New Strategies for Intramolecular Annulations : Intramolecular Additions of Silyloxycyclopropane-Derived Anions ; Application to Hydrindenone Syntheses

Como uma extensão de nosso trabalho em anelações intramoleculares via anions derivados de sililoxiciclopropanos, investigamos a química dos sistemas ciclopentilciclopropanos 6-9, em um esforco visando a preparação de hidrindenonas estereoespecificamente funcionalizadas. As ciclizações intramoleculares de anions derivados do ciclopropano foram menos estereosseletivas e mais complicadas do que aquelas com o corresponente sitema cicloexila. Entretanto, rendimentos modestos de hidrindenonas, tais como 20 e 21, foram obtidos, assim como vários produtos derivados a partir de um deslocamento prototrópico que gerou enolatos de ciclopentanona. Estes últimos produtos possuem os sistemas 5,5-pentalenônicos 22 e 23.


Introduction
For some time, synthetic chemists have sought efficient and stereospecific methods for carbocyclic annulations.Recently, we described a highly stereoselective annulative process which showcased the fluoride induced desilylation of a 2-(triethylsilyloxy)-1-carboethoxycyclopropane, resulting in an intramolecular conjugate addition of a γ-oxo- α-ester enolate onto a tethered vinyl sulfone 1 .In our initial report, fluoride induced cleavage of silyloxycyclopropane 1, obtained in three steps from cyclohexenone, resulted in the formation of the trans-fused decalenone 2 in high yield and in a completely stereoselective manner (Scheme 1).Ultimately, this protocol resulted in the efficient synthesis of a known octahydronaphthalene synthon 3 for dihdrocompactin.
The remarkable stereoselectivity of the intramolecular cyclization is presumably controlled by the cis-double bond of the sulfone diene side chain, which provides for a preferred approach of the enolate to the geometically accessible vinyl sulfone double bond.
Due to the high stereoselectivity achieved and the substitution pattern observed about the six-membered ring resulting from the annulation, we envisioned that our an-nulative process would be ideally suited for the synthesis of hydrindenone natural products, such as pulo'upone 2 4 and the ionophore anitbiotic X-14547A 3 5 (Scheme 2).
We would now like to report our results on the extension of this annulative process toward the synthesis of hydrindenone systems.

Results and Discussion
In order to examine the scope and limitations of the cyclization reaction for the synthesis of hydrindenone systems, we chose to examine the cyclizations of four silyloxycyclopropanes (6, 7, 8, 9) upon desilylation with cesium fluoride in acetonitrile (Scheme 3).We elected to incorporate a methyl sulfone into the side chain, as a related study performed in our group 4 , demonstrated that the methyl sulfone significantly improved cyclization.We also chose to study the cyclizations of compounds 8 and 9, which contain a methyl substituent at carbon 5 and would allow for the synthesis of hydrindenones containing an angular methyl group.
The syntheses of the requisite silyloxycyclopropanes are summarized in Scheme 4. Addition of the cis-tri-nbutylstannylvinyl cuprate 5 to cyclopentenone 10 at -78 °C, followed by trapping the resulting ketone enolate with triethylsilyl chloride at -78 °C, provided an 85% yield of the vinyl stannane 11.Under similar conditions, the addition of the stannylvinyl cuprate to 2-methyl-2-cyclopenten-1-one 12 proceeded in low yields.However, high yields of the addition product 13 were obtained when the reaction mixture was warmed to -20 °C prior to trapping the ketone enolate with triethylsilyl chloride at -78 °C.The attachment of the vinyl sulfone unit was efficiently achieved by a Stille reaction 6  With the silyloxycyclopropanes 6, 7, 8 and 9 in hand, we completed this study by subjecting these compounds to the fluoride induced cyclization.We also examined the effects of varying the equivalents of cesium fluoride, in order to hopefully gain further insight into the role of the fluoride source during the cyclization.The cyclization reactions were performed with both one and five equivalents of anhydrous cesium fluoride in dry acetonitrile at 65 °C.When one equivalent of cesium fluoride was used, the reactions were followed by 1 H-NMR analysis, in order to follow the progress of the reaction.An aliquot of the reaction mixture was removed at regular intervals throughout the reaction, quenched with saturated ammonium chloride, and extracted with ethyl acetate.After drying over anhydrous magnesium sulfate and concentration, the crude reaction mixtures were analyzed by 1 H-NMR.When the reactions were complete, the ratios of the products in the crude reaction mixtures were calculated from 1 H-NMR integrations, as analysis by gas chromatography did not completely separate the diastereomeric products.When five equivalents of cesium fluoride were used, the reactions were followed by TLC analysis and quenched when the starting material was consumed.After workup and purifi-cation by silica gel chromatography, the isolated yields of each product were determined.
Treatment of 6 with five equivalents of cesium fluoride in acetonitrile at 65 °C for three hours resulted in the formation four products (Scheme 5).An inseparable mixture of two hydrindenone products, 20 and 21, were obtained in a 44% yield in a 2.3:1 ratio, as determined by 1 H-NMR, respectively 9 .There were two remaining side products isolated from the crude reaction mixture, the first of these side products, 22, was isolated in a 4% yield, and the second, 23, was isolated in a 10% yield.The formation of these products resulted from the isomerization of the ester enolate to the thermodynamically more stable ketone enolate.Cyclization of the ketone enolate onto the vinyl sulfone of the side chain resulted in the formation of two stereoisomeric sulfone anions A and B. In the case of the syn anion B, the anion intramoleculary condenses onto the ester carbonyl, resulting in the formation of tricyclic product 23 (Scheme 5).
Treatment of silyloxycyclopropane 6 with one equivalent of anhydrous cesium fluoride in acetonitrile at 65 °C proceeded over a nine hour period.Aliquots of the reaction mixture were withdrawn at 30 min, 1 h, 2 h, 4 h, 6 h, and 9 h. 1 H-NMR analysis of these aliquots showed the formation of the same four products as described above.Compounds 21 and 22 were visible in the 1 H-NMR spectrum after 30 min.Compounds 20 and 23 were observed in the aliquot removed at one hour.At the completion of the reaction, the ratio of bicyclo[4.3.0]noneneproducts (20 : 21) was 1:1.6.Apparently there was a change in selectivity as the equivalents of cesium fluoride was increased, as in the five equiva- Examination of the coupling constants for 26 and 27 showed very little variation for both compounds (Scheme 7).Because both compounds exhibit a Jad coupling constant of 8 Hz, it was evident that each possessed a cis -ring fusion.Due to the ambiguity of the remaining coupling constants about the six-membered ring, it was impossible to assign the relative stereochemistry of the remaining stereocenters solely on the basis of the coupling constant data.We believed that 26 and 27 were isomeric at the carboxylate center 10 , but we could not assign the stereochemistry with certainty.To assist in this assignment, we obtained a two dimensional NOESY spectra for each compound.
The interpretation of the NOESY spectrum for 26 was straightforward (Scheme 7 crosspeaks between Ha and Hb, Ha and Hc, and Hc and Hd, indicating that these protons were on the same face of the molecule.Additionally, there was a crosspeak observed between Hb and Hd, and no nOe crosspeaks observed between the the methylene protons adjacent to the sulfone and either Ha or Hb, further proof for the stereochemical assignment.On this basis, we were confident that we correctly assigned the relative stereochemistry for 26.
The interpretation of the data for 27 was somewhat more complicated.The NOESY spectrum exhibited nOe crosspeaks between Hb and Hc, suggesting that these protons may be cis as well.It was difficult to determine the presence or absence of any nOe crosspeaks between Ha and Hb and Ha and Hd due to the fact that these protons exhibit small differences in chemical shifts.In the NOESY spectrum, any nOe crosspeaks between these protons would be close to the diagonal, and without performing any computer optimizations on the spectrum, the diagonal was quite broad and noisy.Despite this problem, we were able to assign a long range nOe between Hb and He, and from this crosspeak, we based our stereochemical assignment.This crosspeak was not present in the spectrum for 26.
The cyclization of 7 with one equivalent of cesium fluoride proceeded over a 12 h period.Again, aliquots were withdrawn at regular intervals, submitted to an aqueous workup and analyzed by 1 H-NMR.In this case, product formation was visible after 4 h, at which time each product was observed.At the completion of the reaction, the crude mixture showed the ratio of 26:27 was 1:1.4,showing very little change from the 1.2:1 ratio of the five equivalent case.
Having completed the cyclizations of 6 and 7, the next step was to examine the cyclizations of the methyl substituted cyclopropanes, 8 and 9.
When 8 was treated with five equivalents of cesium fluoride two products were isolated (Scheme 8).The major product, obtained in a 53% yield, was the bicyclo-[4.3.0]nonenecompound 30, accompanied by a 6% yield of the bicyclo[3.2.1]octene compound 31.The unique bicyclo[3.2.1]octene structure most-likely resulted from an intermolecular equilibration of the ester enolate to the more stable ketone enolate, followed by the closure of the ketone enolate onto the side chain.Proof of the relative stereochemistry of 30 was obtained with the aid of a difference nuclear Overhauser enhancement experiment (Scheme 8).Irradiation of the angular methyl group produced a 2.2% enhancement of the signal corresponding to the methylene protons of the sulfone side chain, indicating that these two groups were on the same face of the molecule.Although the magnitude of the enhancement was small, we thought it was significant, particularly since the distance between these nuclei was probably greater than that often examined by nOe.More importantly, however, a 6.4% enhancement of the signal corresponding to the proton adjacent to the ester group was observed, proof that the ester group was trans to both the angular methyl group and the methylene sulfone side chain.
Analysis of the samples removed over a 12 h period during the treatment of 8 with one equivalent of cesium fluoride, showed a significantly different behavior than that observed for 5 and 7.At 30 min, formation of 32, which results from the quenching of the γ-oxo-α-ester enolate, and the bicyclo[4.3.0]nonene 30 were observed (Scheme 9).At 4 h, the side product 31 was observed with the appearance of the characteristic vinyl protons.At 6 h, the starting material was completely consumed.At this point, 32 and 30 were present in a 1:1 ratio.After 12 h, the reaction was quenched and, after 1 H-NMR analysis, the ratios had not changed (32:30:31 were 1:1:0.2).Lastly, treatment of 9 with five equivalents of fluoride provided three products as shown below (Scheme 10).In this case the major product, isolated in a 52% yield, was a 1:1 mixture of bicylo[3.2.1]octenes 33 and 34, which were later separated by repeating the chromatographic separation.Compound 33 was identical in all respects to compound 31, isolated previously.Compound 34 exhibited a downfield shift of the absorptions corresponding to the methylene protons adjacent to the methyl sulfone.We attributed this shift to be due to a shielding effect by the carbonyl group.The minor compound from this reaction was the desired bicyclo[4.3.0]noneneproduct 35, isolated in a 20% yield.The coupling constant of the proton adjacent to the ester group was 2.7 Hz, very similar to that obtained with 30.The relative stereochemistry of 35 was determined by an X-ray crystal structure.
When 9 was treated with one equivalent of cesium fluoride, four products were observed in the 1 H-NMR spectrum.In the sample removed after 30 min, compound 36, resulting from the quenched γ-oxo-α-ester enolate, was observed (Scheme 11).After one hour, compounds 33, 34, and 35 were observed.At the completion of the reaction, the bridged tricyclic compounds (33, 34) and the bicyclo[4.3.0]noneneproduct 35 were present in a 1:1 ratio, and the non-cyclized compound 36 was present in minor amounts.

General procedure for the preparation of bis(cis-Tri-n-butylstannyl-vinyl)cuprate
A solution of diisopropylamine (2.4 mmol) in dry THF (5 mL) in a dried 3-neck round bottom flask, equipped with a solid addition tube containing cuprous cyanide and a closed pasteur pipette, was cooled to -20 °C.n-Butyllithium (2.4 mmol) was added and the solution was stirred for 30 min.Tributyltin hydride 11 (2.4 mmol) was added via syringe.This solution was stirred for 30 min, and then cuprous cyanide (1.2 mmol) was added via the solid addition tube.The resulting solution was stirred for 1 h at -20 °C.The nitrogen supply was removed, and the acetylene apparatus was connected.Acetylene (2.7 mmol, 61 mL) was added via a pasteur pipette whose tip was immersed beneath the surface of the solution.After completion of the acetylene addition, the reaction mixture was stirred at -20 °C for 30 min.The reaction mixture was cooled to -78 °C using a dry ice/acetone bath, and the enone (1.0 mmol) was added rapidly via syringe.The nitrogen supply was then reattached, and the solution was allowed to warm to -65 °C over 45 min.After cooling to -78 °C, triethylsilyl chloride (2.0 mmol) was added dropwise via syringe.The reaction mixture was allowed to warm to -50 °C slowly, then it was poured into a rapidly stirring ice cold mixture of diethyl ether (15 mL), saturated aqueous ammonium chloride solution (10 mL), and ammonium hydroxide (2.7 mL).After stirring for 20 min, the mixture was placed in a separatory funnel, and the phases were allowed to separate.The or- ganic phase was washed with saturated aqueous ammonium chloride:ammonium hydroxide (4:1) (19 mL), distilled water (10 mL), and saturated aqueous sodium chloride solution (10 mL).The organic phase was dried with anhydrous magnesium sulfate and filtered over celite.
The solvent was removed in vacuo to obtain the crude product, which was further purified using flash column chromatography on silica gel, eluting with hexane, at an elution rate of 2 inches per min, to obtain the title compound as a colorless oil.

General procedure for the palladium-catalyzed coupling reaction
To a stirred solution of E phenylsulfonylvinyl tosylate 14 or Emethylsulfonylvinyl tosylate 15 (1.0 mmol), lithium chloride (2.0 mmol), and bis(triphenylphosphine)palladium(II) chloride (5 mol %) in dry THF (10 mL) was added the appropriate vinyl stannane (1.10 mmol) in dry THF (4 mL).The addition was made by cannula and was complete with a wash of additional THF (2 mL).The reaction flask was equipped with a reflux condensor and heated at 65 °C for 24 h.The reaction mixture was then cooled to room temperature and diluted with diethyl ether (30 mL).The resulting cloudy mixture was washed twice with a solution of 4:1 saturated aqueous ammonium chloride/ ammonium hydroxide (10 mL).The organic phase was washed with distilled water (10 mL) and saturated aqueous sodium chloride solution (10 mL) and then dried over anhydrous magnesium sulfate.After filtration over celite, the solvent was removed to obtain the crude product, which was further purified by flash column chromatography on silica gel.

General procedure for the copper-catalyzed cyclopropanation of the silyl enol ethers
To a stirred suspension of bis(N -benzylsalicylaldiminato)copper(II) (0.006 mmol) in the appropriate silyl enol ether (1.0 mmol) at 70 °C was added a solution of ethyl diazoacetate (3.0 mmol) in dry benzene (4 mL).The addition was regulated by syringe pump and proceeded over 15 h.After the addition was complete, the reaction mixture was cooled to room temperature, and diluted with diethyl ether (10 mL).The resulting mixture was filtered through a short pad of silica gel, which was washed with additional diethyl ether.The solvent was removed to obtain a yellow oil, which was further purified as indicated below.