Synthesis of nitrogen heterocycles

Part I: The first part of this thesis describes efforts towards the Lycopodium alkaloids lycopladine H and lycojaponicumin D and the chemistry developed in the course of these studies. We first pursued a divergent transannular Mannich reaction from a medium-size ring precursor. Extensive screening to suppress dimerization eventually led to a ring-closing metathesis protocol that allowed us to investigate the final steps of the synthesis. An advanced tetraol could be obtained, but we were unable to access the triketone to investigate the final cyclization step. In a second approach, when trying to isomerize a terminal alkyne to the internal alkyne, we observed clean cyclization to the hydrindanone bearing an all-carbon quaternary stereocenter instead. Further investigations revealed that potassium tert-butoxide in DMSO efficiently mediates the ring closure to form a range of 5-5 and 6-5 systems. We realized that hydrindanones form the core of many Lycopodium alkaloids, such as the aromatic fawcettimine-type natural product lycoposerramine R. Leveraging our cyclization, we were able to access (−)-Lycoposerramine R in 7 steps overall including allylic oxidation to the enone to set up a Kröhnke-type pyridone synthesis. In an extension of the method, we adapted the Ciufolini pyridine synthesis to access the two pyridine-containing natural products lycopladine A and carinatine A with the fastest enantioselective syntheses to date, the latter through a newly developed telescoped biscyclization. Part II: The second part of this thesis focuses on our efforts to control glutamate receptors with light in the context of photopharmacology. We developed ATG, a photoswitchable subtype-selective agonist of NMDA receptors. ATG (azobenzene-triazole-glutamate) can be switched into its active cis-form using 740 nm light. Extensive testing in Xenopus oocytes, murine brain slices and retinae demonstrated its potential for NMDA receptor activation in vivo. To complement ATG and its functionally equivalent "cis-locked" stilbene analog STG (stilbene-triazole-glutamate), we next developed PNRA (photoswitchable NMDA receptor antagonist). This photoswitchable hydroxyquinolone-azobenzene represents the first photoswitchable antagonist of NMDA receptors. It shows unusual NMDA receptor subunit selectivity and thus represents a platform for further development. Part III: In the third part of this work, we designed and synthesized a small set of photoswitchable analogues of PPARgamma agonists based on the thiazolidinedione drug rosiglitazone. Preliminary in vitro studies demonstrated the ability to reversibly control PPARgamma with light

Flow-based Methods in Chemical Peptide and Protein Synthesis

Flow chemistry has emerged as a powerful method for on-demand chemical synthesis and modification of peptides and proteins. Herein, we discuss the characteristics of flow chemistry and how they are applied to various aspects of peptide chemistry. We highlight recent advances in automated flow-based peptide synthesis, which extend the length of peptides routinely accessible to single-domain proteins and allow for the collection of time-resolved synthesis data. Applications of this data for the prediction of synthesis outcome and the potential for the development of more sustainable synthesis methods are also discussed. Finally, we will review solutionphase approaches, including flow-based ligation strategies and peptide cyclization. Throughout this review, the current challenges and potential future developments are highlighted

LION Navigator for Transfer to GEO Using Electric Propulsion

GNSS space receivers are widely used for onboard auton-omous navigation of spacecraft platforms in low Earth orbit. Navigation by GNSS up to geosynchronous altitude was made possible through the introduction of a Space Service Volume which defines signal strength up to geo-synchronous altitude. For Galileo, similar definitions are under consideration. On this basis onboard autonomous navigation for commercial communication satellites be-came a realistic possibility, too. Transfer to geostationary orbit is still fully depending on classical RF tracking by ground station for orbit determination. With electrical propulsion, the transfer duration extends to several months. As a consequence onboard autonomous naviga-tion by satellite navigation has become of commercial interest. A GNSS navigation receiver on a spacecraft on transfer orbit has to cope with extreme signal conditions from very low (at perigee) to very high (at super-synchronous apogee) altitude, which is far above the constellation satellites. At this altitude only very rare and weak signals that spill over the limb of the earth can be used. An addi-tional difficulty is the varying spacecraft orientation which is not nadir pointing, as is commonly assumed, but is varying according to the demands of optimal attitude guidance laws and power requirements. By using both GPS and Galileo together the availability of navigation signals is increased. The paper describes the design process to determine basic parameters e.g. number and orientation of receive anten-nas, receiver parameters like C/N0 thresholds, and naviga-tion procedures. Detailed simulations are presented for selected parts of the transfer arc using verified models of the navigation receiver. Finally the geostationary transfer capabilities of the space-borne LION Navigator GNSS receiver are demon-strated in a closed-loop real time test environment under RF stimulation

prototypical implementations

In this technical report, we present prototypical implementations of innovative tools and methods developed according to the working plan outlined in Technical Report TR-B-09-05 [23]. We present an ontology modularization and integration framework and the SVoNt server, the server-side end of an SVN- based versioning system for ontologies in the Corporate Ontology Engineering pillar. For the Corporate Semantic Collaboration pillar, we present the prototypical implementation of a light-weight ontology editor for non-experts and an ontology based expert finder system. For the Corporate Semantic Search pillar, we present a prototype for algorithmic extraction of relations in folksonomies, a tool for trend detection using a semantic analyzer, a tool for automatic classification of web documents using Hidden Markov models, a personalized semantic recommender for multimedia content, and a semantic search assistant developed in co-operation with the Museumsportal Berlin. The prototypes complete the next milestone on the path to an integral Cor- porate Semantic Web architecture based on the three pillars Corporate Ontol- ogy Engineering, Corporate Semantic Collaboration, and Corporate Semantic Search, as envisioned in [23]