RESUMO
The first synthesis of enhygrolide A, a scarce γ-alkylidenebutenolide antibiotic of the obligate marine myxobacterium Enhygromyxa salina, was achieved in five steps and 54% overall yield from tetronic acid. Key steps include (i) organocatalytic reductive alkylation, (ii) iron-catalyzed sp2-sp3 cross-coupling, and (iii) vinylogous aldol condensation. Aside from its brevity and reliance on environmentally sustainable processes, the synthesis demonstrates the serviceability of butenolide pivalates in cross-coupling reactions.
Assuntos
4-Butirolactona/análogos & derivados , Antibacterianos/síntese química , Compostos de Benzilideno/síntese química , Myxococcales/química , 4-Butirolactona/síntese química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Aldeídos/química , Alquilação , Antibacterianos/química , Antibacterianos/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Catálise , Biologia Marinha , Estrutura Molecular , EstereoisomerismoRESUMO
The first synthesis of the tetronamide antibiotic basidalin was accomplished in five steps and 39% overall yield from readily available 4-bromo-2-triisopropylsilyloxyfuran and 2-formyl-1,3-dithiane. Highlights include: (i) regio- and stereocontrolled assemblage of a pivotal (Z)-γ-ylidene-ß-bromobutenolide intermediate by stereodirected vinylogous aldol condensation (SVAC), (ii) installation of the amino group via aza-Michael addition/elimination, and crucially (iii) facile access to basidalin by late-stage dithiane removal.
Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/síntese química , Policetídeos/química , Aldeídos/química , Furanos/síntese química , Furanos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Quinolizinas/química , Estereoisomerismo , Compostos de Enxofre/químicaRESUMO
A stereoselective vinylogous aldol reaction of N-monosubstituted tetronamides with aldehydes is described. The procedure is simple and scalable, works well with both aromatic and aliphatic aldehydes, and affords mainly the corresponding syn-aldol adducts. In many cases, the latter are obtained essentially free of their anti-isomers (dr > 99 : 1) in high yields (70-90%). Experimental and computational studies suggest that the observed diastereoselectivity arises through anti-syn isomer interconversion, enabled by an iterative retro-aldol/aldol reaction.
RESUMO
Detrimental biofilms of bacterial pathogens cause chronic infections with a high-level tolerance to antibiotics. To identify new control agents, we synthesized and tested a total of 14 tetronamides (including 5 new compounds) and 6 denigrin intermediates on the model species Escherichia coli. At a concentration of 50 µg/mL, two tetronamides and two methylated denigrins exhibited significant inhibitory effects against biofilm formation of E. coli RP437, e.g., by 60 and 94%, respectively. Structural analysis of the tested compounds revealed that p-methoxybenzylidene and p-methoxyphenethyl moieties of denigrins are important for biofilm inhibition, while the former group is also essential to the activity against quorum sensing (QS) via AI-2. Specifically, tetramethyldenigrin B has strong inhibitory effects against both E. coli biofilm formation and AI-2-mediated QS and thus provides a promising lead structure for designing better control agents. Consistently, tetramethyldenigrin B also showed inhibitory activity against biofilm formation of uropathogenic E. coli. Together, these findings provide new insights for the rational design of novel biofilm and QS inhibitors.