FULL PAPER

DOI: 10.1002/ejoc.201402461

Sterically Controlled Diels–Alder Cycloadditions: Rapid Entry into the IlludinScaffold

Lars Stevens-Cullinane,[a] Nigel T. Lucas,[a] and Bill C. Hawkins*[a]

Keywords: Cycloaddition / Synthetic methods / Regioselective / Fused-ring systems

Rapid entry into the tricyclic ring system of the illudin familyof natural products was achieved using a Diels–Alder cyclo-addition of allylidenecyclopropane 7 and various cyclic and

Introduction

Fungi are a well-known source of biologically activecompounds,[1] with numerous sesquiterpenes being isolatedincluding the potent anticancer illudins [illudin S (1) andcoprinastatin (2), Figure 1].[2] The illudins possess excep-tional antitumor activity that has been extensively studied,but unfortunately their high cytotoxicity is accompanied bya lack of specificity, as demonstrated by their low thera-peutic indices.[3] As a result of this poor clinical profile, sev-eral structural analogues of the illudins have been synthe-sised and their pharmacological properties evaluated.[4] Themost promising of these to date is irofulven (3, Figure 1)which reached phase II clinical trials for the treatment ofovarian, prostate and thyroid cancers and phase III for pan-creatic cancer but ultimately failed to reach the market.[5]

Figure 1. Bioactive metabolites isolated from fungi: Illudin S (1),coprinastatin (2) and synthetic analogue irofulven (3).

Previous syntheses of the illudins and their analogueshave employed enyne ring-closing metathesis,[6] Pauson–Khand cyclisations,[7] 1,3-dipolar cycloadditions[8] and con-jugate addition/condensation[9] reactions to construct the il-ludin-type scaffold. Although these syntheses do achievethe target molecule, they are not suitable for our program,because they have limited scope for structural modificationand/or are long syntheses in terms of the total number of

[a] Department of Chemistry, University of Otago,P. O. Box 56, Dunedin, New ZealandE-mail: bhawkins@chemistry.otago.ac.nzhttp://neon.otago.ac.nz/chemistry/contacts/profile/bchSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201402461.

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acyclic dienophiles. The reaction proceeds with complete re-gioselectivity and moderate to high stereoselectivity in goodto excellent chemical yields.

steps. Therefore, a synthetic strategy which allows for rapidaccess to this privileged scaffold would be of significantvalue in the design and synthesis of bioactive compounds.

We aimed to develop a convergent and flexible synthesisof the illudin scaffold that will complement existing strate-gies and also allow for the rapid late stage generation ofstructurally diverse analogues. To this end, our retrosyn-thetic analysis of the tricyclic scaffold characteristic of theilludins was built around creating the possibility of struc-tural diversity at each step whilst still having a rapid methodfor the construction of the natural products and analogues.Applying a Diels–Alder disconnection to generic scaffold 4would provide diene 5 and dienophile 6 (Figure 2). Orbitalcoefficient calculations of the HOMO of diene 5 showedthere is a slight difference in the relative magnitudes of theterminal lobes with a slightly larger orbital coefficient atthe cyclopentenyl carbon.[10] This suggests that the regio-chemical outcome in a Diels–Alder cycloaddition wouldshow a slight preference for the 1,2-substituted analoguerelative to the cyclopropane. However, the use of terminallobe orbital coefficients as the sole basis for predictingregiocontrol should be applied with some caution.[11] Weanticipated that the significant steric bulk imparted by thecyclopropane would override orbital coefficient matchingand the 1,3-substituted analogues would predominate, thusgiving rise to the illudin scaffold (Figure 2). Furthermore,this study aims to demonstrate that steric factors can beused to control regiochemical outcome. This is in contrastto the generally accepted thought that, under kinetic con-trol, regio- and stereochemistry is predominately controlledby frontier orbital interactions and is less influenced bysterics.[11,12]

There are few literature reports describing the use of theallylidenecyclopropane moiety as a diene in cycload-ditions,[13] and all but one of these involve terminally un-substituted allylidene cyclopropanes. The one exception isa report detailing the synthesis of several terminally substi-tuted allylidene cyclopropanes. However, only one very elec-

L. Stevens-Cullinane, N. T. Lucas, B. C. HawkinsFULL PAPER

Figure 2. Retrosynthetic analysis of the tricyclic core of the illudins.

tron-rich diene was found to participate in a Diels–Aldercycloaddition with a limited array of electron-poor dieno-philes.[14]

Results and Discussion

This work examines the use of the significant steric bulkand reactivity of cyclopropyl-substituted semicyclic diene 7to access the tricyclic core of the illudins in a single regiose-lective step (Figure 3). Retrosynthetic analysis showed that7 could be accessed through use of an enyne ring closingmetathesis of 8, an approach somewhat limited in itsrequirement of bulky groups to induce close proximity be-tween the reacting groups. However, diene 7 would serve asa good model system to probe the key Diels–Alder cycload-dition step.

Figure 3. Retrosynthetic analysis of model diene 7.

Enyne 8 is available from Pd-mediated enolate additionof malonate 9 to vinylcyclopropane 10 using establishedchemistry.[15] Enyne 8 has been shown to undergo [3+2] cy-cloadditions in the presence of the 1st generation Grubbscatalyst,[16] whereas the 2nd generation Grubbs catalyst hasbeen shown to promote the enyne ring closing metathesispathway.[17] However, the reported yield of diene 7 is lowand the compound relatively impure. To improve on this,we conducted a quick screen using both the 1st and 2ndgeneration Hoveyda–Grubbs (HG) catalysts,[18] as previouswork had shown a significant increase in reactivity andyield when HG-2 was used in a closely related system.[17]

Treatment of enyne 8 with the more active HG-2 (6 mol-%)provided requisite diene 7 in near quantitative yield after2 h at ambient temperature. Despite the proton NMR spec-trum of the crude mixture, indicating clean conversion ofenyne 8 to diene 7,[18] significant decomposition was ob-served after silica gel column chromatography or filtrationthrough Celite with an isolated yield of 77%. It was foundthat isolation of diene 7 was not necessary and that 7 couldsimply be used in the next reaction without purification.

Treatment of crude diene 7 with N-phenylmaleimide intoluene provided a single cycloadduct in 81% yield over twosteps after 18 h of stirring at room temperature. The relativeconfiguration was assigned on the basis of strong NOE in-

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teractions between Ha/Hb, Hb/Hc and Ha/Hc (Table 1, En-try 1), confirming the structure as endo adduct 11.[18] Notraces of the exo adduct were observed. Subjecting purifieddiene 7 to the same reaction conditions did not result in adiminished yield or an observable change in reaction rate.This finding suggests that the cycloaddition was not cata-lysed by any residual ruthenium species. A similar yield ofanalogous cycloadduct 12 was obtained when maleic anhy-dride was used as the dienophile (73%, endo isomer only).The reactivity of diene 7 can be attributed to the strain re-

Table 1. Cycloaddition substrate scope.

[a] Conditions A: toluene, 1.2 equiv., 18 h; B: toluene, 2 equiv.,18 h; C: toluene, 1.2 equiv., sonication, 6 h; D: toluene, 3 equiv.,18 h. [b]% yield over two steps. [c] Unstable on silica. [d] Identityof major and minor isomer is unknown.

Rapid Diels–Alder Entry into the Illudin Scaffold

lease after the cycloaddition making this system far morereactive than typical 1,1-dialkyl-substituted dienes.[13d]

When the unsymmetrical dienophile bromo-N-phenyl-maleimide was subjected to the established cycloadditionconditions the reaction sluggishly proceeded with approxi-mately 60% conversion after 18 h at room temperature. Byincreasing the reaction temperature to 50 °C complete con-sumption of the starting material was observed after 16 h.Temperatures exceeding 90 °C caused extensive decomposi-tion of both cycloadduct 13 and starting diene 7. Increasesin the rate of reaction were observed when the reaction mix-ture was subjected to sonication at 45 °C. After 6 h, TLCanalysis indicated complete consumption of starting diene7. Furthermore, analysis of the proton NMR spectrum ofthe crude indicated the presence of only one isomer, thestructure of which was confirmed by X-ray crystallography(Figure 4) as the endo isomer with the large bromine atomin a 1,3-arrangement relative to the cyclopropane.

Figure 4. X-ray single crystal molecular structure of 13 (dichloro-methane solvate molecule has been omitted for clarity).

Treatment of diene 7 with bromomaleic anhydride pro-vided 14 as the sole stereoisomer in 45% isolated yield. Thisrelatively low yield was attributed to ring opening of theanhydride during purification. To further probe the limitsof regiochemical control, the sterically less encumberedchloro-N-phenylmaleimide was treated with diene 7. Thisprovided the same exclusive regio- and stereochemical out-come as observed with the other cycloadditions (Table 1,Entry 5).

The Diels–Alder cycloaddition of methyl vinyl ketoneand diene 7 proceeded smoothly to provide 16 in 62% yieldas a 2:1 mixture of endo and exo stereoisomers. This mix-ture could be further separated by re-subjecting to silica gelcolumn chromatography with the later eluting endo isomerbeing isolated, with traces of exo stereoisomer, in a 31%yield. Unfortunately, the less polar exo isomer could not beisolated and was heavily contaminated with the endo iso-mer.[18] Under either sonication or conventional heating thecycloaddition of α-chloroacrylonitrile, a ketene equivalent,with 7 proceeded smoothly. Analysis of the olefinic chemi-cal shift region of the crude proton NMR spectrum indi-cated the presence of three cycloadducts in a ca. 3:2:1 ratiowith no resonances attributable to remaining starting mate-rial. During purification by silica gel column chromatog-raphy the minor adduct was found to be unstable and could

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not be isolated. However, the two major cycloadducts 17were recovered as an inseparable mixture of endo and exostereoisomers.[19]

Methyl methacrylate also underwent cycloaddition with7, albeit under more forcing conditions, to provide tricycle18 as an inseparable 3:2 mixture of endo/exo stereoisomersin a 53 % yield. In order to increase the rate of cycload-dition of 7 and methyl methacrylate we examined the useof a Lewis acid. Despite the addition of methylaluminiumdichloride (3 equiv.) to the reaction, heating (40 °C) was re-quired for the cycloaddition to occur, presumably due to aninsufficient population of the higher energy s-cis conforma-tion of diene 7 at lower reaction temperatures. The additionof this Lewis acid to the reaction resulted in a diminishedisolated yield and increased formation of unidentified sideproducts.

Conclusions

We have shown that diene 7 undergoes regioselectiveDiels–Alder cycloadditions with a range of dienophiles inmoderate to high yields providing access to the tricycliccore of the illudins. Furthermore, for this system we havedemonstrated that steric effects have a larger influence thanfrontier orbital interactions on the regiochemical outcome.Efforts to develop a flexible synthesis of the diene portion,which will allow for broadened substrate scope, is currentlyunderway and will be reported in due course.

Experimental SectionGeneral Methods: Thin layer chromatography (TLC) was per-formed on ALUGRAM® aluminium-backed UV254 silica gel 60(0.20 mm) plates. Compounds were visualized with either p-anisal-dehyde or 20% w/w phosphomolybdic acid in ethanol. Columnchromatography was performed using silica gel 60. Infrared spectrawere recorded with a Bruker Optics Alpha ATR FT-IR spectrome-ter. High-resolution mass spectra (HRMS) were recorded with aBruker microTOF mass spectrometer using an electrospray ionis-ation (ESI) source in either the positive or negative modes. 1HNMR spectra were recorded at either 400 MHz using a Varian 400-MR NMR system or at 500 MHz with a Varian 500 MHz AR pre-mium shielded spectrometer. All spectra were recorded from sam-ples in CDCl3 at 25 °C in 5 mm NMR tubes. Chemical shifts arereported relative to the residual chloroform singlet at δ = 7.26 ppm.Resonances were assigned as follows: chemical shift [multiplicity,coupling constant(s), number of protons, assigned proton(s)]. Mul-tiplicity abbreviations are reported by the conventions: s (singlet),d (doublet), dd (doublet of doublets), ddd (doublet of doublet ofdoublets), t (triplet), td (triplet of doublets), q (quartet), qd (quartetof doublets), m (multiplet). Proton-decoupled 13C NMR spectrawere recorded at either 100 MHz with a Varian 400-MR NMRsystem or at 125 MHz with a Varian 500 MHz AR premiumshielded spectrometer under the same conditions as the 1H NMRspectra. Chemical shifts have been reported relative to the CDCl3triplet at δ = 77.16 ppm. Dichloromethane (CH2Cl2), diethyl ether(Et2O), tetrahydrofuran (THF) and toluene were dried using aPURE SOLV MD-6 solvent purification system. All other solventsand reagents were used as received.

L. Stevens-Cullinane, N. T. Lucas, B. C. HawkinsFULL PAPERDiethyl 3-(Cyclopropylidenemethyl)cyclopent-3-ene-1,1-dicarboxyl-ate (7):[17] To a solution of enyne 8 (200 mg, 0.757 mmol) in toluene(40 mL) was added Hoveyda–Grubbs 2nd generation catalyst(28.4 mg, 45.4 μmol) and the mixture stirred at room temperaturefor 2 h. The residue was concentrated in vacuo to afford the crudetitle compound 7 as a black oil, which was used directly in the nextreaction without further purification. An analytically pure samplecould be obtained by subjecting the crude residue to silica gel col-umn chromatography. Elution with 10% ethyl acetate in hexanesprovided the title compound as a colourless oil (160 mg, 80%). 1HNMR (400 MHz, CDCl3): δ = 6.52 (s, 1 H), 5.50 (s, 1 H), 4.20 (q,J = 7.0 Hz, 4 H), 3.27 (s, 2 H), 3.09 (s, 2 H), 1.30–1.22 (m, 8 H),1.14–1.05 (m, 2 H) ppm. HRMS-ESI: calcd. for C15H20O4Na+ [M+ Na]+ 287.1254, found 287.1244.

General Procedures for the Diels–Alder Reactions

General Procedure I: To a solution of 7 (50 mg, 0.19 mmol) in tolu-ene (0.15 m) was added the given dienophile (in excess) and themixture stirred at the listed temperature for 18 h. The solvent wasremoved in vacuo and the residue purified by column chromatog-raphy on silica gel (CH2Cl2/petroleum ether, 3:7 to 1:0) to affordthe cycloaddition adduct.

General Procedure II: To a solution of 7 (50 mg, 0.19 mmol) intoluene (0.15 m) was added the given dienophile (1.2 equiv.) andthe mixture sonicated in a 45 °C water bath in 30 min cycles untilthe starting material had been consumed, as monitored by 1HNMR spectroscopy. The solvent was removed in vacuo and theresidue purified by column chromatography on silica gel (CH2Cl2/petroleum ether, 1:4 to 1:0) to afford the cycloaddition adduct.

Diethyl 1,3-Dioxo-2-phenyl-3,3a,6,8,8a,8b-hexahydro-1H-spiro[cy-clopenta[e]isoindole-4,1�-cyclopropane]-7,7(2H)-dicarboxylate (11):Following General Procedure I, room temperature and 1.2 equiv.dienophile provided 11 (67 mg, 81%) as a yellow oil. IR(ATR):ν̃max = 1728, 1710 (C=O), 1611 (C=C), 1384, 1247, 1191(C-O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.44 (t, J = 7.4 Hz,2 H), 7.36 (t, J = 7.4 Hz, 1 H), 7.22 (d, J = 7.4 Hz, 2 H), 5.43 (q,J = 2.3 Hz, 1 H), 4.27–4.09 (m, 4 H), 3.50 (dd, J = 8.7, 7.4 Hz, 1H), 3.15–3.03 (m, 1 H), 2.92 (s, 2 H), 2.89 (dd, J = 13.4, 10.9 Hz,1 H), 2.76 (dd, J = 13.4, 8.2 Hz, 1 H), 2.43 (d, J = 8.7 Hz, 1 H),1.49–1.39 (m, 1 H), 1.24 (td, J = 7.1, 2.9 Hz, 6 H), 0.94–0.86 (m,1 H), 0.85–0.77 (m, 1 H), 0.51–0.46 (m, 1 H) ppm. 13C NMR(100 MHz, CDCl3): δ = 177.1, 176.5, 171.6, 170.7, 144.1, 131.8,129.0 (2 C), 128.5, 126.5 (2 C), 124.3, 61.53, 61.52, 60.2, 49.8, 44.2,39.2, 38.3, 34.7, 20.3, 14.2, 14.0 (2 C), 11.0 ppm. HRMS-ESI:calcd. for C25H27NO6Na+ [M + Na]+ 460.1731, found 460.1756.

Diethyl 1�,3�-Dioxo-1�,3�,3a�,8�,8a�,8b�-hexahydrospiro[cyclopro-pane-1,4�-indeno[4,5-c]furan]-7�,7�(6�H)-dicarboxylate (12): Follow-ing General Procedure I, room temperature and 1.2 equiv. dienoph-ile afforded 12 (50 mg, 73%) as a yellow oil. IR (ATR):ν̃max = 1758(C=O), 1714 (C=C), 1214 (C–O) cm–1. 1H NMR (400 MHz,CDCl3): δ = 5.38 (q, J = 2.3 Hz, 1 H), 4.25–4.13 (m, 4 H), 3.62(dd, J = 9.4, 7.3 Hz, 1 H), 3.06–2.97 (m, 1 H), 2.93 (s, 2 H), 2.72(s, 1 H), 2.69 (d, J = 3.3 Hz, 1 H), 2.58 (d, J = 9.4 Hz), 1.29 (dt, J

= 9.6, 6.1 Hz, 1 H), 1.24 (dt, J = 9.3, 7.1 Hz, 6 H), 0.92 (dt, J = 9.4,6.0 Hz, 1 H), 0.87–0.77 (m, 1 H), 0.54 (ddd, J = 9.5, 6.5, 4.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.0, 171.4, 171.35,170.4, 144.1, 124.5, 61.72, 61.66, 60.0, 50.1, 45.0, 38.23, 38.19, 34.7,19.8, 15.0, 14.0 (2 C), 11.3 ppm. HRMS-ESI: calcd. forC19H22O7Na+ [M + Na]+ 385.1258, found 385.1234.

Diethyl 8b-Bromo-1,3-dioxo-2-phenyl-3,3a,6,8,8a,8b-hexahydro-1H-spiro[cyclopenta[e]isoindole-4,1�-cyclopropane]-7,7(2H)-dicarboxyl-ate (13): Following General Procedure II, sonication for 6 h in total

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afforded 13 (66 mg, 67%) as a pale yellow solid (m.p. 84–86 °C). IR(ATR):ν̃max = 1717 (C=O), 734 (C–Br) cm–1. 1H NMR (400 MHz,CDCl3): δ = 7.46 (t, J = 7.4 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 1 H),7.25 (d, J = 7.4 Hz, 2 H), 5.42 (q, J = 2.1 Hz, 1 H), 4.26–4.11 (m,4 H), 3.63–3.53 (m, 1 H), 3.30 (dd, J = 13.5, 10.5 Hz, 1 H), 2.97(s, 2 H), 2.83 (s, 1 H), 2.82 (dd, J = 13.6, 8.1 Hz, 1 H), 1.46 (ddd,J = 9.7, 6.6, 5.5 Hz, 1 H), 1.24 (td, J = 7.1, 2.7 Hz, 6 H), 1.07 (ddd,J = 9.7, 6.6, 4.4 Hz, 1 H), 0.87 (ddd, J = 9.7, 6.6, 5.5 Hz, 1 H),0.66 (ddd, J = 9.7, 6.6, 4.4 Hz, 1 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 173.8, 173.0, 171.4, 170.3, 143.4, 131.4, 129.1 (2 C),128.9, 126.3 (2 C), 125.6, 61.7, 61.6, 60.8, 59.7, 57.7, 48.6, 36.6,34.1, 21.8, 15.7, 14.0 (2 C), 10.6 ppm. HRMS-ESI: calcd. forC25H26NO6BrNa+ [M + Na]+ 538.0836, found 538.0789.

Diethyl 8b�-Bromo-1�,3�-dioxo-1�,3�,3a�,8�,8a�,8b�-hexahydrospiro-[cyclopropane-1,4�-indeno[4,5-c]furan]-7�,7�(6�H)-dicarboxylate (14):Following General Procedure II, sonication for 6 h in total; af-forded 14 (38 mg, 45%) as a pale yellow oil. IR (ATR):ν̃max = 1790,1728 (C=O), 1246 (C–O), 575 (C–Br) cm–1. 1H NMR (400 MHz,CDCl3): δ = 5.38–5.36 (m, 1 H), 4.28–4.15 (m, 4 H), 3.53–3.45 (m,1 H), 3.09 (dd, J = 13.4, 10.7 Hz, 1 H), 2.99 (s, 2 H), 2.95 (s, 1 H),2.81 (dd, J = 13.4, 8.0 Hz, 1 H), 1.36–1.31 (m, 1 H), 1.26 (dt, J =9.8, 7.1 Hz, 6 H), 1.10–1.03 (m, 1 H), 0.93–0.84 (m, 1 H), 0.79–0.69 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.3, 170.0,168.7, 168.0, 143.1, 125.7, 61.8 (2 C), 60.9, 59.4, 56.3, 47.3, 38.6,34.3, 21.5, 16.9, 14.01, 13.98, 11.3 ppm. HRMS-ESI: calcd. forC19H21O7BrNa+ [M + Na]+ 463.0363, found 463.0354.

Diethyl 8b-Chloro-1,3-dioxo-2-phenyl-3,3a,6,8,8a,8b-hexahydro-1H-spiro[cyclopenta[e]isoindole-4,1�-cyclopropane]-7,7(2H)-dicarboxyl-ate (15): Following General Procedure II, sonication for 6 h in totalafforded 15 (64 mg, 71%) as a yellow oil. IR (ATR):ν̃max = 1718(C=O), 739 (C–Cl) cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.46 (t,J = 7.4 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.25 (d, J = 7.4 Hz, 2H), 5.43 (q, J = 2.4 Hz, 1 H), 4.28–4.09 (m, 4 H), 3.54–3.44 (m, 1H), 3.19 (dd, J = 13.6, 10.4 Hz, 1 H), 2.94 (s, 2 H), 2.85 (dd, J =13.6, 8.3 Hz, 1 H), 2.65 (s, 1 H), 1.44 (ddd, J = 9.7, 6.6, 5.5 Hz, 1H), 1.24 (td, J = 7.1, 3.9 Hz, 6 H), 1.06 (ddd, J = 9.7, 6.6, 4.4 Hz,1 H), 0.91 (ddd, J = 9.7, 6.6, 5.5 Hz, 1 H), 0.64 (ddd, J = 9.7, 6.6,5.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.8, 172.45,171.4, 170.3, 143.1, 131.3, 129.1 (2 C), 128.9, 126.4 (2 C),125.6, 67.3, 61.67, 61.66, 60.3, 59.8, 48.5, 38.3, 33.3, 21.6, 14.9,14.0 (2 C), 10.6 ppm. HRMS-ESI: calcd. for C25H26NO6ClNa+ [M+ Na]+ 494.1341, found 494.1308.

Diethyl 7�-(1��-Oxoethyl)-1�,6�,7�,7a�-tetrahydrospiro[cyclopropane-1,5�-indene]-2�,2�(3�H)-dicarboxylate (16): Following General Pro-cedure I, 50 °C and 3.0 equiv. dienophile afforded 16 (39 mg, 62 %)as a 2:1 mixture colourless oil. Resubjection of the mixture to silicagel chromatography allowed partial separation of the later-elutingendo isomer, which contained only traces of the exo stereoisomer(19 mg, 31 %). IR (ATR):ν̃max = 1728 (C=O), 1242 (C–O), 833(=C–H) cm–1.

16-endo: 1H NMR (400 MHz, CDCl3): δ = 4.84–4.83 (m, 1 H),4.21–4.13 (m, 4 H), 3.05 (q, J = 5.01 Hz, 1 H), 3.08–2.91 (m, 3 H),2.77–2.70 (m, 1 H), 2.36 (dd, J = 12.4, 7.5 Hz, 1 H), 2.15 (s, 3 H),2.10 (t, J = 12.5 Hz, 1 H), 1.99 (dd, J = 14.0, 4.6 Hz, 1 H), 1.56(dd, J = 14.0, 5.1 Hz, 1 H), 1.26–1.21 (m, 6 H), 0.53–0.49 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 208.8, 172.4, 171.5,137.7, 124.9, 61.5, 61.4, 58.3, 48.2, 40.2, 37.7, 35.5, 35.1, 29.6, 17.0,16.1, 14.0 (2 C), 12.1 ppm.

16-exo: 1H NMR (400 MHz, CDCl3): δ = 4.83–4.79 (m, 1 H), 4.25–4.11 (m, 4 H), 3.12–3.00 (m, 2 H), 2.82–2.74 (m, 1 H), 2.73–2.66(m, 1 H), 2.58–2.47 (m, 2 H), 2.17 (s, 3 H), 1.97 (t, J = 7.2 Hz, 1H), 1.81 (dd, J = 12.8, 11.0 Hz, 1 H), 1.27–1.19 (m, 6 H), 0.68–0.58

Rapid Diels–Alder Entry into the Illudin Scaffold

(m, 2 H), 0.57–0.49 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ= 211.0, 171.93, 171.87, 138.0, 125.9, 61.6, 61.5, 58.5, 53.8, 40.5,38.8, 38.2, 36.5, 28.9, 19.3, 16.0, 14.0 (2 C), 13.1 ppm.

HRMS-ESI: calcd. for C19H26O5Na+ [M + Na]+ 357.1672, found357.1656.

Diethyl 7�-Chloro-7�-cyano-1�,6�,7�,7a�-tetrahydrospiro[cycloprop-ane-1,5�-indene]-2�,2�(3�H)-dicarboxylate (17): Following GeneralProcedure I, 50 °C and 2.0 equiv. dienophile afforded 17 (44 mg,66%) as a (3:2) mixture of endo and exo stereoisomers as a yellowoil. IR (ATR):ν̃max = 1728 (C=O), 1264 (C–O), 734 (C–Cl) cm–1.

17 (Isomer 1): 1H NMR (500 MHz, CDCl3): δ = 4.92–4.91 (m, 1H), 4.25–4.19 (m, 4 H), 3.22 (ddq, J = 11.5, 7.2, 2.4 Hz, 1 H), 3.01(ddd, J = 17.4, 3.4, 2.2 Hz, 1 H), 2.94 (dt, J = 17.4, 2.2 Hz, 1 H),2.73 (dd, J = 13.0, 7.3 Hz, 1 H), 2.66 (d, J = 14.0 Hz, 1 H), 2.36(dd, J = 13.0, 11.3 Hz, 1 H), 1.84 (dd, J = 14.0, 1.1 Hz, 1 H), 1.27(dt, J = 7.1, 3.8 Hz, 6 H), 0.91–0.86 (m, 1 H), 0.83–0.77 (m, 1 H),0.75–0.68 (m, 1 H), 0.67–0.62 (m, 1 H) ppm. 13C NMR (125 MHz,CDCl3): δ = 171.7, 170.7, 132.0, 126.5, 119.1, 61.9, 61.8, 57.8, 57.0,48.2, 45.2, 37.7, 35.3, 17.1, 16.6, 14.02, 13.99, 10.6 ppm.

17 (Isomer 2): 1H NMR (500 MHz, CDCl3): δ = 4.98–4.96 (m, 1H), 4.25–4.19 (m, 4 H), 3.13 (ddq, J = 11.9, 7.1, 2.3 Hz, 1 H), 3.04(t, J = 2.1 Hz, 2 H), 2.87 (dd, J = 13.0, 7.1 Hz, 1 H), 2.59 (dd, J

= 13.2, 1.2 Hz, 1 H), 2.25 (dd, J = 13.0, 11.9 Hz, 1 H), 1.88 (dd, J

= 13.2, 1.1 Hz, 1 H), 1.28 (td, J = 7.1, 0.5 Hz, 6 H), 0.91–0.86 (m,1 H), 0.83–0.77 (m, 1 H), 0.75–0.68 (m, 1 H), 0.67–0.62 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.7, 170.5, 134.2,127.3, 117.0, 61.9, 61.8, 58.5, 57.6, 51.5, 47.4, 37.8, 36.4, 19.3, 16.5,14.02, 13.99, 11.5 ppm.

HRMS-ESI: calcd. for C18H22NO4ClNa+ [M + Na]+ 374.1130,found 374.1101.

Diethyl 7�-(Methoxycarbonyl)-7�-methyl-1�,6�,7�,7a�-tetrahydrospi-ro[cyclopropane-1,5�-indene]-2�,2�(3�H)-dicarboxylate (18): Follow-ing General Procedure I, 90 °C and 3.0 equiv. dienophile; afforded18 (37 mg, 53%) as a pale yellow oil in an inseparable mixture of3:2 endo and exo stereoisomers. IR (ATR):ν̃max = 1732 (C=O), 1243(C–O), 859 (=C–H) cm–1.

18-endo: 1H NMR (400 MHz, CDCl3): δ = 4.73 (s, 1 H), 4.22–4.14(m, 4 H), 3.60 (s, 3 H), 3.08–3.01 (m, 1 H), 2.98 (m, 2 H), 2.79 (dt,J = 17.2, 2.0 Hz, 1 H), 2.56–2.47 (m, 1 H), 1.92 (d, J = 13.4 Hz, 1H), 1.43 (d, J = 13.4 Hz, 1 H), 1.27 (s, 3 H), 1.26–1.21 (m, 6 H),0.53–0.49 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.2,172.4, 171.6, 137.8, 124.2, 61.4, 61.3, 58.7, 51.0, 48.5, 45.7, 44.5,44.0, 38.0, 24.9, 18.0, 15.9, 14.0 (2 C), 12.0 ppm.

18-exo: 1H NMR (400 MHz, CDCl3): δ = 4.81–4.80 (m, 1 H), 4.22–4.14 (m, 4 H), 3.67 (s, 3 H), 2.95–2.89 (m, 1 H), 2.56–2.47 (m, 3H), 2.22 (d, J = 13.3 Hz, 1 H), 1.95 (t, J = 12.5 Hz, 1 H), 1.26–1.21 (m, 6 H), 1.14–1.11 (m, 4 H), 0.44–0.40 (m, 4 H) ppm. 13CNMR (100 MHz, CDCl3): δ = 177.8, 172.0, 171.9, 136.1, 125.1,61.5, 61.4, 58.2, 51.8, 44.8, 42.7, 35.4, 34.7, 17.1, 15.9, 15.6, 14.0(2 C), 10.7 ppm.

HRMS-ESI: calcd. for C20H28O6Na+ [M + Na]+ 387.1778, found387.1745.

X-ray Crystal Structure Determination of 13·CH2Cl2: The crystalwas attached with Paratone N oil to a CryoLoop supported in acopper mounting pin, then quenched in a cold nitrogen stream.Data were collected at 100 K using Cu-Kα radiation (micro-source,mirror monochromated) using an Agilent SuperNova dif-fractometer with Atlas detector. The data processing was under-taken within the CrysAlisPro software;[20] combined analytical nu-meric absorption and multiscan scaling corrections were applied to

Eur. J. Org. Chem. 2014, 4767–4772 © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 4771

the data.[20,21] The structures were solved by direct methods withSHELXS-97, and extended and refined with SHELXL-97.[22] Oneof the OEt groups appeared to be rotationally disordered about theO–C bond and has been modelled over two positions, refining to0.64:0.36 occupancies. A dichloromethane molecule adjacent to thedisordered OEt group has been modelled over three positions (twoco-sited) with occupancies 0.64:0.26:0.10. The non-hydrogen atomswere modelled with anisotropic displacement parameters and a ri-ding-atom model with group displacement parameters used for thehydrogen atoms. Crystal data: C26H28BrCl2NO6, M = 601.30,colourless irregular block, 0.47�0.39�0.23 mm, monoclinic, a =10.4498(1) Å, b = 15.4136(2) Å, c = 15.9641(2) Å, β = 99.975(1)°,V = 2532.45(5) Å3, space group P21/c (#14), Z = 4, μ(Cu-Kα) =4.523 mm–1, 2θmax = 153.7°, 13368 reflections measured, 5223 inde-pendent reflections (Rint = 0.0214). Final R1(F2) = 0.0584[I�2σ(I)], 0.593 (all data). Final wR2(F2) = 0.1558 [I�2σ(I)],0.1567 (all data). GoF = 1.039. CCDC-987779 contains the supple-mentary crystallographic data for this paper. These data can beobtained free of charge from The Cambridge CrystallographicData Centre via www.ccdc.cam.ac.uk/data_request/cif.

Supporting Information (see footnote on the first page of this arti-cle): Copies of the 1H and 13C NMR spectra of all new compoundsalong with 1D NOESY spectra of 11.

Acknowledgments

We thank the University of Otago Research Grant Scheme forfunding and Dr. Eng Wei Tan, Assoc. Prof. David Larsen, Assoc.Prof. Jonathan Morris and Prof. Mark Rizzacasa for helpful dis-cussions. We also thank Ms K. Cho for a sample of chloro-N-phenylmaleimide.

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[18] See Supporting Information for details.[19] The identity of the minor product is unknown; this adduct may

be the result of dimerization of the diene or may be a re-gioisomer.

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G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112.Received: April 21, 2014

Published Online: June 24, 2014