RESUMEN
Highly diastereoselective addition of ethyl cyclobutanecarboxylate anions to Davis-Ellman's imines is reported. This methodology afforded the preparation of enantiomerically and diastereomerically pure 1-substituted 2-azaspiro[3.3]heptanes. This three-step procedure proceeded efficiently (yield up to 90%) and diastereoselectively (dr values up to 98 : 2). This methodology is applicable to the synthesis of 1-substituted 2-azaspiro[3.4]octane and 1-substituted 2-azaspiro[3.5]nonane.
Asunto(s)
Azetidinas/síntesis química , Descubrimiento de Drogas , Compuestos de Espiro/síntesis química , Ácidos Carboxílicos/química , Ciclización , Ciclobutanos/química , Iminas/química , Estereoisomerismo , Sulfonamidas/químicaRESUMEN
Asymmetric synthesis of 1-substituted 2,6-diazaspiro[3.3]heptane is described. This methodology affords excellent yields (up to 89%) and high diastereomeric ratios ( dr up to 98:2) and delivers differentially protected amines within the products.
RESUMEN
A highly efficient method of visible light mediated Ni(II)-catalyzed photoredox N-arylation of Cbz-amines/Boc-amines with aryl electrophiles at room temperature is reported. The methodology provides a common access to a wide variety of N-aromatic and N-heteroaromatic carbamate products that find use in the synthesis of several biologically active molecules and provides a distinct advantage over traditional palladium-catalyzed Buchwald reaction.
RESUMEN
A highly regioselective and diastereoselective addition of 2-azaallyl anions to N- tert-butanesulfinylimines is reported. This methodology affords the preparation of enantiomerically and diastereomerically pure vicinal diamines bearing two adjacent stereocenters. Reactions proceed efficiently (yield up to 94%), diastereoselectively ( dr values up to 98:2:0:0), and site-selectively to deliver products with differentiated amino groups.
RESUMEN
A highly regio- and diastereo-selective ortho-lithiation/addition of anisoles to N-tert-butanesulfinyl imines resulting in the selective formation of chiral α-branched amines is described. This method is also efficient for highly regioselective benzylic lithiation of o-methylanisoles, followed by diastereoselective addition to N-tert-butanesulfinyl imines.
RESUMEN
A highly regio- and diastereoselective lithiation/addition of α-diarylmethanes to N-tert-butanesulfinylimines is reported. This methodology also affords the preparation of enantiomerically pure α-(diarylmethyl) alkyl amines bearing quaternary centers.
RESUMEN
The synthesis of 17 phenoxy substituted 4-chloro-N-(aryl/alkyl)thiophene-2-sulfonamides using a PMB protection/deprotection strategy is described. Nucleophilic displacement of p-methoxybenzyl (PMB) protected 4,5-dichloro-N-(aryl/alkyl)-thiophene-2-sulfonamides was carried out with different phenols under mild basic conditions. Reaction times of 3-6 h and overall yields of 78-98% were achieved with the PMB group in place compared to no reaction without this protecting group. The PMB group was easily and selectively removed in 68-98% yield using TFA in DCM.
Asunto(s)
Química Farmacéutica/métodos , Sulfonamidas/síntesis química , Tiofenos/síntesis química , Dimetilsulfóxido/química , Dimetilsulfóxido/farmacología , Dimetilformamida/química , Dimetilformamida/farmacología , Dioxanos/química , Dioxanos/farmacología , Concentración de Iones de Hidrógeno , Modelos Biológicos , Estructura Molecular , Sulfonamidas/química , Temperatura , Tiofenos/químicaRESUMEN
Procedures were developed for the synthesis of 3-methyl-5-phenylethynyl[1,2,4]triazine (4), 6-methyl-3-phenylethynyl[1,2,4]triazine (5), and 5-methyl-3-phenylethynyl[1,2,4]triazine (6a) as analogues of 2-methyl-6-(phenylethynyl)pyridine (2). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. The most potent of the three analogues was 6a. Twenty additional analogues of 6a were synthesized and evaluated for mGluR5 antagonist efficacy. The most potent compounds were 3-(3-methylphenylethynyl)-5-methyl[1,2,4]triazine (6b), 5-(3-chlorophenylethynyl)-5-methyl[1,2,4]triazine (6c), and 3-(3-bromophenylethynyl)-5-methyl[1,2,4]triazine (6d).
Asunto(s)
Piridinas/química , Triazinas/síntesis química , Triazinas/farmacología , Evaluación Preclínica de Medicamentos , Espectroscopía de Resonancia MagnéticaRESUMEN
Synthetic procedures were developed for the synthesis of 2beta,3beta- and 2alpha,3alpha-diaryltropanes. These compounds are analogues of the 3-aryltropane-2beta-carboxylic acid methyl ester class of monoamine uptake inhibitors, where the 2beta-carbomethoxy group has been replaced by an aryl group. The compounds were evaluated for inhibition of radioligand binding at the dopamine, norepinephrine, and serotonin transporters (DAT, NET, and 5-HTT, respectively). The results showed that the replacement of the 2beta-carbomethoxy group in the 3-aryltropane class with a 2beta-aryl group led to compounds possessing very similar monoamine transporter binding properties. However, the 2beta,3beta-diaryltropanes tended to be more potent at the DAT and more selective for the DAT relative to the NET and 5-HTT. One of the most interesting compounds was 3beta-(4-methylphenyl)-2beta-(4-methylphenyl)tropane (3d), which showed an IC50 of 1.23 nM at the DAT with 289- and 185-fold selectivity for the DAT relative to the NET and 5-HTT. The 2alpha,3alpha-diaryltropanes were much less potent at all three transporters than 2beta,3beta-diaryltropanes.