Recent Approaches Towards the Asymmetric Synthesis of α,α‐Disubstituted α‐Amino Acids

Abstract

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Expanding the threonine aldolase toolbox for the asymmetric synthesis of tertiary α-amino acids

“…With that discovery, the application of TAs was expanded toward the asymmetric synthesis of β-hydroxy-α-alkyl-α-amino acids containing a quaternary stereogenic center. Types of these non-natural tertiary amino acids play a special role in the design of short-chain peptides with limited flexibility and as structural units in a number of biologically active molecules (Vogt and Bräse 2007;Zhang et al 2013). Their direct synthesis by threonine aldolase-catalyzed reactions has become a promising alternative to existing chemical methods due to their sustainability and the high stereospecificity of the biocatalytic route.…”

Axially chiral Ni(II) complexes of α‐amino acids: Separation of enantiomers and kinetics of racemization

“…[2][3][4][5][6] Subsequently, the development of advanced asymmetric methodologies for scalable synthesis of structurally diverse AAs is currently in high demand. [7][8][9][10][11][12][13][14][15][16][17][18] For quite some time, our groups were interested in pursuing new synthetic approaches for preparation of sterically constrained, 19,20 phosphorus, 21,22 and fluorine-containing [23][24][25] AAs. One of the most methodologically prolific directions, inspired by the seminal work by Belokon, 26,27 has been the chemistry of Ni(II) complexes of AAs derived Schiff bases (Scheme 1).…”

Asymmetric Allylation of α‐Ketoester‐Derived N‐Benzoylhydrazones Promoted by Chiral Sulfoxides/N‐Oxides Lewis Bases: Highly Enantioselective Synthesis of Quaternary α‐Substituted α‐Allyl‐α‐Amino Acids

“…If successful, this protocol will create a new quaternary center in the product, which can be derivatized to biologically active a-allyl a-amino acids (Scheme 3). [94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109] Herein, we describe the allylation of N-benzoyl hydrazones derived from a-keto esters employing sulfoxide/N-oxides (R)-1 and (R,R)-2 as chiral organocatalysts, according to the reaction conditions recommended by Kobayashi et al 38 Subsequent chemical manipulation of the enantioenriched hydrazine products allowed for the enantioselective synthesis of 6a-b, two a-allyl a-amino acids derived of L-phenylglycine.…”

“…On the other hand, the stereoselective formation of chiral quaternary centers remains a challenging subject in asymmetric synthesis; thus, we deemed it of interest to examine the applicability of chiral bis‐sulfoxide/ N ‐oxide ( R , R )‐ 2 in the enantioselective allylation of hydrazones derived from α‐keto esters. If successful, this protocol will create a new quaternary center in the product, which can be derivatized to biologically active α‐allyl α‐amino acids (Scheme ) …”