Synthesis and Biological Evaluation of Gramicidin S‐Inspired Cyclic Mixed α/β‐Peptides

Abstract

Via a Mannich reaction involving a dibenzyliminium species and the titanium enolates of Evans' chiral acylated oxazolidinones the β(2)-amino acids (R)- and (S)-Fmoc-β(2)homovaline and (R)-Fmoc-β(2)homoleucine are synthesized. These building blocks were used, in combination with commercially available α- and β(3)-amino acids, for the synthesis of the cyclo-(αβ(3)αβ(2)α)(2) peptide 2 and the cyclo-(αβ(2)αβ(3)α)(2) peptides 3-5. The peptides 2-5 were screened for their ability to inhibit a small panel of Gram-negative and Gram-positive bacterial strains.

A Novel Decalin-Based Bicyclic Scaffold for FKBP51-Selective Ligands

“…After cyclization, the chiral auxiliary (Scheme ) of the unsubstituted bicycles 11a and 11b was cleaved with LiOOH to obtain the free carboxylic acids 12a and 12b , respectively. Bicycle 11c , which is substituted in the 2-position, was first converted to the respective thioester and then hydrolyzed with mercury­(II) trifluoroacetate to yield 12c . Hydrogenation catalyzed by Pd/C provided the respective saturated bicycles 13a – c .…”

“…Bicycle 11c, which is substituted in the 2-position, was first converted to the respective thioester and then hydrolyzed with mercury(II) trifluoroacetate to yield 12c. 36 Hydrogenation catalyzed by Pd/C provided the respective saturated bicycles 13a−c.…”

Design, Synthesis, and Structural Analysis of Turn Modified cyclo-(αβ3αβ2α)2 Peptide Derivatives toward Crystalline Hexagon-Shaped Cationic Nanochannel Assemblies

“…Similarly, the use of anti disubstituted β 3,2 -amino acids 17 could provide a rigid extended cyclic hairpinlike structure (Figure 9, bottom right). The crystallographic packing of molecules 2, 5 4, 6, 7, 14, 16 and the previously synthesized 8 18 are depicted in Figure 10. Compounds 4, 16, and 18 do not form nanotubes in their crystal packing (Figure 10, panels a, b, and c, respectively).…”

“…Intrigued by the monomeric structure of the previously reported cyclo -(αβ 3 αβ 2 α) 2 peptide 2 , as well as its nanochannel crystallographic assembly, we wanted to investigate whether derivatives can be prepared with similar structural properties. Previously, we reported the synthesis of amphiphilic positional isomers of 2 , , in which the β 3 - and β 2 -amino acid residues were swapped in the sequence to yield a series of cyclo -(αβαβα) 2 derivatives. One of the thus obtained strand-modified derivatives of 2 was shown to exert modest antibacterial activity but no further structural insight was obtained from these compounds.…”

“…Previously, we reported the synthesis of amphiphilic positional isomers of 2 , , in which the β 3 - and β 2 -amino acid residues were swapped in the sequence to yield a series of cyclo -(αβαβα) 2 derivatives. One of the thus obtained strand-modified derivatives of 2 was shown to exert modest antibacterial activity but no further structural insight was obtained from these compounds. From these previous studies, we conclude that modifications of the strand regions have a large effect on both structural and biological properties of cyclo -(αβαβα) 2 peptides, and we therefore decided to focus on turn-modified derivatives of peptide 2 .…”