Iridium(I) complexes with bidentate NHC ligands as catalysts for dehydrogenative directed C-H silylation.

A series of (NHC)(cod)Ir(I) complexes bearing NHC-carboxylate ligands were efficiently synthesized and fully characterized. Their solid-state structures confirmed the bidentate coordination mode of these LX-type NHC ligands. These unprecedented iridium(I) complexes demonstrated efficient catalytic activities in dehydrogenative directed C-H silylation of arenes, and allowed for excellent ortho-selectivity control with aromatic silylating agents.

Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase.

Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ΔΔGb values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme.

Rhodium-NHC-Catalyzed gem-Specific O-Selective Hydropyridonation of Terminal Alkynes.

The dinuclear complex [Rh(µ-Cl)(η2 -coe)(IPr)]2 is an efficient catalyst for the O-selective Markovnikov-type addition of 2-pyridones to terminal alkynes. DFT calculations support a hydride-free pathway entailing intramolecular oxidative protonation of a π-alkyne by a κ1 N-hydroxypyridine ligand. Subsequent O-nucleophilic attack on a metallacyclopropene species affords an O-alkenyl-2-oxypyridine chelate rhodium intermediate as the catalyst resting state. The release of the alkenyl ether is calculated as the rate-determining step.

Rhodium(I)-NHC Complexes Bearing Bidentate Bis-Heteroatomic Acidato Ligands as gem-Selective Catalysts for Alkyne Dimerization.

A series of Rh(κ2 -BHetA)(η2 -coe)(IPr) complexes bearing 1,3-bis-hetereoatomic acidato ligands (BHetA) including carboxylato (O,O), thioacetato (O,S), amidato (O,N), thioamidato (N,S), and amidinato (N,N), have been prepared by reaction of the dinuclear precursor [Rh(µ-Cl)(IPr)(η2 -coe)]2 with the corresponding anionic BHetA species. The RhI -NHC-BHetA compounds catalyze the dimerization of aryl alkynes, showing excellent selectivity for the head-to-tail enynes. Among them, the acetanilidato-based catalyst has shown an outstanding catalytic performance reaching unprecedented TOF levels of 2500 h-1 with complete selectivity for the gem-isomer. Investigation of the reaction mechanism supports a non-oxidative pathway in which the BHetA ligand behaves as proton shuttle through intermediate κ1 -HBHetA species. However, in the presence of pyridine as additive, the identification of the common RhIII H(C≡CPh)2 (IPr)(py)2 intermediate gives support for an alternative oxidative route.