15207-28-0

Upstream product

• 917501-50-9 Boc-D-Phe-Pro-Val-Orn(Boc)-OH 
• 13734-41-3 t-Boc-L-valine 
• 73995-50-3 H-Orn(Z)-OBzl 
• 917501-48-5 Boc-D-Phe-Pro-Val-Orn(Z)-OBzl 

Relevant academic research and scientific papers

Chemoselective cyclization of unprotected linear peptides by α-ketoacid-hydroxylamine amide-ligation

Cyclic peptides are important synthetic targets due to their constrained conformation, enhanced metabolic stability and improved bioavailability, which combine to make them promising lead compounds for drug candidates. They are typically synthesized by a multi-step sequence of carefully orchestrated protecting group manipulations and cyclization of side-chain protected linear precursors. In the present manuscript we disclose an alternative approach to the synthesis of peptide macrocycles by the α-ketoacid-hydroxylamine (KAHA) ligation. This reaction allows readily prepared linear peptides to be cyclized without reagents or side-chain protecting groups and delivers a native backbone amide bond at the ligation site. The precursors are prepared with Fmoc-based solid phase peptide synthesis using reagents that we have previously disclosed. No post-cyclization manipulations or deprotections other than purification are required. This protocol was applied to five different cyclic peptide natural products of varying ring sizes and side chain functionalities.

Biomimetic formation of gramicidin S by dimerization-cyclization of pentapeptide precursor on solid support

The biomimetic formation of gramicidin S, cyclo(-d-Phe-Pro-Val-Orn-Leu-)2, by the dimerization and cyclization of pentapeptide precursor without the protection of δ-amino group of the Orn residue was examined on a solid support. The cyclization of H-d-Phe-Pro-Val-Orn-Leu-oxime on a resin with an oxime group of 0.62 mmol/g in 1,4-dioxane directly gave gramicidin S in a 50% yield. The dimerization-cyclization mode on the solid support was similar to that of the biosynthesis of gramicidin S on an enzyme.

Relationship between the cyclization and conformation of pentapeptide active esters related to gramicidin S having no protecting group on the side chain of the ornithine residue

To investigate the contribution of the D-phe-Pro-Val sequence in the direct formation of gramicidin S (GS) by the dimerization-cyclization of pentapeptide-active esters having no protecting group on the side chain of the Orn residue, the cyclization of four H-X-Pro-Y-Orn-Leu-ONSu's (X = L- or D-Phe, Y = L- or D-Val, -ONSu = succinimide ester) was examined. Only H-D-Phe-Pro-Val-Orn-Leu-ONSu gave semi-GS (cyclic monomer) and GS (cyclic dimer) in yields of 15 and 38%, respectively. The active ester with a D-Phe-Pro-D-Val sequence produced exclusively [D-Val]-semi-GS in 58% yield. On the other hand, the active esters having Phe-Pro-Val and Phe-Pro-D-Val sequences did not yield any amount of cyclic monomer and cyclic dimer. The change in the configurations of the Phe and Val residues around the Pro residue greatly affected the CD spectra in ethanol and the 1H NMR spectra in DMSO-d6 of the pentapeptide ethyl esters corresponding to four H-X-Pro-Y-Orn-Leu-ONSu's. A good correlation among the CD spectra, NMR spectra of the pentapeptide ethyl esters, and the main products in the cyclization of the active esters was found.