Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure–Activity Relationships

The bengamides, sponge‐derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half‐life in mice and antitumor efficacy in a melanoma mouse model.     

Formal anti‐Carbopalladation Reactions of Non‐Activated Alkynes: Requirements,Mechanistic Insights,and Applications

Formal anti‐carbopalladation reactions of C? C triple bonds are uncommon, but highly useful transformations. Alkynes can be designed to give anti‐carbopalladation products. Prerequisite is the exclusion of other reaction pathways to provoke the cis–trans isomerization of the syn‐carbopalladation intermediate. Detailed mechanistic studies of this crucial step by experimental and computational means were performed. Application of an intramolecular version for the synthesis of oligocyclic compounds and substituted dibenzofurans is also described.