Recent approaches towards the asymmetric synthesis of α,α-disubstituted α-amino acids

Abstract

The class of alpha,alpha-disubstituted alpha-amino acids has gained considerable attention in the past decades and continues doing so. The ongoing interest in biological and chemical properties of the substance class has inspired the development of many new methodologies for their asymmetric construction, which have not found their way into the general focus of organic chemistry yet. The aim of this review is to provide an overview of the developments in the field since 1998.

Organocatalytic asymmetric approach to spirocyclic tetrahydrothiophenes containing either a butenolide or an azlactone structural motif

“…[10][11][12][13][14][15][16][17][18][19][20][21][22][23] For instance, the tetrahydrothiophene structural motif is present in various natural products and pharmacologically active molecules (Figure 1, top). [10][11][12] 2(3H)-Furanones, commonly known as Δ β,γ -butenolides, are another group of biologically relevant molecules that has been successfully applied in the target-oriented organic synthesis (Figure 1, middle).…”

“…Owing to their interesting biological properties, α,α-disubstituted amino acids occupy a prominent position among biologically relevant compounds (Figure 1, bottom). [19][20][21][22][23][24] Notably, the azlactone moiety serves as a synthetic precursor of α,α-disubstituted amino acid and the azlactone ring opening can be accomplished under acidic conditions. [25][26][27][28][29][30][31] Given the importance of tetrahydrothiophene, butenolide and azlactone scaffolds, the development of methods for their introduction into target molecules, in particular in a stereocontrolled manner, constitutes an important goal in modern synthetic organic chemistry.…”

Stereoselective synthesis towards unnatural proline based amino acids

“…Moreover, non-proteinogenic unnatural amino acids have increasingly become valuable target molecules for drug discovery with expanding synthetic strategies over the last decade. [3][4][5][6][7][8][9] These essential unnatural amino acids includes β-amino acids (β 3 and β 2 ), homo-amino acids, proline and pyruvic acid derivatives Unnatural proline based amino acids are used as important building blocks for pharmaceuticals, biologically active compounds and more recently as organocatalysts. 10,11 Proline is the only amino acid to exhibit helix-inducing properties (as a result of tertiary amide bond formation) when incorporated into a peptide thereby influencing its ligand binding and overall protein activity.…”

“…This helix property promotes the restriction of conformational freedom amongst the amino acid side chains within the peptide structure which allows for resistance towards chemical and enzymatic degradation, increased hydrophobicity and metabolic stability. 2,4 β-Amino acids are another class of compounds that are equally important precursors leading to more complex products with biological and pharmacological activities. 13,14 Moreover β-amino acids are precursors of β-lactams, the most important class of antibiotics.…”

Catalytic Asymmetric Synthesis of Cα-tetrasubstituted α-Amino Acids

“…Therefore, in recent years, the need for efficient and diverse synthesis of optically active compounds with privileged scaffolds stimulated the catalytic asymmetric synthesis of 3,3-disubstituted oxindoles [2], trifluoromethylated compounds [3] and difluoroalkylated compounds [4]. C α -tetrasubstituted α-amino acids represent a type of privileged structural motifs widely occurred in drugs and pharmaceutically active compounds [5]. Some quaternary α-amino acids are drugs.…”