RESUMO
The selective androgen receptor modulator, (S)-(7-cyano-4-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)carbamic acid isopropyl ester, LY2452473, is a promising treatment of side effects of prostate cancer therapies. An acid-catalyzed Fischer indolization is a central step in its synthesis. The reaction leads to only one of the two possible indole regioisomers, along with minor decomposition products. Computations show that the formation of the observed indole is most favored energetically, while the potential pathway to the minor isomer leads instead to decomposition products. The disfavored [3,3]-sigmatropic rearrangement, which would produce the unobserved indole product, is destabilized by the electron-withdrawing phthalimide substituent. The most favored [3,3]-sigmatropic rearrangement transition state is bimodal, leading to two reaction intermediates from one transition state, which is confirmed by molecular dynamics simulations. Both intermediates can lead to the observed indole product, albeit through different mechanisms.
Assuntos
Carbamatos/farmacologia , Indóis/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Carbamatos/síntese química , Carbamatos/química , Humanos , Indóis/síntese química , Indóis/química , Masculino , Conformação Molecular , Simulação de Dinâmica Molecular , Neoplasias da Próstata/metabolismo , Teoria Quântica , Estereoisomerismo , TermodinâmicaRESUMO
A practical method for palladium-catalyzed cyanation of aryl halides using Pd/C is described. The new method can be applied to a variety of aryl bromide and active aryl chloride substrates to effect efficient conversions. The process features many advantages over existing cyanation conditions and the practical utility of the process has been demonstrated on scale.
Assuntos
Hidrocarbonetos Halogenados/química , Nitrilas/química , Paládio/química , Catálise , Estrutura MolecularRESUMO
A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.
Assuntos
Anti-Hipertensivos/síntese química , Indóis/síntese química , Antagonistas de Receptores de Mineralocorticoides , Sulfonamidas/síntese química , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Cristalografia por Raios X , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
[reaction: see text] A palladium-catalyzed cascade carbometalation-cross coupling of alkyne route was developed for the preparation of tetrasubstituted exocyclic alkenes with high stereo- and regiocontrol. The effectiveness of this novel methodology was demonstrated by the synthesis of a number of dibenzoxapines in sufficient quantities to support their further development.