13 research outputs found
Mild Pd-Catalyzed Aminocarbonylation of (Hetero)Aryl Bromides with a Palladacycle Precatalyst
A palladacyclic precatalyst is employed to cleanly generate a highly active XantPhos-ligated Pd-catalyst. Its use in low temperature aminocarbonylations of (hetero)aryl bromides provides access to a range of challenging products in good to excellent yields with low catalyst loading and only a slight excess of CO. Some products are unattainable by traditional carbonylative coupling.National Institutes of Health (U.S.) (Award GM46059)Danish National Research Foundation (Grant DNRF59)Villum FoundationDanish Council for Independent Researc
Palladium-Catalyzed Synthesis of Aromatic Carboxylic Acids with Silacarboxylic Acids
Aryl iodides and bromides were easily converted to their corresponding aromatic carboxylic acids via a Pd-catalyzed carbonylation reaction using silacarboxylic acids as an <i>in situ</i> source of carbon monoxide. The reaction conditions were compatible with a wide range of functional groups, and with the aryl iodides, the carbonylation was complete within minutes. The method was adapted to the double and selective isotope labeling of tamibarotene
Asymmetric Hydroarylation of Vinylarenes Using a Synergistic Combination of CuH and Pd Catalysis
Detailed in this
Communication is the enantioselective synthesis of 1,1-diarylalkanes,
a structure found in a range of pharmaceutical drug agents and natural
products, through the employment of copper(I) hydride and palladium
catalysis. Judicious choice of ligand for both Cu and Pd enabled this
hydroarylation protocol to work for an extensive array of aryl bromides
and styrenes, including β-substituted vinylarenes and six-membered
heterocycles, under relatively mild conditions
Ruthenium-catalysed C‒H amidation for the late-stage synthesis of PROTACs
PROteolysis TArgeting Chimeras (PROTACs) are a powerful modality in drug discovery, offering the potential to address outstanding medical challenges. However, the synthetic feasibility of PROTACs, and the empiric and complex nature of their structure-activity relationships continue to present formidable limitations. As such, modular and reliable approaches to streamline the synthesis of these compounds are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to provide modular access to both fully elaborated PROTACs and drug conjugates. Using readily available dioxazolone reagents, a broad range of inherently present functional groups can guide the C–H amidation on complex bioactive molecules. High selectivity and functional group tolerance enable the late-stage installation of linkers bearing orthogonal functional handles for downstream elaboration. Finally, the single-step synthesis of PROTAC and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools
Palladium-Catalyzed Aminocarbonylation in Solid-Phase Peptide Synthesis: A Method for Capping, Cyclization, and Isotope Labeling
A new synthetic approach
for introducing N-capping groups onto
peptides attached to a solid support, combining aminocarbonylation
under mild conditions using a palladacycle precatalyst and solid-phase
peptide synthesis, is reported. The use of a silacarboxylic acid as
an in situ CO-releasing molecule allowed the reaction to be performed
in a single vial. The method also enables versatile substitution of
side chains, side-chain-to-side-chain cyclizations, and selective
[<sup>13</sup>C] acyl labeling of modified peptides
Silacarboxylic Acids as Efficient Carbon Monoxide Releasing Molecules: Synthesis and Application in Palladium-Catalyzed Carbonylation Reactions
Silacarboxylic acids have been demonstrated to be easy to handle, air-stable carbon monoxide precursors. Different silacarboxylic acids were synthesized from the corresponding chlorosilanes and carbon dioxide, and their decarbonylation, upon treatment with an array of activators, was evaluated. The release of CO from crystalline MePh<sub>2</sub>SiCO<sub>2</sub>H proved to be highly efficient, and it was successfully applied in a selection of palladium-catalyzed carbonylative couplings using near-stoichiometric quantities of carbon monoxide precursor. Finally, the synthesis of MePh<sub>2</sub>Si<sup>13</sup>CO<sub>2</sub>H and its application in carbonyl labeling of two bioactive compounds was demonstrated
Efficient <sup>11</sup>C‑Carbonylation of Isolated Aryl Palladium Complexes for PET: Application to Challenging Radiopharmaceutical Synthesis
We
describe the successful implementation of palladium-aryl oxidative
addition complexes as stoichiometric reagents in carbonylation reactions
with <sup>11</sup>CO to produce structurally challenging, pharmaceutically
relevant compounds. This method enables the first <sup>11</sup>C-carbonyl
labeling of an approved PET tracer, [<sup>11</sup>C]raclopride, for
the dopamine D2/D3 receptor by carbonylation with excellent radiochemical
purity and yield. Two other molecules, [<sup>11</sup>C]olaparib and
[<sup>11</sup>C]JNJ 31020028, were efficiently labeled in this manner.
The technique distinguishes itself from existing methods by the markedly
improved purity profiles of the tracer molecules produced and provides
access to complex structures in synthetically useful yields, hereby
offering a viable alternative to other <sup>11</sup>C-labeling strategies