Thomas L. Andersen

Efficient 11C-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 (11)CO to produce structurally challenging, pharmaceutically relevant compounds. This method enables the first (11)C-carbonyl labeling of an approved PET tracer, [(11)C]raclopride, for the dopamine D2/D3 receptor by carbonylation with excellent radiochemical purity and yield. Two other molecules, [(11)C]olaparib and [(11)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 (11)C-labeling strategies.

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 in situ 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.

Direct Access to α,α-Difluoroacylated Arenes by Palladium-Catalyzed Carbonylation of (Hetero)Aryl Boronic Acid Derivatives

A palladium-catalyzed carbonylative coupling of (hetero)aryl boronates or boronic acid salts with carbon monoxide and α-bromo-α,α-difluoroamides and bromo-α,α-difluoroesters is described herein. The method is useful for the synthesis of a diverse selection of (hetero)aryl α,α-difluoro-β-ketoamides and α,α-difluoro-β-ketoesters, which are useful building blocks for the generation of functionalized difluoroacylated and difluoroalkyl arenes. The method could be further extended to a one-pot protocol for the formation of difluoroacetophenones.

Two-chamber hydrogen generation and application: access to pressurized deuterium gas.

Hydrogen and deuterium gas were produced and directly applied in a two-chamber system. These gaseous reagents were generated by the simple reaction of metallic zinc with HCl in water for H2 and DCl in deuterated water for D2. The setup proved efficient in classical Pd-catalyzed reductions of ketones, alkynes, alkenes, etc. in near-quantitative yields. The method was extended to the synthesis and isotope labeling of quinoline and 1,2,3,4-tetrahydroquinoline derivatives. Finally, CX-546 and Olaparib underwent efficient Ir-catalyzed hydrogen isotope exchange reactions.

Synthesis and evaluation of silanediols as highly selective uncompetitive inhibitors of human neutrophil elastase.

Chronic obstructive pulmonary disease (COPD) is an increasing health problem and is estimated to be the fifth leading cause of death in 2020 according to the World Health Organization. Current treatments are only palliative, and therefore the development of new medicine for the treatment of COPD is urgent. Human Neutrophil Elastase (HNE) is a serine protease that is heavily involved in the progression of COPD through inflammatory breakdown of lung tissue. Consequently, inhibitors of HNE are of great interest as therapeutics. In this article, the development of silanediol peptide isosters as inhibitors of HNE is presented. Kinetic studies revealed that incorporation of a silanediol isoster in the inhibitor structure resulted in an uncompetitive mechanism of inhibition, which further resulted in excellent selectivity. The peculiar mechanism of inhibition and the resulting selectivity makes the presented inhibitors promising leads for the development of new HNE-inhibitor-based therapeutics for the treatment of COPD.

Rapid and Efficient Conversion of 11CO2 to 11CO through Silacarboxylic Acids: Applications in Pd-Mediated Carbonylations

Herein, we present a new rapid, efficient, and low-cost radiosynthetic protocol for the conversion of (11) CO2 to (11) CO and its subsequent application in Pd-mediated reactions of importance for PET applications. This room-temperature methodology, using readily available chemical reagents, is carried out in simple glass vials, thus eliminating the need for expensive and specialized high-temperature equipment to access (11) CO. With this fast and near-quantitative conversion of (11) CO2 into (11) CO, aryl and heteroaryl iodides were easily converted into a broad selection of biologically active amides in radiochemical yields ranging from 29-84 %.

General method for the preparation of active esters by palladium-catalyzed alkoxycarbonylation of aryl bromides.

A useful method was developed for the synthesis of active esters by palladium-catalyzed alkoxycarbonylation of (hetero)aromatic bromides. The protocol was general for a range of oxygen nucleophiles including N-hydroxysuccinimide (NHS), pentafluorophenol (PFP), hexafluoroisopropyl alcohol (HFP), 4-nitrophenol, and N-hydroxyphthalimide. A high functional group tolerance was displayed, and several active esters were prepared with good to excellent isolated yields. The protocol was extended to access an important synthetic precursor to the HIV-protease inhibitor, saquinavir, by formation of an NHS ester followed by acyl substitution.

Application of Methyl Bisphosphine‐Ligated Palladium Complexes for Low Pressure N‐11C‐Acetylation of Peptides

A mild and effective method is described for 11 C-labeling of peptides selectively at the N-terminal nitrogen or at internal lysine positions. The presented method relies on the use of specific biphosphine palladium-methyl complexes and their high reactivity towards amino-carbonylation of amine groups in the presence [11 C]carbon monoxide. The protocol facilitates the production of native N-11 C-acetylated peptides, without any structural modifications and has been applied to a selection of bioactive peptides.

Carbonylative Coupling of Alkyl Zinc Reagents with Benzyl Bromides Catalyzed by a Nickel/NN2 Pincer Ligand Complex

An efficient catalytic protocol for the three-component assembly of benzyl bromides, carbon monoxide, and alkyl zinc reagents to give benzyl alkyl ketones is described, and represents the first nickel-catalyzed carbonylative coupling of two sp3 -carbon fragments. The method, which relies on the application of nickel complexed with an NN2 -type pincer ligand and a controlled release of CO gas from a solid precursor, works well with a range of benzylic bromides. Mechanistic studies suggest the intermediacy of carbon-centered radicals.

Synthesis of Aliphatic Carboxamides Mediated by Nickel NN2‐Pincer Complexes and Adaptation to Carbon‐Isotope Labeling

The development of a nickel-mediated aminocarbonylation utilizing NN2 -pincer Ni-complexes, alkylzinc reagents, stoichiometric carbon monoxide and amines is described for the first time, which can be adapted to late-stage carbon-isotope labeling. This work expands the scope of the highly established palladium-promoted version of the reaction, by allowing carbon-sp3 fragments to take part in the three-component reaction. Finally, the results obtained show a remarkable effect of the pincer ligand for the reductive elimination step with the amine, which is followed by 13 C NMR spectroscopy studies.