First Ring-Expanded Maytansin Lactone Accessed by a New Mutasynthetic Variant

A multiblocked mutant strain (ΔAHBA and Δasm12, asm21) of Actinosynnema pretiosum, the producer of the highly toxic maytansinoid ansamitocin, has been used for the mutasynthetic production of new proansamitocin derivatives. The use of mutant strains that are blocked in the biosynthesis of an early building block as well as in the expression of two tailoring enzymes broadens the scope of chemo-biosynthetic access to new maytansinoids. Remarkably, a ring-expanded macrolactone derived from ansamitocin was created for the first time. © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA

Verbesserte Titankatalysatoren für die intermolekulare Hydroaminierung von Alkinen

Im Rahmen dieser Arbeit konnten verschiedene neue aktive Katalysatoren für die intermolekulare Hydroaminierung von Alkinen vorgestellt werden. Mit Cp2*TiMe2 und Ind2TiMe2 gelang die Identifikation zweier besonders aktiver Verbindungen. Durch die Verwendung von Cp2*TiMe2 konnte zum ersten Mal die Addition sterisch wenig anspruchsvoller Amine (z. B. Benzylamin) an verschiedene Alkine mit sehr guten Ausbeuten realisiert werden. Das Problem der geringen Regioselektivität bei der Hydroaminierung von unsymmetrisch substituierten Alkinen bei Verwendung dieses Katalysators konnte durch den Einsatz von Ind2TiMe2 als Hydroaminierungskatalysator effektiv gelöst werden. Ind2TiMe2 zeichnete sich im weiteren Verlauf dieser Arbeit als ein Katalysator mit hoher Aktivität und ungemein großer Anwendungsbreite aus. So gelang die Addition verschiedenster Amine unabhängig von ihrem jeweiligen sterischen Raumanspruch sowohl an interne als auch an terminale Aryl- und Alkylacetylene mit guten bis sehr guten Ausbeuten. Aufgrund der hohen Regioselektivität der Ind2TiMe2-katalysierten Hydroaminierung von unsymmetrisch substituierten Phenylalkylalkinen, bildete diese Reaktion den Schlüsselschritt bei der Synthese einer kleinen Substanzbibliothek von biologisch interessanten Phenylethylaminen. Desweiteren gelang erstmals die Kombination der intermolekularen Hydroaminierung von Alkinen mit einer anschließenden Hydrosilylierung der primär gebildeten Imine. Sowohl Cp2TiMe2 als auch Me2Si(Cp)(NtBu)Ti(NMe2)2 sind in der Lage beide katalytisch verlaufenden Prozesse, die Hydroaminierung und die Hydrosilylierung, effizient in einem Eintopfverfahren zu katalysieren. Mit dem bislang entwickelten System können die Produkte bei Verwendung von Arylaminen in hohen Ausbeuten erhalten werden. Erste positive Ergebnisse zeigten, dass eine Übertragung auf Alkylamine durchaus in naher Zukunft realisierbar sein sollte

Copper-catalysed selective hydroamination reactions of alkynes

The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity. This methodology was applied to the asymmetric synthesis of ​rivastigmine and the formal synthesis of several other pharmaceutical agents, including ​duloxetine, ​atomoxetine, ​fluoxetine and ​tolterodine.National Institutes of Health (U.S.) (GM58160

Structure and function of the geldanamycin amide synthase from Streptomyces hygroscopicus

Amide synthases catalyze the formation of macrolactam rings from aniline-containing polyketide-derived seco-acids as found in the important class of ansamycin antibiotics. One of these amide synthases is the geldanamycin amide synthase GdmF, which we recombinantly expressed, purified and studied in detail both functionally as well as structurally. Here we show that purified GdmF catalyzes the amide formation using synthetically derived substrates. The atomic structures of the ligand-free enzyme and in complex with simplified substrates reveal distinct structural features of the substrate binding site and a putative role of the flexible interdomain region for the catalysis reaction

Simulation of the plume-surface interaction with a manufactured landing pad

NASA and ESA are working on returning humans to the moon through initiatives such as the Artemis mission and Argonaut Lander of the ESA. To establish lunar surface infrastructure, it is crucial to minimise dust emissions generated by the rocket plume. The aim of this study is to develop a computational model investigating the interaction between the plume and a sintered landing surface. Understanding the erosion process of a sintered landing pad is essential to ascertain how long the lunar landing pad can withstand the stress of the rocket. Current models only demonstrate the interaction between the plume and the surface of a loose layer of regolith, using different concepts in the simulation. The proposed model utilises a multiscale approach, covering both macroscale and microscale to overcome computational limitations. In the macroscale, the rocket plume is calculated using computational fluid dynamics (CFD), while the microscale considers the coupling of CFD and the discrete element method (DEM). Therefore, compressible CFD-DEM coupling is utilised together with a heat transfer model between particles and fluid. Bonded, monodisperse particles with a diameter of 100 μm are considered for describing the sintered landing pad. An interface between different scales is represented by interpolating CFD data from the macroscale rocket simulation to the microscale erosion simulation. The main structure and boundary conditions, as well as an analysis of the impact of different discretisation schemes on the mass flow imbalances are presented in this paper. A first-order time discretisation scheme with a second-order space discretisation scheme leads to the lowest mass imbalance. The primary outcome is that the erosion is contingent upon the melting temperature of the lunar landing pad and the heat flux into the pad