Enantioselective Synthesis of the Platensimycin Core by Silver(I)-Promoted Cyclization of Δ6-α-Iodoketone

A chiral-pool-based synthesis of the platensimycin core was achieved using (S)-lactic acid as an inexpensive starting material. The cyclohexenone ring was closed in a Mukaiyama–Michael domino sequence, while the quaternary stereocenter was created by a highly stereoselective decarboxylative allylation. The spirobicyclic skeleton was constructed by a RCM reaction. A new silver(I)-promoted cyclization reaction of Δ⁶- and Δ⁷-α-iodoketones was developed and applied for the pivotal carbon–carbon bond formation. The scope and limitations of this methodology are also presented.     

Total Synthesis of Aquayamycin

An efficient and practical total synthesis of aquayamycin has been accomplished. The highly oxidized and stereochemically complex tetracyclic ring system was constructed using three key reactions: 1) highly diastereoselective 1,2‐addition of C‐glycosyl naphthyllithium to a cyclic ketone, 2) indium‐mediated site‐selective allylation‐rearrangement sequence of naphthoquinone, and 3) diastereoselective intramolecular pinacol coupling. This synthetic strategy offers a novel and efficient pathway to prepare aquayamycin‐type angucycline antibiotics.     

Divalent Transition‐Metal‐Ion Stress Induces Prodigiosin Biosynthesis in Streptomyces coelicolor M145: Formation of Coeligiosins

The bacterium Streptomyces coelicolor M145 reacts to transition‐metal‐ion stress with myriad growth responses, leading to different phenotypes. In particular, in the presence of Co²⁺ ions (0.7 mM ) S. coelicolor consistently produced a red phenotype. This phenotype, when compared to the wild type, differed strongly in its production of volatile compounds as well as high molecular weight secondary metabolites. LC‐MS analysis revealed that in the red phenotype the production of the prodigiosins, undecylprodigiosin and streptorubin B, was strongly induced and, in addition, several intense signals appeared in the LC‐MS chromatogram. Using LC‐MS/MS and NMR spectroscopy, two new prodigiosin derivatives were identified, that is, coeligiosin A and B, which contained an additional undecylpyrrolyl side chain attached to the central carbon of the tripyrrole ring system of undecylprodigiosin or streptorubin B. This example demonstrates that environmental factors such as heavy metal ion stress can not only induce the production of otherwise not observed metabolites from so called sleeping genes but alter the products from well‐studied biosynthetic pathways.     

AIM‐1: An Antibiotic‐Degrading Metallohydrolase That Displays Mechanistic Flexibility

Antibiotic resistance has emerged as a major threat to global health care. This is largely due to the fact that many pathogens have developed strategies to acquire resistance to antibiotics. Metallo‐β‐lactamases (MBL) have evolved to inactivate most of the commonly used β‐lactam antibiotics. AIM‐1 is one of only a few MBLs from the B3 subgroup that is encoded on a mobile genetic element in a major human pathogen. Here, its mechanism of action was characterised with a combination of spectroscopic and kinetic techniques and compared to that of other MBLs. Unlike other MBLs it appears that AIM‐1 has two avenues available for the turnover of the substrate nitrocefin, distinguished by the identity of the rate‐limiting step. This observation may be relevant with respect to inhibitor design for this group of enzymes as it demonstrates that at least some MBLs are very flexible in terms of interactions with substrates and possibly inhibitors.