Enantioselective Synthesis of β‑Aryloxycarboxylic Esters via Asymmetric Hydrogenation of β‑Aryloxy-α,β-Unsaturated Esters

A novel synthesis of β-aryloxycarboxylic esters via asymmetric hydrogenation of the corresponding β-aryloxy-α,β-unsaturated esters has been demonstrated. Bis(norbornadiene)rhodium(I) tetrafluoroborate (1 mol %) and Walphos W008-1 were used to generate the saturated products with high enantioselectivity and in high yield. The tolerability of the reaction to a diverse range of substituents on the aromatic ring was also explored

Catalytic, Asymmetric, and Stereodivergent Synthesis of Non-Symmetric β,β-Diaryl-α-Amino Acids

We report a concise, enantio- and diastereoselective route to novel nonsymmetrically substituted <i>N</i>-protected β,β-diaryl-α-amino acids and esters, through the asymmetric hydrogenation of tetrasubstituted olefins, some of the most challenging examples in the field. Stereoselective generation of an <i>E-</i> or <i>Z-</i>enol tosylate, when combined with stereoretentive Suzuki-Miyaura cross-coupling and enantioselective hydrogenation catalyzed by (NBD)₂RhBF₄ and a Josiphos ligand, allows for full control over the two vicinal stereogenic centers. High yields and excellent enantioselectivities (up to 99% ee) were obtained for a variety of <i>N</i>-acetyl, <i>N-</i>methoxycarbonyl, and <i>N</i>-Boc β,β-diaryldehydroamino acids, containing a diverse and previously unreported series of heterocyclic and aryl substituted groups (24 examples) and allowing access to all four stereoisomers of these valuable building blocks

Synthesis of Bis-Macrocyclic HCV Protease Inhibitor MK-6325 via Intramolecular <i>sp</i>²–<i>sp</i>³ Suzuki–Miyaura Coupling and Ring Closing Metathesis

A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (<b>1</b>) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular <i>sp</i>²–<i>sp</i>³ Suzuki–Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (<b>1</b>) has been achieved

Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an <i>anti</i>-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales

Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an <i>anti</i>-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales