3264
J . Org. C h e m . 1984,49, 3264-3274
6 0.894 (3 H, t, J = 5.5 Hz), 4.105 (1H, br m, 3-H), 4.80-6.20 (5 H, olefinic protons and ABX system); mass spectrum, m/z (relative intensity) M+ absent, 318 (O.l), 264 (0.2), 149 (0.5), 135 a s ) , 111 IO.^), 94 (ii.a), 55 (65),43 (100). The trans aldehyde 8 (418 mg) was converted to the allylic alcohol 16 in the same way: IR (CHC13) 3600 (OH), 3010 (CH=CH), 967 (CH=CH trans). The 'H NMR spectrum of 16 was similar to that of 10. (4E,8Z)- and (4E,8E)-4,8-Pentacosadienoic Acid, Methyl Ester (11 and 17). A solution of the cis alcohol 10 (420 mg, 1.25 mmol), trimethyl orthoacetate (5 mL), and a few drops of propionic acid was heated under argon at 140 "C for 1h with removal of methanol. Evaporation of the excess trimethyl orthoacetate under vacuum and chromatography on 14.0 g of silica gel with hexane-ether (1:l)as eluent afforded 465 mg (95%) of 11 as a yellowish oil: RfO.79;IR (CHC13)3006 (CH=CH), 1741 (C=O), 966 (CH=CH trans); 'H NMR (300 MHz) 6 0.886 (3 H, t, J = 5.5 Hz), 1.258 (28 H, br s, aliphatic CH,), 2.328 (2 H, t, J = 6.5 Hz,3-CHJ, 2.338 (2 H, t, J = 6.5 Hz, 2-CHJ, 3.682 (3 H, s, OCH& 5.35-5.51 (4 H, br m, olefinic protons); mass spectrum, m/z (relative intensity) 392 (M+, 0.3), 168 (0.6), 136 (2.5),95 (14), 43 (100). Claisen rearrangement of the trans alcohol 16 under the same conditions as for 10 gave the ester 1 7 IR (CHCld 3006 (CH=CH), 1741 (C=O), 966 (CH=CH trans). The 'H NMR and mass spectra of 17 were similar to those of 11. (4E,8Z)- and (4E,8E)-4,8-Pentacosadienol(l2and 18). To a suspension of lithium aluminum hydride (229 mg, 6 mmol) in dry THF (10 mL) was added dropwise a solution of the ester 11 (465 mg) in dry ether (5 mL) at 0 "C, and the mixture was stirred a t room temperature for 1 h. Addition of 986 mg (9 mmol) of oxalic acid dihydrate and fiitration over Celite afforded the alcohol 12: 358 mg (90%);R, 0.36; IR (neat) 3605 (OH), 967 (CH=CH trans); 'H NMR (300 MHz) 6 0.901 (3 H, t, J = 5.5 Hz), 3.671 (2 H, t, J = 6.5 Hz, 1-CH,), 5.435 (4 H, m, olefinic protons); mass spectrum, m/z (relative intensity) M+ absent, 346 (0.11, 207 (1.4), a3 ( 2 0 ~ 5 (65),43 5 (loo). The ester 17 was reduced in the same way to give the alcohol 18. Its spectroscopic data were identical with those of 12. (4E,8Z)- a n d (4E,8E)-4,8-Pentacosadienol Methanesulfonate (13 and 19). A solution of the alcohol 12 (358 mg, 1.18 mmol) in 5 mL of CH2C1, and 0.5 mL of Et3N was treated dropwise with 0.2 mL of MsCl a t 0 "C and stirred for 1 h. The usual workup afforded the mesylate 13: 438 mg (93%) after
purification on chromatography on silica gel using hexane-ether (lzl),R, 0.33. The alcohol 18 was converted to the mesylate 19 in the same way. Both isomers 13 and 19 have the same spectral properties: IR (CHC13) 1371,1350,1178 (OS0,CH3); 'H NMR (300 MHz) 6 0.890 (3 H, t, J = 5.5 HZ), 2.978 (3 H, 8, CH~SO,),4.256 (2 H, t, J = 6 Hz, 1-CH,), 5.432 (4 H, br m, olefinic protons). (4E,8Z)- and (4E,8E)-l-Cyano-4,8-pentacosadiene (14 and 20). The mesylate 13 (410 mg, 0.92 mmol) dissolved in 5 mL of THF was added dropwise to a solution of NaCN (196 mg, 4 "01) in MezSO (5 mL) at 65 "C and stirred for 3 h. The usual workup and chromatography on silica gel with hexane-ether (1:l)as the eluent gave the cyanide 14 in 90% yield (311 mg): IR (neat) 3006 (CH=CH), 2240 (CN), 966 (CH=CH trans); 'H NMR (300 MHz) 6 0.890 (3 H, t, J = 5.5 Hz),2.605 (2 H, t, J = 6 Hz, 2-CH2),5.433 (4 H, br m, olefinic protons); mass spectrum, m/z (relative intensity) 373 (M', 0.3), 218 (0.3), 190 (0.6), 176 (1.5), 97 (12.0),83 (31.2), 55 (67.1), 41 (100). Similarly, the mesylate 19 was converted to the cyanide 20 whose spectroscopic data were identical with those of 14. (5E,9Z)- and (5E,9E)-5,9-HexacosadienoicAcid (15 and 21). The cyanide 14 (290 mg, 0.77 mmol) was hydrolyzed in 2 N KOH/ethanol for 48 h under refluxing conditions to give the acid 15a (159 mg). Similarly, the cyanide 20 afforded the 5E,9E acid 21a. The spectroscopic data of 15b and 21b were identical with those of 9b.
Acknowledgment. Financial support was provided by NIH grant GM 06840. We thank Dr. Lois J. Durham for the 13C NMR spectra. Use of the NMR center at the Stanford 500-MHz and 300-MHz facility (NSF Grant GP 23633) is gratefully acknowledged. P.L.M. and O.P.thank the Swiss National Science Foundation for postdoctoral fellowships. Registry No. 1,1552-12-1;2a, 72195-80-3; 2b, 82861-01-6; 3, 90913-48-7; 4, 90913-49-8; 5a, 52715-55-6; 5b, 90913-50-1; 6, 90913-51-2; 7, 90913-52-3; 8, 90913-53-4; 9a, 90913-54-5; 9b, 90913-55-6; io, 90913-56-7; 11, 90913-57-8; 12,90913-58-9; 13, 90913-59-0;14,90913-60-3;Ha, 90913-61-4; 15b, 90913-62-5; 16, 90913-63-6; 17, 90913-64-7; 18, 90913-65-8; 19, 90913-66-9; 20, 90913-67-0;21a, 90913-68-1;21b, 90913-69-2;(4-carboxybuty1)triphenylphosphonium bromide, 17814-85-6;vinylbromide, 59360-2; trimethyl orthoacetate, 1445-45-0.
A Synthetic Approach to the Quassinoids Clayton H. Heathcock,* Cyril Mahaim,' Matthew F. Schlecht,2 and Thanin Utawanit3 Department of Chemistry, University of California, Berkeley, California 94720 Received February 1 , 1984
A synthetic route to the quassinoids has been developed. Two-stage annelation of 2-methylcyclohexanone with 1-chloro-3-pentanone gives tricyclic dienone 9 (60%), which is oxidized by acetyl chromate in acetic acid to give dienedione 27 (80%). Bisketalization of this material followed by hydrolysis of the conjugated enone ketals provides monoketal30 (77%), along with recovered 27. Ring C of 30 is functionalized by the Stiles and Reich methods to obtain the unsaturated keto ester 33 (73%). The latter material reacts with ketene acetal 35 at 5-6 kbar and room temperature to give an adduct that is desilylated by treatment with aqueous KF; keto diester 39 is produced in 95% yield. Epoxidation of 39 occurs smoothly with m-CPBA to give 46 (88%), which is converted into allylic alcohol 40 by the two-step Sharpleas procedure (78%). Finally, pyridinium chlorochromate induces solvolytic cyclization of 40,affording41 in 55% yield. In the course of the investigation,it was also discovered that P-keto ester 46 is oxidized by m-CPBA to 47 in quantitative yield.
of the group that have been obtained from the genus
The quassinoids are a group of diterpenoids that occur in genera of the family Simaroubaceae.4 Those members
Brucea are known as b r u c e o l i d e ~ . ~In ~ 1973, S. M.
(1) Current address: Sandoz Ltd., Pharmaceutical Division, Chemical Research, CH-4002 Basel, Switzerland.
(2) Current address: Department of Chemistry, Polytechnic Institute of New York, Brooklyn, NY 11201.
0022-3263/84/1949-3264$01.50/0
0 1984 American Chemical Society
Quassinoids
J. Org. Chem., Vol. 49, No. 18, 1984 3265
Kupchan and co-workers reported an investigation of B. antidysenterica Mill., a simaroubaceous tree which is indigenous to Upper Guinea, the Cameroons, and Ethiopia, and which is used in the latter country in the treatment of cancer.lOJ1 Eight quassinoids were isolated, several of which subsequently proved to have significant antitumor and antileukemic properties.12 The most promising of these materials, from the standpoint of potential utility for treatment of cancer, is bruceantin (I). Kupchan's
I
disclosure of the antineoplastic activity of bruceantin focused considerable attention on the quassinoids in general, and on the bruceolides in particular, and several investigations have subsequently turned up other naturally occurring bruceolides.13J4 It has also been found that some quassinoids other than the bruceolides have antineoplastic activity.15-17 The initial findings by the National Cancer Institute that bruceantin is active against the L-1210 lymphoid leukemia, the Lewis lung carcinoma, and the B-16 melanocarcinoma resulted in its being selected for clinical trial.lgZ1 Because of the promising activity that has been found in the series, synthetic studies have been initiated by several research groups. Although no bruceolides have yet been prepared by total synthesis, considerable progress has been made. The most significant advance to date has been Grieco's synthesis of the prototypical quassinoid, quassin itself (2).22 Other synthetic reports have come
1A
from the laboratories of Valenta,23D i a ~Watt,25 , ~ ~ ManKraus,2' and Fuchs.28 In this paper, we report our own. investigations of the quassinoid problem. We will present a reasonably straightforward synthetic route to the quassin skeleton, lacking the tetrahydrofuran ring D that is characteristic of the bruceolides. Although the ultimate product of this investigation is probably not a viable intermediate for conversion into the bruceolides, it may be useful for the synthesis of simpler quassinoids. In addition, the chemistry worked out, to date provides a model study for an eventual assault on the bruceolides. A t the outset, we recognized that the central problems of bruceolide synthesis are elaboration of the heterocyclic D and E rings. Thus, the first problem is the relatively simple task of constructing a suitably functionalized perhydrophenanthrene system to which these rings can be appended. Unsaturated ketone 3 is available in 60% yield by the acid-catalyzed Robinson annelation of 2-methylcyclohexanone with ethyl vinyl ketone.29 Treatment of this n I. NOH, DMSO
0
3
\I.
N O H , DMSO-
~9 0
6: R = E t , X = B r IO: R : M e , X = C I
1. R = E t II: R = M e
enone successively with sodium hydridejdimethyl sulfoxide and bromo ketal 430affords only the 0-alkylated product 5, in 62% yield. However, utilization of the same procedure with the allyl bromide 6 gives the C-alkylated product 7 in 64% yield. Hydrolysis of the vinyl chloride is accomplished by treatment of 7 with mercuric acetate and boron trifluoride etherate in acetic acid. The intermediate unsaturated diketone 8 is cyclized by treatment
2
(3)Current address: Esso Standard Thailand, Bangkok 9,Thailand. (4)Polonsky, J. In "Progress in The Chemistry of Organic Natural Prcducta"; Herz, W., Grisbach, H., Kirby, G. W., Eds.; Springer-Verlag: Berlin, 1973;Vol. 30,p 102. (5)Polonsky, J.; Baskevitch, Z.; Guademer, A.; Das, B. C. Experientia 1967,23,424. (6)Sim,K. Y.;Sims, J. J.; Geissman, T. A. J.Org. Chem. 1968,33,429. (7)Polonsky, J.; Baskevitch, Z.; Das, B.; Mueller, J. C. R. Acad. Sci. Paris 1968,267, 1346. (8)Polonsky, J.; Baskevitch, Z.; Mueller, J. C. R. Acad. Sci. Paris 1969, 268, 1392. (9)Duncan, G.R.;Henderson, D. B. Experientia 1968,24,768. (10)Hartwell, J. L. Lloydia 1971,34,221. (11)Kupchan, S.M.; Britton, R. W.; Ziegler, M. F.; Sigel, C. W. J. Org. Chem. 1973,38,178. (12)Kupchan, S. M.; Britton, R. W.; Lacadie, J. A,; Ziegler, M. F.; Sigel, C. W. J. Org. Chem. 1975,40,648. (13)(a) Lee, K. H.; Imakura, Y.; Huang, H. C. J. Chem. SOC.,Chem. Commun.1977,69. (b) Lee, K. H.; Imakura, Y.; Sumida, Y.; Wu, R. Y.; Hall, I. H. J. Org. Chem. 1979,44,2180.(c) Okano, M.; Lee, K. H.; Hall, I. H.; Boettner, F. E. J. Nut. Prod. 1981,44,470. (14)Phillipson, J. D.; Darwish, F. A. Planta Med. 1981,41,209. (15)Kupchan, S.M.;Lacadie, J. A. J. Org. Chem. 1975,40,654. (16)Wani, M.; Taylor, H. L.; Thompson, J. B.; Wall, M. E.; McPhail, A. T.; Onan, K. D. Tetrahedron 1979,35,17. (17)Polonsky, J.; Varon, Z.; Jacquemin, H.; Pettit, G. R. Experientia 1978,34, 1122. (18)Hartwell, J. L. Cancer Treat. Rep. 1976,60,1031. (19)Douros, J.; Suffness, M. Cancer Chemother. Pharmacol. 1978,1, 91. (20)Castles, T. R.; Bhandari, J. C.; Lee, C. C.; Guarino, A. M.; Cooney, D. A. US.NTIS, PB Rep. 1976,PB-257175;1977,PB-269584. (21)Hamlin, R. L.; Pipers, F. S.; Nguyen, K.; Mihalko, P.; Folk, R. M. US.NTIS, PB Rep. 1977,PB-264128.
R
8 : R = Et 12: R : Me
9: R = M e IS: R = H
with aqueous, methanolic KOH; tricyclic dienone 9 is obtained in an overall yield of 61%. A similar sequence, utilizing the commercially available allyl chloride 10, provides the tricyclic dienone 13,by way of 11 and 12,in an overall yield of 30%. (22)(a) Grieco, P. A.; Ferrino, S.; Vidari, G. J. Am. Chem. SOC. 1980, 102,7586.(b) Grieco, P. A.; Ferrino, S.;Vidari, G.; Huffman, J. C. J. Org. Chem. 1981,46, 1022. (c) Grieco, P. A.; Lis, R.; Ferrino, S.; Jaw, J. Y. Ibid. 1982,47,601. (23)Stojanac, N.; Stojanac, Z.; White, P. S.; Valenta, Z. Can. J. Chem. 1979,57,3346. (24)(a) Dias, J. R.; Ramachandra, R. Tetrahedron Lett. 1976,3685. (b) Dias, J. R.; Ramachandra, R. Synth. Commun. 1977,7,293. (c) Dias, J. R.; Ramachandra, R. J. Org. Chem. 1977,42,3584. (25)(a) Snitman, D. L.; Tsai, M. Y.; Watt, D. S. Synth. Commun. 1978,8,195. (b) Voyle, M.; Kyler, K. S.;Arseniyadis, S.; Dunlap, N. K.; Watt, D. S. J. Org. Chem. 1983,48,470. (26)Mandell, L.; Lee, D. E.; Courtney, L. F. J. Org. Chem. 1982,47, 610. (27)Kraus, G. A.;Taschner, M. J. J. Org. Chem. 1980,45,1175. (28)Dailey, 0.D., Jr.; Fuchs, P. L. J. Org. Chem. 1980,45,216. (29)Heathcock, C. H.; Ellis, J. E.; McMurry, J. E.; Coppolino, A. Tetrahedron Lett. 1971,4995. In this note, the name of the solvent (benzene) was inadvertently omitted. (30)For a previous preparation of dienone 9,see: Mukherjee, S.; Mukherjee, D.; Sharma, M.; Basu, N. K.; Dutta, P. C. J. Chem. SOC., Perkin Trans. 1 1972,1325.
3266 J. Org. Chem., Vol. 49, No. 18, 1984
Heathcock et al.
A more convenient synthesis of 9 was found subsequently. When 2-methylcyclohexanone is treated with 1-chloro-&pentanone (14) and 2-naphthalenesulfonic acid
the ring A double bond, giving a product (presumably 23)
23 14
3
9
in benzene,31there is obtained a mixture of the bicyclic enone 3 (64%) and the tricyclic dienone 9 (18%). Treatment of 3 with sodium hydrideldimethyl sulfoxide and 14 affords a mixture of enedione 8 and aldols 15 and 16. When this mixture is treated with hot, methanolic
IS
24
that retains the ring B and ring C double bonds. Not surprisingly, m-chloroperoxybenzoicacid attacks the ring C double bond, providing 24, and catalytic hydrogenation reduces the ring B double bond, regenerating 9. Having experienced unexpected difficulty in the introduction of functionality into ring B, we turned our attention temporarily to the problem of functionalizing ring C. Allylic oxidation of dienone 9 with chromic anhydride in acetic anhydride-acetic acid gives dienedione 27 in more than 80% yield. Treatment of this material with ethylene
16
KOH, the tricyclic dienone 9 is obtained in 65% yield. The combined yield of 9 in this two-step procedure is 60%, based on 2-methylcyclohexanone. The synthetic strategy that we envisioned called for functionalization of ring B (at C-7) for eventual introduction of the axial lactone oxygen, and functionalization of ring C for attachment of the other terminus of the lactone ring. The method chosen for accomplishing the first goal was ketalization of the ring A enone. With compound 13, standard ketalization with ethylene glycol and toluenesulfonicacid in benzene affords the diene ketal 17, uncontaminated by isomers, in 82% yield.
27
glycol and 2-naphthalenesulfonicacid in refluxing benzene gives a mixture of isomeric bisketals 28 and 29 in quantitative yield. Hydrolysis of the mixture with wet silica gel in methylene chloride36 gives monoketal 30 (77%), along with a small amount of returned dienedione 27.
28
17: R = H 18: R = M e
13. R = H 9'R:Me
19
However, in the case of dienone 9, ketalization provides an approximate 1:l mixture of isomeric ketals 18 and 19. The failure of the double bond to undergo complete isomerization to the distal position in this case is presumably due to the stabilizing effect of the C-4 alkyl The desired movement of the C-4,C-5 double bond into ring B in 9 was achieved by formation of the enol ether 20 (87%) and enol acetate 21 (67%). Oxidation of enol A
A
9 RO
20. R = Et 2 1 : R : MeCO
29
22
ether 20 to trienone 22 is brought about by treatment of 20 with dichlorodicyanobenzoquinone (DDQ).Treatment of enol acetate 21 under similar conditions gives trienone 22, contaminated by a number of by products, in poor yield. The ring B double bond in 22 proved to be unexpectedly inert. The compound is recovered unchanged after treatment with alkaline hydrogen sodium hypochlorite in pyridine,34 and lithium bis( l-methoxy~iny1)cuprate.~~ Surprisingly, osmium tetroxide attacks
30
The success of this ketalization, relative to that of the related dienone 9, in which a 1:l mixture of 18 and 19 is produced, was a fortuitous but welcome result. Integration of the 'H NMR resonance at about 6 5.45 ppm in the mixture of ketals 28 and 29 indicates that the ratio of these two isomers is about 6:1, which agrees relatively well with the isolated yields of 30 and recovered 27 (77% and lo%, respectively) from the two-step procedure of bisketalization followed by hydrolysis. It is possible that the presence of the C-12 geminal dioxy substituent affects the conformation of the tricyclic system in such a way as to slightly favor the C-5,C-6 unsaturated isomer at equilibrium. The facile hydrolysis of the ketals of the conjugated enone systems is p r e ~ e d e n t e d . ~ ~ Reduction of 30 with lithium/ammonia/tert-butyl alcohol provides the saturated ketone 31 in nearly quantitative yield. The syn,trans stereochemistry of 31, expected
31
(31) Zoretic, P.; Branchaud, B.; Maestrone, T. Tetrahedron Lett. 1975, 521. (32) Becker, D.; Brodsky, N. C.; Kalo, J. J.Org. Chem. 1978,43,2557. (33) Wasson, R. L.; House, H. 0. "Organic Syntheses";Wiley: New York, 1963; Collect. Vol. 4, p 552. (34) Marmor, S. J . Org. Chem. 1963, 28, 250.
32
(35) Chavdarian, C. G.; Heathcock, C. H. J. Am. Chem. SOC.1975,97, 3822. (36) Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J. M. Synthesis 1978, 63.
J. Org. Chem., Vol. 49, No. 18, 1984 3267
Quassinoids on the basis of ample analogy13' was eventually confirmed by X-ray analysis (vida infra). Treatment of this material with Stiles' reagent (methoxymagnesium methyl carbonate, MMC),= followed by methylation with diazomethane gives &keto ester 32 in 90% yield. Although the non-enolic nature of this intermediate is vouchsafed by its infrared spectrum (strong absorption at 1710 and 1735 cm-'), its stereostructure remains uncertain, in light of the finding that a related compound (vida infra) exists in a conformation with a boat ring C. Ring C is readied further for installation of the elements of ring D by introduction of unsaturation at C-13,C-14. Treatment of the sodium salt of @-ketoester 32 with 0 COzMe
32
I . NaH, PhSeCl 2. HzOz, CHzClz
33
benzeneselenenyl chloride in THF, after the method of Reich,39provides a mixture of selenides, which is oxidized by hydrogen peroxide in a two-phase system consisting of methylene chloride and pH 7 phosphate buffer. The crystalline unsaturated keto ester 33 is obtained in an overall yield of 84%. Treatment of intermediate 33 with ketene acetals 34 or 35 in the presence of titanium t e t r a c h l ~ r i d e ~or s ~al 1:l mixture of titanium tetrachloride and titanium tetraisopropoxide@results in complete reaction of the unsaturated keto ester moiety, but extensive reaction of the C-3 ketal occurs, leading to complex product mixtures. Although
Treatment of the major product, 36, with aqueous KF provides keto diester 37. Somewhat better results are obtained in the high-pressure reaction of 33 with ketene acetal 35, in that less of
25oc MeCN
33
+
36
H20,THF-
8-14 days
39
the diastereomeric product corresponding to 38 is produced. In addition, it was found that the reaction can be carried out at pressures as low as 5 kbar on a scale that produces 3-5 g of adduct. In actual practice, the crude reaction product is desilylated by treatment with KF in aqueous THF. In a typical run, crystalline 39 is produced in 95% yield for the two steps.44 The stereochemistry depicted at C-14 in adducts 36,37, and 39 is that expected on stereoelectronic grounds (axial attack by the nucleophile); it was confirmed for 39 by subsequent X-ray analysis of a derivative (vide infra). With the elements of ring D installed at C-14, we turned our attention to the proper functionalization of C-7. One appealing scheme that presented itself was the solvolysis of the allylic alcohol 40; it might reasonably be expected that the carbonyl oxygen of the proximate tert-butyl ester would participate as shown to provide a tetracyclic lactone such as 41. To this end, we examined the epoxidation of
H+
40 3 4 , R = Me 35. R : I - B u
such additions are known to proceed without the aid of a catalyst in hot acetonitrile, the reaction of 33 and ketene acetal 34 gives only 10% yield of adduct after 21 h at 155 "C. However, the report by Matsumoto that sluggish Michael addition reactions may be driven to completion under conditions of high pressure42encouraged us to investigate this parameter. Indeed, an acetonitrile solution 0.15 M in 33 and 0.45 M in 34 reacts smoothly at 15 kbar R
Me,SiO
33 + 34
41
the simple unsaturated ketone 31. Treatment of 31 with buffered m-CPBA in methylene chloride at room temperature affords a 7:l mixture of epoxides 42 and 43 (59% yield), along with products resulting from Baeyer-Villiger oxidation (25% yield). On the other hand, the recently introduced tetrachloroacetone peroxyhemiketa16 gives only keto epoxide 42, although the reaction is relatively slow, giving a conversion of 31 to 42 of only 55% after 2.5 days at room temperature. However, the unreacted 31 is readily recovered, and the yield of epoxide, based on consumed reactant, is 82%.
25OC MeCN 15 kbar
36
+
&;%I
37
e o ; 38
for 24 h to give adduct 36 (84%), along with minor amounts of the unsilylated product 37 (9% ) and an isomer presumed to be the C-14 diastereomer 38 (7%).43 (37) Caine, D. Org. React. (N.Y.) 1976, 23, 1. (38) Finkbeiner, H. L.; Stiles, M. J. Am. Chem. Soc. 1963, 85, 616. (39) Reich, H. J.; Renga, J. M.; Reich, I. L. J.Am. Chem. Soc. 1975, 97, 5434. (40) Saigo, K.; Osaki, M.; Mukaiyama, T. Chem. Lett. 1976, 163. (41) Danishefsky, S.; Vaughan, K.; Gadwood, R.; Tsuzuki, K. J. Am. Chem. Soc. 1981,103,4136. (42) Matsumoto, K. Angew. Chem., Znt. Ed. Engl. 1980, 19, 1013.
42
43
Functionalization of keto epoxide 42 by the Stiles and Reich procedures provides unsaturated keto ester 45. Application of the high-pressure ketene acetal addition to this substance provides intermediate 46. We later found that epoxide 46 may also be obtained by oxidation of 39 with m-CPBA in methylene chloride. In contrast to the behavior seen with the simple unsaturated ketone 31, compound 39 gives only epoxide 46, in 88% yield. Significantly, if excess peroxy acid is used, a second oxidation (43) Bunce, R. A.; Schlecht, M. F.; Dauben, W. G.; Heathcock, C. H. Tetrahedron Lett. 1983,24, 4943. (44) We thank Professor W. Pirkle, of the University of Illinois, for carrying out several large-scale reactions for us in his apparatus at Champaign-Urbana. (45) Stark, C. J. Tetrahedron Lett. 1981, 22, 2089.
3268
42
J. Org. Chem., Vol. 49, No. 18, 1984
S,lles
&
c
Heathcock et al.
Me
c ;A*
LO' 44
46
SI
60
I . 35 15 k b o r
- J$
2 . KF, H 2 0
0
H30+
THF
46
5Z
occurs, converting 46 into intermediate 47; the latter substance can be obtained in quantitative yield! Thus, the preferred route to epoxide 46 is the sequence 31 32 33 39 46, which proceeds in an overall yield of more than 70% for the four steps.
--
--
the fact that epoxide 46 is much less soluble in ethanol
0
&;,
L o ;
39
Cope
m CH2C12 -CPBA *
&Aoz+
e o
0'
&:, 46
,,C02Me
m-CPBA CH2CI2
1
6-H,
COZ+
47
We had intended to rearrange the epoxide ring of 47 to an allylic alcohol by the Rickborn-Crandall procedure.& There is an obvious question of regiochemistry, since deprotonation might occur either at C-4 or C-7. However, mechanistic investigations by Kissel and Rickborn have shown that syn elimination is preferred, and we therefore expected elimination to proceed solely from C-7 deprotonation. Thus, we were surprised to find that treatment of the model epoxide 42 with excess lithium diethylamide
48
49
in ether, followed by acidic hydrolysis gives only 49, resulting from deprotonation of 42 at C-4. The reason for this unexpected behavior probably lies in the oxygen substituents at C-3. If the lithium cation of the base is coordinated with the 3@oxygen, intramolecular deprotonation would result in removal of the 4@ hydrogen, leading to the formation of 48.41 Epoxide 42 is successfully rearranged to allylic alcohol 51 by the Sharpless procedure, wherein the epoxide ring is f i s t opened by sodium phenylselenide, and the resulting phenylseleno derivative 50 is then oxidatively eliminated.& By this route, 51 is obtained in an overall yield of 73% from epoxide 42; mild acidic hydrolysis of 51 provides the crystalline dienedione 52 in 93% yield. The Sharpless procedure can also be applied to epoxide 46. In this case, however, the situation is complicated by
53
than epoxide 42 and also by the presence of the methyl ester in 46. Because of the reduced solubility of 46, the reaction must be carried out under more dilute conditions. In addition, a significant amount (10-30%) of nucleophilic demethylation occurs, giving the @-ketoacid corresponding to product 53. Therefore, it is necessary to treat the crude product with diazomethane in order to maximize the yield of 53. By this method, epoxide 46 can be converted into 40 in 78% yield, based on consumed starting material. Initial attempts to bring about solvolytic ring closure of the 6-valerolactone ring (40 41) by the use of aqueous or anhydrous acid were unsuccessful. Treatment of 40 with
-
-
4 0 H20, HCI eT M H F; & &
/
+
OZ+
' +" ; &o
/
54
/
O2H
65
HCl in aqueous THF for periods of time ranging from 4 to 72 h provides a mixture of 54 (38-39%) and acid 55 (14-17%). Control experiments showed that acid 55 is not formed from ester 54. Thus, we believe that the solvolytic ring closure does occur to a degree, but that the product (56) is unstable to acidic conditions, and undergoes elim-
&H+
Me
-X-
/
0
0
0
0
&we ' C02H /
56
56
ination to give 55. Attempts to bring about the reverse of this reaction, Michael addition of the carboxyl group to the 6 position of the dienone of 55, were uniformly unsuccessful. The foregoing hypothesis obviously suggests that the solvolytic cyclization may succeed under anhydrous conditions. However, the use of anhydrous 2naphthalenesulfonic acid in refluxing toluene leads mainly to acid 55 (38% yield) and a trace amount of lactone 41.
40
P-NpS03H toluene
A
(46) (a) Kissel, C. L.; Rickborn, B. J. O g . Chem. 1972,37, 2060. (b) Crandall, J. K.; Lin, L. C. Zbid. 1968,46, 2375. (47) Similar results have been observed by Holland, H. L. and Jahangir Can. J. Chem. 1983,61, 2165. (48) Sharpless, K. B.; Hauer, R. F. J . Am. Chem. SOC.1973,95,2697.
40
55
+
&
Me
0
41
The problem was solved in an unexpected manner. Treatment of allylic alcohol 40 with pyridinium chloro-
J. Org. Chem., Vol. 49, No. 18, 1984 3269
Quassinoids
Figure 1. ORTEP stereoscopic projection of lactone 41.
chromate4gin methylene chloride gives a mixture of the crystalline lactone 41 (55%) and enone 57 (14%).
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CHZC'2 pcc
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