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

Abstract

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 a-arylated amino esters and dipeptide mimetics (27 examples, up to 99 %y ield) from readily available amines, ethyl glyoxylate and electron-rich arenes under mild conditions, in which one CÀCb ond, one CÀNb ond ando ne chiral center were established simultaneously. Ther eaction was also performedo nagram scale, giving compound 4a in 96 %y ield. In addition,t his protocol was successfully applied to the late-stage elaboration of drugm olecules, such as tranylcypromine (TCP or PCPA) andt roxipide.I nterestingly,c ompound 4h inactivated histone lysine specific demethylase 1( LSD1) potently with an IC 50 value of 0.296 mm.T ot he best of our knowledge,c ompound 4h is the first LSD1 inhibitor derived from nonnatural a-arylated amino esters, and therefore could be used as ah it compound for the development of new LSD1 inhibitors. The synthesized nonnatural a-arylated amino esters and dipeptidem imeticsa su nique building blocks may have potential synthetic utilities.

HFIP in Organic Synthesis

“…An HFIP-promoted three-component reaction between amines, ethyl glyoxylate, and electron-rich arenes was reported for the construction of α-arylated amino esters and dipeptide mimetics (Scheme ). The electron-rich arenes react with imine intermediates generated from the condensation of the amines and ethyl glyoxylate. The reaction in THF, dioxane, toluene, DCM, CHCl 3 , MeOH, and i -PrOH led to no product formation and TFE was much less efficient than HFIP.…”

TfOH-Catalyzed N–H Insertion of α-Substituted-α-Diazoesters with Anilines Provides Access to Unnatural α-Amino Esters

“…To date, various methods have been developed to access unnatural α-amino derivatives (Scheme ). The selected existing approaches toward such privilege structures involve: (i) N -alkylation of anilines with α-bromophenylesters; (ii) transfer hydrogenation of imino esters with Hantzsch dihydropyridine by Co-phosphoric acid or Bro̷nsted acid and carboxyl-tailed benzothiazoline using a trifluoroacetic acid (TFA) catalyst; (iii) amination of aryl azides with methyl phenylacetates by Ru­(TPP)­CO or Ru­(TPP)­(py) 2 ; (iv) oxidative dehydrogenative cross-coupling of N -arylglycine esters with phenols by transition-metal catalysts (Cu, Rh, or Ru), N -substituted anilines under CuCl, and α-alkylation of N -arylglycine esters with diacyl peroxides, respectively; (v) reductive coupling of alkyl and arylglyoxylate esters with anilines using Cu/BINAP or HFIP as a catalyst; (vi) N–H insertion of sulfoxonium ylides with anilines in the presence of a catalytic amount of [Ir­(COD)­Cl] 2 or AuCl­(SMe 2 ); (vii) phosphoric acid-catalyzed C–N bond formation of sulfonium ylide esters with p -methoxyphenyl; (viii) urea-catalyzed N–H insertion–arylation of α-nitrodiazoesters with anilines; and (ix) N–H insertion of α-aryl-α-diazoacetates with anilines by transition-metal catalysts (Cu, Rh, Ru, Pd, Ir, or Fe). Despite notable progress in this area, however, among all of these methods, the use of air-sensitive metal reagents or transition-metal catalysts, harsh reaction conditions, and functional group incompatibility all have limitations; consequently, the development of a general methodology for the synthesis of unnatural α-amino esters without the use of metal reagents or transition-metal catalysts using diazo chemistry under mild reaction conditions presents a fundamental and practical challenge yet not resolved.…”