Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines
Hari P. R. Mangunuru, Leila Terrab, Venumadhav Janganati, Nageswara Rao Kalikinidi, Srinivasarao Tenneti, N. Vasudevan, Shada Arun Dixith Reddy, Santhosh Reddy Naini, Praveen Gajula, Daniel Lee, Lalith P. Samankumara, Manasa Mamunooru, Aravindan Jayaraman, Rajkumar Lalji Sahani, Jinya Yin, Chathuranga C. Hewa‐Rahinduwage, Aravind S. Gangu, Anji Chen, Zhirui Wang, Bimbisar Desai, Tai Y. Yue, Chaitanya S. Wannere, Joseph D. Armstrong, Kai Donsbach, Gopal Sirasani, B. Frank Gupton, Bo Qu, Chris H. Senanayake
Abstract
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.