Recent Advances in Catalytic Enantioselective Synthesis of Fluorinated α‐ and β‐Amino Acids

Abstract

Enantioenriched fluorinated α-and βamino acids are often encountered in numerous pharmaceuticals and bioactive molecules, and also of great importance as probes in PET and NMR for studying the behavior of enzymes and for incorporation into peptides and drug candidates. Among various synthetic strategies developed, catalytic enantioselective synthesis proves to be one of the most facile and powerful protocols to construct such privileged structures. The past decade has witnessed considerable progress in the catalytic enantioselective construction of chiral fluorinated α-and β-amino acid derivatives with structural diversity. In this review, we summarize these impressive achievements according to the bond-forming way of fluorinated α-or βamino acids, respectively, and underline the remaining challenges. This information would provide important guidance and some inspiration for the researchers engaged in organic fluorine and medicinal chemistry. nated α-Amino Acids 2.1. α-Fluoro-α-Amino Acids 2.2. α-Fluoroalkyl-α-Amino Acids 3. Catalytic Enantioselective Synthesis of Fluorinated β-Amino Acids 3.1. Electrophilic Fluorination Reactions 3.2. Mannich-Type Reactions with α-Fluorinated (Thio)Esters, Amides or Nitriles 3.3. Catalytic Asymmetric Reactions with Fluorinated Alkenes or Imines 4. Conclusion and Outlook

Enzymatic synthesis of fluorinated compounds

“…In this reaction, 100 mM fluorinated racemic amines were converted to corresponding R -isomers and S -isomers through kinetic resolution (Conversions = 50%; ee S = 90–96%; ee R = 99%). Similar to kinetic resolution, lipases can also catalyze enantioselective hydrolysis reactions to obtain β-fluorinated amino acids, which are key components of many natural products, drugs, and biologically active peptides (Shahmohammadi et al 2020 ; Zhang et al 2020b ). In the presence of i Pr 2 O, Et 3 N, and H 2 O, 25 mM racemic fluorinated β-amino carboxylic ester hydrochloride salts were hydrolyzed into fluorinated R -β-amino carboxylic ester enantiomers (Yields = 38–49%, ee = 94- > 99%) and fluorinated S -β-amino acids (Yields = 48–49%, ee > 99%) (Fig.…”

Efficient Synthesis of New Fluorinated β-Amino Acid Enantiomers through Lipase-Catalyzed Hydrolysis

“…The method was successfully used for the synthesis of ( S )-3-amino-3-phenylpropionic acid, which is a key precursor for the preparation of ( S )-dapoxetine, and a potent selective serotonin reuptake inhibitor (SSRI) used for the treatment of depression, bulimia, or anxiety [ 29 ]. In addition, very recently, Zhang et al summarized a review of the most facile catalytic enantioselective strategies to construct the fluorinated α-amino and β-amino acids [ 30 ].…”

Asymmetric Synthesis of Perfluoroalkylated α‐Amino Acids through Generated Radicals Using a Chiral Ni(II) Complex

“…To date, there exist a plethora of methods for the synthesis of FAAs, [19–23] however, the approaches for obtaining of PFAAs are still rare, especially in an enantioselective manner [24,25] . As a consequence, only several selective examples of asymmetric synthesis of PFAAs have been reported to date [26–33] .…”

“…[15,16] Moreover, the perfluoroalkylated AAs (PFAAs) are incorporated into peptides and proteins for their study and to modify and fine-tune their structures and physicochemical properties. [17,18] To date, there exist a plethora of methods for the synthesis of FAAs, [19][20][21][22][23] however, the approaches for obtaining of PFAAs are still rare, especially in an enantioselective manner. [24,25] As a consequence, only several selective examples of asymmetric synthesis of PFAAs have been reported to date.…”