J . Am. Chem. SOC.1984, 106, 8217-8224 combined acetonitrile layers were concentrated in vacuo to afford 2.68 g of a pale-yellow oil. The oil was chromatographed first over 50 g of silica gel (ethyl acetate-hexane, 25:75,followed by ethyl acetate-hexane, 1:1, and finally ethyl acetate) and then over a Lobar size C column (ethyl acetate-hexane, 25:75,followed by ethyl acetate) to yield 241 mg (8%) of unreacted starting material 34 as a pale-yellow oil. Continued elution gave a fraction which was recrystallized from 4 mL of hexane to yield 627 mg (30%) of one diastereoisomer of 37 as a white solid: mp 93.5-94.5OC; IR (CCIJ 1700 cm-I; NMR (CDCI,, 200 MHz) 6 0.13 (s, 9 H, SiMe,), 1.24-2.71(m, 8 H), 2.82(dt, J = 11, 5 Hz, 1 H, NCH), 3.95(dd, J = 1 1, 5 Hz, NCH), 4.25(ddd, J = 11, 7,5 Hz, 1 H, angular NCH), 7.10-7.40(m,5 H, ArH). Exact mass calcd for C,,H,,NOSSi: m l e 319.1426.Found: m l e 319.1447. Anal. Calcd for C17H2,NOSSi: C, 63.90;H, 7.89.Found: C, 64.00; H, 8.07. The mother liquor was concentrated in vacuo to give 86.6mg (4%) of a colorless oil composed of 37 and 40 (35:65, respectively, by NMR). Characteristic signals of 40: NMR (CDCI,) 6 3.30-3.45(two overlapping t's, J = 7 Hz, at 3.35and 3.40,4 H, NCH,), 6.55(t, J = 7 Hz, 1 H, =CH). Further elution gave 445 mg (25%) of a mixture of 38 and 39 (3:2,respectively, by NMR). A small amount of pure 38 was obtained by further chromatography over a Lobar column as a colorless oil: IR (CCI,) 1695 cm-I; NMR (CDCI,) b 0.19(s, 9 H, SiMe,), 1.37-2.75 (m,8 H), 3.15 (br t, J = 12 Hz, 1 H, NCH), 3.54(dt, J = 12,8 Hz, 1 H, NCH), 3.80(td, J = 9,7 Hz, 1 H , angular NCH), 7.13-7.40(m, 5 H, ArH). Exact mass calcd for C,,H,,NOSSi: m l e 119.1426.Found: mle 3 19.1474.Only an enriched sample of 39 could be obtained: NMR (CDCI,, 200 MHz) 6 3.00(ddd, J = 11, 8,5 Hz, 1 H, NCH), 3.56 (td, J = 11, 8 Hz, 1 H , NCH), 3.96 (q, J = 6 Hz, 1 H, angular NCH). Final elution gave 596 mg (28%) of the most polar diastereoisomer of 37 as a white solid: mp 87-88.5 OC; IR (CCI,) 1695 cm-I; NMR (CDCI,, 200 MHz) 6 0.18 (s, 9 H, SiMe3), 1.42-2.05(m.4 H), 2.13-2.71(m, 4 H), 2.93(td, J = 12,7 Hz, 1 H, NCH), 3.78 (ddd, J = 12,8,5 Hz, 1 H, NCH), 4.01(td, J = 9,7 Hz, 1 H, angular NCH), 7.11-7.50(m, 5 H, ArH). Exact mass calcd for C,,H25NOSSi: m / e 319.1426.Found: m l e 319.1452. Anal. Calcd for CI7H2,NOSSi:C, 63.90;H, 7.89.Found: C, 63.86; H , 7.69.
Acknowledgment. W e thank M r . Richard Weisenberger for
8217
recording mass spectra a t T h e Ohio S t a t e University Chemical Instrument Center. Financial support from the NIH (GM-27647) and NSF (CHE-8205878) are gratefully acknowledged. W e also thank the NIH for a grant (GM-27431) to Ohio State University in support of t h e acquisition of a Bruker W M - 2 0 0 N M R spectrometer used during t h e course of this research. Registry No. (*)-4,18929-90-3; (f)-5,92845-54-0; 6a,92844-96-7; (*)-6b,92844-97-8; 7a,92844-98-9; (f)-7b, 92844-99-0; Sa,92845-00-6; (&)-8b,92845-01-7;(&)-9a, 92845-02-8;9b, 70255L35-5;(*)-loa, 92845-03-9; lob, 92845-04-0; lla,92845-05-1; (*)-lib, 92845-06-2; 12a,92845-07-3; (*)-12b,92845-15-3; (f)-13b,92845-16-4; (*)-14b, 92845-14-2; (f)-15a,92845-08-4; 15b,92845-13-1; (*)-16 (isomer l), 92845-09-5; (*)-16 (isomer 2), 92845-10-8; (*)-17,92845-11-9;(*)-18, 92845-12-0; 19,5615-85-0; 20a,35000-38-5; 20c,16640-68-9; (Z)-2la, (A)92845-17-5; (E)-2la,92845-18-6; (&)-(E)-21a-oI, 92845-47-1; (Z)-2la-ol,92845-48-2; (Z)-2lb,92845-19-7; (E)-21b,92845-20-0; 21b-01,92845-49-3; (Z)-2lc,92845-21-1; (E)-2lc,92845-22-2; (k)(E)-Zlc-ol,92845-50-6;(*)-(Z)-2lc-ol, 92845-51-7;(*)-(Z)-22a, 92845-23-3;(f)-(E)-22a, 92845-24-4;22b, 92845-25-5;(Z)-22c, 92845-26-6; (E)-22c,92845-27-7; (*)-23a,92845-29-9; 23b,92845-33-5; (*)-23c, 92845-35-7; (f)-24a,92845-28-8; (f)-24c,92845-34-6; 25a, 92845-30-2; (f)-26,92845-31-3; (*)-27, 92845-32-4; (&)-29, 8992281-6;30,62761-90-4; (&)-(E)-31, 92845-36-8; (*)-(Z)-31, 92845-37-9; (E)-32,92845-38-0; (2)-32,92845-39-1; (E)-33,92845-40-4; (2)-33, 92845-41-5; (f)-(E)-34, 92845-42-6; (f)-(Z)-34,92845-43-7; (2)-35, 88695-24-3; (E)-35,88850-04-8;(E)-35-01,92845-52-8;(Z)-35-01, 92845-53-9; (Z)-36,92900-58-8; (E)-36,92900-59-9; 37,92845-44-8; 39, 92845-46-0; 40, 92845-45-9;(lR,2S,5R)-2-(2-phenyl-2-propyl)-5methylcyclohexanol, 65253-04-5; (lR,2S,5R)-2-(2-phenyl-2-propyl)-5methylcyclohexanol bromoacetate, 80595-591; acetaldehyde, 75-07-0; paraformaldehyde, 30525-89-4; succinimide, 123-56-8; thiophenol, 10898-5;bromoacetic acid, 79-08-3.
Supplementary Material Available: Experimental procedures for t h e preparation of 6b-llb a n d 20b (6 pages). Ordering information is given on any current masthead page.
Total Synthesis of Guaianolides: ( f)-Dehydrocostus Lactone and ( f)-Estafiatin James H. Rigby* and JoAnn Zbur Wilson Contribution from the Department of Chemistry, Wayne State University, Detroit, Michigan 48202. Received April 12, 1984
Abstract: The total synthesis of two guaianolide sesquiterpenes, (A)-dehydrocostus lactone and (f)-estafiatin, is described. The synthesis starts with 2,4,6-cycloheptatrien-l-one(tropone) and introduces the elements of the five-membered ring through a 1,8-addition of the Grignard reagent derived from 2-(2-bromoethyl)-l,3-dioxolane.A stereocontrolled Lewis acid mediated cyclization reaction generates the requisite cis-fused hydroazulene intermediate. Regio- and stereoselective y-butyrolactone formation via epoxide opening with dilithioacetate followed by the introduction of three exocyclic methylene groups completes the synthesis of (A)-dehydrocostus lactone in twelve steps from tropone. (*)-Estafiatin is constructed in two additional steps from dehydrocostus lactone.
T h e guaianolides comprise one of t h e largest a n d most widely distributed groups of naturally occurring sesquiterpene lactones.' A majority of these species feature a cis-fused hydroazulene skeleton in which a trans-fused y-butyrolactone moiety is appended to t h e seven-membered carbocycle. W i t h approximately 200 representatives currently identified, the great structural diversity (1) Fischer, N. H.; Olivier, E. J.; Fischer, H. D. Fortschr. Chem. Org. Naturst. 1979,38, 47.
0002-7863/84/1506-8217$01.50/0
exhibited by this class of natural products stems principally from t h e level a n d variety of functionalization that can be located a t a number of positions in t h e molecules. M a n y guaianoiides are endowed with a n impressively rich spectrum of biological activity. T u m o r inhibitory* a n d s c h i s t ~ s o m i c i d a las ~ well a s plant growth (2) (a) Jolad, S.D.; Wiedhopf, R. M.; Cole, J. R. J . Pharm. Sci. 1974, 63, 1321. (b) Kupchan, S. M.; Eakin, M. A,; Thomas, A. M. J . Med. Chem. 1971,14, 1147. (c) Lee, K.-H.; Huang, E.-S.;Piantadosi, C.; Pagano, J. S.; Geissman, T.A. Cancer Res. 1971,3 I , 1649.
0 1984 American Chemical Society
8218
J. Am. Chem. SOC., Vol. 106, No. 26, 1984
Scheme I
0
regulatory activity4 are common among members of this group of compounds. In spite of the many obvious attractions these natural products present, the literature currently reveals a conspicuous paucity of synthetic successes. Until recently the only synthetic efforts directed toward the guaianolides were in the form of relay syntheses involving eudesmane and germacrane sesquiterpenes as starting point^.^ To d a t e only two groups have successfully assembled guaianolide species by total ~ y n t h e s i s , ~ ,and ’ a third group has recently disclosed a novel approach to a closely related guaiane species.* This lack of activity in the guaianolide series is in stark contrast to the prodigious synthetic output devoted to the closely related p s e u d ~ g u a i a n o l i d e s . ~ Described herein is the first total synthesis of the guaianolide (f)-dehydrocostus lactone (1)’O and its subsequent conversion into the somewhat more highly functionalized (f)-estafiatin (2).6a At
b?= 0
0
! ? the outset of this investigation, compound 1 and related species were viewed as attractive penultimate synthetic targets from which other more highly oxygenated members of this class of compounds could be conveniently accessed. O u r fundamental strategy initially addressed the problems associated with the construction of an appropriately functionalized cis-fused hydroazulene intermediate. As noted by H e a t h c ~ c k , ~ ~ a t least four complementary strategies for assembling the hydroazulene skeleton can be envisioned. These include transannular cyclization of a ten-membered ring, skeletal rearrangement of a
Rigby and Wilson decalin precursor, introduction of a seven-membered ring onto a five-membered ring, and elaboration of a five-membered ring onto a preexisting seven-membered carbocycle. M a n y of these approaches have been extensively exploited for hydroazulenic sesquiterpene synthesis.’ Surprisingly, the last approach has not received much a t t e n t i ~ n . ~ g We envisaged that a strategy based on fusing the elements of a five-membered ring onto a preformed, highly functionalized seven-membered ring system offered a potentially efficient and versatile entry into cis-perhydroazulenes which in turn could be transformed into guaianolides. T h e limited availability of appropriate starting materials has certainly contributed to the shortage of strategies starting from seven-membered ring species. However, we were particularly intrigued with the possibility of utilizing the high degree of functionalization and unique reactivity exhibited by 2,4,6-cycloheptatrien-l-one (tropone) (3) and its derivatives for the construction of perhydroazulenes (Scheme I). Although the cycloheptatrienones have been the subject of extensive investigation,12 their potential for application to synthetic problems has not been extensively explored until r e ~ e n t 1 y . I ~ Tropone itself is readily available from cycloheptatriene, which is the least expensive functionalized seven-membered ring compound available c ~ m m e r c i a l l y . ’ ~ The unusual propensity for tropone to undergo 1&addition with Grignard reagents15 was viewed as the key carbon-carbon bond forming operation in the initial stages of our synthesis. The resulting dihydrotropone would retain a substantial degree of functionality for further manipulation, and the use of a terminally functionalized three-carbon chain Grignard reagent would provide a handle for subsequent closure to the requisite five-membered ring.16 Slow addition of tropone to 2 equiv of the Grignard reagent derived from 2-(2-bromoethyl)-l,3-dioxolane17 a t 0 OC in T H F resulted in a nearly quantitative conversion to the sensitive 2substituted cyclohepta-3,5-dienone 4.’* Since related adducts
a)
a,
THF, 0’ C , b ) NaBH4, EtOH, 0’ C,
PhCH21, O°C,
(3) (a) Baker, P. M.; Fortes, C. C.; Fortes, E. G., Gassinelli, G.; Gilbert, B.; Lopes, J. N. C.; Pellegrino, J.; Tomassini, T.; Vichnewski, W. J . Pharm. Pharmacol. 1972,24, 853. (b) Vichnewski, W.; Sarti, S. J.; Gilbert, B.; Herz, W. Phytochemistry 1976, IS, 191. (c) Herz, W.; Kumar, N.; Vichnewski, W.; Blount, J. F.J . Org. Chem. 1980, 45, 2503. (4) (a) Rodriguez, E.; Towers, G. H. N.; Mitchell, J. C. Phytochemistry 1976, IS, 1573. (b) Asakawa, Y . ;Takemoto, T. Phytochemistry 1979, 18, 285. (5) (a) Ando, M.; Yamaoka, H.; Takase, K. Chem. Lett. 1982, 501. (b) Edgar, M. T.; Greene, A. E.; Crabbt, P. J . Org. Chem. 1979, 44, 159. (c) Ando, M.; Akahane, A,; Takase, K. Chem. Lett. 1978,727. (d) Ogura, M.; Cordell, G. A,; Farnsworth, N. R. Phytochemistry 1978, 17,957. (e) Ando, M.; Ono, A,; Takase, K. Chem. Lett. 1984, 493. (6) (a) Devreese, A. A,; Demuynck, M.; De Clercq, P. J.; Vandewalle, M. Tetrahedron 1983,39, 3049. (b) Demuynck, M.; Devreese, A. A,; De Clercq, P. J.; Vandewalle, M. Tetrahedron Leu. 1982, 23, 2501. (c) Devreese, A. A.; De Clercq, P. J.; Vandewalle, M. Tetrahedron Lett. 1980, 21, 4767. (7) Posner, G. H.; Babiak, K. A,; Loomis, G. L.; Frazee, W. J.; Mittal, R. D.; Karle, I . L.J. Am. Chem. SOC.1980, 102, 7498. (8) Jacobi, P. A,; Selnick, H. G. J . Am. Chem. SOC.1984, 106, 3041. (9) For an excellent review of the approaches to the pseudoguainolides through 1980, see: Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C. T. In “The Total Synthesis of Natural Products”; ApSimon, J. W., Ed.; Wiley: New York, 1982; Vol. 5 . For some recent developments, see: (a) Ziegler, F. E.; Fang, J.-M. J . Org. Chem. 1981, 46, 8 2 5 . (b) Grieco, P. A,; Majetich, G. F.; Ohfune, Y. J . Am. Chem. SOC.1982, 104, 4226. (c) Grieco, P. A,; Ohfune, Y.; Majetich, G. F.; Wang, C.-L. J. J . Am. Chem. SOC. 1982, 104, 4233. (d) Heathcock, C. H.; Del Mar, E. G.; Graham, S. L. J . Am. Chem. SOC.1982, 104, 1907 and references therein. ( e ) Ziegler, F. E.; Fang, J.-M.; Tam, C. C. J . Am. Chem. SOC.1982, 104, 7174. (f) Schultz, A. G.; Motyka, L. A. J . Am. Chem. SOC.1982, 104, 5800. ( 9 ) Heathcock, C. H.; Tice, C. M.; Germroth, T. C. J . Am. Chem. SOC.1982, 104, 6081. (10) (a) Ito, K.; Iida, T.; Kobayashi, T. Phytochemistry 1984,23, 188. (b) Mathur, S. B.; Hiremath, S. V.; Kulkarni, G. H.; Kelkar, G. R.; Bhatacharyya, S. C.; Simonovic, D.; Rao, A. S. Tetrahedron 1965, 21, 3575.
c ) NaH, C H 3 1 or
ErM
THF.
are prone to double bond m i g r a t i ~ n , ’ ~dienone ~ ’ ~ 4 was usually not purified but immediately subjected to careful reduction to dienol 5 with sodium borohydride a t 0 OC. Facile 1 , s - H shifts that normally characterize the dihydrotropone species appear to (1 1) For other recent hydroazulene approaches, see: (a) Devreese, A. A,; Demuynck, M.; De Clercq, P. J.; Vandewalle, M. Tetrahedron 1983, 39, 3039. (b) Hudlicky, T.; Reddy, D. B.; Govindan, S. V.; Kulp, T.; Still, B.; Sheth, J. P. J . Org. Chem. 1983, 48, 3422. (c) Kozikowski, A. P.; Mugrage, B. B.; Wang, B. C.; Xu, Z. Tetrahedron Lett. 1983, 3705. (d) Metz, P.; Schafer, H.-J.; Henkel, G.; Krebs, B. Tetrahedron Lett. 1983, 1959. (e) Posner, G . H.; Loomis, G. L. Tetrahedron Lett. 1978, 4213. (12) For an excellent review of the chemistry of the cycloheptatrienones, see: Pietra, F. Chem. Reu. 1973, 73, 293. (13) For some recent uses of tropone and its derivatives in synthesis, see: (a) Garst, M. E.; Roberts, V. A,; Prussin, C. J . Org. Chem. 1982, 4 7 , 3969. (b).Rigby, J. H.; Sage, J.-M.; Raggon, J. J . Org. Chem. 1982, 47, 4815. (c) Greene, A. E.; Teixeira, M. A,; Barreiro, E.; Cruz, A,; Crabbe, P. J. Org. Chem. 1982, 47, 2553. (d) Uyehara, T.; Ogata, K.; Yamada, J.; Kato, T. J . Chem. Soc., Chem. Commun. 1983, 17. (14) Radlick, P. J . Org. Chem. 1964, 29, 960. We have been able to double the reported yield of tropone by carefully monitoring the reaction temperature and stirring the reaction mixture. (15) (a) Nozoe, T.; Mukai, T.; Tezuka, J. Bull. Chem. SOC.Jpn. 1961, 34, 619. (b) Chapman, 0. L.; Pasto, D. J.; Griswold, A. A. J . A m . Chem. SOC. 1962. 84, 1213. (16) For a preliminary account of part of this work, see: Rigby, J. H. Tetrahedron Lett. 1982, 1863. (17) Biichi, G.; Wiiest, H. J . Org. Chem. 1969, 34, 1122. (18) Two equivalents of reagent appear to be necessary to obtain maximum yields of adducts. (19) Ter Borg, A. P.; Kloosterziel, H. R e d . Trati. Chim. Pays-Bas 1963, 82, 741.
J . A m . Chem. SOC.,Vol. 106, No. 26, 1984 8219
Synthesis of Cuaianolides be minimized in the absence of the carbonyl group, and the regiochemical integrity of the diene could be maintained over a number of steps. Our attention then turned t o the conversion of the acetal on the three-carbon side chain into a form suitable for closure to the five-membered ring. The need for protecting the alcohol became immediately apparent when all efforts to expose the aldehyde directly from 5 generated only the lactol 8. After considerable
I
8
experimentation methyl and benzyl ethers were chosen as viable forms of alcohol-group protection. This selection was initially predicated on the expectation that these groups would be able to survive a number of operations intact. Although the introduction of the methyl ether proceeded without incident to provide 6a in 85% yield, t h e benzylation was more troublesome. Only poor yields of 6b were obtained with benzyl chloride or bromide a s the alkylating agent. T h e major product of these reactions proved to be substituted cycloheptatriene 7.20 The use of the more reactive benzyl iodide as the alkylating agent gave excellent yields of 6b. In contrast to the situation in the absence of alcohol protection, removal of the acetal now proceeded smoothly on the protected alcohols 6a,b with 5% aqueous T F A in acetone to give the key aldehydes 9a,b in excellent yields. OR
Table I. Effect of Acid on the Cvclization of Aldehvde 9a no. of temp, yield of O C time loa, O/cb entry acid" equiv 1 Et2AICI 2 0 I O min 60 I O min 62 2 SnC1, 2 -78 2 25 4 days 44 3 ZnBr2 2 0 5 rnin 92 4 BF,-Et,O 5 concn TFA 2 25 1.5 h 75 Freshly distilled CH2C12was used as solvent in all cases. Yield of isolated, purified cyclic ether loa. perature gave 10a directly in 77% yield. This remarkable one-step process provided t h e key cyclic ether in yields competitive with the original two-step sequence. T h e geometrical constraints placed on the approach of the tethered aldehyde t o the diene during the formation of cycloadduct2410 ensure that the resulting hydroazulene portion of the molecule possesses a cis fusion.25 In addition, this process fixes the configuration a t C4 relative to the ring fusion, thus providing a potential stereochemical control element for future use. Finally, a fourth asymmetric center a t C, is also present, which may prove useful in the synthesis of members of the Cs-oxygenated series of guaianolides. Thus, this novel protocol provides a n efficient entry into the requisite hydroazulene series if the cyclic ether can be manipulated to reveal the hydroazulene moiety itself in a useful form.26 Reductive fission of allylically activated oxygen-carbon bonds has substantial precedent in the l i t e r a t ~ r e . ~ 'Treatment of 10a with lithium in methylamine a t reflux resulted in the expected smooth scission of the C s carbon-oxygen bond (guaianolide numbering) to give alcohol 11 in 82% yield. Of critical importance OMe
sa , 8 5 % b 75% a ) 5% aq
TFA, acetone, b ) B F 3 e E t 2 0 , '0
82%
!?a , 9 2 % b , 88%
I
C,
CH2C12,
Hd
c ) 5 0 % aq
!!
ME
TFA, C X 2 C l 2 .
T h e stage was set for examining the means for effecting a closure to the five-membered ring. Of critical importance to the successful implementation of this strategy for guaianolide synthesis was the ability to efficiently prepare a cis-fused hydroazulene system since the trans ring fusion is often favored in a n equilibrium process in simple perhydroazulene species.2' It was initially anticipated that a mixture of hydroazulenic diene alcohols would be the principal products resulting from a n acidcatalyzed cyclization of 9.22 However, on treatment with 2 equiv of BF3.Et20 a t 0 O C in CH2C12,aldehyde 9a was rapidly (
