A synthetic approach to terpendoles: decahydrobenzo[ f ]chromenes by an intermolecular Diels-Alder route

Synthesis of decahydro-1H -benzo[ f ]chromene system using intermolecular Diels-Alder reaction has been carried out for the construction of skeleton of terpendole class of terpenoids


Introduction
Indole-diterpenes, isolated from fungi, comprise an important class of architecturally complex and biologically significant metabolites. 1These metabolites exhibit biological activities such as tremogenicity, 1 insecticidal 2 and pollen growth inhibition. 35][6][7][8] On the basis of carbon skeleton, it is proposed that these metabolites are biosynthesized by epoxidation of 3-geranyl geranyl indole and subsequent cationic cyclisation similar to the biosynthesis of terpenes and steroids. 4,5The isolation and structure elucidation of several of these metabolites are well documented. 9ncreasing importance of this class of compounds is evident from the potent inhibitory activity of terpendole C with an IC50 value of 2.1 µM followed by that of terpendoles D (IC50 3.2 µM), A (IC50 15.1 µM), and B (IC50 26.8 µM) (Figure 1). 10 Recently, a novel action of terpendole E on motor activity of mitotic kinesin Eg5 has been reported. 11The most recent indole-diterpene, JBIR-03, has been isolated from the fungus Dichtomomyces cejpii NBRC 103559 and exhibited anti-MRSA activity and antifungal activity while no reported toxicity towards human cancer cells. 12Despite their complex molecular structures and potent biological activities, there has not been much focus on their efficient synthesis. 13In this paper, we report the construction of key skeleton towards indole-diterpenes.The target framework 1 is envisaged by intermolecular Diels Alder reaction of 4a-methyl-5-vinyl-3,4,4a,7,8,8a-hexahydro-2H-chromene (2) and (Z)-ethyl-3-(1H-indol-2-yl)acrylate (3) (Scheme 1).Commercially available 2-methyl-1,3-cyclohexanedione (4) was selected as starting material for the diene intermediate 2, as one of the keto functionality could be used as a handle to construct the pyran ring while the other one for diene formation.The dienophile 3 could be obtained from indole-2-carboxylic acid (5).In the first step, 2-methyl-1,3-cyclohexanedione (4) was subjected to alkylation with allyl bromide under standard reaction conditions (potassium carbonate/acetone/reflux) to obtain the desired allyl, methyl dione (6) along with O-alkylated product (6a) in a ratio of 60:40 of the C to O-alkylation. 14However, use of sodium hydride as a base in dimethylformamide gave exclusively C-alkylated product (6) in 89% yield.Dione (6) was smoothly reduced with sodium borohydride in methanol (93%) to the corresponding diol (7).Hydroboration of the allylic double bond with borane dimethylsulfide complex gave triol (8) in 91% yield.Now, the stage is set for the formation of pyran ring by selective tosylation of primary alcohol which acts as a good leaving group, to facilitate in-situ displacement with ring hydroxyl group.The reaction proceeded as expected when the triol (8) was treated with p-toluenesulfonyl chloride/triethylamine in dichloromethane to afford the bicyclic pyran (9) (70%) in one-pot.The ketone handle for diene formation was generated by oxidation of bicyclic carbinol (9) with pyridinium chlorochromate in dichloromethane resulting in the corresponding ketone (10) (87%).The trans geometry at the ring junction was confirmed by the splitting pattern of the angular proton in 1 H NMR spectrum, which displayed large couplings indicating an axial orientation.Vinylation on (10) (vinylmagnesium bromide, tetrahydrofuran, 65% yield) followed by heating in hexamethylphosphoramide at 210 ºC furnished diene (2) (64%).The dienophile (3) was synthesized from indole-2-carboxylic acid (5), which was subjected to esterification with diazomethane to afford the corresponding methyl ester (11) in 97% yield (Scheme 3).Diisobutylaluminium hydride reduction of the ester at -78 ºC in dichloromethane produced the corresponding 2-formylindole ( 12) in 81% yield.The aldehyde was subjected to Wittig-olefination using (carbethoxymethylene)triphenylphosphorane to obtain ethyl-3-(2indolyl)prop-2-enoate (3) in 95% yield.Having both the diene and the dienophile in hand, the stage is set to carry out Diels-Alder reaction.Diene (2) and dienophile (3), dissolved in dry toluene, were heated in a sealed tube at 110 ºC for 7 days to obtain the desired adduct (1) with 26% yield.The unreacted starting materials were recovered and reused.Compound (1) was fully characterized as its N-Bocderivative (1a) (Scheme 4).

Conclusion
In summary, an advanced complex precursor of indole diterpenoids was accomplished from commercially available starting materials.The use of intermolecular Diels-Alder reaction is significant for the construction of decahydro-1H-benzo[f]chroman framework.

Experimental Section
General.All solvents and reagents were purified by standard techniques.Crude products were purified by column chromatography on silica gel of 60-120 mesh.IR spectra were recorded on Perkin-Elmer 683 spectrometer. 1H and 13 C NMR spectra were recorded in CDCl3 solution on Brucker Avance 300.Chemical shifts were reported in parts per million with respect to internal TMS.Coupling constants (J) are quoted in Hz.Mass spectra were recorded on CEC-21-11013 or Fannigan Mat 1210 double focusing mass spectrometers operating at a direct inlet system or LC/MSD Trap SL (Agilent Technologies).
2-Allyl-2-methyl-1,3-cyclohexanediol (7).The allyl compound 6 (5.8 g, 34.9 mmol) was dissolved in methanol (50 mL).It was cooled to 0 ºC and then sodium borohydride (1.32 g, 34.9 mmol) was added slowly in portions in the period of 0.25 h.The reaction mixture was stirred at room temperature for 4 h.After completion of the reaction, monitored by TLC, methanol was removed in vacuo.The slurry was cooled to 0 ºC and quenched with saturated sodium chloride and extracted with ethyl acetate (3 x 50 mL).The combined organic layer was washed with water (1 x 20 mL), brine (1 x 20 mL) and then concentrated in vacuo.Residue was purified by silica gel column chromatography (hexane: ethyl acetate 7:3) to obtain the diol 7 as a thick oil.
The reaction mixture was stirred overnight at room temperature.After completion of the reaction, monitored by TLC, reaction mixture was diluted with dichloromethane (20 mL).It was washed with 1N hydrochloric acid (3 x 20 mL), water (2 x 20 mL) and brine (1 x 20 mL).The organic layer was dried over anhydrous sodium sulfate and purified by silica gel column anhydrous dichloromethane (50 mL).It was cooled to 0 ºC, triethylamine (8.6 mL, 62 mmol) and catalytic amount of 4-dimethylaminopyridine (0.36 g, 0.3 mmol) was added.The mixture was stirred for another 10 min.p-Toluenesulfonyl chloride (5.6 g, 29.78 mmol) was added in portions at 0 ºC.