Complanadine A and lycodine are representative members of the Lycopodium alkaloids with a characteristic pyridine-containing tetracyclic skeleton. Complanadine A has demonstrated promising neurotrophic activity and potential for persistent pain management. Herein we report a pyrrole strategy enabled by one-carbon insertion and polarity inversion for concise total syntheses of complanadine A and lycodine. The use of a pyrrole as the pyridine precursor allowed the rapid construction of their tetracyclic skeleton via a one-pot Staudinger reduction, amine-ketone condensation, and Mannich-type cyclization. The pyrrole group was then converted to the desired pyridine by the Ciamician–Dennstedt rearrangement via a one-carbon insertion process, which also simultaneously introduced a chloride at C3 for the next C–H arylation. Other key steps include a direct anti-Markovnikov hydroazidation, a Mukaiyama–Michael addition, and a Paal–Knorr pyrrole synthesis. Lycodine and complanadine A were prepared in 8 and 11 steps, respectively, from a readily available known compound.

Lycopodium alkaloid complanadine A, isolated by Kobayashi et al. in 2000, is a complex and unsymmetrical dimer of lycodine. Biologically, it is a novel and promising lead compound for the development of new treatment for neurodegenerative disorders and persistent pain management. Herein, we reported a concise synthesis of complanadine A using a pyrrole-to-pyridine molecular editing strategy. The use of a nucleophilic pyrrole as the precursor of the desired pyridine enabled an efficient and one-pot construction of the tetracyclic core skeleton of complanadine A and lycodine. The pyrrole group was then converted to a 3-chloropyridine via the Ciamician-Dennstedt one carbon ring expansion. A subsequent C–H arylation between the 3-chloropyridine and a pyridine N-oxide formed the unsymmetrical dimer, which was then advanced to complanadine A. Overall, from a readily available known compound, total synthesis of complanadine A was achieved in 11 steps. The pyrrole-to-pyridine molecular editing strategy enabled us to significantly enhance the overall synthetic efficiency. Additionally, as demonstrated by a Suzuki-Miyaura cross coupling, the 3-chloropyridine product from the Ciamician-Dennstedt rearrangement is amenable for further derivatization, offering an opportunity for simplified analog synthesis.