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

Abstract

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.

Chemical and structural investigation of the paroxetine-human serotonin transporter complex

“…Transition metal-catalyzed C-H functionalization can promote the reaction of unactivated C(sp 3 )-H bonds with the aid of a directing group [21][22][23][24][25][26] . Here, C-H functionalization enabled installation of the appropriate aryl group on the pre-existing piperidine ring 27 , providing an attractive and short route to vary this functionality with inherent control of enantiomeric excess.…”

Synthesis of Azetidines via Visible Light-Mediated Intermolecular [2+2] Photocycloaddition

“…Four-membered azetidine heterocycles have seen increased prominence as saturated building blocks in the field of drug discovery in recent years. [1][2][3][4] The well-defined, three-dimensional structure of these sp 3 -rich scaffolds not only provides access to unique chemical space, but has also been correlated to improved pharmacokinetic properties and toxicological benefits. [5][6][7][8][9] However, while the incorporation of azetidines into complex scaffolds is highly desirable, it is often hampered by the limited number of efficient, robust methods for their synthesis.…”

Synthesis of Elaborate Benzofuran-2-Carboxamide Derivatives through a Combination of 8-Aminoquinoline Directed C–H Arylation and Transamidation Chemistry

“…In our group, we identified an interesting opportunity to access a diverse set of benzofuran-2-carboxamide derivatives housing different substituents in the C3 position, by combining 8-aminoquinoline (8-AQ) directed C-H functionalization chemistry with a two-step transamidation protocol for 8-AQ amides that had been previously developed within our lab (Scheme 1c) [59]. Since 8-AQ directed C-H functionalization chemistry [60][61][62] allows for rapid assembly of molecular complexity, it has found extensive use within the fields of drug discovery [63][64][65][66][67][68][69][70] and natural product synthesis [71][72][73][74][75][76][77]. Inspired by this prior art, we sought to leverage this powerful methodology when designing a modular and robust synthetic route towards our target benzofuran-2-carboxamide derivatives.…”