Formation of Optically Active Aromaticα-Amino Acids by Catalytic Enantioselective Addition of Imines to Aromatic Compounds

Abstract

Optically active a-amino acids are vital to life as building blocks of peptides, proteins, and many other natural products. Amino acids are also applied extensively as food additives, pharmaceuticals, and agrochemicals. Furthermore, amino acids are widely used in organic synthesis as targets, and as constituents for reagents and/or catalysts in asymmetric synthesis.The synthesis of optically active nonproteinogenic a-amino acids is an interesting and important research field which has received much attention [1] and the application of asymmetric catalysis towards formation of these compounds from simple starting materials is a fundamental challenge.Recently, catalysts have been developed for enantioselective addition reactions to imines, including processes such as the ene [2] , Mannich-type, [3] allylation, [4] and aza-Diels ± Alder reactions. [5] Reports on the catalytic enantioselective addition of imines to aromatics are very few, and, according to our knowledge, only one example of the addition of an imine to indole and pyrrole systems has been reported. [6] Recently, several catalytic asymmetric Strecker reactions have emerged for the synthesis of optically active, natural, as well as unnatural, aromatic and aliphatic a-amino acids. [7] In this paper we present the development of a catalytic enantioselective addition reaction of imines 1 to electron-rich aromatic compounds 2 leading to protected optically active aromatic a-amino acids 3 [8] (Scheme 1). An advantage of this reaction is that 1 is prepared by an aza-Wittig reaction [9] and used directly without further purification (Scheme 1).

Katalysierte asymmetrische Arylierungen

“…Jørgensen et al verwendeten ein System aus Cu I und Tol‐BINAP für die asymmetrische Addition von elektronenreichen Arenen an α ‐Iminoester 133. Unter optimierten Reaktionsbedingungen (5 Mol‐% des Katalysators in THF bei −78 °C) gelang die Synthese von 159 a mit 96 % ee und in 75 % Ausbeute ausgehend von N , N ‐Dimethylanilin 157 und dem Imin 158 a [Gl.…”

Catalyzed Asymmetric Arylation Reactions

“…Jùrgensen and co-workers used the Cu I /Tol-BINAP catalyst system for the asymmetric addition of electron-rich aromatic compounds to a-imino esters. [133] Optimization of the reaction protocol (5 mol % of catalyst in THF at À 78 8C) allowed the synthesis of 159 a with 96 % ee and in 75 % yield from N,Ndimethylaniline (157) liberate the corresponding N-unprotected amino acid ester. The imine protecting group had a pronounced effect on the absolute configuration of the product: when (R)-Tol-BINAP was used as a ligand, N-alkoxy-and N-benzyloxycarbonylprotected imines of 158 gave the R enantiomer of the corresponding addition products 159, which is in contrast to more bulky N-protecting groups such as Boc or tosyl (Ts), which led to the formation of the S enantiomer of 159.…”

Optically Active Aromatic and Heteroaromatic α-Amino Acids by a One-Pot Catalytic Enantioselective Addition of Aromatic and Heteroaromatic C−H Bonds to α-Imino Esters

“…Recently, we reported the development of a catalytic enantioselective addition of electron-rich aromatic compounds to N -alkoxycarbonyl α-imino esters, The α-imino ester electrophiles were generated via an aza-Wittig reaction (eq 2, Scheme ) and reacted with the aromatic substrates catalyzed by a BINAP−Cu(I) complex without any purification (eq 3, Scheme ).

1

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“…The catalytic enantioselective addition of aromatic and heteroaromatic C−H bonds to α-imino esters, an aza-Friedel−Crafts reaction, is the direct approach to optically active aromatic and heteroaromatic α-amino acids. However, despite the great potential, only very few protocols for the catalytic asymmetric version of this reaction have been reported. , Recently, we communicated the catalytic formation of optically active aromatic α-amino acids by the addition of electron-rich aromatic compounds to α-imino esters using chiral Lewis acid catalysis . Two examples of catalytic enantioselective aza-Friedel−Crafts reactions using furan as the substrate are known from the literature; however, poor results in terms of both yield and enantiomeric excess were obtained .…”