RESUMO
Commercially and readily available MSTFA [2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide] was identified as a highly effective TMS (trimethylsilyl) source for the convenient preparation of cyclic acetals under modified Noyori's conditions. The reactions proceeded smoothly under mild conditions, affording a wide range of the corresponding cyclic acetals with excellent yields in the presence of catalytic TMSOTf (trimethylsilyl trifluoromethanesulfonate). The present method does not require a large excess of diols that can be valuable and does not require presynthesized silylated diols. In contrast to other silylating reagents such as BSA [N,O-bis(trimethylsilyl)acetamide] and BSTFA [N,O-bis(trimethylsilyl)trifluoroacetamide], the application of MSTFA avoided the inhibition of catalytic acetalization by the side product 2,2,2-trifluoro-N-methylacetamide.
RESUMO
pivZPhos, as an effective ligand in the Cu-catalyzed asymmetric hydrogenation of ketones and aminoboration of alkenes, is prepared efficiently from the corresponding triflate of P-chiral dihydrobenzoazaphosphole 1. However, the previous approach to 1 by chiral separation is time-consuming and costly, preventing its production and further application on a large scale. In this report, a practical method for the large-scale preparation of 1 was developed via chiral chemical resolution with (1S,2S)-diaminocyclohexane as an effective resolution reagent.
Assuntos
Alcenos , Cetonas , Catálise , Hidrogenação , EstereoisomerismoRESUMO
A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).
RESUMO
An efficient and practical synthesis of enantiomerically pure P-chiral dihydrobenzooxaphosphole (BOP) core 1 is developed that is amenable to large scale preparation of the related ligand series. The unique epimerization of the P-chiral center of the undesired (R,R)-diastereomeric phosphine oxide 19 through chlorination followed by crystallization makes this chemical resolution method achieve 65% yield of desired (R,S)-diastereomer 12.
RESUMO
(S)-6-(2-Hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1) and (4aR,9aS)-1-(1H-benzo[d]midazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1-H-indeno[2,1-b]pyridine-6-carbonitrile hydrochloride (2) are potent and selective inhibitor of 11ß-hydroxysteroid dehydrogenase type 1 enzyme. These 2 drug candidates developed for the treatment of type-2 diabetes were prepared labeled with carbon-13 and carbon-14 to enable drug metabolism, pharmacokinetics, bioanalytical, and other studies. In the carbon-13 synthesis, benzoic-13 C6 acid was converted in 7 steps and in 16% overall yield to [13 C6 ]-(1). Aniline-13 C6 was converted in 7 steps to 1H-benzimidazole-1-2,3,4,5,6-13 C6 -5-carboxylic acid and then coupled to a tricyclic chiral indenopiperidine to afford [13 C6 ]-(2) in 19% overall yield. The carbon-14 labeled (1) was prepared efficiently in 2 radioactive steps in 41% overall yield from an advanced intermediate using carbon-14 labeled methyl magnesium iodide and Suzuki-Miyaura cross coupling via in situ boronate formation. As for the synthesis of [14 C]-(2), 1H-benzimidazole-5-carboxylic-14 C acid was first prepared in 4 steps using potassium cyanide-14 C, then coupled to the chiral indenopiperidine using amide bond formation conditions in 26% overall yield.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Isótopos de Carbono/química , Radioisótopos de Carbono/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Oxazinas/síntese química , Oxazinas/química , Oxazinas/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Piridonas/síntese química , Piridonas/química , Piridonas/farmacologia , EstereoisomerismoRESUMO
An efficient synthesis of the enantiomerically pure 3,3'-bis-arylated BINOL derivatives is accomplished through the palladium-catalyzed Suzuki-Miyaura coupling of the unprotected 3,3'-dibromo-BINOL with complete retention of enantiopurity. The active catalyst system Pd(OAc)2/BI-DIME has enabled mild reaction conditions at palladium loads as low as 500 ppm.
RESUMO
An efficient asymmetric synthesis of 11-ß-HSD inhibitor 1 has been accomplished in five linear steps and 53% overall yield, starting from the readily available 3-chloro-1-phenylpropan-1-one. The key feature of the synthesis includes an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by the highly effective organocatalyst (S)-3,3'-F2-BINOL under solvent-free and metal-free conditions.
Assuntos
11-beta-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Naftóis/síntese química , Propano/análogos & derivados , 11-beta-Hidroxiesteroide Desidrogenases/química , Catálise , Cetonas/química , Naftóis/química , Propano/síntese química , Propano/química , EstereoisomerismoRESUMO
A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.
Assuntos
Inibidores de Integrase de HIV/síntese química , Integrase de HIV/química , HIV/enzimologia , Acilação , Catálise , Cobre/química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Humanos , Ligantes , Estereoisomerismo , Sulfonamidas/químicaRESUMO
OBJECTIVE: To investigate whether postoperative administration of Shensong Yangxin capsules (SSYX) and dronedarone for atrial fibrillation (AF) can reduce the recurrence of paroxysmal AF after radiofrequency ablation, thus providing a more optimal choice of antiarrhythmic medication during the blank period. METHODS: We included 120 patients with paroxysmal AF who underwent radiofrequency ablation at our hospital between July 2020 and July 2022. They underwent routine circumferential pulmonary vein ablation and, subsequently, left and right atrial pressure monitoring to assess sinoatrial node recovery time under burst 400/300 ms stimulation. Postoperatively, the patients were randomly divided into 2 groups (60 patients each). The control group was administered dronedarone orally for 3 months and the study group was treated with SSYX combined with dronedarone. This study aimed to compare differences in clinical efficacy of the treatment between the 2 groups. RESULTS: The left and right atrial pressures in both groups were higher than those in the preoperative period (Pâ <â .05), with no statistically significant differences between the 2 groups (Pâ >â .05). Sinoatrial node recovery time under burst 400/300 ms stimulation showed no statistical difference between the 2 groups (Pâ >â .05). At 3 months and 1 year postoperatively, the AFEQT scale scores for both groups were lower than those before treatment (Pâ <â .05), with the study group scoring lower than the control group at 3 months (Pâ <â .05). However, no statistically significant difference was observed between the 2 groups at 1 year postoperatively (Pâ >â .05). At 3 months postoperatively, the sinus rhythm maintenance rate and heart rate were higher in the intervention group than in the control group (Pâ <â .05); however, these differences between the 2 groups were not statistically significant at 1 year postoperatively (Pâ >â .05). CONCLUSION SUBSECTIONS: The combination of SSYX and dronedarone could effectively reduce the early recurrence of paroxysmal AF after radiofrequency ablation, increase heart rate, and improve the quality of life.
Assuntos
Antiarrítmicos , Fibrilação Atrial , Ablação por Cateter , Dronedarona , Medicamentos de Ervas Chinesas , Humanos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/cirurgia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Antiarrítmicos/uso terapêutico , Antiarrítmicos/administração & dosagem , Dronedarona/uso terapêutico , Dronedarona/administração & dosagem , Ablação por Cateter/métodos , Resultado do Tratamento , Recidiva , Idoso , Quimioterapia Combinada , CápsulasRESUMO
A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions.