Photoinduced molecular transformations. Part 155. General synthesis of macrocyclic ketones based on a ring expansion involving a selective β-scission of alkoxyl radicals, its application to a new synthesis of (±)-isocaryophyllene and (±)-caryophyllene, and a conformational analysis of the two sesquiterpenes and the radical intermediate in the synthesis by MM3 calculations

Abstract

The method used for a general synthesis of macrocyclic ketones based on a ring expansion involving a selective β-scission of alkoxyl radicals devised by Suginome and Yamada was extended and modified. Thus, cycloalkanones was transformed into the corresponding α-(ω-iodoalkyl)-cycloalkanones by alkylation of the corresponding lithium enolates with either 1,3-diiodopropane or 1,4-diiodobutane. Treatment of these α-iodoalkyl cyclic ketones with samarium iodide gave bicyclic tertiary alcohols. The generation of the alkoxyl radicals from the bicyclic alcohols by irradiation of the corresponding hypoiodites generated with mercury(II) oxide–iodine–pyridine in benzene resulted in a selective β-scission of their ring-junction bond to give high yields of macrocyclic ketones carrying an iodine which can be removed with tributyltin hydride. The method was then applied to new syntheses of (±)-isocaryophyllene and (±)-caryophyllene. Thus, ω-iodopropylation of ethyl 7,7-dimethyl-2-oxobicyclo[4.2.0]octane-3-carboxylate, followed by cyclization of the resulting α-(ω-iodoalkyl)cycloalkanone with samarium diiodide, gave cis-transoid-cis-ethyl 1-hydroxy-4,4-dimethyltricyclo[6.3.0.0^2,5]undecane-8-carboxylate (69%). The ethoxycarbonyl group of this tricyclic alcohol was transformed into a methyl group by the standard method. Irradiation of a solution of the hypoiodite, prepared by the method mentioned above, with Pyrex-filtered light gave the corresponding cis-bicyclo[7.2.0]undecenone (15%), its exomethylene isomer (<11%), and rearranged lactones (21%), all arising from cleavage of the ring-fusion bond of the generated alkoxyl radical. Basic isomerization of the cis-bicycloundecenone to its trans-isomer, followed by Wittig methylenation, gave (±)-isocaryophyllene. Sensitized photoisomerization of (±)-isocaryophyllene in hexane in the presence of methyl benzoate gave (±)-caryophyllene.

The populations of conformers of caryophyllene, isocaryophyllene, and several related compounds, including a radical intermediate in the synthesis, were calculated by the empirical force-field method. The relative populations of conformers comprising the radical intermediate generated by β-scission of the ring-junction bond of the alkoxyl radicals derived from cis-transoid-cis-4,4,8-trimethyltricyclo[6.3.0.0^2,5]undecan-1-ol mentioned above were correlated with the three products.