Tailor‐Made α‐Amino Acids in the Pharmaceutical Industry: Synthetic Approaches to (1R,2S)‐1‐Amino‐2‐vinylcyclopropane‐1‐carboxylic Acid (Vinyl‐ACCA)

Abstract

(1R,2S)-1-Amino-2-vinylcyclopropane-1-carboxylic acid (vinyl-ACCA) is the essential pharmacophoric unit in a new generation of highly potent hepatitis C virus (HCV) NS3/4A protease inhibitors. Currently, there are over a dozen drugs under development that use the special properties of this highly sterically constrained tailor-made amino acid, underscoring the extremely high demand for the asymmetric synthesis of (1R,2S)-

Convenient Asymmetric Synthesis of Fmoc-(S)-6,6,6-Trifluoro-Norleucine

“…Medicinal applications of new organic compounds have always been a major driving force behind the development of organic methodology. In this regard, one can notice two general trends in the design of modern pharmaceutical drugs: the introduction of fluorine-containing substituents and tailor-made amino acids (AAs) [1][2][3][4][5][6][7][8][9][10]. While the strategic fluorination usually leads to improved pharmacokinetics and greater oxidative metabolic stability [9,11,12], the presence of tailor-made amino AAs residues allows for more precise mimicking of the natural peptide-receptor interactions [1][2][3][4][5][6][7][8].…”

“…In this regard, one can notice two general trends in the design of modern pharmaceutical drugs: the introduction of fluorine-containing substituents and tailor-made amino acids (AAs) [1][2][3][4][5][6][7][8][9][10]. While the strategic fluorination usually leads to improved pharmacokinetics and greater oxidative metabolic stability [9,11,12], the presence of tailor-made amino AAs residues allows for more precise mimicking of the natural peptide-receptor interactions [1][2][3][4][5][6][7][8]. Subsequently, fluorine-containing α- [13][14][15][16][17][18][19][20][21] and β-AAs [22][23][24], featuring both structural traits, are currently an increasingly important class of compounds used in bio-medicinal studies and drug design [25][26][27][28].…”

Preparative Method for Asymmetric Synthesis of (S)-2-Amino-4,4,4-trifluorobutanoic Acid

“…Our interest in the structural types of tailor-made AAs includes phosphonic analogs [84][85][86], sterically constrained [87,88] and fluorine-containing AAs [89][90][91], all of which are of increasing importance in modern drug design [2][3][4][5][6][7][8]. Moreover, we carefully study nonlinear chiroptical phenomena, such as self-disproportionation of enantiomers [92][93][94] and its manifestation in the properties of AAs [95,96] and chiral marketed pharmaceuticals [97,98].…”

“…The modern paradigm in drug discovery is based on two major traits. The first includes mimicking the three-dimensional structure of the targeted protein receptor by incorporation of tailor-made amino acids (AAs) [1][2][3][4][5][6][7][8]. The second is to increase the metabolic stability of a drug molecule by the strategic fluorine for hydrogen substitution [9][10][11][12][13].…”

Synthesis of Sulfonimidamide‐Based Amino Acid Building Blocks with Orthogonal Protecting Groups

“…Development of new amide bond isosteres, unnatural amino acids, or secondary structure mimetics for incorporation into pseudopeptides or peptidomimetics is an important research area in peptide drug discovery. These developments aim to modulate physiochemical properties of peptides while keeping/enhancing their biological activity as well as selectivity against biological targets.…”