RESUMO
A general protocol is described for inducing enantioselective halolactonizations of unsaturated carboxylic acids using novel bifunctional organic catalysts derived from a chiral binaphthalene scaffold. Bromo- and iodolactonization reactions of diversely substituted, unsaturated carboxylic acids proceed with high degrees of enantioselectivity, regioselectivity, and diastereoselectivity. Notably, these BINOL-derived catalysts are the first to induce the bromo- and iodolactonizations of 5-alkyl-4( Z)-olefinic acids via 5- exo mode cyclizations to give lactones in which new carbon-halogen bonds are created at a stereogenic center with high diastereo- and enantioselectivities. Iodolactonizations of 6-substituted-5( Z)-olefinic acids also occur via 6- exo cyclizations to provide δ-lactones with excellent enantioselectivities. Several notable applications of this halolactonization methodology were developed for desymmetrization, kinetic resolution, and epoxidation of Z-alkenes. The utility of these reactions is demonstrated by their application to a synthesis of precursors of the F-ring subunit of kibdelone C and to the shortest catalytic, enantioselective synthesis of (+)-disparlure reported to date.
Assuntos
Lactonas/química , Naftóis/química , Alcanos/síntese química , Bromo/química , Catálise , Ciclização , Iodo/química , Estrutura Molecular , Estereoisomerismo , Xantonas/síntese químicaRESUMO
The shortest synthesis to date of (±)-alstoscholarisine E was accomplished in seven linear steps from commercially available reagents and 15.2% overall yield. The approach features a tandem vinylogous Mannich reaction and hetero-Diels-Alder reaction to access the core. A novel tactic to induce diastereoselective reduction of the cyclic vinyl ether was discovered, and a mild procedure to form the bridged aminal ring by partial reduction of the lactam ring via iridium-catalyzed hydrosilylation was developed.
Assuntos
Produtos Biológicos/síntese química , Alcaloides de Triptamina e Secologanina/síntese química , Produtos Biológicos/química , Catálise , Reação de Cicloadição , Éteres Cíclicos/química , Alcaloides Indólicos/química , Irídio/química , Estrutura Molecular , Quinolonas/química , Alcaloides de Triptamina e Secologanina/química , EstereoisomerismoRESUMO
The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.
Assuntos
Ácido Benzoico/química , Fator B do Complemento/antagonistas & inibidores , Indóis/química , Síndrome Hemolítico-Urêmica Atípica/metabolismo , Síndrome Hemolítico-Urêmica Atípica/patologia , Ácido Benzoico/metabolismo , Ácido Benzoico/farmacocinética , Sítios de Ligação , Domínio Catalítico , Fator B do Complemento/metabolismo , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Indóis/metabolismo , Indóis/farmacocinética , Concentração Inibidora 50 , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Simulação de Dinâmica Molecular , Relação Estrutura-AtividadeRESUMO
The BINOL-amidine organic catalyst 1 was previously shown to promote highly efficient enantioselective halolactonization reactions of olefinic acids. As part of these studies, it was discovered that the enantioenriched iodolactones could be easily converted into enantioenriched cis-1,2-disubstituted epoxides. This halolactonization-epoxidation sequence was applied to the synthesis of (+)-disparlure, which resulted in the shortest catalytic enantioselective synthesis to date, requiring only five steps and proceeding in 33% yield.