Cp2TiCl-Promoted Endo-Trig Radical Cyclization to Six- and Seven-Membered Carbocycles: Synthesis of (±)-Isoclavukerin A

• Published in: Journal of organic chemistry 2023-09, Vol.88 (17), p.12677-12697
• Main Authors: Begum, Sabnam, Bhattacharya, Rajarshi, Paul, Shashwati, Chakraborty, Tushar Kanti
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.3c01356

A systematic study is undertaken to investigate the less explored endo-trig radical cyclization in activated olefin-appended epoxides using Cp2TiCl. The radical generated by the Ti­(III)-promoted reductive opening of the epoxy ring promptly underwent endo-trig 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-nor-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.