RESUMO
Described here is an efficient stereoselective synthesis of vibegron enabled by an enzymatic dynamic kinetic reduction that proceeds in a high-pH environment. To overcome enzyme performance limitations under these conditions, a ketoreductase was evolved by a computationally and structurally aided strategy to increase cofactor stability through tighter binding.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3/síntese química , Pirimidinonas/síntese química , Pirrolidinas/síntese química , Biocatálise , Concentração de Íons de Hidrogênio , Cinética , Modelos Moleculares , Oxirredução , Oxirredutases/química , EstereoisomerismoRESUMO
Natural product-like macrocycles were designed as potential antibacterial compounds. The macrocycles featured a D-glucose unit fused into a 12- or 13-member macrolactone. The rings are connected via the C6' and anomeric (C1') positions of the monosaccharide. The new macrocycles/macrolides were characterized by X-ray crystallography. Their structures showed that, in addition to the ester and alkene units, the dihedral angle about the glycosidic linkage (exo-anomeric effect) influenced the overall shape of the molecules. Glycosylation of an available hydroxy group on the macrocycle gave a hybrid macrolide with features common to erythromycin and sophorlipid macrolactone. Weak antibiotic activity (MICs <100 µg/mL) was observed for several of the compounds.
RESUMO
A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described. This synthesis features the first application of iminium organocatalysis on an industrial scale. The key to the success of this organocatalytic transformation was the identification of a dual acid cocatalyst system, which allowed striking a balance of the reaction efficiency and product stability effectively. As such, via an iminium species, the necessnary C-6 stereogenicity was practically established in one operation in >95% ee. Furthermore, we enlisted an unprecedented Doebner-Knoevenagel coupling, which was also via an iminium species, to efficiently construct the C3-C4 bond with desired functionality. In order to prepare telcagepant (1) in high quality, a practical new protocol was discovered to suppress the formation of desfluoro impurities formed under hydrogenation conditions to <0.2%. An efficient lactamization facilitated by t-BuCOCl followed by a dynamic epimerization-crystallization resulted in the isolation of caprolactam acetamide with the desired C3 (R) and C6 (S) configuration cleanly. Isolating only three intermediates, the overall yield of this cost-effective synthesis was up to 27%. This environmentally responsible synthesis contains all of the elements required for a manufacturing process and prepares telcagepant (1) with the high quality required for pharmaceutical use.
Assuntos
Azepinas/síntese química , Azepinas/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Imidazóis/síntese química , Imidazóis/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Azepinas/química , Catálise , Imidazóis/química , Estrutura MolecularRESUMO
The biological activities of a family of novel, lipid-linked 13-membered-ring macro-dilactones are reported. These [13]-macro-dilactones were synthesized by diacylation of functionalized diols, followed by ring-closing metathesis under conditions we had previously reported. Antimigratory, cytostatic and cytotoxic activities of the compounds against cancer cells were evaluated. Compound 13 was the most potent in the series, while compound 10 had the broadest concentration range of subtoxic antiproliferative activity. These compounds share common structural components, namely the [13]-macro-dilactone templated by an octyl alpha-glucoside 4,6-diol.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Glucosídeos/química , Glucosídeos/farmacologia , Lactonas/química , Lactonas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glucosídeos/síntese química , Humanos , Lactonas/síntese química , Lipídeos/química , Neoplasias/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.
RESUMO
Nucleophilic displacement of readily available alpha,alpha-dibromoketones with excess morpholine gave the corresponding ketoaminals, which upon condensation with aminoguanidine in MeOH in the presence of AcOH afforded 5-substituted-3-amino-1,2,4-triazines in >95% regioselectivity and 45-76% isolated yield. [reaction: see text]
RESUMO
Midline frontolimbic networks are engaged in monitoring simple actions. They may also provide evaluative control for more complex decisions. Subjects read a trait-descriptive word and responded either "yes" or "no" within 1,500 ms whether it was self-descriptive. By 300 ms, an electrophysiological discrimination between good and bad words was seen over centromedial regions of the frontal lobe for both friend and self-decisions. By 350 ms, an interaction effect between evaluation and endorsement appeared, and by 500 ms, activity specific to self-evaluation was seen in both anterior and posterior midline sites. An evaluative decision thus begins by recruiting motivational and semantic influences within limbic networks, and these influences appear to shape the development of the decision within multiple neocortical regions.
Assuntos
Tomada de Decisões/fisiologia , Emoções/fisiologia , Lobo Frontal/fisiologia , Sistema Límbico/fisiologia , Adulto , Mapeamento Encefálico , Giro Denteado/fisiologia , Eletroencefalografia , Potenciais Evocados/fisiologia , Feminino , Amigos , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Masculino , Rede Nervosa/fisiologia , Autoavaliação (Psicologia) , Semântica , Processamento de Sinais Assistido por ComputadorRESUMO
Asymmetric hydrogenation of allylic dimethylcarbinamide 2 with 1 mol % of cationic Rh(I)-Josiphos complex in THF under 500 psi of H2 generated the corresponding tertiary carbinamide 1 in 98.5% assay yield and a 94:6 enantiomeric ratio. Upon crystallization, the product was isolated in 91% isolated yield and 95:5 enantiomeric ratio.
Assuntos
Amidas/química , Hidrogênio/química , Rênio/química , Catálise , Cristalização , Espectroscopia de Ressonância Magnética , Espectrofotometria InfravermelhoRESUMO
A convergent, practical, and efficient synthesis of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABA(A) alpha(2/3)-selective agonist, is described. The seven-step, chromatography-free synthesis was demonstrated on a multi-kilogram scale and utilized biaryl bromide 6 and imidazotriazine 22 as key intermediates. Biaryl bromide 6 was prepared via a highly selective aromatic bromination. The regioselective condensation of aminotriazine 15 with chloroacetaldehyde provided the desired imidazotriazine intermediate 22. A highly regioselective palladium-catalyzed arylation in the final step highlights the efficiency of the route.
Assuntos
Agonistas GABAérgicos/síntese química , Hidrocarbonetos Aromáticos/química , Imidazóis/química , Paládio/química , Triazinas/síntese química , Acetaldeído/análogos & derivados , Acetaldeído/química , Brometos/química , Catálise , Receptores de GABA-A , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
[reaction: see text] An asymmetric synthesis of (S)-gamma-fluoroleucine ethyl ester 1 is described. The key transformation involves a lipase-catalyzed dynamic ring-opening of 2-(3-butenyl)azlactone 7b with EtOH to give amide ester (S)-6b in 84% enantiomeric excess. Removal of the N-pentenoyl group with N,N'-dibromodimethylhydantoin in the presence of trifluoroacetic acid afforded the titled compound, which was isolated as its hydrogen sulfate salt in 75% yield and >97% ee.