HFIP‐Promoted de Novo Synthesis of Biologically Relevant Nonnatural α‐Arylated Amino Esters and Dipeptide Mimetics

Abstract

Amino acids are fundamental building blocks and have been extensively used in drug design and organic synthesis. However, unnatural amino acids are relatively less studied. Herein, we reported the first HFIP‐promoted de novo assembly of unnatural α‐arylated amino esters and dipeptide mimetics (27 examples, up to 99% yield) from readily available amines, ethyl glyoxylate and electron‐rich arenes under mild conditions, in which one C‐C bond, one C‐N bond and one chiral centre were established simultaneously. The reaction was also performed on a gram scale, giving compound 4a in 96% yield. Besides, this protocol was successfully applied to the late‐stage elaboration of drug molecules such as tranylcypromine (TCP or PCPA) and troxipide. Interestingly, compound 4h inactivated histone lysine specific demethylase 1 (LSD1) potently with an IC50 value of 0.296 μM. To the best of our knowledge, compound 4h is the first LSD1 inhibitor derived from unnatural α‐arylated amino esters, and therefore could be used as a hit compound for the development of new LSD1 inhibitors. The synthesized unnatural α‐arylated amino esters and dipeptide mimetics as unique building blocks may have potential synthetic utilities.