Synthesis of fused tricyclic systems by thermal Cope rearrangement of furan-substituted vinyl cyclopropanes†

A novel method for the stereoselective construction of hexahydroazuleno[4,5-b]furans from simple precursors has been developed. The route involves the use of our recently developed Brønsted acid catalysed cyclisation reaction of acyclic ynenones to prepare fused 1-furanyl-2-alkenylcyclopropanes that undergo highly stereoselective thermal Cope rearrangement to produce fused tricyclic products. Substrates possessing an E-alkene undergo smooth Cope rearrangement at 40 °C, whereas the corresponding Z-isomers do not react at this temperature. Computational studies have been performed to explain the difference in behaviour of the Eand Z-isomers in the Cope rearrangement reaction. The hexahydroazuleno[4,5-b]furans produced by Cope rearrangement have potential as advanced intermediates for the synthesis of members of the guaianolide family of natural products.


Introduction
Furans and benzofurans occur frequently as sub-units in pharmaceuticals and bioactive natural products. 1,2In many natural products, a furan or benzofuran is embedded in a polycyclic array or a macrocycle and is fused to one or more rings.An interesting and synthetically alluring group of furan-containing natural products comprises compounds that possess a furan or benzofuran fused to a seven-membered ring.Examples include myrrhterpenoid H, 3 frondosin B 4 and liphagal, 5 which have been popular targets in recent years and have been shown to possess biological activities such as neuroprotective activity, 3 binding to interlukin-8 receptors 4 and inhibition of various kinases 4,5 (Fig. 1).
We have recently embarked on a programme directed toward the development of new methods for the concise and efficient synthesis of highly functionalised furans.As part of this programme, we wished to explore whether polycyclic systems containing the cyclohepta[b]furan unit could be synthesised from the cyclopropyl-substituted furans prepared by use of our recently-discovered stereoselective Brønsted acid catalysed cascade reaction (Scheme 1). 6In previous work, we have shown that treatment of the structurally diverse ynenediones 1 with chloroacetic acid results in intramolecular cyclisation to produce the tricyclic products 2 in which a trisubstituted furan is connected to a cyclopropyl substituent at the α position.The reaction is proposed to occur by carbonyl group protonation, and nucleophilic attack of the oxygen onto the central carbon of the putative allenyl intermediate to produce a carbene that reacts with the pendent alkene to form a cyclopropane. 6g. 1 Examples of some bioactive natural products that possess a furan or benzofuran fused to a seven-membered ring.
Scheme 1 Synthesis of cyclopropyl-substituted furans by Brønsted acid mediated intramolecular cascade reactions.† Electronic supplementary information (ESI) available: Copies of NMR spectra ( 1 H and 13 C) for compounds 20-33 and 35-37 plus details of computational studies.See DOI: 10.1039/c8ob00924d Cyclohepta [b]furans can be prepared from simple furfuryl alcohols by formal [4 + 3] cycloadditions reactions (Scheme 2).Pattenden and Winne have shown that the furan-containing diene 3 undergoes an intramolecular acid mediated reaction to produce the fused lactone 4, a tetracyclic compound that comprises most of the core structure of the marine diterpene rameswaralide. 7Winne and co-workers have developed an intermolecular variant of the reaction in which a Lewis acid catalysed reaction of a furfuryl alcohol with a simple diene delivers a cyclohepta[b]furan. 8For example, the reaction was used to convert the furfuryl alcohol 5 into the cyclohepta[b] furan 6 in reasonable yield (Scheme 2).
The groups of Liang and Vicente have reported a one-pot method for the synthesis of fused cyclohepta[b]furans from acyclic precursors by Lewis acid mediated cyclisation of an ynenedione in the presence of a diene (Scheme 2). 9,10For example, treatment of the substrate 7 with zinc(II) chloride in the presence of butadiene, was found to deliver a mixture of the silylated and desilylated products 8. 10 It was proposed that the products result from a formal [4 + 3] cycloaddition reaction, but cyclopropane formation and subsequent Cope rearrangement cannot be ruled out in these cases.
The successful preparation of highly functionalised cyclopropyl-substituted furans by use of our Brønsted acid promoted cyclisation reaction (Scheme 1) prompted us to explore whether these compounds could be rearranged to give fused tricyclic compounds containing an embedded furan.Our general approach to the synthesis of fused tricyclic compounds is depicted in Scheme 3. In the proposed reaction sequence, Brønsted acid promoted cyclisation of an acyclic ynenone 9, which possesses a tethered diene, would be used to produce a vinyl cyclopropane 10.Subsequent Cope rearrangement should deliver the fused tricyclic triene 11 and re-aromatization would result in formation of the furan-containing tricyclic product 12.It was anticipated that, under appropriate reaction conditions, the acyclic precursor 9 could be transformed directly into the fused tricyclic product 12 in a one-pot fashion with the creation of three rings, three bonds and three stereogenic centres in a single operation.
There are just three examples of the thermal Cope rearrangement of 1-furanyl-2-vinylcyclopropanes. 11,12In 1980, Maas and Hummel described the rearrangement of the very simple substrates 13a and 13b to give the 3a,7-dihydro-4Hcyclohepta[b]furans 14a and 14b in low yield by heating them in toluene or deuterated benzene (Scheme 4). 11Aromatized 7,8-dihydro-4H-cyclohepta[b]furans 15a and 15b were obtained when toluene solutions of the substrates were heated at higher temperatures in a sealed tube.The only other example of the reaction is an unusual one published by Barluenga and coworkers, in which the unstable fused tricyclic lactone 17 was prepared by thermal rearrangement of the lactone-containing vinyl cyclopropane 16 at 85 °C. 12A systematic study of the scope of the thermal Cope rearrangement of 1-furanyl-2-vinylcyclopropanes has not been published and there are no examples of the use of the reaction to prepare more complex fused polycyclic systems from cyclopropyl-substituted furans that possess additional rings.

Results and discussion
Exploration of the Cope rearrangement reactions of vinylcyclopropane-substituted furans Our studies commenced with the synthesis of the aldehyde 23, the key intermediate required for the preparation of the Cope rearrangement precursors (Scheme 5).The known alcohol 18 13 was O-protected and the trimethylsilyl group was removed.The resulting terminal alkyne was then formylated to give the propargylic aldehyde 19.Knoevenagel condensation of the aldehyde 19 with acetylacetone produced the ynenedione 20 and this compound was then subjected to an acid-catalysed cascade cyclisation reaction to give the furan 21 in excellent yield and with high diastereoselectivity (>98 : 2).Acid-mediated cleavage of the t-butyldimethysilyl ether and oxidation of the resulting alcohol 22 with the Dess-Martin periodinane afforded the required aldehyde 23 in excellent yield.
The substrates used in our study of the Cope rearrangement reaction were obtained by alkylidenation of the aldehyde 23 using a Wittig reaction (entries 1-4, Table 1) or a Julia-Kocienski reaction (entries 5-7, Table 1).The alkenes 24-27 were obtained with variable yields and with E : Z ratios that were dependent on the alkylidenation reaction that was employed.
Rearrangement of the 1-furanyl-2-alkenylcyclopropane 24 was explored first.When a solution of the substrate was heated in toluene at reflux for 1 hour, the fused tricyclic product 28 was obtained as single diastereoisomer in 36% yield (entry 1, Table 2).Subsequent reactions were performed at lower temp-Scheme 5 Synthesis of the tricyclic aldehyde 23.eratures, which resulted in reduced reaction rates and extended reaction times, but delivered higher yields of the product.The highest yield (63%) of the tricyclic product 28 was obtained when the reaction was performed in toluene at 40 °C (entry 2, Table 2).Inferior yields of this compound were obtained when rearrangement reactions performed in either THF or dichloromethane at 40 °C.Aromatisation to form the furan system did not occur at this reaction temperature.
The Cope rearrangement reactions of substrates 25-27, which contain a non-terminal alkene, were then investigated (Table 2).The substratesprepared and used as E/Z-mixtures were dissolved in toluene and heated at 40 °C.Cope rearrangement of substrate 25 (27 : 73, E : Z), prepared by Wittig olefination, resulted in complete consumption of E-25 in 18 h to give the tricyclic product 29 in 23% yield; ‡ unreacted Z-25 was recovered (40% mass recovery) and the product arising from rearrangement of this isomer was not observed (entry 3, Table 2).The substrate 25 (87 : 13, E : Z) prepared by Julia-Kocienski olefination underwent rearrangement to give the tricyclic product 29 in 50% yield and recovered starting material, enriched in Z-25 (72 : 28, E : Z), was recovered (50% mass recovery) (entry 4, Table 2).Rearrangement of the substrate 26 bearing a bulky isopropyl group was low yielding.Attempted rearrangement of a sample of the substrate 26 in which the Z isomer predominated (12 : 88, E : Z) failed to deliver the expected product and only starting material was recovered (entry 5, Table 2).The tricyclic rearrangement product 30 was obtained in 20% yield when substrate enriched in the E isomer (87 : 13, E : Z) was employed as the substrate and all of the unreacted starting material 26 (85 : 15, E : Z) was recovered after 36 h (entry 6, Table 2).The phenyl-substituted substrate 27 also underwent Cope rearrangement at 40 °C.A sample of the substrate 27 containing approximately equal amounts of both alkene isomers (47 : 53, E : Z) rearranged to give the cycloheptadiene 31 in 43% yield and unreacted isomer Z-27 was recovered without any evidence of Cope rearrangement of this isomer (entry 7, Table 2).When a sample of the substrate 27 enriched in the E isomer (70 : 30, E : Z) was subjected to the rearrangement conditions, the yield of the fused tricyclic product 31 increased to 48% and unreacted starting material (12 : 88, E : Z) was recovered (28% mass recovery) (entry 8, Table 2).
The stereochemical relationship between the C-3a and C-4 stereocentres was confirmed by analysis of 1 H NMR data for the tricyclic ketone 31.Molecular modelling of the compounds 31 and epi-31 revealed an expected dihedral angle (for H-C-C-H) of 53°at C-3a and C-4 in the case of 31 and 175°in the case of epi-31.This would imply a coupling constant of 4 Hz between the protons for ketone 31 and 11-12 Hz for C-4 dia-stereomer (epi-31). 14The observed coupling between the protons is 3.7 Hz, an observation which confirms that we obtained the expected diastereomer from the reaction of the substrate E-27.
The results given in Table 2 reveal that increasing the size of the substituent (R) results in a lower rate of reaction; in the case of isopropyl-substituted substrate E-26, the reaction was incomplete even after 36 hours.The second important observation is that the Z isomers of substrates 25-27 are markedly less reactive than the corresponding E isomers; products arising from Cope rearrangement of the Z isomers were never isolated.This finding can be explained by consideration of the conformations leading to the respective transition states (Scheme 6).Cope rearrangement of cis-1,2-divinylcyclopropane is known to proceed through a boat-like transition state, resulting from an 'endo/endo' orientation of the alkenes in the diene precursor, to give (Z,Z)-1,4-cycloheptadiene. 15 For the E isomers in our study, the alkyl group lies over the furan in the transition state (TS-E) and in the substrate conformation leading to that transition state.In contrast, for the Z isomers there is a highly unfavourable interaction between the alkene substituent (R) and the ring-junction hydrogen (H a ) as well as an eclipsing interaction between the alkene substituent (R) and the furan hydrogen (H b ) in both the transition state (TS-Z) and the conformation leading to that transition state.This means that TS-Z is higher in energy than TS-E and so rearrangement reactions of Z-25-27 to give the products 29-31 will only occur at significantly higher temperatures than the rearrangement reactions of E-25-27.
A complicating feature of the reaction is that Cope rearrangement is potentially reversible.Normally, Cope rearrangement of a divinylcyclopropane to produce a 1,4-cycloheptadiene would favour formation of the larger ring because of relief of ring-strain upon opening of the cyclopropane.However, in the case of our reactions, the aromaticity of the furan is sacrificed during rearrangement and fused tricyclic products that possess a high degree of conformational rigidity are generated.Consequently, it is possible that unfavourable enthalpic and entropic factors in the products 29-31 could counter-balance the energy gain from relief of ring-strain in the substrates 25-27.It is even conceivable that reactions of the Z isomers are disfavoured thermodynamically, which would account for our failure to isolate the products expected from Cope rearrangement of these substrates.
The trisubstituted alkene 36 did not undergo Cope rearrangement when heated at 40 °C as a solution in toluene and so the reaction temperature was increased to 110 °C.After a reaction time of three days, 15% of the starting material was recovered and the fused tricyclic product 37 was isolated in 43% yield (51% yield when recovered starting material is considered).Reducing the reaction time to 24 hours resulted in a lower conversion (32%) but a higher yield (68%) based on the amount of recovered starting material, a finding which suggests that either the substrate or product decomposes when heated at 110 °C for several days.Unfortunately, it was not possible to perform Knoevenagel condensation, acid-catalysed cyclisation and Cope rearrangement in a one-pot fashion to give the tricyclic ketone 37 directly from the aldehyde 34 because of the relatively high reaction temperature (110 °C) required to accomplish Cope rearrangement of the furan 36.
Attempts to perform acid-catalysed cyclisation reactions with other diene-containing ynenediones, analogous to the substrate 35, were hampered by the fact that the propargylic aldehydes bearing tethered dienes, required for the preceding Knoevenagel condensation reaction, underwent competitive intramolecular Diels-Alder cycloaddition and complex mixtures of products were obtained instead of the required ynenediones.

Computational study of the Cope rearrangement of the isomers of the vinylcyclopropane-substituted furan 25
DFT calculations were performed to explain the outcome of the reactions of substrates 25-27 and, specifically, to quantify the effects of the configuration of the 1-propenyl double bond of the substrate (E-25 vs. Z-25) on the Cope rearrangement reaction to give the product 29 (see Scheme 6).The calculated energetic and structural parameters for reactants, transition states, and products of the Cope rearrangement are collated in Table 3.The rearrangement reaction proceeds as expected for a [3,3] sigmatropic process and is largely unaffected by the configuration of the alkene.The distinct double bonds (1-2, 5-6) and single bonds (2-3, 4-5) of the reactant equalise in the transition state and localise again into distinct single and double bonds, respectively, in the product.Concomitant cleavage of the cyclopropane bond 3-4 and formation of the new bond between C 1 and C 6 , creates the cycloheptadiene.
The configuration of the alkene has a minor effect on the relative stability of the reactants E/Z-25, disfavouring the Z isomer both enthalpically and entropically by 5 kJ mol −1 each.In Z-25, the 1-propenyl arm of the cyclopropane is rotated outwards about the single bond 2-3 so that unfavourable steric interactions of the terminal methyl group with the rest of the molecule are avoided, which results in the long 6-1 distance (Fig. 2).However, in the transition state, as the bond 2-3 acquires increasing double-bond character and the propenyl arm approaches the furan, the configuration of TS-Z results in steric clashes of the methyl group with the hydrogens H a and H b (see Scheme 6 and Fig. 2).In contrast, TS-E is sterically less encumbered, which is reflected in a lower enthalpic barrier for rearrangement of E-25 (Δ ‡ E of 108 vs. 121 kJ mol −1 ; barriers calculated relative to the energy of the respective starting com-pound).The entropic barrier is much smaller and similar for the two isomers (−TΔ ‡ S of 20 vs. 15 kJ mol −1 ).The more facile approach of C 1 and C 6 in TS-E is also reflected in a somewhat later transition state: the incipient C 1 -C 6 bond is 0.05 Å shorter in TS-E than in TS-Z and the breaking C 3 -C 4 bond is 0.03 Å longer.
The Gibbs free energy barrier is 8 kJ mol −1 lower for TS-E than TS-Z and so rearrangement of the E-25 is kinetically favoured.In terms of reaction rates, this difference in barrier corresponds to a 20-fold faster rate (at 40 °C) for the rearrangement of the E-25 relative to Z-25.The barrier is largely enthalpic and the entropic contribution is similar in both cases, so increasing the reaction temperature will not affect the kinetic selectivity significantly.
The tricyclic product 29, resulting from the rearrangement of E-25, is also favoured on thermodynamic grounds.The formation of this compound is thermoneutral at 40 °C, whereas the formation of epi-29 from Z-25 is endergonic by 10 kJ mol −1 .The difference stems exclusively from the enthalpic part of the reaction free energy, which is exothermic.Because the product is conformationally rigid, the entropic penalty incurred during formation of the transition state remains 'locked into' the product.The entropic part of the reaction free energy is therefore unfavourable, of similar (or even larger) magnitude than the enthalpic part, and similar for the two isomers.A higher reaction temperature will thus shift the equilibrium further to the left, equally so for both isomers.
The near-zero, or even positive, reaction free energy means that when the temperature is sufficiently high for the forward reaction to proceed at a significant rate, so will the backward reaction; that is, reactant and product are in equilibrium.At 40 °C, the reaction free energies of −1 and +10 kJ mol −1 for 29 and epi-29, respectively, correspond to equilibrium constants of 2.6 and 0.02.

Conclusions
In summary, a new route for the stereoselective construction of hexahydroazuleno [4,5-b]furans from simple acyclic precursors has been developed that involves an acid-catalysed cyclisation reaction to give 1-furanyl-2-vinylcyclopropanes and their subsequent Cope rearrangement.We have shown that Table 3 Relative potential energies (ΔE), entropies (expressed as energies −TΔS), Gibbs free energies (ΔG), and bond lengths between the six carbons involved in the [3,3]-sigmatropic rearrangement reaction (atom numbering defined in Scheme 6).All values have been calculated with M06-2X/def2-TZVP at reaction conditions (T = 313.15K, p = 100 kPa)  E-configured substrates undergo smooth Cope rearrangement at 40 °C but the corresponding Z-isomers do not rearrange at this temperature.A cascade procedure for the direct formation of the tricyclic products from acyclic ynenone precursors was investigated, but in most cases intermediates underwent intramolecular Diels-Alder cycloaddition prior to, or during, the Knoevenagel condensation reaction used to prepare the precursors required for the furan-forming reaction.The Cope rearrangement product 28 maps on the core structure found in sesquiterpene natural products of the guaianolide family, such as the lactones 38 and 39 (Fig. 3). 16,17Studies are in progress to apply this reaction to the synthesis of these and structurally related guaianolides.

Experimental section
Air or moisture-sensitive reactions were performed under an atmosphere of argon in flame-dried glassware.When required, tetrahydrofuran, toluene, dichloromethane and diethyl ether were dried using a Pure-Solv™ solvent purification system.Other dry organic solvents and reagents were purchased from commercial supplies and used without further purification unless otherwise specified.
Reactions were monitored by thin-layer chromatography (TLC) on Merck silica gel 60 plates.The TLC plates were visualised under UV light and stained with acidic ethanolic anisaldehyde solution or potassium permanganate solution.
Melting points were recorded using an Electrothermal IA 9100 instrument.
IR spectra were recorded on a Shimadzu FT IR-8400S ATR instrument.The IR spectrum of each compound was acquired directly on a thin film (liquid) or powder (solid) at room temperature. 1H NMR and 13 C NMR spectra were recorded using a Bruker Avance III 400 MHz or Bruker Avance III UltraShield 500 MHz spectrometer at ambient temperature. 13C NMR spectra were recorded at 101 MHz or 126 MHz.
High resolution mass spectrometry (HRMS) was performed by the analytical service of the University of Glasgow with an Jeol MStation JMS-700 instrument using positive chemical ionization (CI using isobutene) or a positive ion impact (EI) techniques, or on a Bruker micro TOFq High Resolution instrument using positive ion electrospray (ESI) techniques.
(E)-8-(Trimethylsilyl)-2-octen-7-yn-1-ol (18) 13 To a stirred solution of the ethyl (E)-8-(trimethylsilyl)-2-octen-7-ynoate (10.03 g, 42.07 mmol) in dichloromethane (200 mL) was added diisobutylaluminium hydride (93 mL, 1.0 M solution in hexane, 93 mmol) dropwise at −78 °C.The reaction was stirred at −78 °C for 2 h and was then quenched by addition of methanol (50 mL) and of a saturated aqueous solution of Rochelle's salt (200 mL).The mixture was stirred for 3 h at room temperature and the phases were then separated.The aqueous phase was extracted with Et 2 O (2 × 150 mL) and the combined organic extracts were dried over MgSO 4 , filtered and concentrated under reduced pressure to give alcohol 18 (8.24g), which was used for the next step without further purification.
To a stirred solution of alcohol 18 (8.24g, 42.0 mmol) in dichloromethane (130 mL) was added t-butyldimethylsilyl chloride (7.0 g, 46 mmol), imidazole (4.6 g, 68 mmol) and DMAP (50 mg, 0.41 mmol).The solution was stirred for one day at room temperature and the reaction was monitored by TLC.Further t-butyldimethylsilyl chloride (3 g, 0.02 mol), imidazole (2 g, 0.03 mol) and DMAP (10 mg, 0.082 mmol) were added and the solution was stirred for a further day.The reaction was quenched by addition of water (100 mL) and the phases were separated.The aqueous phase was extracted with dichloromethane (3 × 100 mL) and the combined organic extracts were dried over MgSO 4 , filtered and concentrated under reduced pressure.The crude product was purified by flash column chromatography on silica gel ( petroleum ether-Et 2 O, 99 : 1) to afford the title compound (13.0 g, 99% over 2 steps).

Scheme 6
Scheme 6 Transition states for Cope rearrangement of E and Z alkenyl cyclopropane isomers.

Fig. 2
Fig. 2 Optimised structures of the reactants and transition states of the Cope rearrangement reaction.

Table
Conversion of the tricyclic aldehyde 23 into the Cope rearrangement precursors 24-27 a Ratio determined by 1 H NMR analysis.b Yield of isolated product.

Table 2
Cope rearrangement of the 1-furanyl-2-alkenylcyclopropanes 24-27 Entry Substrate (E : Z ratio) a a Ratio determined by 1 H NMR analysis.b Yields of isolated compounds.c Reaction performed at 110 °C.d Only the Z isomer was recovered.e 74 : 26 E : Z mixture of 25 recovered.f 85 : 15 E : Z mixture of 26 recovered.g 12 : 88 E : Z mixture of 27 recovered.