Synthesis 2024; 56(01): 107-117
DOI: 10.1055/a-2107-5159
special topic
Advances in Skeletal Editing and Rearrangement Reactions

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

Brandon S. Martin
a   Department of Chemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
,
Donghui Ma
a   Department of Chemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
b   Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA
,
Takeru Saito
a   Department of Chemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
,
Katelyn S. Gallagher
a   Department of Chemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
,
Mingji Dai
a   Department of Chemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
b   Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA
› Institutsangaben
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



Publikationsverlauf

Eingereicht: 15. Februar 2023

Angenommen nach Revision: 07. Juni 2023

Accepted Manuscript online:
07. Juni 2023

Artikel online veröffentlicht:
03. Juli 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
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