New strategies on intramolecular annulations.

Abstract

An efficient and stereocontrolled annulation strategy, originally developed for the synthesis of octahydronaphthalene precursors to the mevinic acids, was applied towards the synthesis of a variety of bicyclic systems for the purpose of demonstrating the utility of the annulation. This annulation strategy was based on the intramolecular conjugate addition of a $\gamma$-oxo-$\alpha$-ester enolate to a vinyl sulfone. It was discovered that the intramolecular conjugate addition reaction produced the desired bicyclo (4.3.0) non-4-ene system in a nonstereoselective fashion. For example, treatment of ethyl (1RS, 4RS, 5SR)-4- ((1Z, 3E)-4-(phenylsulfony1)-1,3-butadienyl) -1- (triethylsilyloxy)bicyclo (3.1.0) hexane-6-carboxylate with cesium fluoride resulted in the formation of a mixture of bicyclo (4.3.0) non-4-ene products. However, it was discovered that ethyl(1RS, 4RS, 5SR)-5-methyl-4- ((1Z, 3E)-4-(phenylsulfonyl)-1,3-butadienyl) -1-(triethylsilyloxy)bicyclo (3.1.0) hexane-6-carboxylate cyclized cleanly to afford ethyl (1RS, 2RS, 3RS, 6SR)-1-methyl-3-(phenylsulfonylmethyl)-9-oxobicyclo (4.3.0) non-4- ene-2-carboxylate in good yield. The scope and limitations of the cyclization were investigated throughout this study. The intramolecular cyclization of a $\gamma$-oxo-$\alpha$-ester enolate onto 1-(p-toluenesulfonyl)-1,4-pentadienyl side chains, for the synthesis of seven-membered rings, was also studied. Ethyl(1RS, 5RS, 6SR)-5- ((1Z, 4E-5-(p-toluenesulfonyl)-1,4-pentadienyl) -1-(triethylsilyloxy)bicyclo (4.1.0) heptan-7-carboxylate was subjected to the fluoride induced cyclization conditions. The cyclization was not successful, because allylic deprotonation of the side chain occurred and ethyl(1RS, 6RS)-2-oxo-6- ((1Z, 3E)-5-(p-toluenesulfonyl)-1,3-pentadienyl) cyclohexaneacetate was obtained. Efforts were directed towards the development of a new annulation involving the intramolecular cyclization of a dichlorocyclobutanone derived anion. (1RS, 4RS, 5RS)-7,7$\sp\prime$-dichloro-4- ((1Z, 3E)-4-(phenylsulfonyl)-1,3-butadienyl) -1-triisopropylsilyloxy)bicyclo (3.2.0) heptan-6-one was prepared via a (2+2) cycloaddition of dichloroketene onto the corresponding silyl enol ether precursor. However, the anion generated from cesium fluoride desilylation did not cyclize as expected. The dichlorocyclobutanones were dechlorinated and the resulting cyclobutanones were subjected to a fluoride induced ring expansion-cyclization sequence. However, due to the resistance of the triisopropylsilyl group towards desilylation by fluoride, the expected cyclization was not observed. An approach toward the synthesis of eight-membered carbocycles was also examined. It was discovered that cyclopropanation of silyl enol ethers with diethyl diazoglutaconate and rhodium acetate resulted in the formation of rearranged bicyclo (3.3.0) octene-dicarboxylates, rather than the expected silyloxyvinylcyclopropanes. A new annulation was developed for the synthesis of 2-azabicyclo (4.3.0) nonenes. Copper-catalyzed decomposition of (N-(p-toluenesulfonyl)imino)phenyliodinane in the presence of 3- ((1Z, 3E)-4-(phenylsulfonyl)-1,3-butadienyl) -1-(triethylsilyloxy)cyclopentene produced N-(1RS, 5RS)-2-oxo-5- ((1Z, 3E)-4-(phenylsulfonyl)1,3-butadienyl) cyclopentyl) p-toluenesulfonamide, After reduction of the ketone, (1RS, 6SR, 9SR)-3-(phenylsulfonylmethyl)-9-(triethylsilyloxy)-N-(p-toluenesulfonyl)-2-azabicyclo (4.3.0) non-4-ene was obtained from potassium tert-butoxide deprotonation of the sulfonamide.