12 research outputs found
Pd- and Ni-based catalysts for mild C-S bond activation and formation
Die vorliegende Arbeit beschreibt effiziente Synthesemethoden zur Aktivierung und Bildung von C-S-Bindungen unter Ausnutzung thiophiler Wechselwirkungen von Komplexen später Übergangsmetalle. Beschrieben wird im Einzelnen eine Pd-katalysierte Hydro(thio)esterifizierung von terminalen Alkenen unter geringem CO-Druck, welche die entsprechenden (Thio-)Ester in generell guten Ausbeuten bereits bei Raumtemperatur und mittels einer schwachen ko-katalytischen Säure zugänglich machten. Vinylarene lieferten hierbei grundsätzlich die verzweigten Produkte. Weiterhin wird eine Ni-katalysierte Fukuyama-Kupplung von S-Ethylthioestern mit Arylzinkreagenzien bei Raumtemperatur beschrieben. Die dabei enstehenden polyfunktionalen Ketone stellen wertvolle Syntheseintermediate dar. Schlussendlich wird eine Ni-katalysierte Kupplung von in situ-generierten Zinkthiolaten mit reaktionsträgen Arylchloriden aufgezeigt. Aliphatische Thiole lassen sich bei bis zu 60 °C umsetzen, wohingegen die Umsetzung aromatischen Thiolen eine andere Organometallbase benötigte, um eine entschwefelnde Kumada- bzw. Negishi-Kupplung zu vermeiden. Die entsprechenden Arylthioether sind interessante Zielmotive in Pharmazeutika, Agrochemikalien und neuen funktionalen Materialien
A recyclable CO surrogate in regioselective alkoxycarbonylation of alkenes: indirect use of carbon dioxide
Herein, we report a Pd-catalysed alkoxycarbonylation of alkenes based on the use of a recyclable CO2 reduction product, the crystalline and air-stable N-formylsaccharin, as a CO surrogate. The carbonylation proceeds under ambient conditions in an exceptionally complementary regioselective fashion yielding the desired branched products from styrene derivatives and valuable linear esters from alkyl-substituted alkenes
Tandem Acyl Substitution/Michael Addition of Thioesters with Vinylmagnesium Bromide
A tandem
reaction of thioesters with vinylmagnesium bromide is
reported. The initial acyl substitution provides an α,β-unsaturated
ketone which further reacts with the liberated thiolate. This transition-metal-free
synthesis of β-sulfanyl ketones takes place under mild reaction
conditions, whereas the addition of a second Grignard molecule is
almost completely suppressed. The carefully chosen parameters enabled
the transformation of different substrates in moderate to good yields
Regioselective Thiocarbonylation of Vinyl Arenes
A palladium-catalyzed
thioÂcarbonylÂation of styrene
derivatives is reported for the first time. The combination of thiols
as nucleoÂphiles and a bidentate ligand ensures a unique reaction
outcome with high regioÂselectivity toward the more valuable
branched isomer and new reactivity. The ambient reaction conditions
(temperature, catalyst loading) and the use of a CO surrogate render
this transformation a useful method for the synthesis of thioÂesters
from available feedstock. Various functional groups on arene and thiol
substituents are tolerated by the system. Notably, challenging <i>ortho</i>-substituted styrenes are converted with unprecedentedly
high regioÂselectivity
Cross-Coupling of Chloro(hetero)arenes with Thiolates Employing a Ni(0)-Precatalyst
A general and efficient Ni-catalyzed
coupling of challenging aryl
chlorides and in situ generated aliphatic and aromatic
thiolates is described. The employed on-cycle, air-stable defined
Ni precatalysts allow for transformation of a broad scope of substrates.
A variety of functional groups and heterocyclic motifs as well as
structurally varied thiols are tolerated at unprecedented moderate
catalyst loadings and reaction temperatures. Depending on reaction
conditions, aryl thiols can selectively undergo C–S or C–C couplings
Efficient targeted degradation via reversible and irreversible covalent PROTACs
PROteolysis Targeting Chimeras (PROTACs) represent an exciting inhibitory modality with many advantages, including sub-stoichiometric degradation of targets. Their scope, though, is still limited to-date by the requirement for a sufficiently potent target binder. A solution that proved useful in tackling challenging targets is the use of electrophiles to allow irreversible binding to the target. However, such binding will negate the catalytic nature of PROTACs. Reversible covalent PROTACs potentially offer the best of both worlds. They possess the potency and selectivity associated with the formation of the covalent bond, while being able to dissociate and regenerate once the protein target is degraded. Using Bruton’s tyrosine kinase (BTK) as a clinically relevant model system, we show efficient covalent degradation by non-covalent, irreversible covalent and reversible covalent PROTACs, with 85% degradation. Our data suggests that part of the degradation by our irreversible covalent PROTACs is driven by reversible binding prior to covalent bond formation, while the reversible covalent PROTACs drive degradation primarily by covalent engagement. The PROTACs showed enhanced inhibition of B cell activation compared to Ibrutinib, and exhibit potent degradation of BTK in patients-derived primary chronic lymphocytic leukemia cells. The most potent reversible covalent PROTAC, RC-3, exhibited enhanced selectivity towards BTK compared to non-covalent and irreversible covalent PROTACs. These compounds may pave the way for the design of covalent PROTACs for a wide variety of challenging targets.</p