Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications.

Amino acids are vital motifs in the domain of biochemistry, serving as the foundational unit for peptides and proteins, while also holding a crucial function in many biological processes. Due to their bifunctional character, they have been also used for combinatorial chemistry purposes, such as the preparation of DNA-encoded chemical libraries. We developed a practical synthesis for α-heteroaryl-α-amino acids starting from an array of small heteroaromatic halides. The reaction sequence utilizes a photochemically enhanced Negishi cross-coupling as a key step, followed by oximation and reduction. The prepared amino esters were validated for on-DNA reactivity via a reverse amidation-hydrolysis-reverse amidation protocol.

The Potential of Micellar Media in the Synthesis of DNA-Encoded Libraries.

DNA-encoded library (DEL) technology has become widely used in drug discovery research. The construction of DELs requires robust organic transformations that proceed in aqueous media under mild conditions. Unfortunately, the application of water as reaction medium for organic synthesis is not evident due to the generally limited solubility of organic reagents. However, the use of surfactants can offer a solution to this issue. Oil-in-water microemulsions formed by surfactant micelles are able to localize hydrophobic reagents inside them, resulting in high local concentrations of the organic substances in an otherwise poorly solvated environment. This review provides a conceptual and critical summary of micellar synthesis possibilities that are well suited to DEL synthesis. Existing examples of micellar DEL approaches, together with a selection of micellar organic transformations fundamentally suitable for DEL are discussed.

Design, scope and mechanism of highly active and selective chiral NHC-iridium catalysts for the intramolecular hydroamination of a variety of unactivated aminoalkenes.

Chiral, cationic NHC-iridium complexes are introduced as catalysts for the intramolecular hydroamination reaction of unactivated aminoalkenes. The catalysts show high activity in the construction of a range of 5- and 6-membered N-heterocycles, which are accessed in excellent optical purity, with various functional groups being tolerated with this system. A major deactivation pathway is presented and eliminated by using alternative reaction conditions. A detailed experimental and computational study on the reaction mechanism is performed providing valuable insights into the mode of action of the catalytic system and pointing to future modifications to be made for this catalytic platform.

Design and application of diimine-based copper(i) complexes in photoredox catalysis.

Structurally different bis(imino)copper(i) complexes were prepared in a highly modular manner and utilized as copper-based photocatalysts in the ATRA reactions of styrenes and alkyl halides. The new photocatalysts showed good catalytic activity and ensured efficient chemical transformations.

Electronic and Steric Tuning of an Atropisomeric Disulfoxide Ligand Motif and Its Use in the Rh(I)-Catalyzed Addition Reactions of Boronic Acids to a Wide Range of Acceptors.

A novel chiral disulfoxide ligand pair bearing fluorine atoms at the 6 and 6' position of its atropisomeric backbone, ( M, S, S)- and ( P, S, S)- p-Tol-6F-BIPHESO, was synthesized. Complexation to a rhodium(I) precursor gave rise to µ-Cl- and µ-OH-bridged rhodium dimer complexes incorporating the new ( M, S, S)- p-Tol-6F-BIPHESO ligand, while its sibling ( P, S, S)- p-Tol-6F-BIPHESO was not complexed efficiently to the rhodium precursor. The performance of this disulfoxide ligand [( M, S, S)- p-Tol-6F-BIPHESO] in catalysis was tested in both 1,4- and 1,2-addition reactions of arylboronic acids. We show that addition to both cyclic and acyclic enones as well as N-tosylarylimines proceeds with high yields and high enantioselectivities to give the corresponding products. The synthesis of enantiomerically pure p-Tol-6F-BIPHESO is straightforward and inexpensive which, together with the high catalytic performance and wide substrate scope for these addition reactions, makes it a very attractive alternative to more classical chiral ligand entities.

New, potentially chelating NHC ligands; synthesis, complexation studies, and preliminary catalytic evaluation.

Two new N-heterocyclic carbene (NHC) ligands bearing 2-morpholino and 2-piperidinyl naphthyl wingtips were synthesised (2-SIMorNap and 2-SIPipNap). Nuclear magnetic resonance studies, in conjunction with crystal structures and derivatisation of the NHC salts using a chiral counteranion, revealed that the ligand wingtips are oriented anti with respect to each other. From the free carbene, palladium, ruthenium and iridium complexes were prepared. NHC-iridium dicarbonyl complexes were made in order to extract the TEP values for these ligands. The study showed that these NHC ligands are more electron-donating than normal, aryl-substituted NHCs. The palladium complexes were tested in representative Suzuki-Miyaura cross-coupling reactions and compared to the state of the art systems. Ruthenium-catalysed ring-closing metathesis with these ligands was also performed. It was found that Grubbs' 2nd generation catalyst incorporating 2-SIPipNap did not initiate at room temperature and required heating for RCM to occur.

Unusual NHC-Iridium(I) Complexes and Their Use in the Intramolecular Hydroamination of Unactivated Aminoalkenes.

N-heterocyclic carbene (NHC) ligands with naphthyl side chains were employed for the synthesis of unsaturated, yet isolable [(NHC)Ir(cod)](+) (cod=1,5-cyclooctadiene) complexes. These compounds are stabilised by an interaction of the aromatic wingtip that leads to a sideways tilt of the NHC-Ir bond. Detailed studies show how the tilting of such N-heterocyclic carbenes affects the electronic shielding properties of the carbene carbon atom and how this is reflected by significant upfield shifts in the (13) C NMR signals. When employed in the intramolecular hydroamination, these [(NHC)Ir(cod)](+) species show very high catalytic activity under mild reaction conditions. An enantiopure version of the catalyst system produces pyrrolidines with excellent enantioselectivities.

The emergence of sulfoxides as efficient ligands in transition metal catalysis.

Sulfoxides are capable of forming stable complexes with transition metals and there have been many comprehensive studies into their binding properties. However, the use of sulfoxides, particularly chiral sulfoxides, as ligands in transition metal catalysis is rather less well developed. This review aims to describe these catalytic studies and covers new developments that are showing very promising results and that have led to a renewed interest in this field.