RESUMO
Invited for the cover of this issue is the group of Dirk Menche at the University of Bonn. The image depicts the natural product leupyrrin A1 and a synthetic leupylog in balance on an IC50 weighing scale. Read the full text of the article at 10.1002/chem.202002622.
RESUMO
Leupyrrins are highly potent antifungal agents. A structure-activity-relationship study of natural and synthetic derivatives is reported which reveals important insights into the biological relevance of several structural subunits leading to the discovery of highly potent but drastically simplified leupylogs that incorporate a stable and readily available aromatic side chain. For their synthesis a concise strategy is described that enables a short and versatile access.
RESUMO
Full details on the design, elaboration, and application of efficient strategies for the high-yielding total syntheses of leupyrrins A1 and B1 , unique antifungal agents from the myxobacterium Sorangium cellulosum, are reported. A sequential zirconocene-mediated diyne-cyclization, and regioselective opening of the zirconacyclopentadiene intermediate enabled a concise entry into the unique dihydrofuran fragment, whereas another domino reaction was developed for the butyrolactone involving a one-pot lactol opening, stereoselective aldehyde addition and in situ lactonization. Furthermore, an innovative sp2 -sp3 -cross-coupling for pyrrole functionalization and an optimized HATU-mediated amide coupling protocol of two elaborate fragments were established. In addition, an unusual protective group strategy, involving a Teoc-acetonide protected amine in combination with tert-butyl and acetate esters, was successfully elaborated. These tactics and strategies are generally useful and may be also applied in the synthesis of other functionalized compounds. It is expected that the material which was obtained by these total syntheses will enable the further exploration of the biological profile of these potent antifungal agents.
Assuntos
4-Butirolactona/análogos & derivados , Antifúngicos/síntese química , Myxococcales/química , 4-Butirolactona/síntese química , 4-Butirolactona/química , Ciclização , Humanos , Estrutura Molecular , Compostos Organometálicos/química , Zircônio/químicaRESUMO
The total synthesis of leupyrrin B1 was accomplished by an expedient strategy that involves an optimized HATU-mediated amide coupling protocol of elaborate substrates. The generally useful procedure was also successfully applied in an improved total synthesis of leupyrrin A1. Finally, leupyrrins A1 and B1 were evaluated toward a panel of proteases, and human leukocyte elastase was discovered as a molecular target of the leupyrrins.
Assuntos
4-Butirolactona/análogos & derivados , Inibidores Enzimáticos/farmacologia , Elastase de Leucócito/antagonistas & inibidores , 4-Butirolactona/síntese química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Elastase de Leucócito/metabolismo , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The stereochemical determination of the potent antifungal agents leupyrrin A1 and B1 and the total synthesis of leupyrrin A1 are reported. The relative and absolute configuration was determined by a combination of high field NMR studies, molecular modeling, and chemical derivatization. The expedient total synthesis involves a one-pot sequential Zr-mediated oxidative diyne-cyclization/regioselective opening sequence for preparation of the unique dihydrofuran ring, a highly stereoselective one-pot approach to the butyrolactone, a challenging sp(2)-sp(3) Suzuki coupling and a high-yielding Shiina macrolactonization.