A simple method for direct C–H
imidation is reported using
a new perester-based self-immolating reagent and a base-metal catalyst.
The succinimide products obtained can be easily deprotected in situ (if desired) to reveal the corresponding anilines
directly. The scope of the reaction is broad, the conditions are extremely
mild, and the reaction is tolerant of oxidizable and acid-labile functionality,
multiple heteroatoms, and aryl iodides. Mechanistic studies indicate
that ferrocene (Cp2Fe) plays the role of an electron shuttle
in the decomposition of the perester reagent, delivering a succinimidyl
radical ready to add to an aromatic system.
A simple method to convert readily available carboxylic acids into sulfinate salts employing an interrupted Barton decarboxylation reaction is reported. A medicinally oriented panel of ten new sulfinate reagents was created using this method, including a key trifluoromethylcyclopropanation reagent TFCS-Na. The reactivity of six of these salts towards C–H functionalization was field-tested using several different classes of heterocycles.
Solving the puzzles: Total synthesis played a key role in the elucidation of the stereochemistry and verification of the constitution of the complex polymeric natural product psychotetramine. The route features three powerful assembly processes that enabled four rounds of total synthesis‐guided structure determination. The pursuit of this alkaloid also led to an improved procedure for indole–aniline coupling and a highly efficient enantioselective synthesis of psychotrimine.
Bacterial tRNA modification synthesis pathways are critical to cell survival under stress and thus represent ideal mechanism-based targets for antibiotic development. One such target is the tRNA-(N 1 G37) methyltransferase (TrmD), which is conserved and essential in many bacterial pathogens. Here we developed and applied a widely applicable, radioactivity-free, bioluminescence-based highthroughput screen (HTS) against 116350 compounds from structurally diverse small-molecule libraries to identify inhibitors of Pseudomonas aeruginosa TrmD (PaTrmD). Of 285 compounds passing primary and secondary screens, a total of 61 TrmD inhibitors comprised of more than 12 different chemical scaffolds were identified, all showing submicromolar to low micromolar enzyme inhibitor constants, with binding affinity confirmed by thermal stability and surface plasmon resonance. S-Adenosyl-L-methionine (SAM) competition assays suggested that compounds in the pyridine-pyrazole-piperidine scaffold were substrate SAM-competitive inhibitors. This was confirmed in structural studies, with nuclear magnetic resonance analysis and crystal structures of PaTrmD showing pyridine-pyrazole-piperidine compounds bound in the SAM-binding pocket. Five hits showed cellular activities against Gram-positive bacteria, including mycobacteria, while one compound, a SAMnoncompetitive inhibitor, exhibited broad-spectrum antibacterial activity. The results of this HTS expand the repertoire of TrmD-inhibiting molecular scaffolds that show promise for antibiotic development.
An alcohol-directed, nickel-catalyzed
three-component umpolung
carboamination of unactivated alkenes with aryl/alkenylboronic esters
and electrophilic aminating reagents is reported. This transformation
is enabled by specifically tailored O-(2,6-dimethoxybenzoyl)hydroxylamine
electrophiles that suppress competitive processes, including undesired
β-hydride elimination and transesterification between the alcohol
substrate and electrophile. The reaction delivers the desired 1,2-carboaminated
products with generally high regio- and syn-diastereoselectivity
and exhibits a broad scope of coupling partners and alkenes, including
complex natural products. Various mechanistic experiments and analysis
of the stereochemical outcome with a cyclic alkene substrate, as confirmed
by X-ray crystallographic analysis, support alcohol-directed syn-insertion of an organonickel(I) species.
SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3′s enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.
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