Synthesis of 1-substituted cis -bicyclo[3.3.0]octane-3,7-dione derivatives as potential precursors of polyquinanes

The synthesis of several 1-substituted cis -bicyclo[3.3.0]octane-3,7-dione derivatives as potential precursors of a triquinacene having a pyramidalized C=C bond from ethyl cis -3,7-dioxobicyclo-[3.3.0]octane-1-carboxylate is described.

Noteworthy, dihydroxydione 12 is by far the most stable among 12 possible stereoisomers derived from enol 31 by hydrolysis and double intramolecular aldol condensation, as established by theoretical methods (MM3, 9 AM1, 10 and PM3 11 ).However, among the 16 stereoisomers of hydrolysis and monocondensation products derived from enol 31, the precursor of dihydroxydione 12 and several other stereoisomers showed similar stabilities according to the above theoretical methods.
In view of this result and having ether 28 in hand, we attempted an alternative approach to the skeleton of compound 12 in a stepwise way (Scheme 7).To this end, ether 28 was epoxidized with m-chloroperoxybenzoic acid (MCPBA) to give a mixture of stereoisomeric epoxides 32 in a ratio close to 1:3 ( 1 H NMR). Attempts to hydrolyze this mixture under various acidic conditions (MsOH, H2SO4, p-TsOH) gave complex product mixtures with not only the acetal functions hydrolyzed but also the epoxide reacted.When the hydrolysis was carried out with 35% HCl in THF, a stereoisomeric mixture of chlorohydrins 33 was obtained.In order to obtain epoxide 34, we first carried out the hydrolysis of the acetal functions of compound 28 by reaction with Ce(IV) ammonium nitrate. 12Under these conditions, diketone 14 was obtained in 44% yield.Epoxidation of diketone 14 with MCPBA gave a mixture of stereoisomeric epoxides 34 in 63% yield.However, all attempts to transform this compound into the tricyclic derivative 35 on reaction with an excess of lithium hexamethyldisilazide (LiHMDS) in toluene or THF, in the presence of Sc(III) triflate or boron trifluoride etherate 13 were fruitless, always leading to complex mixtures of unidentified products.

Conclusions
In conclusion we have prepared a series of 1-substituted cis-bicyclo [3.3.0]octane-3,7-dionederivatives as potential precursors of a triquinacene having a pyramidalized C=C bond.In spite of very favorable expectations based on different theoretical calculations, the double aldol condensation of compound 31 that should provide the tetracyclic dihydroxydione 12 failed to give any defined product.Also, the intramolecular condensation of diketoepoxide 34 to diketoalcohol 35 failed to give any defined product.Work is in progress to prepare a derivative of general structure 8 through other synthetic approaches.

Experimental Section
General.Melting points were determined with a MFB 595010 M Gallenkamp melting point apparatus. 1H NMR spectra were recorded on Varian-Gemini 200 (200 MHz), Varian Gemini-300 (300 MHz), Varian Mercury-400 (400 MHz), or Varian VXR-500 (500 MHz) spectrometers.13   C NMR spectra were recorded on Varian Gemini-200 (50.3 MHz) and Varian Gemini-300 (75.4 MHz) spectrometers.The 1 H/ 1 H homocorrelation spectra (COSY and NOESY) and the one bond and long range 1 H/ 13 C heterocorrelation spectra (gHSQC and gHMBC, respectively) were performed on a Varian VXR-500 spectrometer.Chemical shifts are given in  scale and the coupling constants in Hz.IR spectra were registered on a FTIR PerkinElmer model 1600 or a PerkinElmer Spectrum RX1 spectrometer.MS and GC/MS analyses were carried out on a Hewlett-Packard HP-5988A spectrometer, the sample being introduced directly or through a gas chromatograph (Hewlett.Packard model 5890 Series II) using a 30-m column (HP-45, 5% diphenyl-95% dimethylpolysiloxane), conditions: 10 psi, initial temperature 100 °C (2 min), then heating at a rate of 10 ºC/min up to 250 ºC, then isothermic.The electron impact (EI, 70 eV) or chemical ionization (CI, CH4) techniques were used.Where not indicated, the electron impact ionization technique was used.Only significant ions are given: those with higher relative ratio, except for the ions with higher m/z values.High resolution MS spectra were performed in an Autospec Micromass spectrometer at the University of Santiago de Compostela.The elemental analyses were determined in a Carlo Erba model 1106 equipment at the IIQAB (CSIC) of Barcelona, Spain.

Attempted conversion of (31) into (12)
To a solution of enol 31 (45 mg, 0.1 mmol) in acetone (1.4 mL), p-TsOH•H2O (5 mg) was added and the mixture was magnetically stirred at room temperature for 24 h.The solution was concentrated in vacuo, water (5 mL) and EtOAc were added, the organic phase was separated and the aqueous one was extracted with EtOAc (2×2 mL).The combined organic phases were dried (anhydrous Na2SO4) and concentrated in vacuo to give and oily residue in which no defined product could be detected ( 1 H NMR).

Mixture of 3,3:7,7-bis(2,2-dimethyl-1,3-propylidenedioxy)-1-[(trans-3,4-epoxycyclopentyl)
methoxymethyl]-cis-bicyclo[3.3.0]octane(trans-32) and its stereoisomer (cis-32).To a magnetically stirred solution of ether 28 (420 mg, 1.0 mmol) in DCM (10 mL) at room temperature, MCPBA (449 mg, 77% content, 2.0 mmol) was added portionwise in 5 min and stirring was continued for 1 h.The organic solution was washed with saturated aqueous NaHCO3 solution (3×10 mL), was dried (anhydrous Na2SO4) and concentrated in vacuo to give an oily residue of the mixture of epoxides 32 (412 mg, 94%) in a ratio close to 1:3 ( 1 H and 13  To a solution of the stereoisomeric mixture of epoxides 32 (77 mg, 0.18 mmol) in THF (5 mL), 35% HCl (50 L) was added and the mixture was stirred for 2 h at room temperature.After diluting with water (5 mL), the mixture was extracted with EtOAc (3×10 mL).The combined organic extracts were washed with saturated aqueous NaHCO3 solution (2×5 mL) and brine (2×5 mL), dried (anhydrous Na2SO4) and concentrated in vacuo to give an oily residue (67 mg) that was subjected to column chromatography (silica gel, 7 g; hexane/EtOAc mixtures).Upon elution with hexane/EtOAc 2:3 a slightly impure stereoisomeric mixture of chlorohydrins 33 was isolated (51 mg, 61%). 1  To a warm (70 °C), magnetically stirred solution of ether 28 (119 mg, 0.28 mmol) in acetonitrile (4 mL), a solution of Ce(NH4)2(NO3)6 (769 mg, 1.4 mmol) in water (4 mL) was added.The stirred mixture was heated to 65 °C for 5 min and was then allowed to cool to room temperature.The mixture was extracted with DCM (3×15 mL), the organic extracts were combined, dried (anhydrous Na2SO4) and concentrated in vacuo to give a residue (54 mg) that was subjected to column A solution of (LHMDS) was prepared by adding a solution of n-BuLi (2.5 M in hexanes, 90 L, 0.23 mmol) to a cold (68 °C, acetone/CO2 bath) solution of hexamethyldisilazane (HMDS, 56 L, 0.27 mmol) in anhydrous toluene (0.5 mL).After stirring for 10 min, a solution of the stereoisomeric mixture of epoxide 34 (24 mg, 0.09 mmol) in anhydrous toluene (0.5 mL) was added dropwise.The reaction mixture was stirred at 68 °C for 1 h and then allowed to warm to room temperature for 24 h.The reaction mixture was quenched by addition of saturated aqueous solution of NH4Cl (1 mL) and was extracted with Et2O (3×10 mL).The combined organic extracts were dried (anhydrous Na2SO4) and concentrated in vacuo to give a residue (12 mg) containing mainly epoxide 34 ( 1 H NMR) The aqueous phase was acidified with 1N HCl (5 mL) and was extracted with Et2O (3×10 mL).The combined organic extracts were dried (anhydrous Na2SO4) and concentrated in vacuo to give a residue (19 mg) consisting mainly of epoxide 34.Procedure 2. The reaction was carried out as in procedure 1 and after the addition of 34, Sc(OTf)3 (1.2 equiv) was added.Epoxide 34 was the main component of the crude product.Procedure 3. The reaction was carried out as in procedure 1 using THF instead of toluene as the solvent, with similar result.Procedure 4. The reaction was carried out as in procedure 3 and after the addition of 34, BF3•Et2O in THF (1.2 equiv) was added.Epoxide 34 was the main component of the crude product.
For the column chromatography, silica gel 60 AC (35-70 M, SDS, ref. 2000027 or 70-200 M, SDS, ref. 2100027) or neutral aluminum oxide (Macherey-Nagel) were used.Except where otherwise indicated, 35-70 M silica gel was used.Thin-layer chromatography (TLC) was performed on aluminum-backed sheets with silica gel 60 F254 (Merck, ref. 1.05554) and spots were visualized with UV light, a 1% aqueous solution of KMnO4 or by placing the sheets in an iodine atmosphere.