RESUMO
An efficient copper-catalyzed synthesis of (annelated) benzimidazoles is reported. This transformation is based on a simple and straightforward one-pot sequence involving a copper-catalyzed cross coupling between o-haloanilines and lactams/amides followed by a subsequent cyclization under acidic conditions. A variety of (annelated) benzimidazoles could be easily obtained in high yields from readily available starting materials, and this procedure could be further applied to the synthesis of the antihypertensive blockbuster drug telmisartan.
RESUMO
The BCD tricyclic core of brownin F was prepared in eight synthetic operations for the first time. Our synthesis features a diastereo-, chemo- and regioselective intramolecular [3 + 2] cycloaddition between a cyclic carbonyl ylide and a γ-alkylidenebutenolide.
Assuntos
Extratos Vegetais/síntese química , Rutaceae/química , Triterpenos/síntese química , Ciclização , Modelos Moleculares , Extratos Vegetais/química , Estereoisomerismo , Triterpenos/químicaRESUMO
The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid ß-peptide (Aß) by Amyloid-ß Precursor Protein (APP) expressing HEK293 cells by affecting the γ-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent γ-secretase complex but more likely interfere with an upstream target involved in γ-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for Aß-lowering activity and supported the involvement of a serine protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC(50) between 10 and 30µM. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular Aß production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Isocumarinas/química , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Ácidos Borônicos/química , Células HEK293 , Humanos , Isocumarinas/síntese química , Isocumarinas/metabolismo , Serina Proteases/metabolismo , TransfecçãoRESUMO
The synthetic utility of γ-alkylidenebutenolides is demonstrated as highly competent dipolarophile partners in both intra- and intermolecular rhodium(II)-catalyzed 1,3-dipolar cycloaddition reactions. The strength of this approach lies in the formation of spiro[6,4]lactone moieties with the concomitant construction of quaternary spiro stereocenters. Typically, the construction of spirolactones involves an esterification step, which has often been reported as a "biosynthetic pathway", and often occurs either as or near to the final step of a total synthesis. Furthermore, a convergent and versatile route is reported for the formation of the (5,7) skeleton of molecules that were isolated from the Schisandra genus. Computational studies were performed to provide an overall picture of the mechanism of the intermolecular [3+2] cycloaddition between 2-diazo-1,3-ketoester and protoanemonin and to rationalize the empirical observations. In particular, we have demonstrated for the first time that the rhodium center plays an important role during the cyclization step itself and reacts with the dipolarophile as a complex with the ylide.
Assuntos
Lactonas/química , Compostos Policíclicos/química , Ródio/química , Compostos de Espiro/química , Reação de Cicloadição , Ligantes , Modelos Teóricos , Estrutura Molecular , EstereoisomerismoRESUMO
An efficient and rapid synthesis of the CDEF ring system of lactonamycinone is reported via a highly chemo- and diastereoselective intermolecular Diels-Alder cycloaddition between trans-1,2-disilyloxybenzocyclobutene and the appropriate γ-alkylidenebutenolide. The feasibility and the total chemoselectivity of the [4 + 2] cycloaddition for the construction of a spirolactone moiety via an intramolecular approach (IMDA) using both partners is also described demonstrating the versatility of the γ-alkylidenebutenolide building block.
Assuntos
Furanos/química , Quinonas/química , Alquilação , Ciclização , Indóis/síntese química , Estrutura Molecular , Naftoquinonas/síntese química , Espironolactona/química , EstereoisomerismoRESUMO
Polycyclic structures fused at a central carbon are of great interest due to their appealing conformational features and their structural implications in biological systems. Although progress in the development of synthetic methodologies towards such structures has been impressive, the stereoselective construction of such quaternary stereocentres remains a significant challenge in the total synthesis of natural products. This review highlights the progress in the formation of 1-oxaspiro[4.n]alkan-2-ones (2≤n≤7) with concomitant formation of the quaternary spiro centre.