Total synthesis of cadalen-15-oic acid

Two routes for the total synthesis of cadalen-15-oic acid 1 are described. Route A which involves 10 steps deals with the conversion of 5-methoxy-α -tetralone 3 into the cadalen-15-oic acid 1 . The transformation of 6-methoxy-α -tetralone 5 into the cadalen-15-oic acid 1 in 9 steps is described in route B. The deoxygenation of the compound 6 with Pd/C, Mg metal and ammonium acetate and the nickel catalyzed cyanation of triflate 14 are the key steps in route A and route B respectively.


Introduction
Cadalen-15-oic acid 1 is a sesquiterpene isolated from the aerial parts of Heterotheca inuloides (Mexican arnica) 1 and the bark of Scorodocarpus borneensis 2 .Its structure was proposed by Delgado G. et al. 1 and Wiart M. et al. 2 on the basis of spectral data.To date only one synthesis of 1 has been reported. 35][6][7][8] As a part of a study aimed at expanding the synthetic utility of 1-tetralone [8][9][10][11][12] we tried to devise an alternative synthesis for the acid 1 which has attracted our attention due to its anti-inflammatory and analgesic activity.Two different routes were developed to achieve the synthesis of the target molecule 1.

Results and Discussion
Two retrosynthetic routes envisaged for the desired cadalen-15-oic acid 1 as depicted in Scheme 1 led us to select the methoxy-α-tetralones 3 and 5 as starting material for its synthesis.In this paper we disclose the strategy designed to achieve the synthesis of the acid 1 from the tetralones 3 and 5.As outlined in Scheme 2 (route A) the hydroxy aldehyde 2, prepared from tetralone 3 by the published procedure 12 was treated with mesyl chloride to produce the corresponding aryl mesylate 6 in 91% yield, which on treatment with 10% palladium-charcoal, magnesium metal and ammonium acetate 13 afforded the compound 7 in 35% yield.Other methods for reductive hydrogenolysis 14,15 were tried in order to improve the low yield, but poor conversions and hydrolysis of sulfonate to naphthol were observed and this is definitively due to the presence of the electron-withdrawing group at the ortho position of aryl mesylate.Finally, the cadalen-15oic acid 1 was prepared by oxidation of the resulting aldehyde 7 with sodium biphosphate, sodium chlorite and sulfamic acid. 16lthough the above synthetic strategy allowed us to obtain the cadalen-15-oic acid 1, the approach proved to be somewhat complicated owing to the difficulty in the hydrodeoxygenolysis of aryl mesylate 6.Therefore, an alternative route B depicted in Scheme 3 was investigated.Treatment of the commercially available 6-methoxy-1-tetralone 5 with methylmagnesium bromide followed by dehydration afforded an olefin, which was easily transformed into the tetralin 8 by catalytic hydrogenation with 5% Pd/C.Oxidation of 8 with 10% chromic acid in acetic acid at 0 o C yielded the tetralone 9 in 62%.Alternative approaches for the syntheses of tetralone 9 have been reported by a lengthy procedure. 17,18reatment of 9 with i-Pr 3 ZnMgCl complex, generated via iPr 2 Zn from inexpensive zinc (II) chloride 19 and iPrMgCl, produced a tertiary alcohol which subsequent dehydration with acid and dehydrogenation with 1.2 equiv of 2,3-dichloro-5,6-dicyanoquinone (DDQ) provided naphthalene 4. The Grignard reaction can also be achieved in presence of cerium chloride 20,21 but as the cerium chloride is expensive zinc chloride was chosen for this experiment.In absence of zinc chloride 19 or cerium chloride, 20,21 the Grignard reaction yields undesired products that result from reduction and aldol reactions.Demethylation of aromatic ether 4 with 48% aqueous hydrobromic acid furnished naphthol 10 in 87% yields whose conversion to trifluoromethanesulfonate ester 11 was performed by mixing 10 with trifluoromethanesulfonic anhydride in the presence of triethylamine.The introduction of triflate group was found essential for its facile transformation to nitrile and subsequently to carboxylic acid.Treatment of trifluoromethanesulphonate ester 11 with potassium cyanide in the presence of tetrakistriphenylphosphinenickel(0) generated in situ from bistriphenylphosphinenickel(II) chloride, 22,23 zinc and phosphine, afforded carbonitrile 12 in 81% yield which was hydrolyzed with ethanolic potassium hydroxide to obtain cadalen-15-oic acid 1 in 65% yield.Its m.p. and spectroscopic data (NMR 1 H and 13 C) were identical with those reported.

Conclusion
In summary two distinct approaches for the synthesis of cadalen-15-oic acid 1 have been described.The key step in the first approach was the hydrogenolysis of the hydroxyl group which provided the acid 1 in moderate yield.In the second approach, the key step was the transformation of hydroxyl group (via triflate and nitrile) to acid group to obtain acid 1 in good yield.
The present synthesis proceeds via intermediates which may prove useful in the synthesis of other sesquiterpenoids.

Experimental Section
General.Unless otherwise stated, IR spectra were taken on Nicolet FT instrument. 1 H NMR and 13 C NMR spectra were recorded on Brucker AM 300 MHz in CDCl 3 using TMS as internal standard.Mass spectra of compounds 7, 8, 9, 10, 11, 12 and 1, were run on (GC/MS) gas chromatography Hewlett Packard 5890 Quadrupolar 5972 Serie S. Mass spectra of compound 6 was recorded on a Thermo Finnigan TSQ Quantum ultra AM (Electron spray ionization) mass spectrometer.Column chromatography was performed on silica gel (Merck grade 60, 70-230 mesh).The spectral and analytical data of all new compounds have been reported in the Experimental Section.Microanalyses were carried out at the Chemistry Department, IVIC, Caracas.

4-isopropyl-6-methoxy-1-methylnaphthalene 4.
To a solution of isopropylmagnesium chloride (2M, 6.5 mL, 12.60 mmol) in dry tetrhydrofuran (5 mL) was added zinc chloride (11 mg, 0.84 mmol) under a nitrogen atmosphere and stirred at room temperature for 1 h.Tetralone 9 (1.60 g, 8.42 mmol) was added dropwise at 0 o C and stirred at room temperature for 6 h.The reaction mixture was quenched by saturated aqueous ammonium chloride and extracted with diethyl ether.To the resulting organic extract was added hydrochloric acid (6N, 8 mL) and stirred for 3 h at room temperature.The aqueous phase was extracted with ether and the combined extracts were dried and concentrated.The residue on chromatographic purification (hexane/ether 9:1) yielded the olefin (1.54 g, 85%) as a light yellow liquid.

4-Isopropyl-1-methylnaphthalene-15-oic acid (cadalen-15-oic acid) 1. First Approach:
To a solution of aldehyde 7 (275 mg, 1.30 mmol) in dioxane (15 mL) were added NaH 2 PO 4 (800 mg, 5.10 mmol) in water (5 mL) and sulfamic acid (186 mg, 1.92 mmol).To the mixture cooled at 5 o C was added slowly sodium chlorite (186 mg, 1.70 mmol) in water (1 mL) below 10 o C followed by the addition of sodium sulfite (195 mg, 1.50 mmol).The mixture was stirred for 15 min and acidifided to pH=2 with hydrochloric acid and extracted with ether.The organic extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo.The resulting material on cooling afforded the compound Second Approach: A mixture of nitrile 12 (241 mg, 1.15 mmol) in aqueous potassium hydroxide (20 mL, 1.8 N, 36 mmol) and ethanol (25 mL) was stirred at 75 o C for 24 h.After removing ethanol in vacuo, the aqueous layer was acidified to pH 3 and extracted with ether.The organic extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure to obtain 1 as white solid (170 mg, 65%) whose m.p. and spectroscopic data were identical with that of obtained by first approach.