T H E J O U R N A L OF VOLUME53, NUMBER 26
Organic Chemistry 0 Copyright 1988 by the American Chemical Society
DECEMBER 23, 1988
Synthesis of the Cannabisativine Skeleton via an Intramolecular Allylsilane-Nitrone Cycloaddition Peter G. M. Wuts*J a n d Yong-Woon J u n g Department of Chemistry, University of Michigan, A n n Arbor, Michigan 48109, and T h e Upjohn Co., 1500-230-4, Kalamazoo, Michigan 49001 Received July 6, 1988
A synthesis of the carbon skeleton of cannabisativine (1) is described. The relative stereochemistry of the stereogenic centers at carbons 17, 18, and 19 was secured by the addition of [y-(trimethylsilyl)allyl]boronate 5 to the oxime 4. The major hydroxylamine 13 of the 1.7:1 mixture was condensed with 3-(benzyloxy)propanal to form nitrone 15, which cyclized to the trans-tetrahydropyridine18 upon treatment with TMSOTf at -40 O C . Deprotection and reduction of the hydroxylamine 18 affords the carbon skeleton of cannabisativine. Stereochemical differences between the thermally induced cyclization of nitrone 15 and the TMSOTf-promoted cyclization are discussed. Cannabisativine (1) is a n unusual macrocyclic spermidine alkaloid isolated from t h e roots and leaves of t h e common marijuana plant, Cannabis sativa L., whose structure was established by single-crystal X-ray analysis.2 T h e skeleton of cannabisativine contains a 13-membered lactam ring annelated t o a 2,6-trans-disubstituted tetrahydropyridine ring. Natsume and co-workers were the f i s t to report a synthesis of this intriguing molecule in 1984.3 Their work was followed in 1985 by Wasserman’s synt h e ~ i s .T ~ h e Natsume approach relied on building u p the skeleton by functionalizing a tetrahydropyridine ring and then appending the 13-membered ring lactam. In contrast, Wasserman chose to build up the spermidine ring followed by tetrahydropyridine ring annelation. Our goal in carrying out a synthesis of cannabisativine was viewed primarily as a problem in construction of the acyclic carbon backbone with its associated stereochemistry followed by a cyclization t o form the trans-2,g-tetrahydropyridine 2 (Scheme I). T h e 13-membered spermidine ring could then be appended by using known techn o l ~ g y . ~ ,Our ~ - ~synthetic design involved allylboronate (1) Address correspondence to this anithor at the Upjohn Co., 1500230-4, Kalamazoo, MI 49001. (2) (a) Elsohly, M. A.; Turner, C. E.; Phoebe, C. H., Knapp, J. E.; Schiff, P. L.; Slatkin, D. J. J . Phorm. Sci. 1978, 67, 124. (b) Slatkin, D. J.; Knapp, J. E.; Schiff, P. L.; Turner, C. E.; Mole, M. L. Photochemistry 1975, 14, 580. (c) Lotter, H. L.; Abraham, D. J.; Turner, C. E. Tetrahedron Lett. 1975,2815. (d) Turner, C, E.; Hsu,M. H.; Knapp, J. E.; Schiff, P. L.; Slakin, D. J. J. Phorm. Sci. 1976, 65, 1084. (3) Ogawa, M.; Kuriya, N.; Natsume, M. Tetrahedron Lett. 1984,25, 969. (4) Wasserman, H. H.; Leadbetter, M. R. Tetrahedron Lett. 1985, 26, 2241. ( 5 ) Ogawa, M.; Nakajima, J.; Natsume, M. Heterocycles 1982,19, 1247. ( 6 ) Bailey, T. R.; Garigipati, R. S.; Morton, J. A,; Weinreb, S. H. J . Am. Chem. SOC.1984, 106, 3240.
Scheme I
w cannabisativine ( 1 )
3
4
methodology to establish the relative chirality a t carbons 17, 18,and 19 (cannabisativine numbering). a-Asymmetric induction in the addition of the allylboronate 5 t o oxime 4 may produce two possible diastereomers due to syn or anti addition with respect to the alkoxy substituent. T h e
0022-3263/88/l953-5989$01.50/0 0 1988 American Chemical Society
5990 J . Org. Chem., Vol. 53, No. 26, 1988
Wuts and Jung
Scheme I1
-
O'H '-
Scheme IV
1 CHpNp ether. 95%
CC14.A
4+555%
2 Lindlar c a r auinoline 91%
6
0 i 0 9 0 4 . NMO. 8 5 % r
2
( CH3) p C ( 0 Me
7 , Z / E = 9 8:l 1
13
97%
Dibal, -78-c.
ran
2 NH40H'HCl/PY, 97%
14
1 7:l
-
-
2 e q u i v of BnOCHzCHzCHO
4 , E / Z = l 9:1
l3
100%
t o l u e n e , -20 n c -
L
8
J
15
Scheme I11
16
10
11
12
resulting hydroxylamine would then be converted t o nitrone 3, which in a key step would be cyclized to the trans-disubstituted tetrahydropyridine with the correctly placed alkene by using methodology previously developed for this purpose.' T h e required oxime 4 for addition of the [y-(trimethylsilyl)allyl]boronate* 5 was prepared in six steps from commercially available 2-octynoic acid as described in Scheme 11. 2-Octynoic acid (6) was esterified with diazomethane in ether, followed by hydrogenation in the presence of Lindlar catalyst/quinoline to give a 9.8:l mixture of the cis and trans unsaturated esters. The major product 7, isolated by flash chromatography, was oxidized with osmium t e t r a ~ x i d e and , ~ the intermediate diol was protected as its acetonide t o afford ester 8 in 83% yield. T h e ester 8 was reduced with diisobutylaluminum hydride'O and treated with hydroxylamine hydrochloride in pyridine t o afford an E / Z mixture (1.9:l) of oximes 4. Although Hoffmannll had previously shown that oximes were suitable substrates for allylboronate addition reactions, we were uncertain as to the degree of a-asymmetric induction we could expect in the reaction with the trimethylsilyl-substituted allylboronate or what the influence of the oxime geometry might be since these aspects of the reaction have never been studied in detail. Hoffmann had shown t h a t the addition of pinacol allylboronate (9) to 2,3-O-isopropylidene-~-glyceraldehyde derivative 10 affords the anti product 11 preferentially by a factor of 2-3:l (Scheme 111). We found t h a t treatment of oxime 4 with
__
(7) Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem., in press. (8) Tsai, D. J. S.; Matteson, D. S. Tetrahedron Lett. 1981,22, 2751. (9) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1972. . -.
(10) Hatch, R. P.; Shringarpure, J.; Weinreb, S.M. J. Org. Chem. 1978,
14 a:i
17
[ (trimethylsilyl)allyl]boronate 5 gave primarily two isomers, 13 and 14, in a 1.7:l ratio in 55% yield after chromatography (Scheme IV). Two other minor isomers were formed in the reaction, but these were not isolated. T h e two new chiral centers a t C4 and C5 in the major adduct 13 were assumed t o be anti on the basis of Hoffmann's work. T h e relative stereochemistry a t C3 and C4 was established by conversion of 13 to the rigid bicyclic isoxazolidine by thermal [3 21 cycloaddition. T h u s a solution of nitrone 15, which was prepared by condensation of 13 with 3-(benzy1oxy)propanal a t -20 "C in toluene, was refluxed for 2 h to provide the mixture of cycloadducts 16 and 17 in quantitative yield in a 14.8:l ratio. These were inseparable by chromatography. At this point, it was crucial to identify the adducts stereochemically. The structures 16 and 17 were assigned on the basis of their 300-MHz 'H NMR spectra. T h e major isomer 16 showed a triplet (4.8 ppm, J3,4= J4,5,= 4.9 Hz, J4,5a= 0.0 Hz) for the bridgehead proton a t C4, while the minor isomer 17 exhibited a doublet (4.69 ppm, J4,5B = 4.9 Hz, J3,4 = J4,k= 0.0 Hz). In the case of 16, the relative stereochemistry between Cz and C3 was assigned to be anti since the value 5.6 Hz for J2,3 falls in the typical range of anti (endo-exo) vicinal protons in the bicyclic iso~azolidines.'~~~
+
OBn
T h e c6 stereochemistry was also assigned in the same manner. T h e large coupling constant (J = 7.7 Hz) for H,,/H6 indicates exo-C6stereochemistry. These spectral details then establish the cis geometry for the side-chain substituents of the latent tetrahydropyridine ring and that the diastereomeric induction in the boronate coupling did indeed proceed t o give primarily the product with the hydroxylamine and the T M S groups in the anti relationship.
43, 4172.
(11) Hoffmann, R. W.; Eichler, G.; Endesfelder, A. Liebigs Ann. Chem. 1983, 2000.
(12) Wuts, P. G. M.; Jung, J.-W. J. Org. Chem. 1988, 53, 1957.
J . Org. Chem., Vol. 53, No. 26, 1988 5991
Synthesis of the Cannabisativine Skeleton Scheme V
S c h e m e VI1 0-
T M S O T f . - 4 0 OC
l5
9-
I
79%
