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

• DOI: 10.1021/jacs.7b06994
• Publication Date: 2017-07-22T03:14:30Z
• Authors: Micah Maetani; Jochen Zoller; Bruno Melillo; Oscar Verho; Nobutaka Kato; Jun Pu; Eamon Comer; Stuart L. Schreiber
• Keywords: Plasmodium falciparum; Stereoisomerism; Hep G2 Cells; Mice, SCID; 540; 01 natural sciences; Article; Catalysis; 620; 3. Good health; 0104 chemical sciences; Antimalarials; Bridged Bicyclo Compounds; Disease Models, Animal; Mice, Inbred NOD; Animals; Azetidines; Humans; Malaria, Falciparum; Palladium

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.