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J Am Chem Soc. 2017 Aug 16;139(32):11300-11306. doi: 10.1021/jacs.7b06994. Epub 2017 Aug 7.

Synthesis of a Bicyclic Azetidine with In Vivo Antimalarial Activity Enabled by Stereospecific, Directed C(sp3)-H Arylation.

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Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
Broad Institute , Cambridge, Massachusetts 02142, United States.
Howard Hughes Medical Institute , Cambridge, Massachussetts 02138, United States.


The development of new antimalarial therapeutics is necessary to address the increasing resistance to current drugs. Bicyclic azetidines targeting Plasmodium falciparum phenylalanyl-tRNA synthetase comprise one promising new class of antimalarials, especially due to their activities against three stages of the parasite's life cycle, but a lengthy synthetic route to these compounds may affect the feasibility of delivering new therapeutic agents within the cost constraints of antimalarial drugs. Here, we report an efficient synthesis of antimalarial compound BRD3914 (EC50 = 15 nM) that hinges on a Pd-catalyzed, directed C(sp3)-H arylation of azetidines at the C3 position. This newly developed protocol exhibits a broad substrate scope and provides access to valuable, stereochemically defined building blocks. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses.

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