Synthesis of Cyclic Peptides

Isolation of a Cyclic Depsipetide, Aspergillicin F, and Synthesis of Aspergillicins with Innate Immune-Modulating Activity

“…These compounds can be synthesized from the linear depsipeptide precursors 7e and 7f through macrolactamization between Pro1 and diMeTyr to avoid racemization. 16 The precursor 7e/7f was synthesized through a combination of solid-and liquid-phase peptide synthesis (Scheme 1). To start with, the introduction of N-Fmoc-L-proline into 2-chlorotrityl chloride resin provided polymer-supported 8.…”

Solid-phase peptide head-to-side chain cyclodimerization: Discovery of C2-symmetric cyclic lactam hybrid α-melanocyte-stimulating hormone (MSH)/agouti-signaling protein (ASIP) analogues with potent activities at the human melanocortin receptors

“…The peptide lactam cyclodimerizations were achieved by construction of the linear tetrapeptide sequences on polystyrene-based Rink amide AM resin at 0.5-0.6 mmol/g loading, consecutive removal of the N -terminal Fmoc and Glu(OAll) protecting groups, and exposure of the deprotected resin-bound peptide to DIC/6-Cl-HOBt in THF over 72 h (Scheme 2). This procedure resulted in a predictably low yield (<5%) of the monomeric cyclic tetrapeptide products due to the high strain within their 11-membered lactam ring[57], and led predominantly to the corresponding 22-membered cyclodimers, which were isolated in 25-30% yields after TFA cleavage off the solid support and HPLC purification (Scheme 2, Method A).…”

“…The complex 1 H NMR spectra of the monomeric cyclic lactams (Figure 5) indicates a presence of three possible cis / trans ω-rotamers, in dynamic equilibrium with one another, as could be expected from a dihedrally strained 11-membered lactam ring[57]. The lack of a well-defined secondary structure in the monomeric cyclic lactam peptides may impair receptor-ligand interaction, and, by the same token, the less strained larger macrocycles may have more stable secondary structures, as evident from the 1 H NMR spectra of the cyclodimeric peptides (such as analogue 12 , Figure 4), which would lead to augmented receptor binding affinity and agonist potency.…”

“…, “bioactive conformation” [39, 54]. It has been previously noted that the success of a peptide cyclization depends strongly on the probability of juxtaposition of the reactive groups of the linear peptide precursor, and is usually encumbered by side reactions, most notably, oligomerizations and cyclooligomerizations[20, 57]. These side reactions become prevalent in syntheses of small strained cyclic peptides, such as N -unsubstituted tri- and tetrapeptides, typically incurring formation of cyclic dimers and trimers (Scheme 1) [57].…”

An efficient strategy for the large-scale synthesis of head-to-tail cyclic peptides

“…Therefore, small head-to-tail cyclic peptides are of considerable interest due to their inherent limited conformational flexibility. In addition, cyclic peptides are more resistant to proteolytic hydrolysis and degradation than their corresponding linear homologues [1,2]. Most synthetic head-to-tail cyclic peptides have been prepared under dilute conditions (10-3-10-4 M) using carbodiimide or azide activation [3,4].…”