J . Org. Chem. 1980,45, 4077-4085
4077
Stereoselective Total Synthesis of (&)-Trichodiene: Biogenetic Precursor of the Trichothecane Sesquiterpenoids Steven C. Welch,* A. S. C. Prakasa Rao, Charles G. Gibbs, and Rayman Y. Wong Department of Chemistry, University of Houston, Houston, Texas 77004
Received April 10, 1980 Two approaches to the total synthesis of (*)-trichodiene (1)are reported from cis-fused lactone 10. Sequential alkylation of lactone 10 was observed to be highly stereoselective as established by the construction of dimtereomeric lactone esters 12 and 14. Lactone ester 12 was utilized to prepare (&)-trichodiene (1) with a high degree of regioselectivity. All attempts to synthesize (A)-bazzanene (2),the diastereomer of (*)-trichodiene (l),from lactone 13 were found to be unsuccessful in the last stage of the synthetic scheme.
The sesquiterpene hydrocarbon (*)-trichodiene (1, Scheme I) was isolated from the extract of mycelium of the fungus Trichothecium roseum Link. The structure of trichodiene (1) was determined by Nozoe and Machida in 1970 via degradation and spectroscopy.' Trichodiene (1) was found to arise, biogenetically, from all trans-farnesyl pyrophosphate via Trichothecium roseum.2 Trichodiene (1) has also been shown to be the biogenetic precursor of the trichothecane family of sesquiterpenoids as characterized by the cytotoxic fungal metabolite (-)-trichodermin (3).2-4 The structure and absolute stereochemistry of (-)-trjchodermin (3) were elucidated by X-ray diffraction, and, therefore, the structure and absolute stereochemistry of trichodiene (1) are now firmly e~tablished.~The trichothecane family of sesquiterpenoids contains a wide variety of biologically active antifungal, antitumor, cytotoxic, and phytotoxic mole~ules.~JThe natural products are potent inhibitors of protein and DNA syntheses in eukaryotic cells. The mode of action of the trichothecanes is thought to occur by binding to eukaryotic polysomes and ribosomes followed by inactivation of the ribosomal cycle.8 In 1969 Matsuo and co-workers isolated (+)-bazzanene (2, Scheme I) from leafy liverworts Bazzania pompeana (Hep~ticae).~ However, Andersen and co-workers in 1977 revised the original structural assignment to that represented by structure 2 on the basis of spectroscopic data and biogenetic considerations.1° Concurrently, Matsuo and Hayashi also revised their original structural assignment and absolute configuration to conform to structure
Scheme I biogenesis
____
--*
-3
-2
-4 Scheme 11. Retrosynthetic Plan
ra
28
-f'3"p, ao- a, Scheme 111. Preparation of Lactone LI
(1) Nozoe, S.; Machida, Y. Tetrahedron 1972,28, 5105-5111; Tetrahedron Lett. 1970, 2671-2674. (2) Evans, R.; Hanson, J. R.; Marten, T.J. Chem. SOC., Perkin Trans 1 1976,1212-1214. Evans, R.; Hanson, J. R. Ibid. 1976,226-239; J. Chem. SOC., Chem. Commun. 1975,231-232. Evans, R.; Holton, A. M.; Hanson, J. R. Ibid. 1973, 465. (3) Machida, Y.; Nozoe, S. Tetrahedron 1972,28, 5113-5117; Tetrahedron Lett. 1972, 1969-1972. Arigoni, D.; Cane, D. E.; Muller, B.; Tamm, C. Helu. Chim.Acta 1973,56, 2946-2949. (4) Godtfredsen, W. 0.; Vangedal, S. Acta Chem. Scand. 1964, 19, 1088; Proc. Chem. SOC. 1964, 188.
(5) For the X-ray structure of trichodermin, see: Abramson, S.; Nilsson, B. Proc. Chem. SOC.,London 1964,188. For the X-ray structure of verrucarin A, see: McPhail, A. T.; Sim, G. A. J. Chem. SOC.C 1966, 1394-1406. (6) For reviews of the trichothecane family of sesquiterpenes, see: Ta", C. Forschr. Chem. Org. Naturst. 1914, 31, 63; Turner, W. B. "Fungal Metabolites"; Academic Press: New York, 1971; pp 219-223. (7) For the structure of verrucarol, see: Gutzwiller, J.; T a " , C. Helu. Chim. Acta 1968,48,157-176. For the structure of diacetoxyscripenol or anguidin (NCI No. NSC-141537),see: Dawkins, A. W. J. Chem. SOC. C 1966,116-123; Dawkins, A. W.; Grove, J. F.; Tidd, B. K. J. Chem. SOC., Chem. Commun. 1965,27-28; Flury, E.; Mauli, R.; Sigg, H. P. Ibid. 1965, 26-27. (8) Ueno, Y. Pure Appl. Chem. 1977,49, 1737. (9) Hayashi, S.; Matsuo, A.; Matsuura, T. Experientia 1969, 1139. Matsuo, A. Tetrahedron 1971,27, 2757-2764. (10) Andersen, N. H.; Bissonette, P.; Liu, C.-B.; Shunk, B.; Ohta, Y.; Tseng, C.-L. W.; Moore, A.; Huneck, S. Phytochemistry 1977, 16, 1731-1751. Ohta, Y.; Andersen, N. H.; Liu, C.-B. Tetrahedron 1977,33, 617-628.
0022-3263/80/1945-4077$01.00/0
OAc
5
lo
C02E!
9
1,
-
loa
6
-7
9
-
08:
8
a (a) NaH, DME. ( b ) BrCH,CH=CH,. (c) RuC1, (catalyst), NaIO,, H,O, t-BuOH. (d) 0,, CH,Cl,, - 7 8 "C. ( e ) Zn, HOAc. ( f ) H,CrO,, acetone. (g) EtI, K,CO,, acetone. ( h ) Br,. HOAc. (il CaCO,. DMA. ( j ) KOH/EtOH/ H,O. (k)H 3 6 + . (1) 2x 'i;Bu,AlH; C,H,, Ci.jiC1,. (m) 10% H,SO,.
2 for (+)-bazzanene on the basis of further degradation and spectroscopy.ll Bazzanene (2) is thought to be the biogenetic precursor of another family of cyclotrichothecanes, one member of which is (+)-gymnomitrol (4).12 Trichodiene (1) and bazzanene (2) are diastereomers. We wish to report, herein, the full details of our successful stereo(11) Matsuo, A.; Hayashi, s. J . Chem. SOC., Chem. Commun. 1977, 566-568. (12) See ref 1-4 in the following paper.
0 1980 American Chemical Society
4078 cJ. Org. Chem., Vol 45, LVo.21, 1980 selective total synthesis of (*)-trichodiene (1) and our attempts to construct (&)-bazzanene (2) via a common synthetic intermedia te.13J4 One of the most difficult tasks that beset the synthetic organic chemist is the construction of two adjacent chiral quaternary centers with a high degree of stereoselectivity. This objective becomes a real dilemma when the two adjacent chiral quaternary centers are free to rotate about a common carbon-carbon single bond as in the diastereomers trichodiene (1) and bazzanene (2). One excellent method which has been utilized to solve this type of stereochemical enigma is to direct sequential alkylation reactions in a cis-fused ticyclic carbonyl compound from the less hindered convex side of the molecule. In a retrosynthetic plan (Scheme 11) it should be possible to construct trichodiene (1) and bazzanene (2) from the respective cyclopentanones 18 and 28 by some type of carbonyl-tomethylene transfer re,zgent or process. Ketones 18 and 28 could be prepared from diastereomerically pure lactones 12 and 14 [R = (CH,),C02Me], respectively. The stereoselective synthesis of lactones 12 and 14 from cis-fused lactone 10 might be realized, hopefully, by sequential methylation and alkylation [R = (CH,),OTHP] or the reverse alkylation [R == (CH,),CH=CH2] and methylation, followed by appropri,zte chemical manipulation. It is in this latter stage of these syntheses that the stereochemical problems associated with trichodiene (1) and bazzanene (2) need to be solved Finally, in a retrosynthetic sense, lactone 10 should be readily available from 2,5-dimethylcyclohexanone (5) in a limited number of synthetic steps. Thus the synthesis begins with ketone 5. Ketone 5 (Scheme 111) is alkylated regioselectivity in the following manner. The thermodynamically more stable A1z2 enolate anion is generated with sodium hydride in 1,2-dimethoxyethane. Conia reports that selective generation of the A1,, eiiolate anion is reinforced by both methyl substitutents at positions 2 and 5.15 Carefully controlled quenching of this enolate anion with allyl bromide at 0 "(2 affords ketoalkene 6 in 74% yield after fractional distillation. Two methods of oxidative cleavage of alkene 6 were explored. Ozonolysis16 of alkene 6 in dichloromethane at -78 "C followed by reduction with zinc (13)For previously reported synthetic efforts within the trichothecane family of sesquiterpenoids, see: (trichodermin) (a) Colvin, E. W.; Malchenko, S.; Raphael, R. A,; Roberts, J. S. J . Chem. SOC.,Perkin Trans. 1 1973,198S-1977; (b) Colvin, E. W.; Raphael, R. A.; Roberts, J. S. Chem. (c) Masoka, N.; Commun. 1971,858-859; (12,13-epoxytrichothec-9-ene) Kamikawa, T. Tetrahedron Lett. 1976, 1691-1694; (d) Fujimoto, Y.; Yokura, S.; Nakamura, T.; Morikawa, T.; Tatsuno, T.; Kenkysho, R. Ibid. 1974,25%3-2526: (13-nort1ichothec-9(lO)-ene)(e) Masuoka, N.; Kamikawa, T.; Kubota, 'l'.Cheni. Lett. 1974,751-754;.(trichoenone) (0 Yamakawa, K.; Sakaguchi, R.; Nakamura, T.; Watanake, K. Ibid. 1976, 991-992; (other synthetic approaches) (9) Colvin, E. W.; Malchenko, S.; Raphael, R. A.; Roberts, J. S. J . Chem. SOC.,Perkin Trans. 1 1978, 658462; (h) Trost. B.; Rigby, J. H. J. Org. Chem. 1978,43,2938-2940; (i) Snider, B. B.; Amin, S. G. Synth. Commun. 1978, 8 , 117-125; 6 ) Anderson, W. K.; LaVoie, E. J.; Lee, G. E. J . Org. Chem. 1977, 42, 1045-1050; Anderson, W. K.;Lee, G. E. Ibid. 1980, 45,501-506; (k) Goldsmith, D. J.; Lewis, A. J.; Still, W. C., Jr. Tetrahedron Lett. 1973, 4807-4810; (I) Goldsmith, r).J.: Helmes, C. T., Jr. Synth. Commun. 1973, 231-235; (m) Still, W. C., Jr.; Lewis, A. J.; Goldsmith, D. J. Tetrahedron Lett. 1971,1421-1424; (n) Still, W.C., Jr.; Goldsmith, D. J. J . Org. Chem. 1970,35,2282-2286;( 0 ) Curie, M. J . Chem. Soc., Perkin Trans. 2 1973, 24@243; (p) Pearson, A. J.; Raithby, P. R., J . Chem. Soc., Perkin Trans. 1 1980,395-399; (r) Still, U'. C.; Isai, M.-Y. J. Am. Chem. Soc.'1980,102, 3654-3685; (s) Kodama, M.;Takahashi, T.; Kurihara, T.; It6, S. Tetrahedron Lett. 1980,2811-2012. (14)For previous reports on the sythesis of trichodiene (l),see: Welch, S.C.; Rao, A. S. C. P.; Gibb's,C. G. Synth. Commun. 1976,485-488;(b) Welch, S.C.; Rao, A. S. C. P.: Wong, R. Y. Ibid. 443-445; (c) Welch, S. C.; Won{:, R. Y. Tetrahedron Lett. 1972, 1853-1856. (15)(a) Conia, J.-M. Rec. Chem. Prog. 1963,24,42-62.(b) House, H. Ibid. 1967, 28, 98-120; "Modern Synthetic Reactions", 2nd ed; W. A, Benjamin: Menlo Park, C.4, 1972;Chapter 9. (16) Bailey, P. S. Chem. R e v . 1958,58,925-1010.
Welch et al. Scheme IV. Alkylation of Lactone
loa
H
Y
ra
r_? d
l
1
(a) LDA, DME. ( b ) CHJ. ( c ) Br(CH,),OTHP, HMPA. ( d ) p - T s O H , CH,OH. ( e ) H,CrO,, acetone. ( f ) CH,N,, Et,O. ( 9 ) Br(CH,),CH=CH,, HMPA. ( h ) OsO, (catalyst), NaIO,, H,O, t-BuOH. a
powder in acetic acid, oxidation with Jones reagent,17 and esterificationla with ethyl iodide in the presence of anhydrous potassium carbonate in acetone affords keto ester 7 in 75% overall yield. Alternatively, oxidation of alkene 6 with sodium metaperiodate in aqueous tert-butyl alcohol in the presence of a catalytic amount of ruthenium trichloride followed by esterification gives keto ester 7 in 88% overall yield.lg Bromination of keto ester 7 followed by dehydrobromination of the crude bromo ketone with anhydrous calcium carbonate in refluxing N,N-dimethylacetamide (DMA) produces enone 8 in 88% yield.z0 Saponification of enone ester 8 with potassium hydroxide in aqueous ethanol gives keto acid 9 in 95% yield after acidification. Reductive lactonization of keto acid 9 to lactone 1013,a9bJ4 in 90% yield was smoothly accomplished by sequential treatment of keto acid 9 with 2 equiv of diisobutylaluminum hydridez1in benzenedichloromethae at 0 "C followed by quenching the 10% sulfuric acid a t 0 "C. This lactonization presumably proceeds via intramolecular attack of the carboxylic acid group on an intermediate allylic carbonium ion. Examination of a Dreiding stereomodel for this lactonization intermediate suggests that this cyclization should be highly regioselective and should produce the desired cis-fused y-lactone 10. This stereochemical outcome is confirmed by NMR spectroscopy. The dihedral angle subtended by the allylic oxymethine proton and the vinyl proton is approximately 40". The predicted coupling constant, based upon the Karplus equation,z2would be between 4 and 5 Hz. The observed coupling constant for the allylic oxymethine doublet at 6 4.24 is 4 Hz. The respective dihedral angle for a trans-fused lactone is about 90" which is associated with a vicinal coupling constant near zero according to the Karplus equation.22 These data are fully consistent with a cis-fused y-lactone for structure 10, and no trans-fused y-lactone was observed or isolated. Lactone 10 also was prepared by Raphael and c o - w o r k e r ~in~ their ~ ~ . ~synthesis of (-)-trichodermin (3). Methylation of lactone 10 (Scheme IV) by generating the enolate anion with lithium diisopropylamide (LDA) in DME followed by the addition of methyl iodide gives (17)(a) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. L. J . Chem. Soc. 1946,39-45. (b) Djerassi, C.; Engle, R. R.; Bowers, A. J . Org. Chem. 1956, 21, 1547-1549. Eisenbraun, E. J., "Organic Syntheses"; Wiley: New York, 1973;Collect. Vol. 5,pp 310-314. (18)Ireland, R. E.; Evans, D. A.; Glover, D.; Rubottom, G. M.; Young, H. J . Org. Chem. 1969,34,3717-3729. 1963,85, (19)Stork, G.; Meisels, A,; Davies, J. E. J . Am. Chem. SOC. 3419-3425. (20)Marshall, J. A.; Andersen, N. H. J . Org. Chem. 1966,31,667473. 1952,2852-2856. (21)Macbeth, A. K.; Shannon, J. S. J . Chem. SOC. (22)Bhacca, N.S.; Williams, D. H. "Applications of NMR Spectroscopy in Organic Chemistry"; Holden-Day: San Francisco, 1966:pp 49-52.
Synthesis of (*)-Trichodiene Scheme V. Synthesis of
J. Org. Chem., Vol. 45, No. 21, 1980 4079 (5
FTrichodiene ( l)a
(a) Ca, NH,, T H F , HMPA, -33 "C. ( b ) H,O'. (c) H,CrO,, acetone. ( d ) CH,N,, Et,O. (e) NaN(SiMe,),, DME. ( f ) DBU, xylene, A . (g) Chromatography on 1 5 % AgN0,-silica gel 60 using 2.5% Et20-97.5% petroleum ether ( b p 30-60 "C) a s a n eluant. ( h ) Ph,P=CH,, Me,SO, A . (i) HCl(g), CH,Cl,, -20 "C. ( j ) 2,4,6-Collidine, A . (k) DBU, 2,4,5-collidine, A . (1) LiAlH,, Et,O. ( m ) 1 5 % NaOH, H,O. ( n ) Li, NH,, Et,O, EtOH. (0)C h r o m a t o g raphy on 1 5 % AgN0,-silica gel 60 using 25% Et,0-75% petroleum ether ( b p 30-60 "C) as an eluant.
the corresponding monomethyl lactone, 10A,13a,23in quantitative yield. Alkylation of methyl lactone 10A by generation of the enolate anion with LDA in DME followed by quenching with 4-bromobutyl tetrahydropyranyl ethera dissolved in hexamethylphosphoric triamide (HMPA) and subsequent methanolysis in the presence of p-toluenesulfonic acid affords lactone alcohol 11 in 83% overall yield. This alkylation appears to be highly stereoselective. It is expected that this alkylation should take place from the less hindered convex side of the cis-fused bicyclic enolate anion. Oxidation of alcohol 11 with excess Jones reagent" in acetone and esterification of the resulting acid with an ethereal solution of diazomethane produces a mixture of lactone esters 12 and 14 in 81% yield as a 96:4 ratio of diastereomers, respectively. These two isomers are readily distinguishable by GLC, LC, NMR, and melting point. The reverse alkylation sequence to that mentioned above resulted in incomplete methylation and poor stereoselectivity in the second stage. However, alkylation of lactone 10 with 5-bromo-1-pentene in HMPA followed by methylation under similar conditions to those utilized earlier gives lactone 13 in 86% overall yield. Oxidative cleavage of alkene 13 with sodium metaperiodate in aqueous tert-butyl alcohol in the presence of a catalytic amount of osmium tetraoxide produces an intermediate aldehyde.25 Oxidation of this aldehyde with Jones reagent" in acetone followed by esterification with an ethereal solution of diazomethane affords a mixture of lactone esters 12 and 14 in 67% overall yield as a 2:98 ratio of diastereomers, respectively. Thus the stereochemical problems associated with the syntheses of diastereomers trichodiene (1) and bazzanene (2) are resolved with a (23) Herrmann, J. L.; Schlessinger, R. H. J . Chem. SOC.,Chem. Commun. 1973,711-712. (24)(a) Starr, D.;Hixon, R. M. "Organic Syntheses"; Wiley: New York, 1943;Collect Vol. 2,pp 571-572. (b) Ferdinandi, E.S.; Just, G. Can. J. Chem. 1971.49. 1070-1084. (25)Pappo, R.;Allen, D. S.; Lemieux, R. U.; Johnson, W. S. J . Org. Chem. 1956,21,478-479.
reasonably high degree of stereoselectivity.26 Hydrogenolysis of the allylic carbon-oxygen bond of lactone alcohol 11 (Scheme V) is smoothly effected by calcium metal in liquid ammonia-HMPA-tetrahydrofuran (THF) at -33 0C.27 Acidification affords a carboxylic acid alcohol which when oxidized with Jones reagent17 in acetone followed by esterification with an ethereal solution of diazomethane gives diester 15 in 64% overall yield as a 36:64 ratio of tri- to disubstituted alkenes, respectively. Other metals (Li, Na, K, or Zn) and conditions proved to be much less efficient in terms of the regioselectivity of the desired trisubstituted alkene isomer. Dieckmann condensation2* of diester 15 with 4 equiv of sodium bis(trimethylsilyl)amideZ9in DME followed by quenching with 5% HCl at 0 "C produces @-ketoester 16 in 97% yield. Decarboxylation of P-keto ester 16 with 1,5-diazabicyclo[5.4.0]undec-5-ene(DBU)30in refluxing xylene for 16 h produces enones 17 and 18 in 98% yield in a 64:36 ratio, respectively. These enones were separated by high-pressure LC on 15% silver nitrate impregnated silica gel 603' with 2.5% ether-97.5% petroleum ether (bp 30-60 "C) as an eluant. Trichoenone (18)was converted into (kbtrichodiene (1)in 51% yield with 10 equiv of methylenetriphenylphosphorane Wittig reagenP2 in scrupulously dried dimethyl sulfoxide, despite the fact that previous r e p o r t ~ ' J ~indicated ~ 9 ~ ~ that this reaction was unsuccessful. The IR, NMR (60 and 100 MHz), and mass spectral data for synthetic (&)-trichodiene (1) and the corresponding mono- as well as the diepoxide" of 1 were identical with the respective data r e p ~ r t e d l - ~ Jfor l the natural substance. Because of the poor regioselectivity in the construction of trichoenone 18 by the aforementioned rdute, an alternative synthesis of enone 18 was devised and explored. Dieckmann condensation2*of lactone ester 12 (Scheme V) with 3.5 equiv of sodium bis(trimethyl~i1yl)amide~~ in DME followed by quenching with 10% HC1 at 0 "C produces @-ketoester 19 in 97% yield. All attempts to hydrolyze and decarboxylate P-keto ester 19 under acid, base, or neutral conditions gave only the lactone carboxylic acid corresponding to lactone ester 12. The hydroxyl function of compound 5 could not be esterified under ordinary conditions (Ac20,pyridine; Ac20, HOAc, HClO,; MsCl, Et3N, CH2C1,; p-TsC1, pyridine). However, treatment of allylic alcohol 19 with anhydrous hydrogen chloride gas in dichloromethane at -20 "C affords an unstable tertiary allylic chloride, presumably by SN2' rearrangement. Dehydrochlorination of this intermediate chloride by heating it in 2,4,6-collidine at 180-185 "C for 25 min produces diene 20 in 86% overall yield from alcohol 19. Decarboxylation of 0-keto ester 20 with DBU30 in 2,4,6(26)Shortly after preliminary communication of our successful syntheses of (&)-trichodiene(1)we received a personal communication from Professor W. Kreiser, University of Braunschweig. Professor W. Kreiser and M. Scholtz (Ph.D. Dissertation, 1976)have prepared lactone 12 [R = (CH2)J, Scheme 111 and characterized this compound by X-ray diffraction in conjunction with Professor U. Thewalt. Professor W. Kreiser and M. Scholtz also have synthesized lactone 12 [R = (CH2)3C02Me]as well as structures 15 and 17-19 independently. We thank Professor W. Kreiser for providing us with this information. (27)Birch, A. J.; MacDonald, P. L.; Powell, V. H. J . Chem. SOC.C 1970, 1469-1476. (28)Thyagarajan, B. S. Chem. Reu. 1954, 54, 1029. Wolf, D. E.; Folkers, K. Org. React. 1951,6,410-468.Hauser, C. R.;Hudson, B. E. Ibid. 1942,1, 266-302. (29)Kriiger, C.; Rochow, E. G.; Wannagat, U. Chem. Ber. 1963,96, 2132-2137. (30)Parish, E. J.; Miles, D. H. J . Org. Chem 1973, 38, 1223-1225. (31)Gupta, A. S.;Dev, S. J . Chromatogr. 1963,12,189-195. (32)Maercker, A. Org. React. 1965,14,270-490. Corey, E.J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345-1353. Greenwald, R.; Chayakovsky, M.; Corey, E. J. J . Org. Chem. 1963,28,1128-1129.
4080 J. Org. Chem., Vol. 45, No. 21, 1980
Welch et al. Table I
Scheme VI. Synthesis of ( + FBazzanenone ( 2
reagents and conditionse
I !!
a ratio 6 3
(C,H.LP=CH,. Me,SO CH,c
