Synthesis of the tetracyclic skeleton of <i>Aspidosperma</i> alkaloids via PET-initiated cationic radical-derived interrupted [2 + 2]/ <i>retro</i> -Mannich reaction

Natural products with topologically complex architectures are important sources in drug discovery. The pursuit of conciseness and efficiency in the total synthesis of natural products promotes continuous innovation and the development of new reactions and strategies. In this work, a PET-initiated cationic radical-derived interrupted [2 + 2]/<i>retro</i>-Mannich reaction of N-substituted cyclobutenone provided a facile approach to the direct construction of the ABCE tetracyclic framework of <i>Aspidosperma</i> alkaloids. DFT calculations showed that the rate-determining step of the key PET reaction involved C19-C12 bond formation and C19-C3 bond cleavage. Investigation of the bond length changes along the IRC path, spin density, and NBO analysis indicated that this process is neither strictly concerted nor stepwise, but falls in between, and involves a formal 1,3-C shift.