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DOI: 10.1055/a-2107-5159
Concise Total Synthesis of Complanadine A Enabled by Pyrrole-to-Pyridine Molecular Editing
This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health (GM128570).
Abstract
The Lycopodium alkaloid complanadine A, isolated in 2000, is a complex and unsymmetrical dimer of lycodine. Biologically, it is a novel and promising lead compound for the development of new treatments for neurodegenerative disorders and persistent pain management. Herein, we report 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 converted into a 3-chloropyridine via 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, the 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 Suzuki–Miyaura cross-coupling, the 3-chloropyridine product from the Ciamician–Dennstedt rearrangement is amenable for further derivatization, offering an opportunity for simplified analogue synthesis.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2107-5159.
- Supporting Information
Publication History
Received: 15 February 2023
Accepted after revision: 07 June 2023
Accepted Manuscript online:
07 June 2023
Article published online:
03 July 2023
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