Cp2Ti(III)Cl-Mediated Endo- and Exo-Radical Cyclization: Synthesis of a Tri-nor-guaiane Sesquiterpene Isoclavukerin A, Terpenoid Bicyclic Lactones and Synthetic Studies Towards the Total Synthesis of Scabrolide A

Abstract

Radical cyclization strategy always gives an expedient access to complex molecular scaffolds present in many bioactive natural products. In this research work, a systematic study is undertaken to investigate the less explored endo-trig radical cyclization in activated olefin-appended epoxides using Cp2Ti(III)Cl. The radical generated by the Ti(III)-promoted reductive opening of the epoxy ring promptly underwent an endo-trig cyclization giving an access to differently 1,3-disubstituted six- and seven-membered carbocycles in good yields and diastereoselectivity enabling a successful synthesis of a naturally occurring tri-nor-guaiane sesquiterpene, (±)-isoclavukerin A. The Cp2Ti(III)Cl-mediated reductive epoxide opening and concomitant cyclization protocol was also successfully applied in the alkenoate-appended epoxide derived from D-(+)-malic acid to achieve the first stereoselective total syntheses of three fungal secondary metabolites – monoterpenoid (+)-pestalotiolactone A, meroterpenoid (-)-myrotheciumone A and an iridoid lactone (+)-scabrol A in excellent overall yields. The last part of this thesis work delineates synthetic approaches toward the total synthesis of furanobutenolide derived norcembranoid natural product, scabrolide A, a highly congested [5-6-7] carbocyclic scaffold with six stereocenters, from a preassembled bicyclic lactone having the requisite stereocentres derived from (S)-malic acid using the Cp2Ti(III)Cl-mediated reductive epoxide opening and concomitant cyclization protocol as a key step.