An iterative approach to higher polyquinanes

A simple cyclopentane annulation strategy has been developed using inexpensive reagents. Starting from the readily available bicyclo[3.3.0]octane system several polyquinanes were prepared by iterative annulation procedure and herein we report a short and a convenient route to a new C 20 -hexaquinane system


Introduction
Several strategies for the synthesis of polycyclopentanoids 1-3 were pursued over the last two decades due to their intricate structural properties.Recently, Mehta 4 proposed that polyquinane 1 may adopt a helical or a loop-like shape.To assemble such compounds, iterative cyclopentane annulation strategy is an attractive option.

1
In our studies directed towards the synthesis of 1, we considered 2 as a potential precursor 5 which could be prepared utilizing two directional synthesis 6a starting from dione 4 involving the intermediate 3 (Figure 1).At each stage, the reactions that are to be executed in a two-fold manner would drastically reduce the number of steps to acquire a novel polycyclopentanoid framework 2. Further, the symmetry profile has been maintained throughout the synthetic strategy which inturn simplifies the spectral data.The easy accessibility of hexaquinane 2 that is suitably functionalized, with cis fused ring junction, would open up new avenues for further synthetic exploration towards the target molecule 1.Although hexaquinane of type 2 with a different disposition of the carbonyl groups was prepared using protective group strategy, unwanted interactions between the carbonyl and the methylene groups would prevent its elaboration to higher polyquinanes.6b Thus, the first stage of our approach to the unknown polypentanoid framework 2 involves the conversion of cis-bicyclo [3.3.0]octanedione unit 4 to tetraquinane 3 by bis-cyclopentane annulation procedure.Execution of cyclopentane annulation in a two-fold manner requires a method, which involves the fixing new carbonyl group at the β-position with respect to the original location during the simultaneous creation of two new cyclopentane rings.
The cyclopentane annulation strategy with appropriate stereochemistry at the ring junctions has been depicted in Scheme 1.The first step involves the reaction of the carbonyl compound 5 with allyl magnesium bromide 7 followed by the hydroboration-oxidation sequence.][10][11][12][13] Treatment of the lactone with methanesulphonic acid-P 2 O 5 mixture generates the enone 8. 14,15 In the last step, the stereochemical control at the ring junctions may be achieved by catalytic cis-addition of the hydrogen to the olefin 8.The sequence of steps explained above was well implemented and the cornerstone of the methodology is the utilization of inexpensive reagents without the involvement of protective groups.

Results and Discussion
The starting material cis-bicyclo [3.3.0]octane-3,7-dione 4, was prepared in multigram quantities using the Weiss-Cook reaction 16 by 2:1 condensation of dimethyl-1,3-acetonedicarboxylate 17 with glyoxal followed by hydrolysis and decarboxylation.The first stage towards the realization of the strategy involves the elaboration of the cis-bicyclo [3.3.0]octane-3,7-dione 4 to the tetracyclic dione 3 by the application of cyclopentane annulation strategy in a two-fold manner as exemplified in Scheme 2. Reaction of the dione 4 with excess of allylmagnesium bromide gave a mixture containing the homoallylic alcohols 10 and 11 as represented in Scheme 2. The unsymmetrical alcohol 10 and symmetrical alcohol 11 were isolated by silica-gel column chromatography (9:1, 89%).The eleven-line 13 C NMR spectrum confirmed the unsymmetrical nature of the minor alcohol 10.The major alcohol 11 bears a C 2 -symmetry, which is in agreement with the six-line 13 C NMR spectrum.The homoallylic alcohols 10 and 11 were converted to the respective lactones by the hydroboration-oxidation sequence.In the subsequent experiments, the mixture of 10 and 11 were directly converted to the corresponding lactones 12 and 13 by one-pot operation (67%).

ISSN 1424-6376
Page 81 © ARKAT USA, Inc The stereochemistry of the dilactones 12 and 13 is of no consequence because the stereochemistry at spiro centers would be destroyed in the next step to generate the tetracyclic enones 14 and 15.
9][20] However, our attempts to obtain the bis-lactone by one-step procedure as represented in Scheme 3 proved ineffective and the reductive coupling product 16 21  When the lactone mixture 12 and 13 was treated with methanesulphonic acid containing 8% P 2 O 5 , the tetracyclic enones 14 (50%) and 15 (16%) were formed.Hydrogenation of the tetracyclic system 14 in ethyl acetate containing 10% Pd/C at 3 atm.pressure produced the saturated tetracyclic dione 3 (74%).In principle, catalytic hydrogenation of the bis-enone 14 may furnish three possible isomers 3, 17 and 18 where the stereochemistry at the ring junctions is different.However, the required isomer 3 was obtained by purifying the catalyst 14 prior to the reaction according to the procedure reported in the literature.The tetraquinanes containing trans ring junctions are not considered due to the strain involved in such systems.In an iterative approach, 3 was successfully elaborated to a novel hexacyclic system 2 as represented in Scheme 4. Reaction of dione 3 with excess allylmagnesium bromide gave a mixture containing the homoallylic alcohols 19 and 20, which was purified by silica gel column chromatography (79%).The allylic alcohol 19 was converted to the lactone 21 via the hydroboration-oxidation sequence (81%).The minor alcohol 20 was also converted to the lactone 22 by the hydroboration-oxidation sequence (67%).The 13 C NMR of 19 and 21 exhibited ten signals suggesting the presence of C 2 -symmetry whereas compounds 20 and 22 exhibited twenty-lines characteristic of their unsymmetrical nature.The treatment of the bis-lactones 21 and 22 with P 2 O 5 in methanesulphonic acid yielded not only the desired product 24, but also a novel transannular isomer 23 in equal proportions (combined yield, 26%).The IR spectrum of the compound 23 (13%) had two notable features, a normal carbonyl absorption at 1734 cm -1 and two sharp peaks at 1682 and 1612 cm -1 characteristic of an α,β-unsaturated system.The mass spectral data of compound 23 (m/z 294) established its molecular formula as C 20 H 22 O 2 .Further, the presence of twenty carbon atoms was apparent in the proton-decoupled 13 C NMR spectrum.Although the formation of 23 is very intriguing, we are unable to postulate any reasonable mechanism for the formation of heptacyclic α,β-unsaturated enone.The structure of 23 was later established by X-ray diffraction analysis. 23Catalytic hydrogenation of 24 resulted in the formation of hexacyclic dione 2 (70%) with the desired stereochemistry at the ten junctions and is represented in Scheme 4.

Conclusions
In our efforts directed towards the synthesis of complex polyquinane frameworks like 1, the bicyclic dione 4 was elaborated to C

Compound (10) and (11).
To activated magnesium turnings (15 g, 0.61 mol), allyl bromide (20 mL, 0.23 mol) in dry ether (80 mL) was added at 0 °C and the mixture was stirred for 1-2 h at RT.The dione 4 (8 g, 0.05 mol) in dry THF (30 mL) was then added to the Grignard reagent at 0 °C and stirred for another 1-2 h at rt.The reaction mixture was poured into the saturated ammonium chloride solution (100 mL) and the THF was removed at reduced pressure.The reaction mixture was extracted with ethyl acetate (250 mL) and the organic layer was washed with water, brine and dried.The solvent was evaporated, and the crude product was purified by silica gel column chromatography.To activated magnesium turnings (0.7 g, 28.8 mmol), allyl bromide (3 mL, 34.66 mmol) in dry ether (30 mL) was added at 0 °C and the mixture was stirred for 1-2 h at RT.The dione 3 (148 mg, 0.67 mmol) in dry THF (30 mL) was then added to the Grignard reagent at 0 °C and stirred for another 1-2 h at rt.The reaction mixture was poured into the saturated ammonium chloride solution (100 mL) and the THF was removed at reduced pressure.
The reaction mixture was extracted with ethyl acetate (250 mL) and the organic layer was washed with water, brine and dried.The solvent was evaporated, and the crude product was purified by silica gel column chromatography.To a stirred solution of the diol 20 (93 mg, 0.31 mmol) and NaBH 4 (130 mg, 3.43 mmol) in dry THF (25 mL), freshly distilled BF 3 .OEt 2 (1 mL, 8.1 mmol) in dry THF (10 mL) was added at 0 °C over a period of 30 min.The reaction was stirred at RT for 1-2 h and cooled to 0 °C.Freshly prepared Jones reagent (5 mL) was added dropwise.The solution was stirred at RT for 2-3 h and the THF was removed at reduced pressure.The reaction mixture was extracted with ethyl acetate (150 mL) and the organic layer was washed with water, brine and dried.Removal of the solvent gave the crude lactone, which was charged on a silica gel column.
The reaction was done according to the general procedure.Elution of the column with 70% pet ether-ethyl acetate furnished the pure lactone 22 (78 mg, 77%
up an alternate synthetic route to 1 by application of suitable cyclopentane annulation strategy.Further, a simple and straightforward methodology developed here may find application in the synthesis of various natural products bearing the cyclopentanoid frameworks.Visualization of the spot on TLC plate was achieved either by exposure to iodine vapor, or UV light.Flash chromatography was performed using Acme's silica gel (100-200 mesh) and the column was usually eluted with ethyl acetate and petroleum ether mixture.Melting points are uncorrected.Infrared spectra (FT-IR) were recorded as KBr pellets unless otherwise mentioned.UV spectra were taken in CH 3 OH solvent.Dry THF and diethyl ether were obtained by distillation over sodium-benzophenone ketyl.Allyl bromide was purified according to the standard procedure.Boron trifluoride etherate was distilled over CaH 2-symmetrical C 20 -hexaquinane 2 by the application of iterative cyclopentane annulation strategy.The hexaquinane 2 was prepared in a 8 step sequence with a reasonable yield.The accessibility of the hexaquinane derivatives such as 2 in good quantities would open 2 .Yields reported are isolated yields of the materials.Allyl bromide was purchased from E-Merck India, boron trifluoride etherate and methanesulphonic acid from Lancaster Synthesis Ltd., (U.K.). 1 H NMR spectra were recorded on EM-300 spectrometer.300 MHz 1 H and 75.4 MHz 13 C NMR spectra were recorded on Bruker spectrometer.
Compound (2).The enone 24 (38 mg, 0.13 mmol) in ethyl acetate (20 mL) was hydrogenated with 10% Pd/C (10 mg) at 3 atm pressure for 3 h.The reaction mixture was filtered and the solvent was removed at reduced pressure.The dione was further purified using a silica gel ISSN 1424-6376Page 87 © ARKAT USA, Inc column.