A novel dipeptidomimetic containing a cyclic threonine

Abstract

An efficient and simple two-step procedure for the formation of hydroxy-Freidinger lactams is presented. The methodology allows assembly of the cyclic threonine motif (cThr) in solution and on solid support during conventional peptide synthesis.

Probing Anti-inflammatory Properties Independent of NF-κB Through Conformational Constraint of Peptide-Based Interleukin-1 Receptor Biased Ligands

“…Such so-called Freidinger-Veber lactams (e.g., Agl and Hgl) restrict backbone conformation by limiting rotation about the ϕ - , ψ - , and ω-dihedral angles such that Agl and Hgl residues prefer to situate at the i +1 residue in β-turn sequences contingent on sequence stereochemistry (Freidinger, 2003; St-Cyr et al, 2017). Moreover, in the case of Hgl, the hydroxyl group side chain orientation is locked due to restriction of the χ-dihedral angle (Sicherl et al, 2010). Although Freidinger-Veber lactams have been used to study a wide range of biologically active peptides (Freidinger, 2003), to the best of our knowledge, the application of all stereoisomers of the heterocyclic dipeptide in a sequence has yet to be explored.…”

“…The syntheses of all four Agl-Val and eight Hgl-Val diastereomers of peptide 1 (e.g., 5 and 6 ) were performed by approaches featuring preparation of the N -Fmoc-dipeptides in solution, followed by their incorporation into the final peptides using solid-phase peptide synthesis. Although effective means for introducing Agl and Hgl residues directly on solid phase have been developed (Jamieson et al, 2009, 2013; Ronga et al, 2010; Sicherl et al, 2010; St-Cyr et al, 2010; Boutard et al, 2011), the construction of dipeptide building blocks in solution prior to coupling on resin was selected to ensure significant amounts of each isomer for biological studies, as well as to minimize concerns of epimerization during peptide assembly. The N -Fmoc-Agl-Val-OH dipeptide building blocks 7 were synthesized by extension of the original method for Agl residue assembly featuring alkylation of the thioether of N -Boc-methionyl dipeptide ester, followed by intramolecular displacement of the resulting sulfonium ion under basic conditions (Freidinger et al, 1980, 1982).…”

“…The synthesis of Hgl peptides in solution and on solid phase has been accomplished using oxiranyl glycine (Sicherl et al, 2010; St-Cyr et al, 2010, 2017). For preparation of N -Fmoc-Hgl-Val-OH diastereomers 12 possessing the trans -lactam residue, oxiranyl glycines (2 R ,3 R )- and (2 S ,3 S )- 18 were prepared from N -Fmoc- d - and l -methionine methyl esters ( R - and S - 15 ) using a modification of the reported three-step protocol in which N -Fmoc-vinylglycine methyl ester 17 was synthesized by a flow process featuring elimination of N -Fmoc-methionine sulfoxide methyl ester 16 using 2,4-dichlorotoluene at 200°C, and epoxidation of olefin 17 was performed by microwave irradiation using m -CPBA in toluene at 80°C (Figure 3).…”

“…N -Fmoc-( R )-Methionine methyl ester [( R )-15] and N -Fmoc-( R )-Methionine sulfoxide methyl ester [( R )-16] were prepared by a modified version (vide infra) of the previously described method (Sicherl et al, 2010).…”

The Reactivity of Potassium Carbanions with Epoxides

“…Seperation of the potassium ion was successful after potassium carbonate was reacted with 2-benzylphenol20 . The resulting structure [K(2-Benzylphenol)3 ][2-Benzylphenolate]illustrates the interaction of potassium with the phenolic oxygen atom and benzyl ring20 (Figure 1.5).…”