3595
J. Org. C h e m . 1991,56,3595-3601
Studies on the Synthesis of the Diterpenoid Mold Metabolite Sordaricin. Exploration of a Prospective Biogenetic Intramolecular [4 21 Cycloaddition
+
Lewis N. Mander and Ralph P. Robinson**' Research School of Chemistry, Awrtralian National University, GPO Box 4, Canberra, A.C.T. 2601, Australia Received November 12,1990
In a model study directed toward the synthesis of the diterpenoid sordaricin 3, the main carbon skeleton waa established via intramolecular [4 21 cycloadditions of the 5,bcyclopentadienyl derivatives 24 and 30. These intermediatea were prepared by two similar routes, beginning with the alkylation of either the norbomenyl ester 14 or its enantiomer with iodide 16. The oxygenated two-carbon bridge in each of the resulting adducts waa then cut away by a sequence of oxidative processes to form the diene component for the cycloadditions. For 24 this began with the Bayer-Villiger oxidation (21 22) and for 30, Vedejs a-hydroxylation of 27, followed by periodate cleavage. In the latter case, the benzyloxy group waa introduced into the dienophile moiety by selective epoxidation of the isopropenyl group followed by amide-initiated elimination.
+
-
Sordarin (4) is an unusual diterpene glycoside with antifungal properties isolated from the ascomycete Sordaria araneosa Cain.? The structures of both the sugar residue and the aglycon, sordaricin (3), are unique: although the biosynthetic precursor of the latter, cycloaraneosen (1): shares a common skeleton with the fusicoccin diterpenes! It is tempting to speculate that the biogenetic route from 1 to 4 might conceivably proceed by means of an enzyme mediated intramolecular [4 + 21 cycloaddition akin to the conversion 2 3.6J as indicated in Scheme I (the point at which the sugar moiety is appended and the precise level of oxidation are indeterminant). We have accordingly commenced an exploration of this prospect within the context of a total synthesis of 4, the details of which are reported in this paper! A positive outcome for the desired Diels-Alder process was far from assured, given the propensity for [1,5] sigmatropic shifts in cyclopentadienyl systems? The simple trienone 5, for example, affords only 9 (Scheme 11), although the more reactive dienophile moiety in 6 leads to a 3 2 mixture of cycloadducta 8 and 10.lo There is a much more favorable gap between the activation energies required for rearrangement and cycloaddition in 5,5-dialkylcyclopentadienes," and this has been exploited by Fallis and co-workers in a synthesis of sinularene based on the cyclization of 11 to 12 (Scheme II1).l2 It was of some concern, however, that although 11 and its C(4)
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(1) Preaent addrees: P f m r Central Reeearch, Eastern Point Road, Groton, CT 06340. (2) Hauser, D.; S' g, H. P. Helv. Chim. Acta 1971, 54, 1178-1190. (3) V l w l h . A. T.3h.D. Dmrtation,- Eidaenossiechen Techniechen Hochschule, Zurich, 1972. (4) Borschberg, H.J. PbD. Dwrtation, Eidgenoeeiachen Techniechen Hochachule, Zurich, 1975. (6) Barrow, K. D.; Barton, D. H. R.;Chain, E.; Ohnsorge, U. F. W.; Sharma, R. P.; J. Chem. SOC.,Perkin Trans. 1 1975, 1690-1599. (6) It waa considered unlikely that 4 waa an artafact of a thermally induced cycloaddition. (7) For other speculations regarding biogenetic intramolecular [4 + 21 cycloadditions, see: b u s h , W. R.;Myers, A. G. J. Org. Chem. 1981,46, 1609-1611. Rouah, W.R.;Peaeckis, 5.M.;Walk, A. E. J. Org. Chem. 1984,49,3429-3432. Tnkeda, K.; Sato, M.;Ymhii, E. TetrahedronLett. 1986,27, 3903-3908 and references cited therein. (8) We are grateful to Professors Vasella and Arigoni for bringing this problem to ow attention and for helpful d-ions and suggestions. (9) Ciganek, E.Org. React. 1984,32, 1-374. (10) Wallquiet, 0.;b y , M.;Dreiding, A. S. Helu. Chim. Acta 19113,66,
1891-1901. (11) Activation parameters for the rearrangement of 1,5,64rimethylcyclopentadiene: AH* = 40.3 kcal mol-', AS*= -1 eu (DeHaan, J. W.; Klooeteniel, H. Recl. Z'rau. Chim. Pay8-Baa 1968,87, 298-307). (12) Antrrak, K.; Kingston, J. F.; F a i r , A. G. Can. J. Chem. 1986,69, 993-996.
Scheme I
2
i 10
3
OH
Scheme I1
5 R=H 6 R=C02Me
7 R=H, 0% 8 RaCCqMe, 54%
9 R=H, 74% 1 0 R=C02Me,39% Scheme I11 OCOPh
11
epimer react at 67 OC, the 4S,5S and 4R,5S diastereomers failed to react a t temperatures as high as 180 OC. Moreover, the parent system lacking both the isopropyl and alkoxy groups was found to be inert at 195 OC.19 (13) Gallacher, G.; Ng, A. S.; Attah-Poh, S. K.; Antczak, K.; Alward, S. J.; Kingston, J. F.; Fallis, A. G.Can. J. Chem. 1984,62, 17091716.
0022-3263/91/ 1956-3595$02.50/0 0 1991 American Chemical Society
Mander and Robinson
3896 J. Org. Chem., Vol. 56,No.11, 1991 Scheme IV
16
(86%)
$+
& I
20
0
0
1. H g 2 , NaOH
O m o n
2. BFz.Et20
0
MoOs.Py.HMPT
O Me0
23
1. LAH4
i
b
(79% net)
w' 22
2. NalOd
3. DBU
cn=o
(62%)
I
CH=O
relbx, toluene 20h
Med
24
(80%)
_
&25
The formation of 3 was expected to be favored on the basis of both frontier molecular orbital and geometrical considerations (the product of the alternative dienophile orientation requires the C-ring to adopt a boat conformation). However, inspection of a molecular model of 2 shows that the trans relationship between the functionalized side chains attached to the cyclopentane ring forces the dienophile moiety away from what might be assumed to be the preferred geometry for the transition-state structure leading to 3.14 There are also three contiguous quaternary centers in 3 generating steric strain, which is aggravated by the buttressing interaction between the isopropyl group and the carboxyl.16 Given these uncertainties, we chose first to study the intramolecular DielsAlder reactions of the model system 24 which could be expected to be more reactive than 2 and could be more easily prepared (Scheme IV). Regardless of biosynthetic considerations,retroaynthetic analysis of 3 and its analogues guided by the Diels-Alder transforml6 leads logically to an efficient, convergent (14) Townshend, R. E.; Rammuni, C.; Segal, C.; Hehre, W. J.; Salem, L. J . Am. Chem. SOC.1976,98,2190-2198. (15) MM2 calculations on structures 3,26,and further analogues using the Still-Steliou program MODEL indicate a destablizing energy of -6 kcal mol-' associated with the three angular groups plus a further -4 kcal mol-' from the isopropyl substituent.
strategy based in a formal sense on the C(5)dkylation of the cyclopentadienyl ester enolate 13 with alkyl halide 16, which may be prepared as the racemate from citral in four steps," or enantiomerically pure from (+)-camone (17)in nine steps.'8 Because both regio- and stereoselectivity could be expected to be problematical in the alkylation of 13, however, we sought an operationally equivalent molecule to the cyclopentadienyl system which would resolve both of these control problems. C-Methylation of bromo ester 15 at C(7) [equivalent to C(5) in 13 and 241 has been reported to proceed with good diastereofacial selectivity anti to the bromo group in 78% yield (up to 10% of the 7-epimer was also f~rmed).'~We could envisage that one of the two-carbon bridges in the norbornyl moiety could be cleaved with deletion of one carbon center while the remaining carbon would become the carbonyl group in 24. Moreover, both enantiomers of 15 were readily available from norbomadiene,20allowing a useful degree of flexibility in our synthetic planning. Alkylation of (f)-16 with (f)-16, however, furnished a mixture of four diastereomers in which the facial selectivity was only -21, an outcome that was attributed to the greater bulk of 16 and the higher temperature required for this conversion. We therefore proceeded to examine the equivalent alkylation of ester 14, which was obtained as a mixture of 7-epimers by treatment of 15 with DBU. In this case, the a-facial selectivity was complete: reaction of (+)-14 with (4-12 produced only (+)-18 in 84% yield. The configuration at C(7) in this product was inadvertently confirmed when reduction by Red-AI (Aldrich) furnished not only carbinol 19, but the isomeric ketal 20 as well.21 The merest traces of water in the reaction medium or any subsequent exposure to acid led to the formation of variable amounts of the latter compound. After protection of the hydroxy function in 19 as the methyl ether, the ketone function was liberated to afford 21, and the oxygenated bridge of the norbornenyl moiety cleaved by means of a Baeyer-Villiger reaction under alkaline conditions. The resulting hydroxy acid was then lactonized by means of an intramolecular SN2'-like process to form 22.22 The superfluous atoms in the lactone ring were excised by a sequence beginning with a Vedejs hyd r ~ x y l a t i o nto~ ~form 23, followed by reduction to the hydroxy lactol and cleavage with sodium periodate to the P-formyloxy aldehyde. The task was then completed by heating with DBU, which gave the cyclopentadienyl carboxaldehyde 24. In spite of all our trepidations, this product underwent a smooth [4 + 21 cycloaddition in toluene at reflux, affording only a single product after 20 h. 'H and I3C NMR spectra were fully consistent with the assignment of structure 25.24 (16) Corey, E. J.; Cheng, X.-M.The Logic of Chemical Synthesis; Wiley Interscience: New York, 1989. (17) Prepared from the parent aldehyde which waa obtained by the method of Cookson, R. C.; Hudec, J.; Knight, S. A.; Whitear, B. R. D. Tetrahedron 1964, 19, 1995-2007. (18) Obtained from the parent methyl eeter, which waa prepared by the method of Wolinsky, J.; Gibson, T.; Chan,D.; Wolf, H. Tetmhedron 1966,21, 1247-1261. (19) Crieco, P. A.; Pogonoweki, C. S.; Burke, S. D.; Niehizawa, M.; Miyaahita, M.; Masaki, Y.; Wang, C.-L. J.; Majetich, G. J. Am. Chem.Soc. 1977,99,4111-4123. (20) Peel, R.; Sutherland,J. K. J. Chem. SOC.,Chem. Commun. 1974, 151-153. (21) Formation of ketal 20 occurred more easily when LiAlH, was used aa the reducing agent. (22) This procedure is b a d on a sequence described in ref 19. Yields are reduced because of a competing reaction involving the isopropenyl group. (23) Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978,49, 188-196.
Synthesis of Sordaricin
J. Org. Chem., Vol. 56,No.11, 1991 3597 Scheme V
(-------
Table I. 'F NMR Data ( 6 ) 15
(cf.4Scheme s l p 4)*
11
26
ent.-l4
I
(66%)
sordaricane
1. ArCO3H
2. C&jN(iPr)NLi 3. NaH, PhCH2Br
carbon 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
BnO
BnO 7
(75% net)
27
1. Hg106
2. CH2N2
3. H2Cr04-acetone
Me0 P
. Pb(Ok)4, CU(OAc)Z,C& PY
I
2. DBU,DMF, 85"
29
MeOOC.
nooc
I 3-
18
30
Me0
(62%)
toluene, reflux,32h (89%)
-- ..
C0,Me
1
--3329 24-
CH,OR
31 R = B n - 3 2 R=AcZ8
Having established the feasibility of the cycloaddition in this way, we proceeded to explore methods for hydroxylation of the isopropenyl group and to develop a more efficient procedure for the oxidative fission of the norbornenone moiety. The successful outcome of these investigations is outlined in Scheme V. The new sequence, for which yields were consistently good to excellent, began with the (-)-enantiomer of 14. This was converted into ketone 26 in the same way as for the preparation of the previously employed diastereomer 21. Alkene bonds in norbomenes tend to react very readily with electrophiles, but presumably because of the deactivating influence of the adjacent carbonyl group in 26, the propenyl group could be selectively oxidized to a mixture of diastereomeric epoxides, which was treated with lithium cyclohexyl(isopropy1)amide (LICA)= to afford the desired allylic alcohol. This was protected as the benzyl ether 27 and converted by the Vedejs reagent23into a mixture of epimeric a-ketols 28 (exolendo = -2:3). These were cleaved by periodic and the resulting carboxy aldehyde was isolated as its methyl ester. Oxidative decarboxylation of the derived acid 29 with lead tetraacetaten afforded a mixture of allylic acetates, which were cleanly eliminated with DBU to the cyclopentadiene 30. The intramolecular cycloaddition then proceeded with equal ~
(24) The racemic C(6) diaatereomeric mixture WBB available from -p experiments and when a solution in toluene WBB heated under reflux for an extended period, 6-epi-24 WBB recovered largely unchanged, although a very small amount of an impure isomeric cycloadduct assumed to arise from this isomer waa obtained. (25) Crandall, J. K.; Apparu, M. Org. React. 1983,29, 345-443. (26) Only the exo isomer waa cleaved by NaIO,. (27) Kochi, J. Org. React. 1972, 19, 279-421.
25
31
32
33
128.6 139.3 49.6 36.0 47.9 70.7 67.3 32.2 42.3 32.8 27.3 29.7 45.7
130.7 138.6 47.5 32.0 50.2 64.4 67.2 31.6 41.1 32.0 26.7 28.8 40.3
130.8 139.7 47.9 32.5 49.1 65.4 67.5 32.3 41.7 31.9 27.1 29.2 41.4
22.7 205.4 78.6 18.0
75.1 172.8 77.9 17.6
69.3 173.1 78.2 18.0
149.2 130.5 45.8 32.5 49.3 70.1 67.3 31.2 41.6 31.7 27.8 29.2 45.2 28.4 21.5 22.7 70.3 173.0 70.8 18.0
facility as before to give 31 in an excellent overall yield. Spectroscopiccomparison of 31 and 32= with 33 [obtained by degradation of sordaricin (3)],29indicated that the respective skeletons were the same, apart from the isopropyl group. 13C NMR spectra (Table I)30were especially diagnostic and showed excellent agreement, after making allowance for the expected discrepancies arising from the minor differences between the two structures. The only apparent anomaly in these comparisons is the downfield shift for C(13) in 33 relative to 31 and 32. However, it seems reasonable to assume that C(13) in the latter compounds is shifted upfield by ca. 4 ppm because of the antiperiplanar relationship between what appears to be the preferred orientation of the y-oxygen substituent and the C(5)-C(13) bond.31 In 33, this conformation would be disfavored by nonbonded interaction with the isopropyl group, and so the shift of 45.2 ppm for this compound then matches that of the desoxy analogue, 25 (45.7 ppm). The possibility that 4 was an artefact of a simple, thermally induced cycloaddition was never considered to be likely, but may now be fully discounted. The formation of 25 and 31 at relatively moderate temperatures, however, is consistent with an enzyme-catalyzed conversion for the biosynthetic intermediate, a prospect that is the subject of a continuing investigation. Our efforts to utilize 31 as ~~
(28) In an exploratory study to determine the optimal stage for the introduction of the 17-OH group, the isopropylene group in 24 waa selectively oxidized to give a mixture of epimeric epoxides, following which, treatment with LICA and cycloaddition gave a modest overall yield of the 17-hydroxy derivative of 25. Because of the low yields in this sequence we had transferred our attention to the alternative and more efficient approach outlined in Scheme V, but the availability of this compound enabled ua to prepare 32 (via acetylation, oxidation, and methylation) so aa to allow additional spectroscopic comparisons with 33. (29) This sample waa kindly provided by Professors Arigoni and Borschberg, Eidegenossischen Technischen Hochschule, Zurich. (30) The trivial name sordaricane is proposed for the carbon skeleton of sordaricin derivatives. The numbering system follows that used by Vaaella (ref 2). (31) Eliel, E. L.; Bailey, W. F.; Kopp, L. D.; Willer, R. L.; Grant, D. M.; Bertrand, R.; Christensen, K. A.; Dallin, D. K.; Duch, M. W.; Wenkert, E.; Schell, F. M.; Cochran, D. W.; J . Am. Chem. SOC. 1975, 97, 323-330.
3598 J. Org. Chem., Vol. 56, No. 11, 1991
an intermediate in the total synthesis of sordaricin 3 will be described later.
Experimental Section Organic extracts were routinely dried over anhydrous MgSO,. Chromatography refers to “flash chromatography” on Merck Kieselgel 60. Optical rotations and IR spectra were measured in CHCl, solutions. NMR spectra were recorded in CDC13at 200 MHz (‘H). Methyl (1’S,4’R)-Bicyclo[2.2.l]hept-5’-bne-2’-spiro-2[1,3]dioxolane-7’~-carboxylate (14). A degassed solution of bromo ketal 15 (3.41 g, 11.7 “01) in p-xylene (13.5 mL) and DBU (17 mL) was heated at reflux under argon for 11.5 h. The cooled mixture was diluted with ether and washed with 1 N HCl and brine. The product was diesolved in methanol (70 mL) and treated with ethereal CHIN2until TLC indicated disappearance of carboxylic acid, and then the solvent was removed under reduced pressure. Chromatography on Si02 with 1:l EhO/hexane as eluant furnished ester 14 as a -1:l mixture of 7-epimers (1.94 g, 79%), [aImD +116.7” (C 4.82), ,,Y 1730 cm-’. ‘H NMR ( ~ y n (7s) epimer) 1.57 (d, 1 H, J = 13.7 Hz, H3a), 1.99 (dd, 1 H, J = 13.7,3.9 Hz, H3@),2.97 ( 8 , 1 H, H7), 3.03 (br 8, H4), 3.19 (br 8, Hl), 3.62 ( 8 , 3 H, OMe), 3.9 (m, 4 H, OCH2CH20),6.07 (dd, 1H, J = 5.4,2.7 Hz, H5), 6.31 (dd, 1H, J = 5.4,2.7 Hz, H6); (anti (7R) epimer) 1.57 (dd, 1 H, J = 13.7, 2.8 Hz, HBa), 1.99 (dd, 1 H, J = 13.7, 3.7 Hz, H3@),2.77 (br 8, 1 H, H7), 3.07 (br s, H4), 3.19 (br 8, Hl), 3.68 (s,3 H, OMe), 3.9 (m, 4 H, OCH2CH20),6.16 (dd, 1H, J = 5.8,2.9 Hz, H5), 6.31 (dd, 1H, J = 5.8,2.9 Hz, H6). MS m / z 210 (M+,33): 195 (5), 151 (loo),86 (45). HRMS: calcd for CllH1404 210.0892, found 210.0894. [(lR$R$R)-5-Methyl-2-( 1’-methylethenyl)cyclopentyl]methyl Iodide (16). p-Toluenesulfonyl chloride (1.7 g, 8.9 “01) was added to a cooled solution of carbinol in pyridine at 0 OC under argon. The sealed mixture was allowed to stand for 3 days at 4 “C then poured onto ice and extracted with ether. The ether extract was washed with NaHC03solution (ZX), 1N HCl, NaHC03, and brine. A solution of this product in DMF (27 mL) at 0 “C was treated with NaHC03 (0.54g, 6.42 mmol) and LiI (2.55 g, 19.05 mmol), stirred at 0 OC for 1 h and 10 min, and then warmed to 75 OC. After 7 h the mixture was kept at room temperature overnight, diluted with ether, and washed Wth NaHC03, HI0 (3x), and brine. The product was chromatographed on silica (3 X 17 cm) with hexane as eluant to afford pure iodide 16 (1.50 g, 86%), [a]=D -54” (c, 5.41, hexane), Y , 1640 ~ cm-’. ‘H NMR: 0.87 (d, 3 H, CH-Me), 1.68 (d, 3 H, J = 0.7 Hz,=CMe), 2.90 (apparent t, 1 H, J = 10.3 Hz, CH21),3.23 (dd, 1H, J = 5.9, 3.6 Hz, CH21),4.72, 4.74 (2 br 8, 2 X 1 H, =CHI). 13C NMR 7.7 (CH21),14.9 (Me), 19.2 (Me), 30.5 (CHI), 32.1 (CHI), 36.4 (CH), 49.8 (CH), 51.0 (CH), 111.5 (-CHI), 146.8 (4). HRMS cald for C1,,H1,l 264.0375, found 264.0375. Methyl ( ltS,4’R,7’R ,1”R,2”R ,5”R )-7’4 [I”-Methyl-t“(l’”-methylethenyl)cyclopentyl]methyl]bicyclo[2.2.l]hept5’-ene-Y-spim2-[ 1,3]dioxolane-7’-carboxylate(18). A solution of n-BuLi in hexane (1.6 M, 12.8 mL, 20.5 mmol) was added to a mixture of THF (40 mL) and diisopropylamine (2.85 mL, 20.3 mmol) at -30 OC under an argon atmosphere, stirring was continued at -30 to -20 “C over a period of 0.5 h, and then the temperature was lowered to -78 OC. A solution of ester 14 (3.77 g, 17.93 ”01) in THF (40 mL) (dried over 4-A molecular sieves) was injected dropwise at a rate of 0.3 mL/min with the aid of a syringe pump. After the mixture was stirred at -78 OC for 75 min, HMPT (3.6 mL, 20.7 “01) was added, and the resulting mixture was warmed to 0 OC. A solution of iodide 16 (5.6 g, 21.2 mmol) in THF (dried over 4-A molecular sieves) (6 mL + 6 mL rinse) was added, and the mixture was stirred at room temperature overnight (16 h). After the reaction was quenched with H20 (5 mL), the THF was removed in vacuo and the residue taken up in ether, and washed with H20 (2X) and brine. The crude product was chromatographed on silica gel (5 X 17 cm) using 3:2 hexane/ether as eluant. The pure ketal ester 18 was obtained as a V k I u s oil, 5.21 g (84%), [aIBD +6.9’ (c 3.24, U1727, 1640 m-’. ‘H NMR 0.72 (d, 3 H, J = 7.3 Hz, CHMe), 1.56 (d, 3 H, J = 0.5 Hz, =CMe), 2.75 (br 8, 1 H, H4), 3.03 (br s, 1 H, Hl), 3.64 (s,3 H, OMe), 3.8-3.9 (m, 4 H, OCH2CH20),4.62,4.67 (2 br s,2 x 1 H, ..;;CHI), 6.07 (dd, 1 H, J 5.7, 3.2 Hz, H5), 6.24 (dd, 1 H, J = 5.7, 2.9 Hz, H6). 13CNMR 15.7 (Me),18.4 (Me), 27.3 (CHI),
Mander and Robinson 29.1 (CHI), 33.1 (CHI), 35.4 (CH), 39.3 (CHI), 44.3 (CH), 50.9 (OMe), 51.2 (CH), 57.0 (CH), 64.3,64.4 (OCHICHIO), 72.0 (c), 111.2 (
