RESUMO
Hydrogen bonds can play a prominent role in organometallic catalysis, as shown for the title reaction, in which a counteranion directs the cyclization through the formation of hydrogen bonds that likely involve a proton of the π-allyl/palladium species itself. The reaction allows access to four out of the eight stereoisomers of 2,5-disubstitued 3-hydroxy-tetrahydrofurans and thus fragments of complex natural products.
Assuntos
Furanos/química , Paládio/química , Catálise , Ciclização , Furanos/síntese química , Ligação de Hidrogênio , Estrutura Molecular , Estereoisomerismo , TermodinâmicaRESUMO
A series of combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various inâ vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells. B-ring-constrained derivatives that contain an oxindole ring (in contrast to compounds with a benzofuranone ring) as well as analogues bearing a six-membered lactone core fused to the trimethoxyphenyl ring are endowed with significant biological activity. The most potent compound of this series (oxindole 9 b) is of particular interest, as it combines chemical stability and a biological activity profile characteristic of a vascular-disrupting agent.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Células Endoteliais/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Estilbenos/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Catálise , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Compostos Heterocíclicos/química , Humanos , Camundongos , Paládio/química , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismoRESUMO
Two series of 2-aroyltrimethoxyindoles were designed to investigate the effects of the replacement of the trimethoxyphenyl ring of phenstatin with a trimethoxyindole moiety. These compounds were efficiently prepared through a domino palladium-catalyzed sequence from 2-gem-dibromovinylanilines substituted by three methoxy groups and arylboronic acids under carbon monoxide atmosphere. These novel heterocyclic combretastatin A4 analogues were evaluated for their cell growth inhibitory properties and their ability to inhibit the tubulin polymerization.
Assuntos
Descoberta de Drogas/métodos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Indóis/química , Indóis/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Tubulina (Proteína)/químicaRESUMO
A novel and fully chemo- and stereoselective three component strategy leading to Z-α-chloroacrylates by a Pd(0)-catalyzed reaction of CO (1 atm) with 1,1-dichloro-1-alkenes and various alcohols is disclosed. This catalytic approach compares favourably with the Wittig type strategies as α-chloroacrylates of pure Z configuration are obtained in high yield.
Assuntos
Acrilatos/química , Alcenos/química , Paládio/química , Catálise , Estereoisomerismo , Especificidade por SubstratoRESUMO
A convenient one-pot synthesis of 2-aroylindoles using a domino palladium-catalyzed C,N-coupling/carbonylation/C,C-coupling sequence is described. The reaction involved easily prepared 2-gem-dibromovinylanilines and boronic acids under carbon monoxide. Optimized reaction conditions allowed the construction of a wide variety of highly functionalized 2-aroyl-/heteroaroylindoles in satisfactory yields.
Assuntos
Carbono/química , Indóis/química , Indóis/síntese química , Nitrogênio/química , Paládio/química , Compostos de Anilina/química , Ácidos Borônicos/química , Monóxido de Carbono/química , CatáliseRESUMO
An efficient synthetic route toward the synthesis of highly substituted arylethylidene-isoquinolinones/isochromanones is reported. The tandem carbopalladation/Suzuki-Miyaura coupling sequence stereoselectively provided various functionalized polycyclic compounds in moderate to excellent yields.