Preparation of functionalised bicycles by means of vinyl ketene-cyclohexadienone electrocyclisations: an entry into terpenoid precursors

Cyclohexene derivatives 12 and 14 having an oxygen-functional group at C-(4) were found to undergo smooth vinylketene-cyclohexedienone cyclisations to furnish the highly functionalised bicyclic compounds 13 , 15 and 16 in good chemical yields.


Introduction
Previous work [1][2][3] has demonstrated not only synthetic value of vinylketene-cyclohexadienone cyclisations in the preparation of complex molecules but also the interesting stereoselection observed therein.In a previous communication 2 , we disclosed the stereochemical features of some divinylketene-cyclohexadienone cyclisations.Herein the full details of the preparation of bicyclic compounds reported above that can potentially be elaborated into precursors for terpenoids such as forskolin 1 will be described.The observation 4 that an oxygen functionality at C-8 of bicycle 2 can make the system rather unstable due to a potential retro-Prins type reaction driven by aromatisation of the dienone (Scheme 1) system prompted the search for a more stable molecule with a view to elaboration into forskolin precursors.
The diketone 3 was identified as a possible solution to the problem, as the C-7 keto group could be transposed to C-8 by a sequence involving reduction, dehydration in the correct regiochemical sense followed by epoxidation and reduction at a suitable juncture to give a system having the oxidation pattern of forskolin (Scheme 2).Furthermore, the ketone could also lend itself to further elaboration at its α-carbon atoms by standard chemistry.Simple disconnection of 3 unveiled the readily available ketone 5 (Scheme 3).However, instead of trying the scheme with the acetylene 4, which is not commercially available, the readily accessible simpler analogue 6 (see Scheme 4) was used.

Results and Discussion
Diketone 5 was selectively protected using ethylene glycol in refluxing benzene in the presence of cat.p-TSA to give ketone 7 in 80% after distillation. 5Coupling with the lithium acetylide of tetrahydropyrannylated 3-butyn-1-ol 6 gave the desired propargylic alcohol 8 in high yield.The 1 H NMR displayed an olefinic singlet at 5.25 ppm and two methylene signals at 2.55 ppm and 3.55 ppm attributable to the methylene groups of the side chain.The dioxolane and tetrahydropyran groups were then removed straightforwardly by exposure to cat.pyridinium tosylate in refluxing ethanol.This afforded the diol 9 in 89% overall yield from 6 after purification by chromatography.The 1 H NMR of 9 displayed an olefinic singlet at 5.85 ppm and two side chain triplets at 2.50 ppm and 3.75 ppm attributable to the propargylic and carbinolic methylene groups respectively.It is worth noting that the dioxolane could be selectively removed by brief exposure to cat.p-TSA in aqueous acetone.The diol 9 was partially hydrogenated in the presence of Lindlar's catalyst to afford the desired cis-alkene 10 in 89% yield after purification by chromatography.The olefinic protons appeared as a multiplet at 5.65 ppm while the allylic and homoallylic protons resonated at 2.65 ppm and 3.75 ppm as multiplets respectively.Alkene 10 was subsequently oxidized into spirolactone 11 by exposure to Jones' reagent; the product was obtained in 45% yield as white crystals (mpt: 86-88°C) after purification by chromatography.The 1 H NMR spectrum displayed the olefinic peaks of the lactone moiety at 6.04 pm and 5.85 ppm as a doublet of triplets attributable to the β-H and γ-H of the lactone, respectively.The lactone methylene appeared as a triplet at 3.15 ppm while the remaining olefinic proton exhibited a fine doublet at 5.90 ppm due to allylic coupling.Subsequently it was found that the spirolactone could be obtained in 78% yield by reaction of 10 with PCC at ambient temperature.Spirolactone 11 underwent smooth reductive fragmentation using freshly prepared samarium(II) iodide 6 to give the acid 12 in nearly quantitative yield.The 1 H NMR of 12 showed the two side chain olefinic protons as a doublet of triplets at 5.85 ppm and a fine doublet of doublets at 6.10 ppm, the latter being due to the proton further away from the acid group.
With the acid in hand, generation of the vinyl-ketene was attempted using the standard protocol of conversion of the acid to the corresponding acid chloride by reaction with oxalyl chloride followed by dehydrohalogenation with triethylamine.Unfortunately under these conditions, only decomposition was observed.Reaction in refluxing dichloromethane with the milder reagent 2-chloro-N-methylpyridinium iodide (2-CNMPI) in the presence of triethylamine gave the expected bicycle 13 in 60% as yellow needles (mpt: 86-87 o C) after purification by chromatography.The 1 H NMR spectrum of 13 displayed the three olefinic protons of the dienone moiety as a doublet at 5.98 ppm, a doublet of doublets at 7.05 ppm and another doublet at 6.30 ppm attributable to the α,β and γ-protons respectively.The C-8 methylene group appeared as an AB quartet at 2.75 ppm while that at C-6 resonated as a triplet at 2.40 ppm.Dienone 13 could also be obtained in 43% yield by exposure of acid 12 to acetic anhydride.Having obtained a viable route to the desired bicycle, the synthesis of other derivatives was investigated, especially those that would be amenable to elimination reactions.With this in mind, ketoacid 12 was straightforwardly reduced, using sodium borohydride in methanol at -78°C, to give the expected hydroxyacid 14 in nearly quantitative yield.This was then exposed to an excess of acetic anhydride in pyridine containing a catalytic amount of DMAP, whereupon the bicycle 15 was obtained as a mixture of diastereomers in 68% overall yield from the spirolactone 11 after silica gel chromatography.Capillary GC analysis revealed a 7:3 product ratio of isomers.The major product 15a exhibited three olefinic signals at 5.89 ppm (doublet), 7.00 ppm (doublet of doublets) and 6.22 ppm (doublet).The acetoxy methine appeared as a multiplet at 5.13 ppm.The C-8 protons appeared as a pair of doublets of doublet at 1.69 ppm and 2.21 ppm.The minor isomer 15b had similar signals as the major one except for the C-7 methine proton, which appeared as a highly symmetrical triplet of triplets, indicating a symmetry element between the C-6 and C-8 atoms.Furthermore there was a significant NOE between the C-7-proton and the angular methyl group.Ring opening of cyclohexadienones to the corresponding dienylketenes is known to occur photochemically. 7In the present study it was noted that upon thermolysis of the dienones 15 in refluxing o-dichlorobenzene for 10 hours, a different product mixture was isolated and was found to contain 15a and 15b in the ratio of 1:3.This rearrangement presumably occurs by a mechanism similar to the Barton-Quinkert reaction, involving a formal cycloreversion of the dienone system followed by ring closure to give the more stable isomer as the major product.
Having secured a method to prepare the acetates 15, we turned our attention to the preparation of derivatives more amenable to elimination reactions.To this end hydroxy acid 14 was exposed to thionyl chloride in the presence of pyridine.The reasoning behind the approach was that under these conditions, it was hoped that the alcohol would dehydrate toward the existing double bond prior to generation of the ketene intermediate thereby giving the desired product.Unfortunately, the use of thionyl chloride and pyridine resulted in decomposition.Similarly, exposure to triflic anhydride in pyridine at 0°C gave a very complex mixture.Finally, reaction with mesyl chloride in pyridine gave a mixture of mesylates 16 in 50% yield from spirolactone 11.The reaction occurs presumably through the formation of a mixed anhydride of the carboxylic acid with mesyl chloride and subsequent elimination to give the vinylketene intermediate.The 1 H NMR spectrum showed the olefinic signals associated with the dienone moiety at 5.80, 6.95 and 6.15 ppm attributable to the protons in the α, β and γ-positions respectively with respect to the carbonyl group.The mesylate methine proton appeared as a broad multiplet centred at 5.00 ppm.Elimination of the mesylate proved troublesome: thus treatment with DBU in refluxing chloroform gave a very low yield of regioisomeric alkenes 17.Potassium t-butoxide in refluxing THF also gave similar results, except that the elimination was faster (Scheme 6).Whilst the methodology described in this paper appears to be reasonably versatile in so far as it allows easy access to functionalised bicyclic systems, there is still the need for an efficient elimination reaction.For future work, the possibility of performing a selenium-based elimination of hydroxy-acid 14 prior to cyclisation will be examined.Furthermore it seems that there is good stereoselection in the electrocyclisation reaction only when the substituent on the cyclohexene is adjacent to the site of cyclisation. 2

Experimental Section
General Procedures.Infrared spectra were run as thin films.The NMR spectra were run at 300 MHz for 1 H NMR in CDCl 3 solution using tetramethylsilane (TMS) as internal standard.Mass spectra and high-resolution mass spectra (HRMS) were measured using the electron impact (EI) technique.Infra red spectra were recorded as thin films.Chromatography refers to the flash column technique over Merck Kiesel gel 60H (230-400 mesh) and thin layer chromatography was carried out using plates precoated with Merck silica 60F 254 .Ether and petrol (fraction boiling between 40 o and 60 o C) were distilled prior to use.Tetrahydrofuran was dried by refluxing over sodium and benzophenone under nitrogen and then distillation.Dichloromethane, acetonitrile, pyridine and triethylamine were dried by refluxing over calcium hydride and were then distilled.

Thermolysis of bicycles 15
The bicycle 15 (29.0 mg) was refluxed in o-dichlorobenzene for 10 hours under nitrogen.Then the solvent was taken off on an oil-pump and the residue was purified by chromatography (1:1 petrol/ether) to afford product as a yellow oil (21 mg; 71%).δ H 15b (CDCl 3 ) 6.97 (1H, dd, J=10.0 Hz and J=6.0 Hz); 6.17  Hydroxy acid 14 (89 mg; 0.397 mmol) was dissolved in dry methylene chloride (4 ml) and the solution was cooled to 0°C.Triethylamine (0.65 ml, 4.8 mmol; excess) was added followed by methanesulphonyl chloride (92 µl; 1.192 mmol; 3.0 eq).The solution was stirred under nitrogen at 0°C and slowly allowed to warm up to room temperature over 3 hours.Then the reaction mixture was taken up in methylene chloride (30 ml) and washed with sodium bicarbonate solution (1 x 10 ml), concentrated on the rotary evaporator.The residue was purified by chromatography (SiO 2 ; 2:1 Et 2 O/Pet) to afford the product 16 as a yellow oil (57.0 mg; 50%).