0576142 - ÚOCHB 2024 RIV DE eng J - Journal Article
Klychnikov, Mikhail - Pohl, Radek - Císařová, I. - Hájek, Miroslav - Jahn, Ullrich
Concise Total Syntheses of (+)-Brefeldin A, Diastereomers and Analogs and Their Biological Activity.
ChemistryEurope. Roč. 1, č. 2 (2023), č. článku e202300030. ISSN 2751-4765
R&D Projects: GA ČR(CZ) GA16-18513S
Institutional support: RVO:61388963
Keywords : brefeldin A * Golgi apparatus * macrolactones * natural products * total synthesis
OECD category: Organic chemistry
Method of publishing: Open access
https://doi.org/10.1002/ceur.202300030

Brefeldin A is an important natural product and biochemical tool with cell-modulating and other diverse biological activities. To explore its chemical space, a generally applicable strategy for total syntheses of naturally occurring (+)-brefeldin A (BFA), 2-epi-BFA, their diastereomers and analogs with varying macrocyclic ring size is reported. The five-membered ring fragment was constructed by a short three-step sequence consisting of tandem nucleophilic epoxide opening/Brook rearrangement/radical oxygenation and subsequent thermal radical cyclization based on the persistent radical effect. Further key steps are asymmetric aldehyde vinylation, which enables control of the absolute configuration at the allylic hydroxy group of BFA, cross-metatheses reactions for attachment of the northern and southern side chains to the cyclopentane unit and final Shiina macrolactonization. The cytotoxic activity of all compounds was determined, and several analogs proved to be similarly active as BFA, providing insight about regions of the skeleton that can be varied or have to be conserved with respect to their biological activities. Fluorescence microscopy revealed that BFA and some non-natural analogs disassemble the Golgi apparatus in cells with large variation of the disassembly and subsequent reassembly times.
Permanent Link: https://hdl.handle.net/11104/0345736