Abstract
Design and synthesis of pseudo‐natural products (PNPs) through recombination of natural product (NP) fragments in unprecedented arrangements enables the discovery of novel biologically relevant chemical matter. With a view to wider coverage of NP‐inspired chemical and biological space, we describe the combination of this principle with macrocycle formation. PNP‐macrocycles were synthesized efficiently in a stereoselective one‐pot procedure including the 1,3‐dipolar cycloadditions of different dipolarophiles with dimeric cinchona alkaloid‐derived azomethine ylides formed in situ. The 20‐membered bis‐cycloadducts embody 18 stereocenters and an additional fragment‐sized NP‐structure. After further functionalization, a collection of 163 macrocyclic PNPs was obtained. Biological investigation revealed potent inducers of the lipidation of the microtubule associated protein 1 light chain 3 (LC3) protein, which plays a prominent role in various autophagy‐related processes.
Highlights
The structures of natural products (NPs) have inspired a wealth of research programs aimed at the discovery of new compound classes endowed with biological activity, and NPs are a rich source of drugs.[1]
In pseudo-natural products (PNPs) natural product derived fragments are combined in unprecedented arrangements currently not accessible by known biosynthesis pathways.[6]
We describe the implementation of this strategy in the synthesis of 20-membered macrocyclic PNPs composed of two cinchona-alkaloid fragments and two pyrrolidine fragments. Biological investigation of these novel macrocyclic PNPs led to the identification of potent upregulators of the lipidation of the microtubule associated protein 1 light chain 3 (LC3) protein, which plays a prominent role in various autophagy-related processes
Summary
The structures of natural products (NPs) have inspired a wealth of research programs aimed at the discovery of new compound classes endowed with biological activity, and NPs are a rich source of drugs.[1]. Azomethine ylides formed in situ by deprotonation from these amino acid ester imines could subsequently undergo stereoselective 1,3-dipolar cycloadditions with diverse olefins (Scheme 1C).[20,21,22,23] Thereby novel macrocycles 6 and 7 would be formed with embedded pyrrolidine fragments which are themselves the defining scaffold of numerous natural products.[24,25,26] If both hemispherical cycloadditions follow the same stereochemical path, the resulting dimers will be C2-symmetrical. We describe the implementation of this strategy in the synthesis of 20-membered macrocyclic PNPs composed of two cinchona-alkaloid fragments and two pyrrolidine fragments Biological investigation of these novel macrocyclic PNPs led to the identification of potent upregulators of the lipidation of the microtubule associated protein 1 light chain 3 (LC3) protein, which plays a prominent role in various autophagy-related processes
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