Issue in Honor of Prof. S. Swaminathan ARKIVOC 2005 (xi) 218-225
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 accessible3 ester 4 into the diazomethyl ketone 10 , (ii) aryl participated intramolecular cyclisation4 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 ß-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 1H and 13C 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 –20oC 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, 1H NMR and 13C 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 ammonia6 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 (±)-
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