Gram-scale asymmetric synthesis of fluorinated amino acids using a chiral nickel(II) complex

Abstract

Fluorinated amino acids play an important role in the field of peptide and protein engineering. Although several different syntheses have been published in recent decades, obtaining fluorinated amino acids on a gram-scale still poses a challenge. Furthermore, the described pathways to obtain fluorinated amino acids are based on different synthetic strategies, making a uniform approach from similar starting materials highly interesting. Chiral Ni(II) complexes were introduced as powerful tools in the synthesis of non-canonical amino acids. In this work, we present a strategy for the synthesis of a diverse range of fluorinated amino acids from the corresponding Ni(II) complex on a gram-scale from which the products can be obtained in enantiopure form (>94%ee). In addition, we describe syntheses for alkyl iodide building blocks which are required for the alkylation reactions with the corresponding Ni(II) complex. Finally, we characterized the synthesized fluorinated amino acids with regard to their hydrophobicity and α-helix propensity.

Rational design of amphiphilic fluorinated peptides: evaluation of self-assembly properties and hydrogel formation

“…[36][37][38][39] In current attempts, we have extended this strategy to the synthesis of a diverse range of aliphatic fluorinated amino acids with different side chain patterns. 40 In this work, we designed an amphipathic motif including lysine and the well-studied non-proteogenic amino acid α-aminobutyric acid (Abu), which has been reported as a suitable hydrophobic building block for SAPs. 41,42 The varying degree of fluorination was adjusted by the iterative incorporation of its derivatives (2S)-4-monofluoroethylglycine (MfeGly), (2S)-4,4-difluoroethylglycine (DfeGly) and (2S)-4,4,4-trifluoroethylglycine (TfeGly).…”

“…36–39 In current attempts, we have extended this strategy to the synthesis of a diverse range of aliphatic fluorinated amino acids with different side chain patterns. 40…”

Fluorine-induced polarity increases inhibitory activity of BPTI towards chymotrypsin

“…Fluorinated amino acids were synthesized according to literature. 20,49 Peptide synthesis All proteins were synthesized by Fmoc based SPPS on a Liberty Blue automated microwave-assisted peptide synthesizer (CEM Corporation, Matthews, NC, USA) in a 0.1 mmol scale on a Cl-MPA ProTide LL resin (0.22 mmol g À1 resin substitution). Resin loading was carried out according to standard protocol with 1.0 M DIEA and 0.125 M KI in DMF.…”

Gram-Scale Asymmetric Synthesis of Fluorinated Amino Acids Using a Chiral Nickel(II) Complex

“…The described Ni­(II) complex 1 was recently used in the asymmetric gram-scale preparation of trifluoroethylglycine (TfeGly) (Scheme ). These results indicated the great potential of the Ni­(II) complex 1 in the synthesis of fluorinated amino acids. , In this work, we report on the development of a general procedure that enables access to a broad range of differently fluorinated amino acids based on the Ni­(II) complex 1 .…”