Ruthenium-Catalyzed trans-Selective Hydrostannation of Alkynes

In contrast to all other transition-metal-catalyzed hydrostannation reactions documented in the literature, the addition of Bu3SnH across various types of alkynes proceeds with excellent trans selectivity, provided the reaction is catalyzed by [Cp*Ru]-based complexes. This method is distinguished by a broad substrate scope and a remarkable compatibility with functional groups, including various substituents that would neither survive under the conditions of established Lewis acid mediated trans hydrostannations nor withstand free-radical reactions. In case of unsymmetrical alkynes, a cooperative effect between the proper catalyst and protic functionality in the substrate allows outstanding levels of regioselectivity to be secured as well

Two Enabling Strategies for the Stereoselective Conversion of Internal Alkynes into Trisubstituted Alkenes

An expedient method for the C-methylation of alkenylstannanes with formation of trisubstituted alkenes is described, which relies on the use of MeI in combination with copper thiophene-2-carboxylate (CuTC) as promotor and tetra-n-butylammonium diphenylphosphinate as an effective tin scavenger; in some cases, it proved beneficial to further supplement the mixture with catalytic amounts of Pd(PPh3)4. Under these conditions, the reaction is robust, high yielding, and compatible with many functional groups that might not subsist under more traditional conditions used to C-alkylate organotin derivatives. A qualitative analysis of the reaction profile suggested that the in situ formation of a reactive organocopper intermediate and its interception by MeI is only barely faster than O-methylation of the phosphinate additive by the same alkylating agent. To guarantee high yields and prevent net protodestannation from occurring, the reaction protocol had to be optimized such that these competing processes are properly decoupled. The new method is particularly well suited for the stereoselective preparation of the (E)-2-methylbut-2-en-1-ol motif that is present in numerous natural products. Alternatively, this particular target structure can be accessed starting from α-hydroxy alkenylsiloxane precursors, which get C-methylated upon exposure to CuI/LiOtBu and MeI by what is thought to be a Brook rearrangement/ alkylation sequence. The required substrates are best prepared by ruthenium-catalyzed trans-hydrosilylation or trans-hydrostannation of propargyl alcohols

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

Hydroxy-Directed Ruthenium-Catalyzed Alkene/Alkyne Coupling: Increased Scope, Stereochemical Implications, and Mechanistic Rationale

The recognition of the dual binding mode of propargyl and allyl alcohols to [Cp*Ru] fragments fostered the development of a highly regioselective intermolecular Alder-ene-type reaction of alkynes with 1,2-disubstituted alkenes. The increased substrate scope opens new perspectives in stereochemical terms. As the loaded catalyst is chiral-at-metal, stereochemical information is efficiently relayed from the propargylic site to the emerging C−C bond. This interpretation is based on the X-ray structure of the first Cp*Ru complex carrying an intact enyne ligand, and provides valuable insights into bonding and activation of the substrates. Computational data draw a clear picture of the principles governing regio- and stereocontrol

Half-​Sandwich Ruthenium Carbene Complexes Link trans-​Hydrogenation and gem-​Hydrogenation of Internal Alkynes

The hydrogenation of internal alkynes with [Cp*Ru]-based catalysts is distinguished by an unorthodox stereochemical course in that E-alkenes are formed by trans-delivery of the two H atoms of H2. A combined experimental and computational study now provides a comprehensive mechanistic picture: a metallacyclopropene (η2-vinyl complex) is primarily formed, which either evolves into the E-alkene via a concerted process or reacts to give a half-sandwich ruthenium carbene; in this case, one of the C atoms of the starting alkyne is converted into a methylene group. This transformation represents a formal gem-hydrogenation of a π-bond, which has hardly any precedent. The barriers for trans-hydrogenation and gem-hydrogenation are similar: whereas DFT predicts a preference for trans-hydrogenation, CCSD(T) finds gem-hydrogenation slightly more facile. The carbene, once formed, will bind a second H2 molecule and evolve to the desired E-alkene, a positional alkene isomer or the corresponding alkane; this associative pathway explains why double bond isomerization and over-reduction compete with trans-hydrogenation. The computed scenario concurs with para-hydrogen-induced polarization transfer (PHIP) NMR data, which confirm direct trans-delivery of H2, the formation of carbene intermediates by gem-hydrogenation, and their evolution into product and side products alike. Propargylic −OR (R = H, Me) groups exert a strong directing and stabilizing effect, such that several carbene intermediates could be isolated and characterized by X-ray diffraction. The gathered information spurred significant preparative advances: specifically, highly selective trans-hydrogenations of propargylic alcohols are reported, which are compatible with many other reducible functional groups. Moreover, the ability to generate metal carbenes by gem-hydrogenation paved the way for noncanonical hydrogenative cyclopropanations, ring expansions, and cycloadditions

Ruthenium-Katalysierte trans-Hydrostannierung von Alkinen und Verwandte Reaktionen

Eine Ruthenium-katalysierte trans-selektive Hydrostannierung interner Alkine wurde entwickelt. Neben der für die Übergangsmetallkatalyse unüblichen trans-Addition, zeichnet sich die Reaktion durch eine hohe Toleranz gegenüber funktionellen Gruppen aus. Besonders wenn Alkine mit einer nahen protischen Funktionalität in Kombination mit einem [Cp*RuCl]-Katalysator verwendet wurden, konnte außerdem eine exzellente Regioselektivität erreicht werden (Schema 1). Untersuchungen der Bindungsmodi eines propargylischen Alkohols und des Stannans an katalytisch relevante [„Cp“RuCl]-Fragmente via Kristallstrukturanalyse legten nahe, dass Interligand-Interaktionen des aziden Protons am Alkin beziehungsweise des Zinns mit dem Chlorid-Liganden die Reaktionspartner für die Reaktion optimal ausrichten und die Regioselektivität bestimmen (Abbildung 1). Auf diese Art konnte auch die Regioselektivität anderer trans-Hydrometallierungen kontrolliert werden. Die Anwendbarkeit dieser neu entwickelten Reaktion auf komplexere Zielstrukturen wurde durch die Totalsynthese von 5,6-Dihydrocineromycin B unter Beweis gestellt. In Kombination mit einer Alkinmetathese und einer zu diesem Zweck optimierten Stille-Kupplung konnte das in der Natur oft vorkommende (E)-2-Methylbut- 2-en-1-ol Strukturmotiv (rot) im Makrozyklus selektiv dargestellt werden (Schema 2). Die aktivierende und dirigierende Wirkung der Wasserstoffbrücke einer protischen Funktionalität in der Nähe eines π-Systems wurde des Weiteren dazu benutzt, eine Ruthenium-katalysierte, regio- und diastereoselektive Alken-Alkin Kupplung zu entwickeln (Schema 3). Anhand einer regio- und stereoselektiven syn-Addition von Dimethylzink an (homo-)propargylische Ether konnte zudem gezeigt werden, dass [Cp*Ru]-Komplexe auch in Carbometallierungs-Reaktionen katalytische Aktivität aufweisen (Schema 4). Zuletzt wurde eine Ruthenium-katalysierte, reduktive Zyklopropanierung entwickelt, die über ein durch geminale Hydrierung entstehendes Ruthenium-Carben verläuft (Schema 5)

Zur Betrachtung manipulationsbedingter Belastungsreaktionen in den Vitalparametern eines sehr früh geborenen Kindes

Hintergrund: Ziel der Diplomarbeit war es, die physiologischen Reaktionen eines sehr frühgeborenen Kindes auf Routinemaßnahmen zu untersuchen. Veränderungen der Herzfrequenz, Atemfrequenz und der Sauerstoffsättigung, die oft als Überlastungsindikatoren herangezogen werden, wurden einer genaueren Betrachtung unterzogen. Hierbei war eine Prüfung hinsichtlich signifikanter Veränderungen zwischen den Zeiteinheiten vor, während und nach den Manipulationen von Interesse. Neben einer Erörterung der Phänomene Stress und Schmerzen bei Frühgeborenen wird in der Arbeit ebenfalls ein Einblick über Ausmaß und Inhalt von Manipulationen gegeben, mit denen frühgeborene Kinder auf der Intensivstation konfrontiert sind. Methode: Auf der neonatologischen Intensivstation der Charité in Berlin wurde eine Beobachtungsstudie an einem frühgeborenen Kind (26 SSW, 6…g) durchgeführt. Jede Manipulation am Kind sowie die korrespondierenden Vitalparameter wurden aufgezeichnet und statistisch ausgewertet (Friedman-Test, Wilcoxon-Test). Ergebnisse: Bei den betrachteten Vitalparametern ließen sich zwischen den drei Zeitfenstern signifikante Veränderungen nachweisen (Herzfrequenz p = 0.01, Atemfrequenz p = 0.00, Sauerstoffsättigung p = 0.00), die einen für Belastungsreaktionen typischen Verlauf zeigten. Die 96 beobachteten Handlungen ließen sich in sechs übergeordnete Kategorien unterteilen. Fazit: Die untersuchten Parameter sind reliable Indikatoren für die Stressbelastung Frühgeborener. Durch die Untersuchung konnten ebenfalls die Möglichkeiten und Begrenzungen der Anwendung einer systematischen Beobachtung auf der neonatologischen Intensivstation dargestellt werden.Background: The aim of the thesis for a degree was to investigate the physiological responses of a very preterm infant to procedures that are routinely performed in intensive care nurseries. Changes in heart rate, respiration rate and oxygen saturation, which are usually used as stress indicators, were examined. The values of the three measures during the procedures were compared with values before and after the procedures. Beside a discussion of stress and pain in preterm infants, the diploma dissertation outlines the handlings to which preterm infants are exposed at the neonatal intensive care unit. Design: A very preterm infant (26 GW, 6…g) was observed in the neonatal intensive care unit of the Charité Hospital in Berlin. Each manipulation on the child and the corresponding physiological responses were recorded and evaluated (Friedman-test, Wilcoxon-test). Results: Significant differences were found among pre-, peri- and post - procedures for all three outcome measures (heart rate: p = 0.01, respiration rate: p = 0.00, oxygen saturation: p = 0.00), which showed a stress characteristic course. In total, 96 manipulations were observed which could be subdivided into six superior categories. Conclusion: The examined physiological responses appear to be reliable indices of stress on a very preterm infant. The examination showed as well the possibilities and limitations of an observation study in the NICU environment

Computational Investigations into the Mechanisms of Trans-Selective Hydrogenation and Hydrometalation of Alkynes

An overview on the mechanisms of the trans-selective hydrogenation and hydrometalation of alkynes using a CpRuL catalyst is provided. Unlike the more common mode of hydrogenation, syn, this select ruthenium catalyst system uniquely favors the products resulting from anti-addition across the alkyne π-system. The primary focus is summarizing the results of computational studies on the mechanism of these reactions, including key experimental supporting evidence. This chapter addresses hydrogenation, hydrosilylation, hydrostannation, and hydroboration. An overview of the mechanisms for all of these processes is highlighted