Vioprolides are a promising class of anticancer and antifungal lead compounds produced by the myxobacterium Cystobacter violaceus Cb vi35. Previously nothing had been reported about their biosynthesis, including the origin of the unusual 4-methylazetidinecarboxylic acid (MAZ) moiety. We describe the vioprolide biosynthetic gene cluster and solve the production obstacle by expression in three heterologous hosts. Starting from unstable production in the wild type at the single-digit mg L scale, we developed a stable host that eventually allowed for yields of up to half a gram per liter in fermenters. Gene inactivations coupled with isotope feeding studies identified an S-adenosylmethionine (SAM)-dependent enzyme and a methyltransferase as being responsible for the generation of the MAZ building block by a proposed mechanism unprecedented in bacteria. Furthermore, nonnatural vioprolide derivatives were generated via rational genetic engineering.
The first total synthesis of vioprolide D was accomplished in an overall yield of 2.0 % starting from methyl (2S)‐3‐benzyloxy‐2‐hydroxypropanoate (16 steps in the longest linear sequence). The cyclic depsipeptide was assembled from two building blocks of similar size and complexity in a modular, highly convergent approach. Peptide bond formation at the C‐terminal dehydrobutyrine amino acid of the northern fragment was possible via its (Z)‐diastereoisomer. After macrolactamization and formation of the thiazoline ring, the (Z)‐double bond of the dehydrobutyrine unit was isomerized to the (E)‐double bond of the natural product. The cytotoxicity of vioprolide D is significantly higher than that of its (Z)‐diastereoisomer.
Die Vioprolide sind eine vielversprechende Klasse von Leitverbindungen gegen Krebserkrankungen und Pilzinfektionen, die vom Myxobakterium Cystobacter violaceus Cb vi35 produziert werden. Bislang weiß man nichts über ihre Biosynthese, einschließlich des Ursprungs der ungewöhnlichen 4‐Methylazetidincarbonsäure (MAZ). Hier wird der Biosynthese‐Gencluster der Vioprolide beschrieben und die Produktionsproblematik durch Expression in drei heterologen Wirten gelöst. Ausgehend von der instabilen Produktion im einstelligen mg/L‐Maßstab im Wildtyp wurde ein stabiler Wirtstamm entwickelt, der in Fermentern Ausbeuten von bis zu einem halben Gramm pro Liter erzielt. Gen‐Inaktivierungen in Verbindung mit Isotopen‐Fütterungsstudien identifizierten ein S‐Adenosylmethionin(SAM)‐abhängiges Enzym und eine Methyltransferase, die für die Bildung des MAZ‐Bausteins über einen bei Bakterien bisher unbekannten Mechanismus verantwortlich sind. Darüber hinaus wurden nichtnatürliche Vioprolid‐Derivate durch den Einsatz rationaler Genmanipulationen erzeugt.
Organoboron compounds continue contributing substantially to advances in organic chemistry with their increasing role as both synthetic intermediates and target compounds for medicinal chemistry. Particularly attractive methods of their synthesis are based on the direct borylation of C−H bonds of available starting materials since no additional pre-functionalization steps are required. However, due to the high abundance of C−H bonds with similar reactivity in organic molecules, synthetically useful C−H borylation protocols demand sophisticated strategies to achieve high regio- and stereoselectivity. For this purpose, selective transition-metal-based catalysts have been developed, with group 9-centered catalysts being among the most commonly utilized. Recently, a multitude of diverse strategies has been developed to push the boundaries of C−H borylation reactions with respect to their regio- and enantioselectivity. Herein, we provide an overview of approaches for the C−H borylation of arenes, alkenes, and alkanes based on group 9-centered catalysts with a focus on the recent literature. Lastly, an outlook is given to assess the future potential of the field.
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