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.

Keywords: alkaloid; complanadine; molecular editing; ring expansion; total synthesis.

Figure 1.

Complanadine natural products, biosynthesis, prior total syntheses, and our synthetic plan.

Scheme 1.

Total synthesis of complanadine A and analogs.