RESUMO
Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming the bioactive triphosphate 2-NTP. 2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for 1 have prompted interest in oral approaches to generate 2-NTP. Here, we describe the discovery of a 5'-isobutyryl ester prodrug of 2 (GS-5245, Obeldesivir, 3) that has low cellular cytotoxicity and 3-7-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved presystemically to provide high systemic exposures of 2 that overcome its less efficient metabolism to 2-NTP, leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350-400 mg twice daily. Importantly, all SARS-CoV-2 variants remain susceptible to 2, which supports development of 3 as a promising COVID-19 treatment.
Assuntos
COVID-19 , Pró-Fármacos , Chlorocebus aethiops , Humanos , Animais , SARS-CoV-2 , Tratamento Farmacológico da COVID-19 , Nucleosídeos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , RNA Viral , Antivirais/farmacologia , Antivirais/uso terapêutico , FuranosRESUMO
Leustroducsin B exhibits a large variety of biological activities and unique structural features. An efficient and highly convergent total synthesis of Leustroducsin B was achieved in 17 longest linear and 39 total steps by disconnecting the molecule into three fragments having similar levels of complexity. These pieces were connected via a highly efficient chelate-controlled addition of a vinyl zincate to an α-hydroxy ketone and a silicon-mediated cross-coupling. The stereochemistry of the central and western fragments was set catalytically in high yields and excellent de by a zinc-ProPhenol-catalyzed aldol reaction and a palladium-catalyzed asymmetric allylic alkylation.
Assuntos
Lactonas/síntese química , Espectroscopia de Ressonância Magnética , Compostos Organofosforados/síntese química , PironasRESUMO
A general protocol for the palladium-catalyzed dearomative trimethylenemethane [3+2] cycloaddition reaction with simple nitroarene substrates is described. This methodology leads to the exclusive formation of the dearomatized alicyclic products without subsequent rearomatization. The reaction is tolerant toward a broad range of heterocyclic and benzenoid substrates. The use of chiral bisdiamidophosphite ligands enabled the development of an enantioselective variant of this transformation, representing one of the rare examples of an asymmetric catalytic dearomatization process.
Assuntos
Hidrocarbonetos Aromáticos/química , Metano/análogos & derivados , Paládio/química , Catálise , Reação de Cicloadição , Ligantes , Metano/química , Estrutura Molecular , Nitroquinolinas/química , EstereoisomerismoRESUMO
ß,ß-Disubstituted nitroalkenes readily undergo palladium-catalyzed [3 + 2] cycloaddition with trimethylenemethane to generate nitrocyclopentanes in excellent yield and enantioselectivity. The reaction provides access to heavily substituted cyclopentanes containing up to three contiguous stereocenters, and the products may be converted to both cyclopentylamines and cyclopentenones. A rare dependence of the sense of chirality of the cycloadducts was observed to be exclusively dependent on the structure of the palladium-bound trimethylenemethane intermediate.
Assuntos
Alcenos/química , Alcenos/síntese química , Ciclopentanos/química , Ciclopentanos/síntese química , Metano/análogos & derivados , Nitrocompostos/química , Nitrocompostos/síntese química , Paládio/química , Catálise , Reação de Cicloadição , Metano/química , Estrutura Molecular , EstereoisomerismoRESUMO
We report the first total synthesis of the complex C-aryl glycoside isokidamycin, the epimer of the naturally-occurring pluramycin antibiotic kidamycin. The synthesis features a highly efficientDiels-Alder reaction between a substituted naphthyne and a glycosylatedfuran to form the anthracene core bearing a pendant angolosamine C-glycoside. The regiochemical outcome of the Diels-Alder reaction was controlled by employing a disposable silicon-tether to link the reactive napthyne and the glycosyl furan, rendering the cycloaddition intramolecular. The benzopyranone moietyof the aromatic nucleus was appended by cyclization of a functionalized vinylogous amide onto an advanced anthrol intermediate. The vancosamine amino glycoside was introduced by an OâC-glycoside rearrangement that produced the ß-anomer. Subsequent refunctionalizations then led to isokidamycin.
RESUMO
A general and mild protocol for achieving the carbonylative cross-coupling of sterically-hindered, ortho-disubstituted aryl ketones is reported. The commercially available PEPPSI-IPr catalyst is shown to efficiently promote the carbonylative cross-coupling of hindered ortho-disubstituted aryl iodides to give diaryl ketones; traditional phosphine catalysts are less effective. Carbonylative Suzuki-Miyaura cross-couplings provide a diverse array of biaryl ketones in good to excellent yields. The same catalyst is also shown to catalyze a carbonylative Negishi cross-coupling reaction, utilizing a variety of alkynyl zinc reagents to give the corresponding alkynyl aryl ketones. Application of this new methodology to the synthesis of the natural product luteolin is reported.
RESUMO
An atom-economical method for the direct synthesis of [3.1.0]- and [4.1.0]-bicyclic frameworks via Ru-catalyzed redox bicycloisomerization of enynols is reported. The presented results highlight the unique reactivity profile of propargyl alcohols, which function as ß-oxocarbene precursors, in the presence of a ruthenium(II) complex. Furthermore, a rare case of a formal vinylic C-H insertion reaction is described.
Assuntos
Alcenos/química , Alcinos/química , Metano/análogos & derivados , Propanóis/química , Rutênio/química , Catálise , Ciclização , Metano/química , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
The synthesis of isokidamycin, which represents the first total synthesis of a bis-C-aryl glycoside natural product in the pluramycin family, has been completed. The synthesis features the use of a silicon tether as a disposable regiocontrol element in an intramolecular Diels-Alder reaction between a substituted naphthyne and a glycosyl furan and a subsequent OâC-glycoside rearrangement.
Assuntos
Aminoglicosídeos/química , Aminoglicosídeos/síntese química , Estrutura MolecularRESUMO
A mild and general protocol for the carbonylative cross-coupling of sterically hindered ortho-disubstituted aryl iodides is reported. Carbonylative Suzuki-Miyaura couplings of a variety of aryl boronic acids provide an array of substituted biaryl ketones in modest to excellent yield. A carbonylative Negishi coupling that utilizes alkynyl nucleophiles is also described.