Synthesis and determination of absolute configuration of a non-peptidic αvß6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis.

A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).

C-H activation/functionalization catalyzed by simple, well-defined low-valent cobalt complexes.

A facile C-H activation and functionalization of aromatic imines is presented using low-valent cobalt catalysts. Using Co(PMe3)4 as catalyst we have developed an efficient and simple protocol for the C-H/hydroarylation of alkynes with an anti selectivity. Deuterium-labeling experiments, DFT calculations coupled with the use of a well-defined catalyst have for the first time shed light on the elusive black box of cobalt catalyzed C-H functionalization.

Discovery of ( S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvß6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis.

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αvß1, αvß3, αvß5, αvß6, and αvß8 integrins. Numerous analogs with high affinity and selectivity for the αvß6 integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αvß6 integrin in a radioligand binding assay (p Ki = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.

C2-Alkylation and Alkenylation of Indoles Catalyzed by a Low-Valent Cobalt Complex in the Absence of Reductant.

Herein an extremely versatile, well-defined, low-valent cobalt catalyst [Co(PMe3)4] capable of intermolecular and intramolecular imine-directed C2-alkylation and alkenylation of indoles is reported. The reaction proceeds in the absence of reducing agents or additives, affording a range of substituted indoles and dihydropyrroloindoles in high yields and regioselectivities. With the aid of deuterium labeling studies and DFT (Density Functional Theory) calculations, a mechanism is proposed that is based on a Ligand-to-Ligand Hydrogen Transfer pathway.

Regio- and Stereoselective Hydrosilylation of Unsymmetrical Alkynes Catalyzed by a Well-Defined, Low-Valent Cobalt Catalyst.

Herein, the use of a well-defined low-valent cobalt(I) catalyst [HCo(PMe3)4] capable of performing the highly regio- and stereoselective hydrosilylation of internal alkynes is reported. The reaction can be applied to a variety of hydrosilanes, symmetrical and unsymmetrical alkynes, giving in many cases a single hydrosilylation isomer. Experimental and theoretical studies suggest the key step to be a hydro-cobaltation and that the reaction proceeds through a classical Chalk-Harrod mechanism.