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HFIP‐Promoted de Novo Synthesis of Biologically Relevant Nonnatural α‐Arylated Amino Esters and Dipeptide Mimetics
Author(s) -
Li Zhonghua,
Yu Bin
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201904395
Subject(s) - dipeptide , chemistry , amino acid , enantiopure drug , yield (engineering) , stereochemistry , amino esters , tranylcypromine , combinatorial chemistry , organic synthesis , organic chemistry , biochemistry , enantioselective synthesis , catalysis , enzyme , materials science , monoamine oxidase , metallurgy
Amino acids are fundamental building blocks, which have been extensively used in drug design and organic synthesis. However, nonnatural amino acids are relatively less studied. In this work, the authors report the first HFIP‐promoted de novo synthesis of nonnatural 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 center were established simultaneously. The reaction was also performed on a gram scale, giving compound 4 a in 96 % yield. In addition, this protocol was successfully applied to the late‐stage elaboration of drug molecules, such as tranylcypromine (TCP or PCPA) and troxipide. Interestingly, compound 4 h inactivated histone lysine specific demethylase 1 (LSD1) potently with an IC 50 value of 0.296 μ m . To the best of our knowledge, compound 4 h is the first LSD1 inhibitor derived from nonnatural α‐arylated amino esters, and therefore could be used as a hit compound for the development of new LSD1 inhibitors. The synthesized nonnatural α‐arylated amino esters and dipeptide mimetics as unique building blocks may have potential synthetic utilities.