3 (3) 1.01 (3) O(22mi) Nonbonding distance between corresponding atoms of 20R and 2 0 s epimers.
a n d isoatisine (2) .2-4,13 Our work confirms t h e earlier conc l u s i o n ~ a' n~d~, in ~ ~particular, shows t h a t t h e hydroxyl group a t C(15) h a s a /3 orientation in t h e atisines, while it is a in veatchine (8). Bond lengths a n d angles a r e given in T a b l e s I a n d I1 for all four structures. Figures 1-4 show stereoscopic drawingsI6 of t h e molecules of t h e atisinium ion (5, Figure l ) , veatchine (8, Figure 2), isoatisine (2, Figure 3), a n d dihydroatisine (7, Figure 4). T h e torsion angles for t h e various rings in all four structures a r e shown in T a b l e 111. R i n g E is found t o a d o p t a c h a i r conformation in dihydroatisine, isoatisine, a n d veatchine. T h i s lends additional support t o t h e interpretation of t h e 'HN M R spectrum of atisine t h a t t h e earlier postulate of conformational isomerism in atisine8 (involving a n equilibrium between chair a n d boat conformations of ring E) is incorrect. T h e t e r n a r y iminium structure of atisinium chloride forces ring E t o assume a flattened chair conformation. It is also interesting to observe t h a t ring E is slightly flattened a t t h e fusion t o ring F in isoatisine, b u t not in veatchine. Rings A a n d B have essentially identical c h a i r geometries
1.314 (4) 0.95 (4) 1.00 (3) 0.99 (3) 0.96 (4) 0.99 (4) 1.473 ( 2 )
interatomic distance dihydroatisine isoatisine 1.324 (7) 0.91 (9) 0.99 (4) 0.95 (3) 1.08 ( 5 ) 1.05 (6) 1.464 ( 5 )
0.98 (3) 1.14 (4) 1.03 (3) 1.10 (4) 1.293 (3) 1.469 (4) 0.97 (2) 1.492 (2) 1.51 I (3)
I .02 (4) 1.06 (4) 1.547 (8) 1.547 (8)
1.05 (3) 1.05 (3)
1.19 ( 5 ) 1.09 (6)
1.409 (3)
veatchine
1.313 (4) 0.92 (3) 0.99 (4) 0.95 (3) 1.06 (3) 0.86 (3) 1.440 (3) 1.437 (3) 1.20 (2)
0.89 (4) 1.331 (6) 0.92 (4) 0.93 (5) 1.14 (5) 0.85 ( 5 ) 0.82 ( 5 ) 1.462 ( 5 )
0.95 (4) 0.94 (4) 1.477 (3) 1.459 ( 5 ) 1.31 I (6) 1.254 (7) 1.254 (7) I .oo (3) 1.02 (3) 1.466 (4) 1.45 1 (8) 1.530 ( 5 ) 1.451 (8) 1.40 ( I ) 0.96 (4) 1.12 (4) 0.70 (4) 1.427 (4)
1.263 (9) 1.210 (12) 1.270 ( 2 1 ) 1.12 (2) 1.00 (3)
1.07 (4) 1.14 (4) 1.450 (8) 1.14 ( 5 )
1.04 (6) 1.288 ( 1 3 ) O
0.85 (4) 1.01 (5)
0.83 (3)
1.44 ( 1 ) I .27 (5) I .05 (6) 0.84 (6) 1.532 ( 8 ) "
in all four compounds. Ring B differs slightly, but significantly, from a n ideal geometry by being flattened along the C(8)-C(9) edge. T h e f a c t t h a t this bond is also t h e point of fusion of ring B t o ring C a n d t h e bicyclo[2.2.2]octane f r a g m e n t suggests t h a t this bond acts a s a "hinge" in transferring steric effects f r o m o n e e n d of t h e molecule t o t h e other. T h e torsion angles of t h e bicyclo[2.2.2]octane system deviate from their ideal values m o F in isoatisine t h a n in dihydroatisine or atisinium chloride ( A = 2 . 9 4 O for atisinium chloride, 4.72' for dihydroatisine, a n d 1 1.14' for isoatisine; is t h e average absolute deviation of t h e torsion angles from t h e ideal values of 0, 60, or -60'). However, interactions between eclipsed hydrogens in a n ideal [2.2.2] system support a n expectation t h a t t h e minimum energy conformation of this moiety should be slightly skewed. Molecular mechanics calculations have shown t h a t a skewed model of bicyclo[2.2.2]octane is approximately 0.08 k c a l / m o l lower in energy t h a n t h e eclipsed ( D 3 h ) conformation.I7 T h e observation t h a t ring E is m o r e distorted in isoatisine t h a n in either dihydroatisine or veatchine suggests t h a t t h e is0 closure of t h e oxazolidine ring allows ring E t o a b s o r b
Pelletier, De Camp, M o d y
/ C20 Diterpenoid Alkaloids
7979
Table 11. Bond Angles (deg) (Estimated Standard Deviations in Parentheses)
atoms C(2)-C( 1)-C( IO) C ( 1 ) -C (2) -C (3) C ( 2 ) - c (3)-C( 4) C(3)-C(4)-C(5) C(3)-C(4)-C(18) C( 3) -C( 4) -C( 19) C(5)-C(4)-C(18) C(S)-C(4)-C( 19) C ( 18)-C(4)-C(19) C(4)-C( 5)-C( 6) C(4)-C(5)-C( IO) C(6)-C(5)-C( I O ) C ( 5)-C( 6)-C( 7) C(6)-C(7)-C(8) C ( 7)-C( 8)-C(9) C(7)-C(S)-C( 14) C(7)-C(8)-C( 15) C(9)-C(S)-C( 14) C(9)-C(S)-C( 15) C( 14)-C(8)-C( 1 5 ) C(S)-C(S)-C( I O ) C(8)-C(9)-C(I I ) C(IO)-C(9)-C(11) C(I)-C(lO)-C(5) C(I)-C(IO)-C(9) C( I)-C( 10)-C(20) C(5)-C( IO)-C(9) C(5)-C( 10)-C(20) C(9)-C( 10)-C(20) C(9)-C( I 1)-C( 12) C(1 l ) - C ( I 2 ) - C ( l 3 ) C ( 1 l)-C( 12)-C( 16) C ( 13)-C( 12)-C( 16) C( 12)-C( 13)-C( 14) C( 12)-C( 13)-C( 16) C( 14)-C( 13)-C( 16) C(8)-C( 14)-c( 13) C(8)-C(lS)-C( 16) C(8)-C( 15)-O( 15) C(16)-C(15)-0(15) C(12)-C(16)-C(15) C( 12)-C( l6)-C( 17) C( 13)-C( 16)-C( 15) C(13)-C(16)-C(17) C ( 15)-C( 16)-C( 17) C(4)-C( 19)-N C(4)-C( 19)-O(22) N-C(19)-O(22) C ( 10)-C (20)-N C( 1 0)-C(20)-0(22ma) C ( 1 O)-C(20)-0(22mi) N-C(20)-0(22ma) N-C(20)-0(22mi) C(22)-C(21)-N C(22ma)-C(21)-N C(22mi)-C(21)-N C ( 2 1 )-C(22)-0(22) C(2 1 )-C(2 1 )-O(22a) C (2 1 ) -C( 22) -0(22b) C(2 1 )-C(22)-0(22C) O(22a)-C( 22) -0(22 b) 0(22a)-C(22)-0(22c) 0(22b)-C(22)-0122~) C(2 1 )-C(22ma)-0(22ma) C ( 2 1 )-C(22mi)-0(22mi) C ( 19)-Y-C(20) C ( 19)-N-C(21) C(20)-N-C(21) C( 19)-0(22)-C(22) C(20)-0(22ma)-C(22ma) C ( 20) -0(22mi ) -C( 22mi)
atisinium chloride
dihydroatisine
isoatisine
veatchine
112.5 (2) 112.1 (2) 114.1 (2) 109.4 (2) 108.0 (2) 1 1 1.0 (2) 1 1 1.7 (2) 109.2 ( 1 ) 107.5 (2) 114.4 (2) 108.8 (1) 110.3 ( I ) 111.5 (2) 113.1 (2) 110.8 ( I ) 110.6 (2) 1 11.1 (2) 111.1 ( I ) 107.1 (2) 105.9 (2) 115.1 (2) 109.5 ( 1 ) 1 14.9 (1) 110.1 (2) 108.0 (2) 104.5 (2) 111.1 ( I ) 109.7 (2) 113.3(1) 110.6 (2) 108.4 (2) 108.9 (2) 109.1 (2) 109.4 (2)
115.5 (3) 112.4 (3) 114.4 (3) 108.7 (3) 107.5 (3) 111.8 (3) 1 12.4 (3) 109.5 (3) 106.9 (3) 115.9 (3) 108.7 (3) 112.1 (3) 110.8 (3) 114.0 (3) 110.4 (3) I 1 1.5 (3) 110.5 (3) I 13.0 (3) 107.8 (3) 103.4 (3) 1 17.9 (3) 109.1 (3) 1 1 5.2 (3) 108.7 (2) 106.8 (3) 110.6 (3) 109.7 (2) 108.8 (3) 112.2 (2) 110.6 (3) 108.1 (3) 107.9 (3) 109.8 (3) 109.2 (3)
116.0 (2) 110.5 (2) 114.7 (2) 108.0 (2) 108.2 (2) 108.0 (2) 111.6(2) 110.9 (2) 110.0 (2) 116.5 (2) 109.4 (2) 1 1 1.4 (2) 110.5 (2) 114.0 (2) 112.4 (2) 111.7 (2) 109.0 (2) 1 1 1.9 (2) 106.2 (2) 105.3 (2) 118.9 (2) 108.5 (2) 114.5 (2) 109.2 (2) 106.1 (2) 110.9 (2) 109.2 (2) 107.9 (2) I 13.4 (2) 109.8 (2) 108.4 (2) 108.6 (2) 108.4 (2) 108.9 (2)
116.4 (3) 1 12.7 (3) 116.3 ( 3 ) 108.0 (3) 107.5 (3) 112.8 (3) 110.8 (3) 109.0 (3) 108.8 (3) 1 15.8 ( 3 ) 109.6 (3) 112.1 ( 3 ) 1 1 1.3 (3) 113.2 (3) 111.2(3) 113.8 (3) 110.8 (3) 1 12.3 (3) 109.1 (3) 98.9 (3) 118.6 (3) 1 1 1.5 (3) 115.0 (3) 107.4 (3) 107.3 (3) 109.9 ( 3 ) 109.1 (3) 107.5 (3) 115.3 (3) 115.3 (3) 1 1 1.0 (3)
I 11.3 (2) 109.5 (2) 114.1 (2) 107.2 (2) 112.3 (2) 124.5 (3)
1 1 1.5 (3)
I I I .5 (2) 108.6 (2) 114.7 (2) 112.3 (2) 112.3 (2) 124.4 (2)
109.6 (3) I 12.5 (3) 109.6 (3) I 12.7 (3) 123.5 (4)
123.2 (3) 114.1 (2)
123.8 (4) 1 1 3.9 (3)
123.2 (2)
1 13.7 (2)
123.2 (2) 116.1 (2) 112.8 (2) 107.0 (2) 112.8 (2)
I 11.3 ( I )
1 1 1.6 (3)
102.0 (2)
109.2 (3) 110.0 (3) 102.6 (3) 101.3 (3) 104.8 (3) 108.9 (3) 111.3 (3) 107.8 ( 3 ) 127.5 (4) 124.7 (4) 110.7 (3) 122.8 (4) 122.8 (4) 124.9 (4) 104.5 (3) 107.9 (4) 102.2 (4) 105.8 (5)
113.1 ( 1 )
105.5 (2)
I 15.5 (6) 121.3 (7) IOO.0 ( I O ) 100.6 (7) 107.6 (IO) I 1 1.7 ( I I ) 124.2 ( I ) 116.2 (2) 119.5 (2)
I 12.0 (3) 110.5 (3) 108.7 (3)
1 17.2 (2)
102.5 (2) I 1 I .8 (2) 107.2 (2)
105.9 ( 5 ) 105.9 (7) 113.1 (3) 115.1 (4) 101.1 (3) 107.6 (4) 108.9 (6)
Journal of the American Chemical Society
1980
/
100:25
/ December 6 , 1978
Table 111. Torsion Angles (deg) (Estimated Standard Deviations in Parentheses) angle atoms
atisinium chloride
dihydroatisine
isoatisine
veatchine
-44.9 (4) 56.5 (4) -64.5 (3) 61.9 (3) -51.6 (4) 42.9 (4)
-48.8 (3) 57.8 (3) -62.1 (2) 59.7 (2) -52.5 (3) 46.2 (3)
-42.0 ( 5 ) 52.6 (4) -62.9 (4) 62.8 (3) -52.7 (4) 42.3 ( 5 )
-57.0 (4) 48.7 (4) -44.7 (4) 46.7 ( 3 ) -52.1 (3) 58.5 (4)
-56.6 (2) 43.0 (3) -37.3 (2) 43.0 (2) -54.3 (2) 63.0 (2)
-58.7 (4) 47.7 (4) -41.7 (4) 43.3 (4) -5 1 .O (4) 60.7 (4)
-3.1 (4) 62.0 (4) -64.7 (4) 8.6 (4) 50.8 (4) -53.0 (4)
-18.7 (2)
71.0(2) -53.6 (2) -9.4 (3) 61.3 (2) -44.0 (2)
37.4 (4) -43.6 (4) 63.7 (4) -72.5 (4) 66.6 (3) -50.0 (4)
-2.7 (4) -56.6 (4) 52.7 (4) 8.6 (4) -65.3 (3) 61.8 (3)
-14.0 (3) -50.9 (3) 64.0 (2) -9.4 (3) -53.5 (2) 67.0 (2)
Ring A C( 1 )-C(Z)-C(3)-C(4) C ( 2) -C( 3) -C(4)-C( 5 ) C ( 3) -C( 4) -C( 5 ) -C( IO) C(4)-C(S)-C( lO)-C(l) C(5)-C( IO)-C(l)-C(2) C( IO)-C( I)-C(2)-C(3)
-49.9 (3) 55.9 ( 2 ) -60.3 ( 2 ) 60.6 (2) -55.1 (2) 49.0 (3)
C(5)-C(6)-C(7)-C(8) C(6)-C( 7)-C( 8)-C(9) C(7)-C(8)-C(9)-C(lO) C( 8)-C(9)-C( 10)-C( 5) C(9)-C( IO)-C(5)-C(6) C( 1O)-C(5)-C(6)-C(7)
-57.7 (2) 51.0 (2) -47.6 ( 2 ) 49.7 (2) -53.5 (2) 58.2 (2)
C(8)-C(9)-C( 1 1)-C( 12) C(9)-C( 1 I)-C( 12)-C( 13) C(11)-C(12)-C(13)-C(14) C(l2)-C(13)-C(l4)-C(8) C ( 13)-C( 14)-C(8)-C(9) C( 14)-C(8)-C(9)-C(I 1)
-1.0 ( 2 ) 60.7 (3) -63.4 (3) 6.5 (3) 53.1 (2) -55.4 (2)
C(8)-C( 15)-C( l6)-C( 12) C( 15)-C( l6)-C( 12)-C( 13) C(l6)-C(l2)-C(l3)-C(14) C(l2)-C(l3)-C(l4)-C(8) C(13)-C( 14)-C(8)-C(IS) C(14)-C(8)-C( I5)-C(16) C(8)-C( I5)-C( 16)-C( 13) C ( l5)-C( l6)-C( l3)-C( 14) C( l6)-C( l3)-C( 14)-C(8) C(l3)-C(l4)-C(8)-C(l5) C(l4)-C(S)-C(lS)-C(16)
2.4 (3) -60.7 (3) 54.9 (3) 6.5 (3) -62.8 (2) 57.4 (2)
C(8)-C(9)-C(I I)-C(12) C(9)-C(I l ) - C ( l 2 ) - C ( l 6 ) C ( l I)-C(12)-C(16)-C(15) C( 12)-C( I6)-C( I5)-C(8) C( 16)-C(15)-C(8)-C(9) C ( 15)-C(8)-C(9)-C( I I ) C(S)-C(S)-C( 1 I)-C( 12) C(9)-C( 1 I)-C( 12)-C( 13) C ( l I)-C(12)-C(13)-C(16) C( 12)-C(l3)-C(l6)-C(15) C( I3)-C( l6)-C( I5)-C(8)
- 1 .o (2)
Ring B
Ring C
Ring D
-8.4 (4) -22.2 (4) 44.1 (3) -48.3 (3) 34.5 (3) Ring C / D
-57.7 (2) 57.3 (3) 2.4 (3) -61.1 (2) 59.7 (2)
-3.1 (4) -56.7 (4) 60.9 (4) -2.7 (4) -58.0 (3) 60.5 (3)
-18.7 (2) -46.4 (2) 66.6 (2) -14.0 (3) -51.7 (2) 70.3 (2)
-55.1 (4) 57.7 (3) -58.4 (3) 56.9 (3) -53.1 (4) 52.0 (4)
-45.3 (3) 55.9 (2) -60.8 (2) 55.1 (2) -46.3 (3) 41.1 (3)
-82.9 (3) 58.5 (4) 37.4 (4) -43.6 (4) -48.1 (4) 93.8 (4) -8.4 (4)
Ring E N-C( 19)-C(4)-C(5) C( 19)-C(4)-C(S)-C( I O ) C(4)-C(S)-C( 1 O)-C(20) C(5)-C( 10)-C(20)-N C( IO)-C(20)-N-C( 19) C ( 20) - N ( 1 9) - C (4) -
c
C ( 10)-C(20)-N -C(21) C(2O)-h -C(2 I )-C(22) N-C(2 1 )-C(22)-0(22) W C ( 2 I )-C(22)-0(22a) N C ( 2 I ) C ( 22) - O(2 2b) N-C(2 1 )-C(22)-0(22C) C(4)-C( I9)-N-C(2 I ) C( 19)-N-C(21 )-C(22) -
~
-39.7 (2) 61.3 (2) -53.7 (2) 26.8 (3) -5.3 (3) 12.1 (3)
N-Hydroxyethyl Side Chain 177.2 (2) -175.5 (3) 70.0 (2) -156.7 (4) 52.2 (2) 54.8 (6) -67.0 (9) 169.9 ( 1 0) - 170.3 (2) 173.4 (3) -107.5 (2) 79.9 ( 5 ) Ring F (Oxazolidine Ring)
N-C(2 I )-C(22)-O(22) C(2 1 )-C(22)-0(22)-C( 19) C(22)-0(22)-C( I9)-N O(22)-C( 19)-N-C(21) C( I9)-N-C(2 I )-C(22)
21.4 (3) -5.3 (3) -19.4 (3) 36.9 (3) -38.4 (3)
-58.6 (4) 59.9 (4) -55.4 (4) 53.2 (4) -54.1 (4) 55.3 (4)
Pelletier, De Camp, Mody
/ C20 Diterpenoid Alkaloids
798 1
Table 111 (Continued)
atoms
atisinium chloride
dihydroatisine
isoatisine
veatchine 15.1 ( 5 )
N-C(2 l)-C(22ma)-0(22ma)
12.6 (6)
C(21)-C(22ma)-0(22ma)-C(20) C(22ma)-0(22ma) -C( 20)-N O(22ma)-C( 20)-N-C( 2 1) C(20) -N -C( 2 1) -C(22ma) N-C( 2 1)-C( 22mi)-0(22mi)
-35.3 ( 5 )
44.2 (4) -34.4 (4) -4.6 (8) -16.6 (9) 31.2 ( 7 )
C(21)-C(22mi)-O(22mi)-C(20) C(22mi)-O(22mi)-C(20)-N O(22mi)-C( 20)-N-C(2 1) C(20)-N-C(21)-C(22mi) O( 15)-C( 15)-C( 16)-C( 17)
C(9)-C(8) . . . C( 12)-C( 11) C(14)-C(8). . , C(12)-C(13) C(l5)-C(8). . . C(12)-C(16)
-32.5 ( 5 ) 20.9 (6) Skew of Bicyclo[2.2.2]octane System 57.4 (3) 53.6 (5) -.5 (1) -1.8 (2) 3.8 (2) 5.1 (2) 1.4 (2) -1.5 (2)
34.9 (3) -11.2 (1) -5.5 (2) -8.1 (2)
the conformational strain of the molecule in isoatisine, while the bicyclooctane moiety does so when the oxazolidine ring is either closed in the normal position or opened. Special attention should be paid to the “torsion” angles involving the nonbonded, bridgehead atoms C(8) and C(12) in atisinium chloride, dihydroatisine, and isoatisine. These values show that the bicyclo[2.2.2]octane system in isoatisine differs from that in the other two cases by a rotation of -9.4’ around the C(8)--C(12) axis, which is quite close to the value of f7.0’ found in the molecular mechanics minimi~ation.~’ Both values differ significantly from those of Ermer and Dunitz,’* who found that the bicycle[ 2.2.21octane fragment in bicyclo [ 2.2.21 octane1,4-dicarboxylic acid showed D3h symmetry within one standard deviation. The oxazolidine ring F differs significantly in conformation in the structures of veatchine and isoatisine; from the values in Table 111, it can be seen that it assumes an N-flap envelope conformation in isoatisine. An envelope conformation with C(20) at the flap is found for the minor epimer in veatchine, while a twist conformation is found for the major epimer. These differences do not appear to be sufficiently large that they can be solely responsible for the greater stability of the is0 form relative to the normal form. Indeed, it must be noted that the C(20)-0(22ma) and C(20)-0(22mi) bond lengths in veatchine are both much shorter (and presumably stronger) than expected for a C - 0 single bond, while the corresponding bond in isoatisine is of normal length. The disorder at the oxazolidine oxygen may have resulted in some apparent shortening of the C - 0 bonds due to thermal motion. The magnitude of such shortening may be estimated to be 0.08-0.13 8, from a comparison of the C(21)-C(22) bond length in isoatisine with equivalent distances in veatchine. This estimate must be taken as an upper limit, since C(22)-O(22) in isoatisine does not differ significantly from the corresponding bond lengths in veatchine.
The structure of veatchine reveals only a single hydrogen bonding interaction between the nitrogen as acceptor and the I5o-hydroxyl group as donor (0(15)-N’ = 3.048 (4), H(lSOH).-N’ = 2.27 (6) A;’ = x - l , y , z ) . Unexpectedly, the nitrogen atom of isoatisine is not involved in any close intermolecular encounters (Le., less than 3.6 A). However, the oxazolidine ring oxygen is the acceptor in a hydrogen bond with the 15a-hydroxyl group (O(15)-O(22)’ = 2.992 (3), H(150H)*-0(22)’ = 2.29 (4) A; ’ = x ‘12, ’/1 - ,v, 1 - z ) . This stands in contrast to veatchine, in which neither of the disordered oxazolidine oxygens particpates in any hydrogen bonding; packing forces, therefore, cannot account for the disorder observed in veatchine. Because of the disorder found in the crystal of dihydroatisine, it proved impossible to locate the hydrogen of either hydroxyl group. Donor-acceptor relationships, therefore, cannot be resolved. The difference maps showed evidence that the hydroxyl group of the N-P-hydroxyethyl side chain can rotate freely, principally occupying the three positions included in the refinement with partial site occupancy. The three positions correspond to conformations in which the 22-hydroxyl group is either synclinal, - synclinal, or trans to the nitrogen atom. I n the first two positions, the intermolecular distance to O(15)’ is sufficiently short to imply hydrogen bonding (0(22a)-0(15)’ = 2.798 ( 7 ) , 0(22b)--.0(15)’ = 2.805 ( I O ) A; ’ = 1 - x, ‘/2 y , ’/2 - z ) . In the third, the distance to N is too great to suggest hydrogen bonding (0(22c)-N’’ = 3.25 (2) A; ” = ’ / 2 - x, 1 - y, z l/2), but those to other disordered hydroxyl groups are not (0(22c)-.0(22a)” = 2.82 (2), 0(22c)--0(22b)” = 2.68 (1) A). It would appear to be possible for the conformation of one hydroxyethyl group to influence that of its neighbor, leading to short-range ordering. However, no evidence for the doubling of the unit cell volume which would then be necessary was found.
Intermolecular Interactions and Crystal Packing I n each of the structures reported here, the possibilities for hydrogen bonding are limited by the small number of potential donor and acceptor atoms. In the case of atisinium chloride, it is not surprising that the packing is determined by the interactions of the positive N atom with the CI- ion (N-CI’ = 3.886 (2), N-CI” = 3.924 (2) A; ’ = 1 - X, ‘/2 y . ‘/2 - Z , ” = x - ‘ / 2 , ‘/l- y, - z ) . I n addition, the chloride ion accepts hydrogen bonds from both hydroxyl groups (0(15)-CI = 3.247 (2), H(lSOH)-CI = 2.43 (4), and 0(22).-CI”’ = 3.131
Absolute Configuration of C20 Diterpenoid Alkaloids The stereochemistry of the CZOditerpenoid alkaloids from Garrya and Aconitum species has been indicated from chemical correlation and optical rotatory dispersion studies.’ Our work confirms these earlier conclusions. On the basis of Hamilton’s testI9 ( R = 0.038, R, = 0.037 for the given enantiomorph, R = 0.055, R, = 0.064 for the opposite) applied to the data for atisinium chloride, the absolute configuration of the atisinium ion is 4S,5S,8R, 10R, 12R, 15s; because of the unsaturation at C(20), no direct evidence can be obtained from this structure for the configuration of this center in atisine. An indirect argument is presented below.
+
(2),H(220H)-.CI”‘=2.13(5)A;”’=x‘/2,’/2-y, 1 -z).
+
+
+
+
7982
Journal of the American Chemical Society
/
100:25
/
December 6, 1978
c I181
c I221
c 1221
‘.‘EFTChINE
VERTCHINE
Figure 2. A stereoscopic drawing of veatchine. The disordered atoms of the minor epimer are shown as open circles
- ,^.
