Hybrid macrocycle formation and spiro annulation on cis-syn-cis-tricyclo[6.3.0.02,6]undeca-3,11-dione and its congeners via ring-closing metathesis

Summary We have developed a simple methodology to transform cis-syn-cis-triquinane derivative 2 into the diindole based macrocycle 6 involving Fischer indolization and ring-closing metathesis (RCM). Various spiro-polyquinane derivatives have been assembled via RCM as a key step.


Synthesis of compound 9 Method A
To a suspension of NaH (8.2 mg, 0.34 mmol) in DMF (5 mL), the diindole 8 (50 mg, 0.15 mmol) was added at rt under nitrogen. Then, the reaction mixture stirred at rt for 15 min.
Next, methyl iodide (0.03 mL, 0.34 mmol) was added in a dropwise manner, and then the stirring was continued for 24 h at rt. After termination of the reaction (TLC monitoring), the reaction mixture was diluted with ethyl acetate (10 mL), and the organic layer was washed with water, brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure.

Synthesis of compound 10
To a suspension of NaH (16.3 mg, 0.70 mmol) in DMF (10 mL), the diindole 8 (100 mg, 0.3 mmol) was added at rt under nitrogen. Then, the reaction mixture stirred at rt for 15 min.

Synthesis of compound 11
A solution of diallyldiindole 10 (65 mg, 0.16 mmol) in dry CH 2 Cl 2 (15 mL) was degassed with N 2 for 10 min. Then, G-II (7.5 mol %) was added stirring was continued for 24 h at rt.

General procedure for the allylation of 2 and 3a-d
To a suspension of NaH (6 equivalents) in THF (20 mL), added the dione 2 (or 3a-c) at rt under nitrogen and the reaction mixture was stirred at rt for 10 min. Later, allyl bromide was added to the reaction mixture in a dropwise manner, and stirring was continued overnight at rt. After termination of the reaction (TLC monitoring), the reaction mixture was diluted with ethyl acetate (10 mL), washed with water, brine and dried over Na 2 SO 4 , concentrated at reduced pressure. The crude product obtained was purified by silica gel column chromatography with appropriate mixture of EtOAc-petroleum ether to yield the allylated product 12 (or 14a-d) [4].

General procedure of the ring-closing metathesis of 12 and 14a-d
A solution of compound 12 (or 14a-d) in dry CH 2 Cl 2 (20 mL) was degassed with N 2 for 10 min, then G-I (10 mol%) was added and stirring was continued for 12-24 h at rt. After termination of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography with an appropriate mixture of EtOAc/petroleum ether to deliver the desired RCM product 13 (or 15a-d) [4].

General procedure for the hydrogenation of 13 and 15a-d
The solution of compounds 13 (or 15a-d) in EtOAc (10 mL), 10 mol % Pd/C (1 mmol) was added and the reaction mixture was stirred at rt under H 2 pressure (1 atm) for 6-24 h. After termination of the reaction (TLC monitoring), the reaction mixture was filtered through using a Celite-pad and the solvent was removed under reduced pressure. The crude product was purified by silica-gel column chromatography by using an appropriate mixture of EtOAc/petroleum ether to yield the desired hydrogenated product 7 (or 16a-d) [4].