CpTiCl-Promoted Radical Cyclization to Six- and Seven-Membered Carbocycles: Synthesis of (±)-Isoclavukerin A.

A systematic study is undertaken to investigate the less explored radical cyclization in activated olefin-appended epoxides using CpTiCl. The radical generated by the Ti(III)-promoted reductive opening of the epoxy ring promptly underwent cyclization, giving access to differently 1,3-disubstituted six- and seven-membered carbocycles in good yields and diastereoselectivity. This protocol was successfully employed in the construction of 5,7- and 6,7-fused bicyclic frameworks entailing a de novo synthesis of (±)-isoclavukerin A belonging to tri--guaiane class of sesquiterpene natural products in eight simple steps from commercially available starting materials. Besides the Ti(III)-mediated reaction serving as a key step in the synthesis, a sequential [2,3]-sigmatropic rearrangement/syn-elimination of an allyl sulfenate intermediate successfully rendered the highly constrained diene moiety in the hydroazulene core of the target molecule.