RESUMO
Previous syntheses of the biologically active 2-aminated benzoxazoles have relied on forcing thermal conditions to generate the products directly from the corresponding thiols. The resulting yields have ranged from moderate to poor. A mild and high-yielding alternative one-pot chlorination-amination procedure is described. Compounds with a variety of substitution patterns are reported and the methodology has been successfully extended to benzothiazoles. Palladium catalysis on suitably activated examples has been employed to generate the desired compounds of interest.
Assuntos
Benzotiazóis/síntese química , Benzoxazóis/síntese química , Hidrocarbonetos Halogenados/química , Aminação , Benzotiazóis/química , Benzoxazóis/química , Catálise , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , TemperaturaRESUMO
A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (1) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular sp(2)-sp(3) Suzuki-Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (1) has been achieved.
Assuntos
Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Catálise , Hepacivirus/efeitos dos fármacos , Compostos Macrocíclicos/química , Estrutura Molecular , Inibidores de Proteases/químicaRESUMO
A novel synthesis of ß-aryloxycarboxylic esters via asymmetric hydrogenation of the corresponding ß-aryloxy-α,ß-unsaturated esters has been demonstrated. Bis(norbornadiene)rhodium(I) tetrafluoroborate (1 mol %) and Walphos W008-1 were used to generate the saturated products with high enantioselectivity and in high yield. The tolerability of the reaction to a diverse range of substituents on the aromatic ring was also explored.
Assuntos
Derivados de Benzeno/síntese química , Ácidos Carboxílicos/síntese química , Derivados de Benzeno/química , Ácidos Carboxílicos/química , Catálise , Ésteres , Hidrogenação , Estrutura Molecular , Ródio/química , EstereoisomerismoRESUMO
A practical and scaleable synthesis of the gamma-secretase inhibitor 1 is reported. The inhibitor consists of a central trisubstituted cyclohexane core with appended propionic acid, 2,5-difluorophenyl, and 4-chlorophenylsulfonyl moieties. Two alternative synthetic strategies, proceeding by way of a common disubstituted cyclohexanone derivative 5, were studied. In the preferred route, conjugate reduction of acrylonitrile derivative 4 with L-Selectride configures the desired relative stereochemistry of the cyclohexane core with >99.9:0.1 dr. A second strategy, based on catalyst-controlled hydrogenation of racemic cyclohexene derivative 2, is more convergent but less diastereoselective (up to 75:25 dr). The common cyclohexanone intermediate 5 was constructed by a regioselective Diels-Alder condensation of a 1,1-disubstituted vinyl sulfone 6 with 2-trimethylsiloxybutadiene.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Cicloexenos/química , Inibidores Enzimáticos/síntese química , Secretases da Proteína Precursora do Amiloide/metabolismo , Inibidores Enzimáticos/química , Conformação Molecular , Estrutura Molecular , EstereoisomerismoRESUMO
The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite beta-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.