Concise Total Synthesis of Complanadine A Enabled by Pyrrole-to-Pyridine Molecular Editing

Abstract

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.

Convergent and Efficient Total Synthesis of (+)-Heilonine Enabled by C–H Functionalizations

“…Our continued interest in using carbonylation chemistry and C–H functionalization to streamline total synthesis of medicinally important natural products prompted us to embark on the total synthesis of heilonine with the goal to establish a general and efficient approach to access both natural and synthetic analogs for comprehensive biological evaluations. So far, there is only one total synthesis of heilonine, which was reported by Rawal and Cassaidy in 2021 in 21 LLS steps (30 steps total; Figure B) .…”

Total Syntheses of Phleghenrines A and C

“…Our continued interest in the total synthesis and biological studies of lycopodium alkaloids with the therapeutic potential to treat various neurodegenerative disorders prompted us to pursue the total synthesis of the phleghenrine alkaloids. Retrosynthetically (Figure ), similar to our total synthesis of lyconadins A and C, we decided to install the 2-pyridone moiety in the end by using the Fukuyama-Yokoshima 2-pyridone synthesis .…”