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.

(–)-Magellanine, (+)-magellaninone, and (+)-paniculatine are three natural products isolated from the Lycopodium family that share a unique 6-5-5-6-fused tetracyclic diquinane core skeleton. Several members of this family have potent s anti-inflammatory and acetylcholinesterase-inhibitory properties and are under development for the treatment of Alzheimer’s and other neurodegenerative diseases. Several research groups have undertaken the formal and total syntheses of this class of natural products. This review highlights over 20 reported total syntheses of these three alkaloids and the development of synthetic methods for the assembly of their core skeletons.