RESUMO
Herein, we report the enantioselective synthesis of a functionalized aza-octahydropentalene and its elaboration to a model tetracyclic core structure of calyciphylline B-type alkaloids.
Assuntos
Alcaloides/síntese química , Compostos Aza/química , Ciclopentanos/química , Compostos Policíclicos/síntese química , Alcaloides/química , Estrutura Molecular , Compostos Policíclicos/química , EstereoisomerismoRESUMO
Herein we describe the first synthetic efforts toward the total synthesis of isodaphlongamineâ H, a calyciphyllineâ B-type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1-aza-perhydrocyclopentalene core, representing ringsâ A andâ E of all calyciphyllineâ B-type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4-conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamineâ H in a total of 24 steps from the commercially available compound 2-carbethoxycyclopentanone. Isodaphlongamineâ H exhibits promising inhibitory activity against a panel of human cancer cell lines.
Assuntos
Alcaloides/química , Alcaloides/síntese química , Alcaloides/farmacologia , Modelos MolecularesRESUMO
Pd(II)-catalyzed alkene aminopalladation and allylic C-H activation are two competing reaction sequences sharing the same reaction conditions. This study aimed at understanding the factors that bias one or the other path in the intramolecular oxidative cyclization of two types of N-tosyl amidoalkenes. The results obtained are in accord with the initial generation of a high-energy cyclic (5- or 6-membered) aminopalladated intermediate. However, this latter species can evolve only if the following specific conditions are met: the availability of distocyclic ß-H elimination pathway, the presence of a strong terminal oxidant, or the availability of a carbopalladation pathway. Conversely, the cyclic alkylpalladium complex is only a latent species in equilibrium with the initial substrate and cannot evolve. Such a reactivity hurdle leaves the way open for alternative reactivities such as allylic C-H activation of the olefinic substrate to generate a η(3)-allyl complex followed by its interception by the nitrogen nucleophile, [3,3]-sigmatropic rearrangement, or decomposition. This study proposes a unifying mechanistic picture that connects these competing mechanisms.
RESUMO
Parasitic infections recognized as neglected tropical diseases are a source of concern for several regions of the world. Aminoglycosides are potent antimicrobial agents that have been extensively studied by biochemical and structural studies in prokaryotes. However, the molecular mechanism of their potential antiprotozoal activity is less well understood. In the present study, we have examined the inâ vitro inhibitory activities of some aminoglycosides with a 6'-hydroxy group on ringâ I and highlight that one of them, 6'-hydroxysisomicin, exhibits promising activity against a broad range of protozoan parasites. Furthermore, we have conducted X-ray analyses of 6'-hydroxysisomicin bound to the target ribosomal RNA A-sites in order to understand the mechanisms of both its antibacterial and antiprotozoal activities at the molecular level. The unsaturated ringâ I of 6'-hydroxysisomicin can directly stack on G1491, which is highly conserved in bacterial and protozoal species, through π-π interaction and fits closer to the guanidine base than the typically saturated and hydroxylated ringâ I of other structurally related aminoglycosides. Consequently, the compound adopts a lower energy conformation within the bacterial and protozoal A-sites and makes pseudo pairs to either A or G at positionâ 1408. The A-site-selective binding mode strongly suggests that 6'-hydroxysisomicin is a potential lead for the design of next-generation aminoglycosides targeting a wide variety of infectious diseases.