Totalsynthesen von 5,6-Dihydrocineromycin B, Radicinol und 3-epi-Radicinol sowie Synthesen der vermeintlichen Strukturen von 3-Methoxy-3-epi-Radicinol und Orevactaene

Totalsynthese und „late-stage“ Modifizierung von (‒)-5,6-Dihydrocineromycin B (‒)-Dihydrocineromycin B (I, Schema 1) ist ein 14-gliedriges antibiotisches Makrolacton aus einer Naturstofffamilie mit möglicherweise großem Potential zur Bekämpfung von Methicillin-resistentem Staphylococcus aureus (MRSA). Der Mangel relevanter biologischer Daten für I und die ineffizienten bekannten Möglichkeiten zum Aufbau der in polyketidischen Naturstoffen häufig vorkommenden (E)-2-Methyl-2-but-2-en-1-ol Substruktur (blau) ermutigten uns eine neue Strategie zur Synthese dieses Naturstoffs zu entwickeln. Unser Ansatz kombinierte ringschließende Alkinmetathese mit einer regioselektiven Ru-katalysierten trans-Addition von Bu3SnH an das so erhaltene Zykloalkin III und einer abschließenden Stille-Kupplung mit Iodmethan. Die vielseitigen Verwendungsmöglichkeiten des Alkenylstannans II erlaubten neben der Synthese des Naturstoffs auch die Herstellung zahlreicher Derivate. Schema 1. Retrosynthetische Analyse von 5,6-Dihydrocineromycin B (I). Goldkatalysierte Synthese von 4-Oxo-2-Pyronen Die von Fürstner und Mitarbeitern zuvor entwickelte AuI-katalysierte Pyronsynthese ermöglicht den einfachen Aufbau substituierter Pyrone unter bemerkenswert milden Bedingungen (Schema 2). Der Aufbau des benötigten tert-Butylesters (VI) stellte sich jedoch für sterisch anspruchsvolle Zyklisierungsvorläufer als problematisch heraus. Es war uns möglich zu zeigen, dass die analoge Zyklisierung durch die Verwendung von 2-TMS-Ethanolestern (VII) durchgeführt werden kann, welche sich einfacher darstellen lassen. Diese Modifikation der goldkatalysierten Pyronsynthese wurde in den ersten Totalsynthesen von Radicinol (VIII), 3-epi-Radicinol (IX) und vermeintlichem 3-Methoxy-3-epi-Radicinol (X) eindrucksvoll zur Schau gestellt. Mithilfe einer Säure-mediierten SN2- Substitution an C3 konnten die drei genannten Verbindungen aus der gemeinsamen Vorstufe XI X hergestellt werden. Bedauerlicherweise stimmen die gemessenen nicht mit den in der Literatur veröffentlichten Daten für X überein, was eine falsche Strukturaufklärung nahelegt. Schema 2. Vergleich der benutzten Ester in der goldkatalysierten Pyronsynthese und retrosynthetische Analyse von Radicinol (VIII), 3-epi-Radicinol (IX) und 3-Methoxy-3-epi-Radicinol (X). Darauffolgend wurde die Modifikation der goldkatalysierten Pyronsynthese als Schlüsselschritt in der Synthese des hochkomplexen Orevactaene (XII, Schema 3) angewandt. Das sensitive Heptaen und der hochoxidierte Bizyklus sowie die Nichtzuordnung der relativen Konfiguration von vier der sieben stereogenen Zentren in der Literatur machten die Synthese reizvoll. Dies erforderte die Entwicklung einer Strategie, die die individuelle Synthese jedes der 16 möglichen Diastereomere erlaubte. Daher wurde eine hochkonvergente Route mit zwei aufeinanderfolgenden sp2–sp2 Kupplungsreaktionen zur Verknüpfung der Fragmente XIII, XIV und XV entworfen. Die Synthese zweier möglicher Diastereomere von Orevactaene (XII) konnte abgeschlossen werden. Allerdings zeigten die gemessenen analytischen Daten, dass die Struktur des Bizyklus von Orevactaene (XII) vom Isolationsteam grundlegend falsch zugeordnet wurde. Schema 3. Retrosynthetische Analyse von Orevactaene (XII).Total Synthesis and Late Stage Modification of (‒)-5,6-Dihydrocineromycin B (‒)-Dihydrocineromycin B (I, Scheme 1) is a 14-membered antibiotic macrolide, belonging to a family that exhibits potential for treatment against methicillin-resistant Staphylococcus aureus (MRSA). The lack of relevant biological data for I in particular and of efficient methods for the formation of the naturally abundant (E)-2-methyl-2-but-2-en-1-ol motif (blue) encouraged us to develop a new synthetic strategy. Our approach combined ring-closing alkyne metathesis to furnish cycloalkyne III, followed by a regioselective Ru-catalyzed trans-hydrostannation and the concluding Stille-coupling with methyl iodide. The versatility of vinyl-tributyltin intermediate II was demonstrated by late stage diversification that allowed various analogues of the natural product to be prepared. Scheme 1. Retrosynthetic anaylsis of 5,6-dihydrocineromycin B (I). Gold-Catalyzed 4-Oxo-2-Pyrone Synthesis Fürstner and coworkers previously developed a AuI-catalyzed cyclization which enabled facile synthesis of substituted pyrones under remarkably mild reaction conditions (Scheme 2). However, the preparation of sterically demanding cyclization precursors containing bulky tert-butyl ester (VI) was found to be challenging. We established that the analogous cyclization can be effected with the corresponding 2-TMS-ethanol-ester (VII) which is more readily prepared. This modification of the gold-catalyzed pyrone synthesis was applied to the first total syntheses of radicinol (VIII), 3-epiradicinol (IX), and putative 3-methoxy-3-epi-radicinol (X). Through acid-promoted SN2 reactions at C3 position of common intermediate XI, the three targets could be synthesized in a divergent fashion. Unfortunately, the analytical data of X did not match those reported in the isolation studies, which suggests structural misassignment in the original report. XII Scheme 2. a) Comparison of the used esters in the gold-catalyzed pyrone cyclization; b) Retrosynthetic analysis of radicinol (VIII), 3-epi-radicinol (IX) and 3-methoxy-3-epi-radicinol (X). Subsequently the gold-catalyzed pyrone synthesis was applied as a key step to prepare a highly complex natural product, Orevactaene (XII, Scheme 3). The sensitive heptaene and the highly oxidized bicyclic structure in the natural product renders its synthesis challenging. Furthermore, the lack of configurational assignment of four stereogenic centers in the literature called for a strategy that could allow the formation of all sixteen possible diastereoisomers. Therefore, by employing the highly convergent strategy, involving two late-stage sp2–sp2 cross-coupling reactions between fragments XIII, XIV, and XV, two stereoisomers of Orevactaene (XII) were synthesized. However, their analytical data did not support the proposed structure of XII, but rather indicate that the bicyclic structure was fundamentally misassigned by the isolation team. Scheme 3. Retrosynthetic analysis of orevactaene (XII)

Novel Model Predictive Control of a PM Synchronous Motor Drive; Design of the Innovative Structure, Feasibility and Stability Analysis, Efficient Implementation, Experimental Validation

This text focuses on advanced torque control of permanent magnet synchronous motor drives. A novel modular structure is introduced to simplify the design and implementation of Model Predictive Control (MPC). The layout consists of the control and the control framework. The dynamic control is the novel virtual flux controller, which is used to reach desired reference values, and the state observer, which is used to reduce effects of non-modeled system properties. The control framework consists of static mappings to simplify the control problem. Besides the alpha-beta and d-q transformations, a reference generation procedure is used to generate state references based on optimality criteria. Also, the actuation scheme is part of the control framework and defines the available input set and the resulting control properties. The first method actuates directly switch states, i.e. voltage vectors, which yield an integer set named Finite Control Set (FCS). The other method actuates duty cycles via modulation, which yield the Convex Control Set (CCS). A stability analysis is carried out for both, CCS-MPC and FCS-MPC. MPC is called stable, if it is feasible and convergent, which can be ensured using the main MPC stability theorem. However, stringent computation requirements make it difficult to apply the theorem in practice. Thus, the Lyapunov based MPC approach is applied to the motor drive, which provides stability guarantees independent of the prediction horizon. A stability constraint based on control Lyapunov functions (CLF) ensures convergence to the origin and the resulting optimal control problem is shown to be feasible for all time. In other words, a control input can be found at each sampling instant, which satisfies all constraints and yields a stable closed-loop system. The properties of CCS-MPC are derived using a nonlinear controller and the constrained closed-loop system is shown to be stable in the sense of Lyapunov. The stability properties of FCS-MPC are more complex due to the integer input set. Using set-theoretical methods, it is shown that a sufficiently large control error can be steered towards the origin. In other words, the proposed FCS-MPC is shown to be set stable, i.e. the control error is guaranteed to converge to a well-defined neighborhood of the origin. MPC requires that a Constrained Finite Time Optimal Control (CFTOC) problem is solved at each sampling time. Small sampling periods and limited computation capabilities of embedded hardware require the CFTOC to be sufficiently simple, which is achieved using the virtual flux model in the static reference frame. The problem size is contained using a sufficiently small prediction horizon and efficient algorithms are necessary to provide a result within a sampling period. The CFTOC of the proposed CCS-MPC is a (convex) linear or quadratic programming problem, which can be solved using existing efficient algorithms. To provide a minimal approach, an efficient algorithm is introduced to solve the one-step-ahead prediction CFTOC analytically. FCS-MPC results in a mixed integer programming problem and is therefore more difficult to solve with standard numerical methods. In practice, the CFTOC is solved by enumeration, which is combined with branch-and-bound, i.e. branch-and-cut, techniques to improve the computational efficiency. The control algorithms have been developed on a Software-in-the-Loop (SiL) platform based on Matlab/Simulink and the code is implemented without modification on an experimental test-bench. The evaluation confirms the design and implementation of CCS-MPC and FCS-MPC and shows good results in dynamic and steady-state operation. The two MPC approaches have complimentary properties, which can be used to target different applications. CCS-MPC achieves a constant switching frequency and is a promising alternative to proportional-integral (PI) vector control. The concept can be combined with different modulation schemes, e.g. the Symmetric Space Vector Modulation (SSVM) and the Discontinuous Space Vector Modulation (DSVM) are used in this text. FCS-MPC takes the inverter switching into account and achieves an approximately constant switching ripple but a variable switching frequency. The concept is most profitably applied to systems where a high sampling frequency compared to the switching frequency is desired, e.g. high power or servo drives. Moreover, FCS-MPC lacks Pulse Width Modulation (PWM) harmonics in its current spectrum. Consequently, it is advantageous in terms of acoustic noise since emphasized tones are missing. However, the distinguished PWM harmonics of CCS-MPC are simpler to filter. In summary, it can be said that the work on advanced torque control of permanent magnet synchronous motor drives has produced an innovative strategy. The introduction of a new structure has significantly simplified the model predictive control problem, the concept of stability in particular. Moreover, this structure results in the implementation of simple algorithms, which can be computed efficiently

Gold- or Silver-Catalyzed Syntheses of Pyrones and Pyridine Derivatives: Mechanistic and Synthetic Aspects

3-Oxo-5-alkynoic acid esters, on treatment with a carbophilic catalyst, undergo 6-endo-dig cyclization reactions to furnish either 2-pyrones or 4-pyrones in high yields. The regiochemical course can be dialed in by the proper choice of the alcohol part of the ester and the π-acid. This transformation is compatible with a variety of acid-sensitive groups as witnessed by a number of exigent applications to the total synthesis of natural products, including pseudopyronine A, hispidine, phellinin A, the radininol family, neurymenolide, violapyrone, wailupemycin and an unnamed brominated 4-pyrone of marine origin. Although the reaction proceeds well in neutral medium, the rate is largely increased when HOAc is used as solvent or co-solvent, which is thought to favor the protodeauration of the reactive alkenyl-gold intermediates as the likely rate-determining step of the catalytic cycle. Such intermediates are prone to undergo diauration as an off-cycle event that sequesters the catalyst; this notion is consistent with literature data and supported by the isolation of the gem-diaurated complexes 12 and 15. Furthermore, silver catalysis allowed access to be gained to 2-alkoxypyridine and 2-alkoxyisoquinoline derivatives starting from readily available imidate precursors

Selective Formation of a Trisubstituted Alkene Motif by trans-Hydrostannation/Stille Coupling: Application to the Total Synthesis and Late-Stage Modification of 5,6-Dihydrocineromycin B

Countless natural products of polyketide origin have an E-configured 2-methyl-but-2-en-1-ol substructure. An unconventional entry into this important motif was developed as part of a concise total synthesis of 5,6-dihydrocineromycin B. The choice of this particular target was inspired by a recent study, which suggested that the cineromycin family of antibiotics might have overlooked lead qualities, although our biodata do not necessarily support this view. The new approach consists of a sequence of alkyne metathesis followed by a hydroxy-directed trans-hydrostannation and a largely unprecedented methyl-Stille coupling. The excellent yield and remarkable selectivity with which the signature trisubstituted alkene site of the target was procured is noteworthy considering the rather poor outcome of a classical ring-closing metathesis reaction. Moreover, the unorthodox ruthenium-catalyzed trans-hydrostannation is shown to be a versatile handle for diversity-oriented synthesis

Leuchtende Inszenierungen von Kindheit im Schatten des Regenbogens

Julian Rothenstein & Olga Budashevskaya (Hrsg.). 2013. Schatzkammer der Revolution. Russische Kinderbücher von 1920-1935. Bücher aus bewegten Zeit

Polyunsaturated C-Glycosidic 4-Hydroxy-2-pyrone Derivatives: Total Synthesis Shows that Putative Orevactaene Is Likely Identical with Epipyrone A

Orevactaene and epipyrone A were previously thought to comprise the same polyunsaturated tail but notably different C-glycosylated 4-hydroxy-2-pyrone head groups. Total synthesis now shows that the signature bicyclic framework assigned to orevactaene is a chimera; the compound is almost certainly identical with epipyrone A, whose previously unknown stereochemistry has also been established during this study. Key to success was the ready formation of the bicyclic core of putative orevactaene by a sequence of two alkyne cycloisomerization reactions using tungsten and gold catalysis. Equally important was the flexibility in the assembly process gained by the use of heterobimetallic polyunsaturated modules whose termini could be selectively and consecutively addressed in a practical one-pot cross-coupling sequence

Transformation Strategies for the Supply Chain: The Impact of Industry 4.0 and Digital Transformation

This research focuses on the impact of 'Industry 4.0' and 'Digital Transformation' on information sharing and decision making across the supply chain (SC). Following a qualitative approach, the findings are threefold: First, it is shown that the possibility of an entire SC integration based on new technologies is still at distance. Current burdens are the missing willingness to exchange far-reaching information even with long-term partners and the missing technological interface standards in order to enable a trouble-free communication alongside the SC. Second, the impact of Industry 4.0 and the Digital Transformation on decision making is greatly connected to information sharing. An increasing amount of decisions is prepared, recommended or even fully automated by information systems. However, usually, the human being still has the last word. Third, companies' preparations for these impacts differ greatly. Whereas some companies rely on classical phase-based strategies and long-term visions, others do not have a long-term plan at all