J. Org. Chem. 1990,55,2725-2736 Table VI. NMR Data of 1H CeDB 2.44 (s, 6 H), 1.23 (s, 6 H), 1.18 (s, 9 H) 2.44 (s, 6 H), 1.21 (s, 6 C7D, H), 1.18 (s, 9 H) CD3CN 2.36 (s, 6 H), 1.14 (s, 9 H), 1.10 (s, 6 H) CD30D 2.42 (s, 6 H), 1.19 (9, 9 H), 1.14 (s, 6 H)
7 in Various Solvents 13c
83.78, 67.26, 38.87, 27.02, 22.95 83.79, 67.32, 38.88, 27.07, 23.03 84.41, 67.75, 38.95, 27.11, 22.57 85.21, 68.44, 38.90, 27.11, 21.77
stirred a t 0 "C for 5 min, the mixture was stirred with ether a t room temperature for 2 h. The ether layer was separated and dried with K2C03and Na2SO4 After rotary evaporation of the solvent, the yellow residue (6 g) was relatively clean 7 as shown by NMR analysis. Vacuum distillation gave the pure azoalkane, bp 66.5-67.5 "C (-25 mm). NMR data in four solvents are listed in Table VI. MS (45 eV): 85 (601, 70 ( l o o ) , 59 (12), 57 (17), 56 (42), 55 (25), 44 (13), 43 (13), 42 (23), 41 (37), 39 (18), 28 (25), 15 (30).
Acetone Dimethylenamine (9) was prepared according to the literature procedure,'l NMR (C6D6)6 3.88 (br s, 1 H), 3.73 (s, 1 H), 2.38 (s, 6 H), 1.72 (d, 3 H, J = 0.6 Hz). Crude 9 polymerized on attempted distillation, and it degraded into a mixture on standing for 4 days in the freezer under nitrogen. Attempts to purify 9 by GC gave 10 instead: NMR (C6D6)6 5.78 (m, 1 H), 4.06 (s, 1 H), 4.01 (d, 1 H, J = 0.8 Hz), 2.45 (s, 6 H), 1.79 (d, 3 H, J = 1.1 Hz), 1.61 (d, 3 H, J = 1.3 Hz); MS (70 eV) 125 (17), 110 (loo),95 (30), 94 (22), 42 (27), 39 (20), 15 (43).
2-(Dimethylamino)-2,3,3-trimethylbutane(8) was synthesized as described in the literat~re.'~The crude product was purified by preparative GC: 'H NMR (C6De)6 2.30 ( s , 6 H), 0.96 ( ~ , H), 9 0.93 (s,6 H);13C NMR (C&) 6 59.96,42.29,40.49,27.07, 21.09.
Thermolysis Kinetics. Thermolysis kinetics were done in sealed 1-cm Pyrex UV cells in a constant-temperature oil bath shielded from fluorescent lights. Solutions were degassed by at least three freezethaw cycles. The bath temperature was recorded by a platinum thermometer and a H P Model 3456 6 l l 2 digit volmeter. The reaction was followed by the decay of the UV absorption maximum around 380 nm. Thermolysis Product Study. All solutions for thermolysis were degassed by a t least three freeze and thaw cycles. Product (71) Ahlbrecht, H.; Raab, W. Synthesis 1980, 320. (72) Vejdelek, 2. J.; Trcka, V. Experientia 1959,15,215;Chem. Abstr. 1960,54, 31771.
2725
analysis was done in sealed NMR tubes heated at an appropriate temperature (110-130 "C) in the same bath as used for kinetics. A dry solution of 7 in CD3CN was obtained by stirring the wet solution with CaHz followed by trap to trap distillation on the vacuum line into an NMR tube. In the trapping experiment, tetrabutylammonium cyanide was first placed in the NMR tube and pumped to dryness. Dried 7 solution (see above) in CD3CN was then distilled into the NMR tube, and the reaction was followed by NMR spectroscopy. In the reaction of 7 with acetic acid, the HOAc-C6D6 solution and the solution of 7-C6D8 were degassed separately. The acetic acid solution was then distilled into the frozen 7 solution at -196 OC. The combined solution was first allowed to react a t room temperature for 30 h in the dark and was then heated at 100 OC for 20 min to complete the reaction. For GC-MS analysis, the tube was usually opened after thermolysis, and the reaction mixture was analyzed immediately to avoid air oxidation of the products and escape of volatile components. Products were identified by 'H and 13CNMR analyses, or by GC-MS comparison with authentic material. The product ratio was estimated from NMR peak area or peak height. Nitrogen volumes were obtained on a Topler pump and the gas purity was checked by GC on a 5-1\ molecular sieves column. An NMR tube sealed to a 7 / 2 5 standard taper joint was used for the nitrogen yields. Photolysis of 7. All photolyses were done in degassed solution in sealed NMR tubes using an Oriel 500-W high-pressure mercury perchlorate lamp with a 2,7-dimethyl-3,6-diacyclohepta-l,6-diene filter. Products were identified and quantified by the same methods used in thermolysis. Quantum Yield. A Hanovia 450-W medium-pressure mercury lamp with 366-nm light filter was used for this purpose. The quantum yield was obtained from the nitrogen volume ratio of 7 relative to DTBD standard with NMR tubes on a merry-goround apparatus a t an average temperature of 20 "C. Solutions of 0.3 M 7-C6D6 and 0.82 M DTBD-C6D6 were used. The tubes were removed frequently for NMR analysis. Caution wm exercised to make sure that all light was absorbed by the samples during the photolysis. After the photolysis, about 25% of DTBD and 63% of 7 were decomposed.
Acknowledgment. Financial support from the National Science Foundation and the Robert A. Welch Foundation is gratefully acknowledged. We thank Professor Joachim G. Shantl for helpful discussions. Supplementary Material Available: NMR spectra of 7 and its decomposition products as described in ref 32 (7 pages). Ordering information is given on any current masthead page.
Synthesis of Polyquinanes. 3. Total Synthesis of (*)-Hirsutene: The Intramolecular Diels-Alder Approach1p2 Daniel D. Sternbach*a and Carol L. Ensinger4 Department of Chemistry, Paul M . Gross Chemical Laboratory, Duke University, Durham, North Carolina 27706
Received M a y 1, 1989 The highly efficient (19% overall yield) 20-step synthesis of the linearly fused triquinane (f)-hirsutene (11) is described. The key step in this sequence is an intramolecular Diels-Alder reaction of the substituted cyclopentadiene 16d, which contains all but two of the carbon atoms found in hirsutene. During this intramolecular Diels-Alder reaction, two of the three carbocyclic rings found in hirsutene are formed. The third ring is formed by the aldol cyclization of 29. The successful synthesis of (*)-hirsutene demonstrates the synthetic utility of the intramolecular Diels-Alder strategy for the synthesis of linearly fused triquinanes.
Over the last 15 years much effort has been devoted to the syntheses of polyquinane natural products as well as
to the application of the intramolecular Diels-Alder reaction to problems of general synthetic interest. In the
(1) For Part 2 of this series, see: Sternbach, D. D.; Hughes, J. W.; Burdi, D. F.; Banks, B. A. J . Am. Chem. SOC.1985, 107, 2149.
(2) Taken from the doctoral dissertation of Carol Lee Ensinger, Duke University, February, 1988.
0022-3263/90/1955-2725$02.50/00 1990 American Chemical Society
2726 J. Org. Chem., Vol. 55, No. 9, 1990
Sternbach and Ensinger Scheme I
R.
5A
5B
8
9
case of polyquinanes, this attention has been the result of the intriguing and varied structures of these molecules and the potent biological properties that some of these compounds possess. On the other hand, the implementation of the intramolecular Diels-Alder reaction has been due to the inherent advantages of this method over its bimolecular ~ o u n t e r p a r t . ~ As part of a our research program, we have coupled these two areas of endeavor in an attempt to establish a general method of constructing cyclopentanoid natural products of the types 1-4.
2
1 DlqulnrM
Umuty F u o d Trlquinw
3
4
Angululy Fuud Tliqulnrm
[3.3.3]Propllrrw
Strategy The strategy to be employed for the synthesis of hirsutene is an outgrowth of our generalized method for the (3) Present address: Glaxo Research Laboratories, 5 Moore Drive, Research Triangle Park, NC 27709. (4) Present address: Pharmaceuticals Research and Development, Medical Products Department, E. I. Dupont de Nemours & Co., Experimental Station, Wilmington, DE 19880-0402. (5) For some recent reviews, see: Ciganek, E. Org. React. 1984,32, 1. Fallis, A. G. Can. J. Chem. 1984,62,183.
5c
10
construction of cyclopentanoids. This method is based on the single observation that all polyquinanes, regardless of substitution or presence of rings of other sizes, are built around a core bicyclo[3.3.0]octane (diquinane) ring system. Our approach uses as the key step the jntraIpolecular Diels-Alder (IMDA) reaction of a cyclopentadiene and a dienophile tethered by a three-carbon chain (Scheme I). It has previously been shown that in cases where rapid 1,5-hydride shifts can occur to one of the three possible isomers 5a-c, only the 1-substituted isomer (5c) cyclizes. Moreover, these examples demonstrated an exclusive preference for the tethering chain to possess the exo orientation in the product (6).’p6 As a result of this regioand stereochemical control, cleavage of the olefin in 6 would lead to a cis-fused diquinane (7) possessing defined relative stereochemistry of R2, R3, and the newly generated aldehydes. With respect to the syntheses of triquinane natural products, judicious placement of an acetyl group (as R1,R2, or R3) or its equivalent in the IMDA precursor ( 5 ) should permit aldol cyclization with one of the aldehydes in 7 to lead to either 8,9, or 10. Herein we wish to describe the successful application of this strategy to the total synthesis of (*)-hirsutene (11).
Results and Discussion The mold metabolite hirsutene (11) was first isolated from the hydrocarbon extracts of fermented micelium of Coriolus consors.’I Its structure was determined through a combination of spectral analysis and original synthesis.’ Considerable interest has been devoted of late to the synthesis of l l . ’ g 8 While much of this is due to its rela(6) (a) Corey, E. J.; Glass, R. S.J. Am. Chem. SOC.1967,89,2600. (b) Fallis, A. G.; Breitholle, E. G. J. Org. Chem. 1978,43, 1964. (c) Landry, D. W. Tetrahedron 1983, 39, 2761. (d) For an example in which the IMDA reaction was carried out at temperatures where 1,5-hydride shifts were slow relative to cyclization, see: Wallquist, 0.;Rey, M.; Dreiding, A. S.Helu. Chim. Acta 1983,66, 1891. (7) Nozoe, S.; Furukawa, J.; Sankawa, U.; Shibata, S. Tetrahedron Lett. 1976, 195.
J. Org. Chem., Vol. 55, No. 9,1990 2727
Synthesis of Polyquinanes tionship to the antitumor and antibiotic congeners hirsutic acidg (12), complicatic acidlo (13), and coriolin" (141, some is also the result of the close similarity between the hirsutane and capnellane families of sesquiterpenes (compare 11 and capnellene 15).
11
12
13
\\
h n
k 14
15
The synthetic plan called for the construction of a generalized Diels-Alder precursor (16) that might be generated by either of two possible modes where R represents either acetyl or an equivalent (eq 1). In the first cn,
A
16.-d
L Ra COCH3,
171-d
A
0
COzM..
CHOHCH3,
P CHzOH
(1)
method (path A), alkylation of cyclopentadiene anion with a suitable halide or sulfonate alkylating agent would give the IMDA precursor directly, assuming that the dienophile is not susceptible to nucleophilic attack. By the second method (path B), condensation of the anion with an appropriate aldehyde would provide a fulvene (17), the exocyclic double bond of which would require reduction for conversion to 16. Once again, the dienophile would have to be resistant to nucleophiles and, additionally, reducing agents. Path A, although appealing for its directness, was not likely to be successful since the requisite alkylating agent would be neopentylic. Path B, on the other hand, necessitated two steps, but appeared to be a viable alter(8) (a) Cossy, J.; Belotti, D.; Pete, J. P. Tetrahedron Lett. 1987,4547. (b) Mehta. G.: Murthv. A. N.: Reddv. D. S.:Reddv. A. V. J. Am. Chem. SOC. 1986,'108,3443. -(c) Iyoda, M.;Kushida, T.; Kitami, S.; Oda, M. J. Chem. SOC.,Chem. Commun. 1986,1049. (d) Curran, D. P.; Rakiewicz, D. M. J.Am. Chem. SOC. 1985,107,1448. (e) Funk, R. L.; Bolton, G. L.; Daggett, J. U.; Hanaen, M. M.; Horcher, L. H. M. Tetrahedron 1985,41, 3479. (0 Hua, D. H.; Sinai-Zingde, G.; Venkataraman, S. J.Am. Chem. SOC.1985,107,4088. (9) Disanayaka, B. W.; Weedom, A. C. J. Chem. SOC.,Chem. Commun. 1985,1282. (h) Ley, S.V.; Murray, P. J.; Palmer, B. D. Tetrahedron 1985,41,4765. (i) Hewson, A. T.; MacPherson, D. T. J . Chem. SOC.,Perkin Trans. I1985,2625. (j) Dawson, B. A.; Ghosh, A. K.; Jurlina, J. L.; Stothers, J. B. J . Chem. SOC., Chem. Commun. 1983, 204. (k) Wender, P. A.; Howbert, J. J. Tetrahedron Lett. 1982,3983. (1) Magnus, P.;Quagliato, D. A. Organometallics 1982, 1, 1243. (m) Little, 1981,103, 2744. (n) Greene, A. R. D.; Muller, G. W. J . Am. Chem. SOC. E. Tetrahedron Lett. 1980, 3059. ( 0 ) Hudlicky, T.;Kutchan, T. M.; Wilson, S. R.; Mao, D. T. J. Am. Chem. SOC. 1980,102,6351. (p) Tatsuta, K.;Akimoto, K.; Kinoshita, M. J . Am. Chem. SOC.1979, 101,6116. (9) (a) Comer, F. W.; McCapra, F.; Qureshi, I. H.; Scott, A. I. Tetrahdron 1967,23,4761. (b) Comer, F. W.; Trotter, J. J. Chem. SOC. B 1966, 11. (10) Mellows, G.; Mantle, P. G.; Feline, T. C.; Williams, D. J. Phytochemistry 1973, 12, 2717. (11) (a) Takeuchi, T.; Takahashi, S.; Iinuma, H.; Umezawa, H. J . Antibiot. 1971,24,631. (b) Takeuchi, T.; Iinuma, H.; Iwanaga, J.; Takahashi, S.; Takita, T.; Umezawa, H. J. Antibiot. 1969, 22, 215.
native since we have previously demonstrated1J2 the feasibility of adding alkyllithiums to sterically hindered fulvenes. Obviously, the choice of R group had to be made carefully. Functional groups a-d (eq 1) quickly emerged as the best choices. The unmasked acetyl group a was most desirable since this would provide an activated dienophile and obviated the need for functional group manipulation after the Diels-Alder reaction. However, the activated dienophile was potentially susceptible to nucleophilic attack by cyclopentadiene anion and/or a wide variety of reducing agents. These potential complications thus precluded the use of carboxyl group b as well. Therefore, fully reduced equivalents of the acetyl and carboxyl moieties such as c and d were possibilities. The primary alcohol d suffered from the obvious drawbacks that it needed to be both oxidized and homologated before aldolization. This left secondary alcohol c as the best available option, needing only to be oxidized to be suitable for the aldol cyclization. Potentially, this oxidation might be combined with the Diels-Alder reaction, providing directly a tricyclic product analogous to 6, since the resultant enone should be an extremely active dienophile. We began our synthesis with the construction of IMDA precursor 16c (Scheme 11). The known aldehydeI3 18 was protected as its acetal (95%) and ozonolyzed to yield 19 (100%). Homologation of 19 with diethyl 2-oxobutane3-phosphonate14in refluxing T H F gave (88%) of the desired (E)-enone, which was reduced using the conditions developed by Luche15 (Nal3H4/CeCl3.7H20)to provide an 88% yield of an allylic alcohol as the sole product. Removal of the acetal protecting group with 1:l 10% HC1/ T H F generated the aldehyde 20 needed for fulvene formation, in quantitative yield. Condensation with cyclopentadiene using the slightly modified conditions of Little16 (pyrrolidine, MeOH, Na2S0,) afforded fulvene 17c (96%). Reduction of the exocyclic double bond of the fulvene" with LiA1H4 in THF proceeded smoothly to provide the Diels-Alder precursors 16c as a mixture of double-bond regioisomers in 99% yield. The overall yield for this seven-step protocol from 18 was 70%. After several unsuccessful attempts to oxidize 16c with concomitant cyclization, the Oppenauer oxidationla was tried, using acetone as the hydride acceptor and Al(O-i-Pr)3 as catalyst in refluxing toluene. This reaction provided the tricyclic ketone 21 directly in 47% yield. Ozonolytic cleavage of the double bond in 21 yielded the keto dialdehyde as the expectedlg mixture of hydrates. Unfortunately aldol cyclization of 22 yielded, at most, only a trace of the desired enone 23. Presumably the angular aldehyde was too sensitive to withstand the aldol conditions. With the hope of making a more stable derivative, the dialdehyde was oxidized to the diacid (24) with Jones reagent (89% yield). We hoped to carry out cyclization to the linearly fused triquinane by using a protocol developed by Cbates and co-workers in (12) Sternbach, D. D.; Hughes, J. W.; Burdi, D. F. J . Org. Chem. 1984, 49, 201. (13) (a) Salomon, R. G.; Ghosh, S. Org. Synth. 1984, 62, 125. (b) Magnus, P. D.; Nobbs, M. S. Synth. Commun. 1980, 10, 273. These procedures work best when the Vigreaux column described in ref 13a is used. (14) Corbel, B.; Medinger, L.; Haelters, J. P.; Sturtz, G. Synthesis 1985, 1048. (15) Luche, J.-L. J. Am. Chem. SOC.1978, 100, 2226. (16) Little, R. D.; Stone, K. J. J. Org. Chem. 1984, 49, 1849. We wish to thank Professor Little for providing a preprint of this publication. (17) Little, W.F.;Koestler, R. C. J. Org. Chem. 1961, 26, 3247. (18)Djerassi, C. Org. React. 1951, 6, 207. (19)For another example of hydrate formation, see ref 1 and also Martel, A.; Just, G. Tetrahedron Lett. 1973, 1517.
2728 J . Org. Chem., Vol. 55, No. 9, 1990
Sternbach and Ensinger
Scheme 11. Approaches to Hirsutene through Precursor 16c"
Z Z q OH
Me Me
