RESUMO
We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide.
Assuntos
Benzimidazóis/farmacologia , Cicloexanos/química , Receptores CCR2/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Microssomos/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The asymmetric synthesis of the antibacterial natural product, streptophenazine G, has been achieved by employing asymmetric alkylation and asymmetric aldol reactions using chiral oxazolidinones as the key steps. The originally proposed structure for streptophenazine G has been revised, and its absolute configuration has been determined to be 1'S,2'R,6'S. The asymmetric total synthesis of 6'-epi-streptophenazine G is also described.
Assuntos
Antibacterianos/química , Antibacterianos/síntese química , Produtos Biológicos/química , Produtos Biológicos/síntese química , Fenazinas/química , Fenazinas/síntese química , Streptomyces/química , Alquilação , Estrutura Molecular , EstereoisomerismoRESUMO
A total synthesis of both diastereomers of the originally proposed structure for streptophenazine A (1) has been achieved. However, both synthetic compounds are different from the natural product. Re-examination of NMR data reported for streptophenazine A and a concise total synthesis of both diastereomers of 17 (17a and 17b) led to the structural revision of streptophenazine A to 17b. Asymmetric synthesis of (-)-streptophenazine A was also conducted, and its absolute configuration was determined to be 1'S,2'R.
Assuntos
Fenazinas/química , Fenazinas/síntese química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Estereoisomerismo , Streptomyces/químicaRESUMO
An efficient enantioselective synthesis of benzyl (1S,2R,4R)-4-(tert-butoxycarbonylamino)-2-(hydroxymethyl)cyclohexylcarbamate 2, an essential intermediate for a series of potent CCR2 antagonists, is described. The key step in the sequence is an iodolactamization to yield the highly functionalized (1R,2S,4S,5S)-tert-butyl 2-(benzyloxycarbonylamino)-4-iodo-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate 11. An examination of the reaction mechanism within the 2-step iodolactamization sequence led to the discovery of a single-pot transformation of increased efficiency.
