Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines.

Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps. We identified a facile synthetic protocol via a highly enantioselective one-step process for epinephrine and a two-step process for norepinephrine starting from unprotected α-ketoamines 1b and 1a, respectively. This newly developed enantioselective ruthenium-catalyzed asymmetric transfer hydrogenation was extended to the synthesis of many 1,2-amino alcohol-containing drug molecules such as phenylephrine, denopamine, norbudrine, and levisoprenaline, with enantioselectivities of >99% ee and high isolated yields.

Design and Discovery of Water-Soluble Benzooxaphosphole-Based Ligands for Hindered Suzuki-Miyaura Coupling Reactions with Low Catalyst Load.

We report a new class of highly effective, benzooxaphosphole-based, water-soluble ligands in the application of Suzuki-Miyaura cross-coupling reactions for sterically hindered substrates in aqueous media. The catalytic activities of the coupling reactions were greatly enhanced by the addition of catalytic amounts of organic phase transfer reagents, such as tetraglyme and tetrabutylammonium bromide. The optimized general protocol can be conducted with a low catalyst load, thereby providing a practical solution for these reactions. The viability of this new Suzuki-Miyaura protocol was demonstrated with various substrates to generate important building blocks, including heterocycles, for the synthesis of biologically active compounds.