Generation of [5.5.n] Tricyclic Ring Systems by Radical-Promoted Inter- And Intramolecular [3 + 2] Cycloadditions

Article abstract of DOI:10.1021/jo9706133

A new method for the synthesis of [5.5.n] tricyclic ring systems via radical fragmentation and double cyclization is described. The general process (Scheme 1) involves addition of an alkylthio radical to an alkenylcyclopropane 1 to generate the cyclopropylcarbinyl radical which opens to the homoallylic radical; this radical then adds to an alkene or alkyne radical trap to give a new alkyl radical which then adds back to the thioalkyl allylic system to generate, after loss of the alkylthio radical, the bi- or tricyclic product, 2, thus making the process analogous to a [3 + 2] cycloaddition. Thus addition of the butylthio radical (generated by photolysis of dibutyl disulfide) to the bicyclo-[3.1.0]hex-2-en-6-yl carboxylate 3 in the presence of an alkene or alkyne-either an acyclic radical trap, e.g., ethyl vinyl ether, isopropenyl acetate, methyl acrytate, or methyl propiolate, or a cyclic one, e.g., cyclopentenone, dihydrofuran, cyclopentenyl acetate, or cyclopentene-affords the desired bi- or tricyclic products 9-16 in yields of 54-88%. One can also use 6-vinylbicyclo[3.1.0]hexan-2-one (4) as the alkenylcyclopropane unit. Trapping of the radical generated by addition of butylthio radical to 4 with ethyl vinyl ether or cyclopentene affords the bi- and tricyclic products 17 and 18 in 66-68% yields. The products are formed as diastereomeric mixtures in all cases. This cyclization process can also be carried out in an intramolecular fashion, e.g., isomerization of the ketones 25 and 27 or the esters 28-30 with butylthio radical to give the tricyclic products 31-35 and 41-43. The use of dimethyl-substituted alkenes gives reasonably good diastereoselectivity favoring the cis-syn-cis isomer over the cis-anti-cis isomer, e.g., 7.5:1 for 33 over 34 and 4.2:1 for 41 over 42. The structures of the diastereomeric products were proven by comparison of the NMR spectra of the saturated analogues, which are known for the unsubstituted series and differ in their symmetry properties for the dimethyl-substituted case. These results indicate that the cyclization of a stabilized 5-hexenyl radical, e.g., 45 in Scheme 8, is reversible and leads to the most stable final product.