A new total synthesis of ( ± )-isolongifolene involving an aryl participated diazoketone cyclisation strategy

A facile total synthesis of ( ± )-isolongifolene has been successfully accomplished involving aryl participated intramolecular cyclisation of 1,1,4-trimethyl-2-diazoacetyl-6-methoxyindane as the key reaction


Introduction
The bridged tricyclic sesquiterpene longifolene 1 undergoes rearrangement in the presence of acid to provide an isomeric hydrocarbon known as isolongifolene 2. 1 Isolongifolene 2 incorporates a novel tricyclo[6.2.1.0 1,6]undecane skeleton and its structure was confirmed by its synthesis 2 from camphene-1-carboxylic acid 3.A formal total synthesis of isolongifolene was achieved by Piers and Zbozny 5 involving intramolecular alkylation of an appropriate octalone derivative.Besides the construction of the tricyclo[6.2.1.0 1,6]undecane framework, the total synthesis of isolongifolene is associated with the difficulty in the generation of gem-dimethyl groups in two of the three rings and an isolated double bond in ring A. We report herein an aryl participated diazoketone cyclisation strategy to accomplish a very convenient and efficient total synthesis of (±)-isolongifolene.The salient features of our synthesis are (i) facile conversion of the easily accessible 3 ester 4 into the diazomethyl ketone 10 , (ii) aryl participated intramolecular cyclisation 4 of 10 to provide in high yield the tricyclic dienedione 11 as a key intermediate to 2, and (iii) efficient transformation of 11 into isolongifolene involving regioselective conjugate addition of lithium dimethylcuprate to 11 followed by removal of the two carbonyl groups from the rings A and C of the resulting enedione 12.

Results and Discussion
Our synthesis of (±)-isolongifolene 2 from methyl 3-(2-methyl-4-methoxyphenyl)propanoate 4 is outlined in Scheme 1. Grignard reaction of the ester 4 with an excess of methyl magnesium iodide followed by intramolecular cyclisation of the resulting carbinol with polyphosphoric acid provided the indane derivative 5 in 72% overall yield.Oxidation of 5 with chromic acid in acetic acid afforded the indanone 6 (73%).Having a convenient route to 6, we turned our attention to convert 6 into the diazomethyl ketone 10.The ketone 6 was treated with dimethyl carbonate in the presence of sodium hydride to afford the β-ketoester 7 as a crystalline compound in 83% yield.Reduction of 7 with sodium borohydride followed by catalytic hydrogenolysis of the crude product in methanol in the presence of perchloric acid provided the ester 8 in 85% yield.Saponification of 8 furnished the acid 9 which was converted via the corresponding acid chloride into the diazomethyl ketone 10 in excellent yield.The spectral characteristics of the compounds 5-10 as revealed through their 1 H and 13 C NMR spectra were fully in accord with their structures.Intramolecular cyclisation of the diazoketone 10, shown in Scheme 2, was effected by treatment with trifluoroacetic acid in dichloromethane at -20 o C to afford the crystalline dienedione 11 in 77% yield.
Conjugate addition of lithium dimethylcuprate to 11 in the presence of boron trifluoride etherate furnished the enedione 12 (62%).The construction of the basic tricarbocyclic framework of isolongifolene 2 was thus accomplished in a convenient manner.The IR, 1 H NMR and 13 C NMR spectra of the dienedione and the enedione were in full accord with the structures 11 and 12, respectively.
In order to complete a synthesis of isolongifolene 2 from the enedione 12, it was necessary to remove the two carbonyl groups from the rings A and C of 12. Treatment of 12 with ethanedithiol and boron trifluoride etherate in methanol at room temperature furnished the monothioacetal 13 as the sole product in 90% yield.Desulfurisation of 13 with sodium and ethanol in liquid ammonia 6 followed by treatment of the crude product with Jones reagent afforded the enone 14 in high yield.The spectral and analytical data of the compound 14 agree with the assigned structure.Huang-Minlon reduction of 14 followed by chromatography of the crude product over neutral alumina and elution with light petroleum afforded pure (±)-isolongifolene 2 in 76% yield.The identity of synthetic 2 was secured through 1 H NMR, 13 C NMR, DEPT experiments, and microanalytical data.Also, the spectral data of 2 agreed very well with those reported in the literature.

Scheme 2
In conclusion, a facile total synthesis of the bridged sesquiterpene artefact isolongifolene has been acomplished involving aryl participated intramolecular cyclisation of an appropriately substituted diazomethyl ketone as the key reaction.

Experimental Section
General Procedures.The compounds described here are all racemates.IR spectra were recorded on Perkin-Elmer model PE 298 and Shimadzu FTIR-8300 spectrophotometers.Unless otherwise stated, 1 H and 13 C NMR spectra were recorded in CDCl 3 solution at 300 MHz and 75 MHz respectively on a Bruker DPX-300 spectrometer with SiMe 4 as standard.Moisture sensitive reactions were carried out using standard syringe-septum technique.Anhydrous solvents were obtained by standard procedures.All solvent extracts were dried over anhydrous Na 2 SO 4 .Product purities were routinely checked by TLC.Ether refers to diethyl ether and light petroleum refers to the fraction of petroleum ether in the boiling point range 60 -80 0 C.

1,1,4-Trimethyl-6-methoxyindane (5).
To a stirred suspension of MeMgI [prepared from magnesium turnings (5.3 g, 0.22 g-at.) and MeI (32 g, 0.225 mol)] in anhydrous ether (70 mL) was added slowly under nitrogen a solution of the ester 4 (10 g, 0.048 mol) in ether (20 mL).The mixture was stirred at room temperature for 30 min and then refluxed for 5 h.It was then cooled in an ice-bath and decomposed carefully with saturated aqueous NH 4 Cl (60 mL).The organic layer was separated and the aqueous phase extracted with ether (2x30 mL).The combined ether solution was washed with water (2x30 mL) and dried.Evaporation of the solvent furnished the crude product as an oil (10 g) [IR (film) 3404, 2968, 1608, 1502 cm -1 ; 1 H 3 PO 4 (89%, 35 mL)] at 90 0 C for 1 h.The reaction mixture was cooled, decomposed with crushed ice, and extracted repeatedly with ether.The combined ether extract was washed successively with water, saturated aqueous NaHCO 3 until alkaline, water again until neutral, and then dried.Removal of the solvent followed by distillation of the residue at 105-108 o C (bath temp.)/ 0.8 mm Hg furnished the indane 5 (6.58 g, 72%) as a colourless oil; 1

3,3,7-Trimethyl-5-methoxyindan-1-one (6).
A solution of CrO 3 (6 g, 0.06 mol) in 80 % aqueous AcOH (30 mL) was added slowly with stirring to a solution of the indane 5 (6.3 g, 0.033 mol) in glacial AcOH (40 mL) at 5 0 C.After the addition, the mixture was stirred at 10 0 C for 5 h, allowed to stand at room temperature for 12 h and then diluted with water (70 mL).Solid Na 2 CO 3 was added in portions to neutralise most of the acetic acid and the product was extracted with ether (3x50 mL).The combined ether extract was washed with aqueous NaHCO 3 and water, dried and concentrated.The residue was distilled to furnish the indanone 6 (4.94 g, 73 %) as a colourless oil, b.p. 138 -140 0 C (bath temp.)/ 0.6 mm Hg; IR (film) 1697, 1598 cm -1 ; 1  ]undec-2,5-diene-4,9-dione (11).A solution of the diazoketone 10 (1.5 g, 5.81 mmol) in dry CH 2 Cl 2 (25 mL) was added during 3 min under nitrogen to a stirred solution of trifluoroacetic acid (30 mL) in CH 2 Cl 2 (30 mL) at -20 0 C. The mixture was stirred at -20 0 C for another 3 min and then diluted with CH 2 Cl 2 (50 mL).The dichloromethane solution was washed with water (3x25 mL), dried and concentrated.The crude product was purified by chromatography over silica gel (30 g).Elution of the column with ether : light petroleum (2:3) furnished the crystalline dienedione which was recrystallised from a mixture of ether and petroleum ether to afford colourless plates of 11 (0.97 g, 77 %), m.p. 179 -180 0 C; IR (KBr) 1749, 1668, 1626 cm -1 ;  Cu was stirred for 5 min, cooled to -50 0 C, and 0.7 mL (5.52 mmol) of freshly distilled BF 3 .Et 2 O was added.After the mixture was stirred for 5 min, a solution of the dienedione 11 (0.9 g, 4.16 mmol) in dry THF (5 mL) was added dropwise.The mixture was stirred at -50 0 C for 15 min, an additional 0.7 mL (5.52 mmol) of BF 3 .Et 2 O was added, and the mixture stirred at -40 0 C for 3 h.The reaction mixture was then allowed to reach 0 o C and poured into saturated aqueous NH 4 Cl (50 mL).Concentrated NH 4 OH solution (12 mL) was added to dissolve the precipitated copper salts and the product was extracted with ether (3x60 mL).The combined ether extract was washed with water (3x40 mL), dried and concentrated.The residue was purified by chromatography over silica gel (25 g).The fractions eluted with ether : light petroleum (1:3) furnished a crystalline material which was recrystallised from a mixture of ether and petroleum ether to afford the enedione 12 (0.]undec-5-en-9-one (14).A solution of the thioacetal 13 (0.55 g, 1.78 mmol) in dry ether (15 mL) and EtOH (1 mL) was added under nitrogen to distilled liquid ammonia (80 mL).To this mixture was added Na metal (0.8 g, 0.035 g-at.) with stirring during 2 min.After 5 min, EtOH was added dropwise until the blue colour disappeared.The ammonia was allowed to evaporate.The residue was diluted with water (25 mL) and extracted with ether (3x30 mL).The combined ether extract was washed with water (2x25 mL), dried, and concentrated.The residue, dissolved in acetone (25 mL), was treated with dropwise addition of Jones reagent at 10 o C until the colour of the reagent persisted for 2 min.A few drops of methanol were added to destroy the excess reagent.The reaction mixture was diluted with water (50 mL) and extracted repeatedly with ether.The combined organic extract was washed with water, aqueous NaHCO 3 , water and dried.The residue remaining upon evaporation of the solvent was purified by chromatography on silica gel (10 g).Elution of the column with ether : light petroleum (1: 9) furnished the enone 14 (0.32 g, 82%) as a colourless oil; IR (film) 1749, 1461 cm -1 ; (±)-Isolongifolene (2).A mixture of the ketone 14 (0.28 g, 1.28 mmol), hydrazine hydrate (4 mL, 99%), hydrazine dihydrochloride (1.1 g) and diethylene glycol (14 mL) was heated to 125°C in an atmosphere of nitrogen and kept at that temperature for 2 h.The reaction mixture was then cooled to 80 o C and solid pellets of potassium hydroxide (2 g) were added.The temperature was gradually raised to 210 o C by distilling off low boiling materials.The reaction mixture was maintained at 210-220 o C for 3 h, then cooled, poured into water (25 mL), and extracted with ether (3x30 mL).The distillate containing the low boiling materials was also diluted with water (20 mL) and extracted with ether (3x20 mL).The combined ethereal extract was washed with cold dilute hydrochloric acid (20 mL, 3N), water (2x30 mL), and dried.After removal of ether, the residue was purified by chromatography on neutral alumina (10 g).Elution with light petroleum furnished (±)-isolongifolene (2) (0.2 g, 76%) as a colourless oil;