Aryl
halides are a fundamental motif in synthetic chemistry, playing
a critical role in metal-mediated cross-coupling reactions and serving
as important scaffolds in drug discovery. Although thermal decarboxylative
functionalization of aryl carboxylic acids has been extensively explored,
the scope of existing halodecarboxylation methods remains limited,
and there currently exists no unified strategy that provides access
to any type of aryl halide from an aryl carboxylic acid precursor.
Herein, we report a general catalytic method for direct decarboxylative
halogenation of (hetero)aryl carboxylic acids via ligand-to-metal
charge transfer. This strategy accommodates an exceptionally broad
scope of substrates. We leverage an aryl radical intermediate toward
divergent functionalization pathways: (1) atom transfer to access
bromo- or iodo(hetero)arenes or (2) radical capture by copper and
subsequent reductive elimination to generate chloro- or fluoro(hetero)arenes.
The proposed ligand-to-metal charge transfer mechanism is supported
through an array of spectroscopic studies.
We report a copper-catalyzed strategy
for arylboronic ester synthesis
that exploits photoinduced ligand-to-metal charge transfer (LMCT)
to convert (hetero)aryl acids into aryl radicals amenable to ambient-temperature
borylation. This near-UV process occurs under mild conditions, requires
no prefunctionalization of the native acid, and operates broadly across
diverse aryl, heteroaryl, and pharmaceutical substrates. We also report
a one-pot procedure for decarboxylative cross-coupling that merges
catalytic LMCT borylation and palladium-catalyzed Suzuki–Miyaura
arylation, vinylation, or alkylation with organobromides to access
a range of value-added products. The utility of these protocols is
highlighted through the development of a heteroselective double-decarboxylative
C(sp2)–C(sp2) coupling sequence, pairing
copper-catalyzed LMCT borylation and halogenation processes of two
distinct acids (including pharmaceutical substrates) with subsequent
Suzuki–Miyaura cross-coupling.
Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography F-isotopologue validated our liver-targeting approach.
We report a modular three-component dynamic kinetic resolution (DKR) that affords enantiomerically enriched hemiaminal esters derived from azoles and aldehydes. The novel and scalable reaction can be used to synthesize valuable substituted azoles in a regioselective manner by capping (e.g., acylation) of the equilibrating azole-aldehyde adduct. With the use of a prolinol-derived DMAP catalyst as the chiral Lewis base, the products can be obtained in high chemical yield and with high enantiomeric excess. The DKR was performed on a multikilogram scale to produce a tetrazole prodrug fragment for a leading clinical candidate that posed formidable synthesis challenges.
A one-pot, four-component Pd-catalyzed coupling has been developed for the synthesis of unsymmetrical 1,2-diketones from aryl halides and alkyl zincs employing tertbutyl isocyanide as a CO source. The intermediate 1,2diketones have been elaborated to quinoxalines. Mechanistic studies help to rationalize the high selectivity for the bis-vs monoinsertion product.
The first described reaction between N-tosylhydrazone and SO2 is reported to provide alkyl sulfonamides in the presence of various amines. In this procedurally simple method, hydrazones of both unsaturated aldehydes and ketones proceed in moderate to excellent yields. Primary and secondary aliphatic amines are accommodated in this reaction, which provides a novel route to sulfonamides.
Discovery efforts leading to the identification of ervogastat
(PF-06865571),
a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor
that has advanced into clinical trials for the treatment of non-alcoholic
steatohepatitis (NASH) with liver fibrosis, are described herein.
Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential
development risks of the prototype liver-targeted DGAT2 inhibitor
PF-06427878. Key design elements that culminated in the discovery
of ervogastat are (1) replacement of the metabolically labile motif
with a 3,5-disubstituted pyridine system, which addressed potential
safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor,
and (2) modifications of the amide group to a 3-THF group, guided
by metabolite identification studies coupled with property-based drug
design.
Targeting of the human ribosome is an unprecedented therapeutic modality with a genome‐wide selectivity challenge. A liver‐targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell‐free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18F‐isotopologue validated our liver‐targeting approach.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.