Synthesis of protected enantiopure (R) and (S)-α-trifluoromethylalanine containing dipeptide building blocks ready to use for solid phase peptide synthesis

Abstract

Considering the increasing importance of fluorinated peptides, the development of efficient and reliable synthetic methods for the incorporation of unnatural fluorinated amino acids into peptides is a current matter of interest. In this study, we report the convenient Boc/benzyl and Cbz/tert-butyl protection of both enantiomers of the quaternarized amino acid α-trifluoromethylalanine [(R)- and (S)-α-Tfm-Ala]. Because of the deactivation of the nitrogen atom of this synthetic amino acid by the strong electron withdrawing trifluoromethyl group, the peptide coupling on this position is a challenge. In order to provide a robust synthetic methodology for the incorporation of enantiopure (R)- and (S)-α-trifluoromethylalanines into peptides, we report herein the preparation of dipeptides ready to use for solid phase peptide synthesis. The difficult peptide coupling on the nitrogen atom of the α-trifluoromethylalanines was performed in solution phase by means of highly electrophilic amino acid chlorides or mixed anhydrides. The synthetic effectiveness of this fluorinated dipeptide building block strategy is illustrated by the solid phase peptide synthesis (SPPS) of the Ac-Ala-Phe-(R)-α-Tfm-Ala-Ala-NH2 tetrapeptide.

Orthogonal 19F‐Labeling for Solid‐State NMR Spectroscopy Reveals the Conformation and Orientation of Short Peptaibols in Membranes

“…For the last ones, enantiomericallyp ure CF 3 -Ala was prepared and linked to thep receding amino acid (Leu/Ile) to yield dipeptide buildingb locks suitable for automated fluorenylmethyloxycarbonyl( Fmoc)s ynthesis, by following specific protocols (see the Supporting Information). In addition, four selectively 15 N-labeled HZ peptides werep repared with either 15 N-Leu or 15 N-Ile in one of the positions 3, 4, 7, and 8.…”

“…Herein, we have combined four orthogonal NMR probes: (R)-and (S)-trifluoromethylalanine ((R)-CF 3 -Ala, (S)-CF 3 -Ala) [8,11] are used to replacee ach Aib side chain one-by-one,w hereas 3-(trifluoromethyl)bicyclopent[1.1.1]-1-yl-glycine (CF 3 -Bpg) [12] in combination with 15 N-amide [13] in as uitable backbone position are used to replace single leucine or isoleucine residues (Figure 1A). This set of labels fulfils all criteria outlined above:1 )it providesachemical varietyt hat allows conservative substitutions of many sites, including Aib;2 )the orthogonal labels (S)-CF 3 -Ala, (R)-CF 3 -Ala, CF 3 -Bpg, and amide- 15 Ns ample four distinctly different director axes ( Figure 1B); and 3) they are rigidly connected to thep eptide backbone.R egarding 4), routine and efficient SPPS has been demonstrated forCF 3 -Bpg incorporation. [12] However,p eptidec oupling reactions were difficult in the case of a-disubstituted CF 3 -Ala isomersd ue to the low nucleophilicity of the nitrogen atom.…”

“…[12] However,p eptidec oupling reactions were difficult in the case of a-disubstituted CF 3 -Ala isomersd ue to the low nucleophilicity of the nitrogen atom. [8,11,14] This problem has been bypassed by preparing enantiomerically pure dipeptide building blocks in solution, in which Leu or Ile is coupled to CF 3 -Ala. [15] The dipeptides, including 19 F-labeled Aib analogues, could then be successfully introduced into peptaibols by means of microwave-assisted SPPS.…”

Trifluoromethylated Proline Surrogates as Part of “Pro–Pro” Turn‐Inducing Templates

“…The N‐terminal coupling to α‐trifluoromethylated amino acids is a challenging exercise because the CF 3 group strongly deactivates the nucleophilicity of the amino group, which prevents easy couplings and the general use of automated SPPS. However, activation by acyl chloride or mixed anhydride formation proved to be highly efficient . Access to the tripeptides Fmoc‐( R )‐Pro–( R / S )‐TfmOxa–( S )‐Val‐OH ( 21 a , b ) was hence developed in solution by means of a four‐step synthesis (Scheme A).…”

Trifluoromethylated proline surrogates as part of ‘Pro-Pro’ turn-inducingtemplates for the design of b -hairpin mimetics

“…However,a ctivation by acyl chloride or mixed anhydride formation provedt ob ehighly efficient. [27] Access to the tripeptides Fmoc-(R)-Pro-(R/S)-TfmOxa-(S)-Val-OH (21 a,b)w as hence developedi ns olution by means of af our-step synthesis (Scheme1A). Prepared as ar acemic mixture, [25] and after saponification of 17,H -TfmOxa-OH( 2)w as coupled to readily available Fmoc-(R)-Pro-Cl 18.A fter hydrolysis, unreacted Fmoc-(R)-Pro-OH was esterified directly in situ, whereas 2a,b remained untouched due to the low reactivity of their carboxylic acid functionality.I nt he absence of such aw orkup,r emaining Fmoc-(R)-Pro-OH systematicallyc oeluted with dipeptides 19, which reduced the yield drastically,w hile increasing the amount of deletionp eptideins ubsequent steps.…”