RESUMEN
We report an alternative approach to the unnatural nucleobase fragment seen in remdesivir (Veklury). Remdesivir displays broad-spectrum antiviral activity and is currently being evaluated in Phase III clinical trials to treat patients with COVID-19. Our route relies on the formation of a cyanoamidine intermediate, which undergoes Lewis acid-mediated cyclization to yield the desired nucleobase. The approach is strategically distinct from prior routes and could further enable the synthesis of remdesivir and other small-molecule therapeutics.
Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Amidinas/química , Antivirales/química , Antivirales/síntesis química , Adenosina Monofosfato/síntesis química , Adenosina Monofosfato/química , Adenosina Monofosfato/uso terapéutico , Alanina/síntesis química , Alanina/química , Alanina/uso terapéutico , Antivirales/uso terapéutico , COVID-19 , Técnicas de Química Sintética , Infecciones por Coronavirus/tratamiento farmacológico , Ciclización , Pandemias , Neumonía Viral/tratamiento farmacológicoRESUMEN
The SARS-CoV-2 pandemic has prompted scientists from many disciplines to work collaboratively toward an effective response. As academic synthetic chemists, we examine how best to contribute to this ongoing effort.
RESUMEN
Transient strained cyclic intermediates have become valuable intermediates in modern synthetic chemistry. Although silyl triflate precursors to strained intermediates are most often employed, the instability of some silyl triflates warrants the development of alternative precursors. We report the syntheses of silyl tosylate precursors to cyclohexyne, 1,2-cyclohexadiene, and 1,2-cycloheptadiene. The resultant strained intermediates undergo trapping in situ to give cycloaddition products. Additionally, the results of competition experiments between silyl triflates and silyl tosylates are reported.
Asunto(s)
Cicloheptanos/síntesis química , Ciclohexenos/síntesis química , Silanos/química , Compuestos de Tosilo/química , Reacción de Cicloadición , Cicloheptanos/química , Ciclohexenos/química , Estructura Molecular , EstereoisomerismoRESUMEN
We report the discovery of a novel class of compounds that function as dual inhibitors of the enzymes neutral sphingomyelinase-2 (nSMase2) and acetylcholinesterase (AChE). Inhibition of these enzymes provides a unique strategy to suppress the propagation of tau pathology in the treatment of Alzheimer's disease (AD). We describe the key SAR elements that affect relative nSMase2 and/or AChE inhibitor effects and potency, in addition to the identification of two analogs that suppress the release of tau-bearing exosomes in vitro and in vivo. Identification of these novel dual nSMase2/AChE inhibitors represents a new therapeutic approach to AD and has the potential to lead to the development of truly disease-modifying therapeutics.
Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Inhibidores Enzimáticos/farmacología , Esfingomielina Fosfodiesterasa/antagonistas & inhibidores , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/uso terapéutico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Relación Estructura-ActividadRESUMEN
We report the conversion of amides to carboxylic acids using nonprecious metal catalysis. The methodology strategically employs a nickel-catalyzed esterification using 2-(trimethylsilyl)ethanol, followed by a fluoride-mediated deprotection in a single-pot operation. This approach circumvents catalyst poisoning observed in attempts to directly hydrolyze amides using nickel catalysis. The selectivity and mildness of this transformation are shown through competition experiments and the net-hydrolysis of a complex valine-derived substrate. This strategy addresses a limitation in the field with regard to functional groups accessible from amides using transition metal-catalyzed C-N bond activation and should prove useful in synthetic applications.
Asunto(s)
Amidas/química , Ácidos Carboxílicos/síntesis química , Níquel/química , Ácidos Carboxílicos/química , Catálisis , Hidrólisis , Estructura MolecularRESUMEN
The chemistry of strained cyclic alkynes has undergone a renaissance over the past two decades. However, a related species, strained cyclic allenes, especially heterocyclic derivatives, have only recently resurfaced and represent another class of valuable intermediates. We report a mild and facile means to generate the parent 3,4-oxacyclic allene from a readily accessible silyl triflate precursor, and then trap it in (4+2), (3+2), and (2+2) reactions to provide a variety of cycloadducts. In addition, we describe a catalytic, decarboxylative asymmetric allylic alkylation performed on an α-silylated substrate, to ultimately permit access to an enantioenriched allene. Generation and trapping of the enantioenriched cyclic allene occurs with complete transfer of stereochemical information in a Diels-Alder cycloaddition through a point-chirality, axial-chirality, point-chirality transfer process.
Asunto(s)
Alcadienos/metabolismo , Reacción de Cicloadición/métodos , Catálisis , Humanos , EstereoisomerismoRESUMEN
For over a century, the structures and reactivities of strained organic compounds have captivated the chemical community. Whereas triple-bond-containing strained intermediates have been well studied, cyclic allenes have received far less attention. Additionally, studies of cyclic allenes that bear heteroatoms in the ring are scarce. We report an experimental and computational study of azacyclic allenes, which features syntheses of stable allene precursors, the mild generation and Diels-Alder trapping of the desired cyclic allenes, and explanations of the observed regio- and diastereoselectivities. Furthermore, we show that stereochemical information can be transferred from an enantioenriched silyl triflate starting material to a Diels-Alder cycloadduct by way of a stereochemically defined azacyclic allene intermediate. These studies demonstrate that heteroatom-containing cyclic allenes, despite previously being overlooked as valuable synthetic intermediates, may be harnessed for the construction of complex molecular scaffolds bearing multiple stereogenic centres.