RESUMO
We report herein an efficient, stereocontrolled, and chromatography-free synthesis of the novel broad spectrum antibiotic GDC-5338. The route features the construction of a functionalized tripeptide backbone, a high-yielding macrocyclization via a Pd-catalyzed Suzuki-Miyaura reaction, and the late-stage elaboration of key amide bonds with minimal stereochemical erosion. Through extensive reaction development and analytical understanding, these key advancements allowed the preparation of GDC-5338 in 17 steps, 15% overall yield, >99 A % HPLC, and >99:1 dr.
Assuntos
Antibacterianos/síntese química , Oligopeptídeos/química , Catálise , Ciclização , Bactérias Gram-Negativas , Paládio/química , EstereoisomerismoRESUMO
A direct ß-coupling of cyclic ketones with imines has been accomplished via the synergistic combination of photoredox catalysis and organocatalysis. Transient ß-enaminyl radicals derived from ketones via enamine and oxidative photoredox catalysis readily combine with persistent α-amino radicals in a highly selective hetero radical-radical coupling. This novel pathway to γ-aminoketones is predicated upon the use of DABCO as both a base and an electron transfer agent. This protocol also formally allows for the direct synthesis of ß-Mannich products via a chemoselective three-component coupling of aryl aldehydes, amines, and ketones.
Assuntos
Química Orgânica/métodos , Cetonas/química , Aldeídos/química , Aminas/química , Catálise , Elétrons , Radicais Livres , Iminas/química , Estrutura Molecular , Oxirredução , Oxigênio/química , Fotoquímica/métodos , EstereoisomerismoRESUMO
The direct conversion of aliphatic carboxylic acids to the corresponding alkyl fluorides has been achieved via visible light-promoted photoredox catalysis. This operationally simple, redox-neutral fluorination method is amenable to a wide variety of carboxylic acids. Photon-induced oxidation of carboxylates leads to the formation of carboxyl radicals, which upon rapid CO2-extrusion and F(â¢) transfer from a fluorinating reagent yield the desired fluoroalkanes with high efficiency. Experimental evidence indicates that an oxidative quenching pathway is operable in this broadly applicable fluorination protocol.
Assuntos
Ácidos Carboxílicos/química , Hidrocarbonetos Fluorados/síntese química , Catálise , Descarboxilação , Halogenação , Hidrocarbonetos Fluorados/química , Estrutura Molecular , Oxirredução , Processos FotoquímicosRESUMO
The direct ß-coupling of cyclic ketones with aryl ketones has been achieved via the synergistic combination of photoredox catalysis and organocatalysis. Diaryl oxymethyl or aryl-alkyl oxymethyl radicals, transiently generated via single-electron reduction of ketone precursors, readily merge with ß-enaminyl radical species, generated by photon-induced enamine oxidation, to produce γ-hydroxyketone adducts. Experimental evidence indicates that two discrete reaction pathways can be operable in this process depending upon the nature of the ketyl radical precursor and the photocatalyst.
Assuntos
Cetonas/química , Compostos Orgânicos/química , Catálise , Ciclização , Oxirredução , Processos FotoquímicosRESUMO
Novel routes to the naturally occurring indole alkaloid cycloclavine and its unnatural C(5)-epimer are described. Key features include the rapid construction of the heterocyclic core segments by two Diels-Alder reactions. An indole annulation was accomplished by a late-stage intramolecular Diels-Alder furan cycloaddition, and a methylenecyclopropane dienophile was used for a stereoselective intramolecular [4 + 2] cycloaddition to give the cyclopropa[c]indoline building block present in cycloclavine.
Assuntos
Alcaloides Indólicos/química , Ciclização , EstereoisomerismoRESUMO
The key steps of a versatile new protocol for the convergent synthesis of 3,4-disubstituted indoles are the addition of an alpha-lithiated alkylaminofuran to a carbonyl compound, a microwave-accelerated intramolecular Diels-Alder cycloaddition and an in situ double aromatization reaction.