Design, Synthesis, and Application of an Optimized Monofluorinated Aliphatic Label for Peptide Studies by Solid‐State ¹⁹F NMR Spectroscopy

Abstract

A conformationally restricted monofluorinated α‐amino acid, (3‐fluorobicyclo[1.1.1]pentyl)glycine (F‐Bpg), was designed as a label for the structural analysis of membrane‐bound peptides by solid‐state 19F NMR spectroscopy. The compound was synthesized and validated as a 19F label for replacing natural aliphatic α‐amino acids. Calculations suggested that F‐Bpg is similar to Leu/Ile in terms of size and lipophilicity. The 19F NMR label was incorporated into the membrane‐active antimicrobial peptide PGLa and provided information on the structure of the peptide in a lipid bilayer.

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

“…To investigate its use as a synthetic probe, the 19 F‐labeled amino acid 3‐(trifluoromethyl)BCPglycine 327 a (CF 3 ‐Bpg=3‐(trifluoromethyl)bicyclopent‐[1.1.1]‐1‐yl‐glycine) was synthesized (Figure ) . The presence of the nonconjugating BCP linker reduced electronic transmission across the amino acid as compared to an aromatic ring, leading to less racemization .…”

Bicyclo[1.1.1]pentane‐Derived Building Blocks for Click Chemistry

“…For the synthesis of alkynes 3 , we envisaged the use of the Ohira–Bestmann reagent ( 9 ), which is known to convert aldehydes into terminal acetylenes . Both primary amines 10 and aldehydes 11 could be obtained from the bicyclo[1.1.1]pentane‐derived carboxylic acids 12 , which are known and accessible compounds for most of the substituents R 1 planned in this study …”

Enantioselective synthesis of chiral BCPs

“…The synthesis of chiral BCP α-amino acids was further pursued by the groups of Ulrich and Mykhailiuk. They reported the synthesis and application of a monofluorinated aliphatic amino acid (F-Bpg, 40) with the aim of using it in the determination of interatomic distances in membrane-active peptides by solidstate 19 F NMR spectroscopy. 19 Their synthetic sequence starts with diacid 33, 20 via the transformation of one of the carboxylic acid groups into a fluorine atom using Selectfluor and AgNO 3 .…”

“…They reported the synthesis and application of a monofluorinated aliphatic amino acid (F-Bpg, 40) with the aim of using it in the determination of interatomic distances in membrane-active peptides by solidstate 19 F NMR spectroscopy. 19 Their synthetic sequence starts with diacid 33, 20 via the transformation of one of the carboxylic acid groups into a fluorine atom using Selectfluor and AgNO 3 . 21 Carboxylic acid 34 is then converted into ester 35, and a subsequent reduction provides aldehyde 36 which is used in a Strecker reaction affording diastereomers 37 and 38.…”