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 F NMR spectroscopy. The compound was synthesized and validated as a F 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 F 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 as ynthetic 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 70). [412] The presence of the nonconjugating BCP linker reduced electronic transmission across the amino acid as compared to an aromatic ring, leading to less racemization. [89] Furthermore, the loss of HF is avoideda si nt he CF 3 -Ala derivative 327 b,a si st he low reactivity of the aminocarboxylate moiety 327 c as ar esult of steric hindrance, under solid-phase peptides ynthesis conditions (SPPS).…”

A General Amino Acid Synthesis Enabled by Innate Radical Cross‐Coupling

“…Beyond esoteric interest, AAs containing phenyl bioisosteres are well known to modulate pharmacokinetic properties. [16] Existing synthetic strategies to access bicyclo[2.2.2]octane, [17] cubane, [18] and [1.1.1]propellane [19] AAs require multiple functional group interconversions followed by an asymmetric Strecker reaction that typically proceeds with moderate diastereoselectivity. [2] In contrast, the current protocol provides these valuable compounds ( 14 , 15 , and 21 ) in one step with excellent stereochemical control.…”

“…Additionally, functional groups including esters ( 14 , 15 , 21 , 27 , 45 and 48 ), carbamates ( 11 , 13 , 17 , 25 , 28 , 30 – 35 , 37 , 43 and 49 ), ketones ( 26 , 41 and 46 ), ethers ( 16 , 19 , 23 , 30 , 31 and 40 ), acetonides ( 48 and 51 ), enones ( 50 and 53 ), olefins ( 44 and 52 ), and chlorides ( 16 and 47 ) remained intact under the mild reaction conditions. Though not the first reported synthesis in many cases ( 10 , 12 , 21 , 23 – 25 , 36 , 48 and 49 ), [19] this method marks a significant improvement, as previous routes relied on laborious sequences (3–7 steps) that resulted in poor stereo-control.…”

Synthesis of complex unnatural fluorine-containing amino acids

“…Stereoselective access to cyclobutane and cyclobutane derived amino acids has been pursued by several groups [ [129] , [130] , [131] ]. One example was reported by Haufe and co-workers who disclosed the synthesis of cis‐and trans‐1‐amino‐3‐fluoro‐3‐methylcyclobutanecarboxylic acids in 2016 ( Scheme 36 ) [ 132 ].…”