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

Identification and biological characterization of indoline-based autophagy inhibitors

Autophagy is a vital catabolic process involved in the degradation of cellular components, which plays an important role in cancer and neurodegenerative disorders. Due to their high complexity, the pathways regulating autophagy have not been fully elucidated. The development of specific autophagy modulators and the identification of their cellular targets can provide valuable insight into the regulation of this process and, ultimately, its role in disease. Herein, a potent inhibitor of starvation-induced autophagy (IC50 = 520 +- 550 nM) was identified using a phenotypic screen. In a series of secondary assays, the compound was validated as an autophagy inhibitor. The structure–activity relationship for this compound class was derived from a synthesized compound collection of structural analogs and used for the preparation of a chemical probe for affinity-based proteomics ("pull-down"). Glutamate dehydrogenase (GDH) and calpain-1 were isolated by means of affinity-based proteomics but devalidated as targets of the inhibitor in various biophysical and biochemical assays. The ATP-gated ionotropic receptor P2X4 and the Ragulator component LAMTOR5 were the most promising targets determined by thermal proteome profiling and are currently under evaluation.Targets predicted using a computational approach based on chemical similarity included 5-hydroxytryptamine (5-HT) receptors and multiple kinases—rapidly accelerated fibrosarcoma (RAF1) and related kinases, pyruvate kinase (PK), and abelson murine leukemia viral oncogene homolog 1 (ABL1). Whereas no modulating effect on the predicted kinases was observed, the autophagy inhibitor was a potent antagonist of the G-protein-coupled serotonin receptor 5-HT6 (IC50 = 1 µM). However, as known antagonists of the receptor did not inhibit autophagy, 5-HT6 was considered an off-target. Given the strong antagonistic effect seen, G-protein-coupled receptors need to be further evaluated as potential targets of the identified inhibitor. The successful target identification of this potent inhibitor could help deliver further understanding of the complex mechanisms that regulate autophagy.Autophagie ist ein lebensnotwendiger katabolischer Prozess, der am Abbau zellulärer Komponenten beteiligt ist und eine wichtige Rolle bei Krebs und neurodegenerativen Krankheiten spielt. Aufgrund der hohen Komplexität der Autophagie-regulierenden Signalwege konnten diese noch nicht vollständig entschlüsselt werden. Die Entwicklung spezifischer Autophagie-Modulatoren und die Identifizierung ihrer zellulären Zielproteine können einen wertvollen Einblick in die Regulierung von Autophagie und letztendlich ihre Rolle in Krankheiten gewähren. Im Rahmen dieser Arbeit wurde mittels phänotypischem Screening ein potenter Inhibitor von durch Aushungern induzierter Autophagie identifiziert (IC50 = 520 +- 550 nM). In einer Reihe sekundärer Assays wurde diese Verbindung als echter Autophagie-Inhibitor validiert. Die Struktur-Aktivitätsbeziehung für diese Verbindungsklasse wurde aus einer hergestellten Substanzkollektion abgeleitet, anhand derer eine chemische Sonde synthetisiert wurde. Glutamatdehydrogenase (GDH) und Calpain-1 wurden durch Affinitätschromatographie isoliert, allerdings anschließend in verschiedenen biophysikalischen und biochemischen Assays als Zielproteine des Autophagie-Inhibitors devalidiert. Mittels thermischem Proteomprofiling wurden der ATP-abhängige Ionenkanal P2X4 und die Ragulator-Komponente LAMTOR5 als vielversprechendste Zielproteine identifiziert und werden derzeit untersucht. 5-Hydroxytryptaminrezeptoren und mehrere Kinasen—rapidly accelerated fibrosarcoma (RAF1) und verwandte Kinasen, Pyruvatkinase (PK) und abelson murine leukemia viral oncogene homolog 1 (ABL1)—waren unter den Zielproteinen, die durch rechnergestützte Ansätze anhand von strukturellen Ähnlichkeiten vorausgesagt wurden. Während kein Effekt auf die PK beobachtet wurde, war der Autophagie-Inhibitor ein potenter Antagonist des G-Protein-gekoppelten Serotoninrezeptors 5-HT6 (IC50 = 1 µM). Da allerdings bekannte Antagonisten dieses Rezeptors Autophagie nicht inhibierten, wurde 5-HT6 als „Off-Target“ bezeichnet. Angesichts des beobachteten starken antagonistischen Effekts, müssen G-Protein-gekoppelte Rezeptoren genauer als mögliche Zielproteine des identifizierten Inhibitors untersucht werden. Die erfolgreiche Identifizierung des Zielproteins dieses Inhibitors könnte dazu beitragen, weitere Einsicht in die komplexen Autophagie-regulierenden Mechanismen zu ermögliche

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

Stereo- and Regioselective Alkyne Hydrometallation with Gold(III) Hydrides

The hydroauration of internal and terminal alkynes by gold(III) hydride complexes [(C^N^C)AuH] was found to be mediated by radicals and proceeds by an unexpected binuclear outer-sphere mechanism to cleanly form trans-insertion products. Radical precursors such as azobisisobutyronitrile lead to a drastic rate enhancement. DFT calculations support the proposed radical mechanism, with very low activation barriers, and rule out mononuclear mechanistic alternatives. These alkyne hydroaurations are highly regio- and stereospecific for the formation of Z-vinyl isomers, with Z/E ratios of >99:1 in most cases