RESUMO
An efficient approach to the parallel synthesis of benzimidazoles from anilines is described. Library approaches to vary the N1 and C2 vectors of benzimidazoles are well established; however, C4-C7 variation has traditionally relied on 1,2-dianiline building blocks, providing limited chemical space coverage. We have developed an amidine formation/oxidative cyclization sequence that enables anilines as a diversity set for benzimidazole C4-C7 SAR generation in parallel format. The amidine annulation was achieved using PIDA or Cu-mediated oxidation to access both N-H and N-alkyl benzimidazoles. This library protocol has now been utilized for analog production in four medicinal chemistry projects. Additionally, the synthesis of aza-benzimidazoles from aminopyridines was achieved via an analogous sequence.
Assuntos
Benzimidazóis/síntese química , Compostos de Anilina/química , Benzimidazóis/química , Química Farmacêutica/métodos , Ciclização , Oxirredução , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-AtividadeRESUMO
The structure of the capsular polysaccharide (CPS) of serotype Ia group B Streptococcus (GBS) has been characterized for years, but its repeating unit, which is a challenging pentasaccharide with a branch and a difficult α-sialic acid linkage, has not been synthesized yet. In this report, an effective synthesis was developed for the serotype Ia GBS CPS repeating unit, which had a reactive functionality linked to its main-chain reducing end to enable further elaboration, such as coupling with carrier proteins. The target molecule was accomplished by a convergent [2 + 3] glycosylation strategy employing a sialo-disaccharide as donor and a branched trisaccharide as acceptor. The strategy was designed to suit the synthesis of oligomers of the repeating unit.
Assuntos
Polissacarídeos Bacterianos/síntese química , Streptococcus/química , Glicosilação , Estrutura Molecular , Ácido N-Acetilneuramínico/química , Polissacarídeos Bacterianos/química , Infecções EstreptocócicasRESUMO
An enantiocontrolled synthesis pathway has been developed to provide formation of tricyclic amine 7, representing the ABC ring system of the complex alkaloid daphnicyclidin A (1). Our efforts describe preparation of the Z-hexahydro-(1H)-azocine 29 and cyclization to construct the novel 4-azabicyclo[5.3.2]dodecane 31. Transannular reductive amination following the deprotection of 31 gave the desired tertiary amine 7.