Preparation of ‘side‐chain‐to‐side‐chain’ cyclic peptides by Allyl and Alloc strategy: potential for library synthesis

Abstract

Automated and manual deprotection methods for allyl/allyloxycarbonyl (Allyl/Alloc) were evaluated for the preparation of side-chain-to-side-chain cyclic peptides. Using a standard Allyl/Alloc deprotection method, a small library of cyclic peptides with lactam bridges (with seven amino acids) was prepared on an automatic peptide synthesizer. We demonstrate that the Guibe method for removing Allyl/Alloc protecting groups under specific neutral conditions [Pd(PPh3)4/PhSiH3)/DCM] can be a useful, efficient and reliable method for preparing long cyclic peptides on a resin. We have also manually synthesized a cyclic glucagon analogue containing 24 amino acid residues. These results demonstrated that properly controlled palladium-mediated deprotection of Allyl/Alloc protecting groups can be used to prepare cyclic peptides on the resin using an automated peptide synthesizer and cyclic peptides with a long chain.

Structure–activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position

“…Then, the peptide resin was washed with DCM (3× 50 mL, 2 min), DMF (3× 50 mL, 1 min) and again with DCM (4× 50 mL, 2 min)and the process was repeated. The removal of Allyl and Alloc groups under neutral conditions with catalytic amounts of Pd(PPh 3 ) 4 in the presence of PhSiH 3 and complete absence of oxygen [18] permitted orthogonal deprotection of the side chain-protecting groups used during the synthesis. Then the peptideresin was suspended in 20 mL of N-methyl-pyrrolidone (NMP), followed by cyclization of the peptidevia the free carboxylic acid sidechain ofAsp and the free amino group side chain of Lys by addition of HBTU (6 equiv.…”

“…The peptides (Table 1) were synthesized by methods previously developed in our laboratory [18] using N α -Fmoc chemistry with an appropriate orthogonal protection strategy. Coupling was carried out with standard in situ activating reagents used N α -Fmoc SPPS, such as the uronium salts (HBTU) in the presence of a tertiary base (DIPEA), to generate HOBt esters.…”

“…Coupling was carried out with standard in situ activating reagents used N α -Fmoc SPPS, such as the uronium salts (HBTU) in the presence of a tertiary base (DIPEA), to generate HOBt esters. The cyclization of the peptides was performed on the solid support after removing the Allyl and Alloc protecting groups under neutral conditions with catalytic amounts of Pd(PPh 3 ) 4 in the presence of PhSiH 3 and argon [18], assuring an orthogonal deprotection of the side chainprotecting groups used during the synthesis. One concern was that Trp residues are extremely susceptible to alkylation by cations produced during the cleavage process.…”

The cyclization of peptides and depsipeptides

“…The impetus created by the demands for cyclic peptide libraries has spawned new approaches to side-chain lactamization. An allyl/allyloxycarbonyl strategy [55] for lactam bridge formation has been tested on a small library with seven amino acid residues. The Guibe method [(PPh 3 ) 4 /PhSiH 3 /DCM] proved efficient in removing the allyl/allyloxycarbonyl groups under neutral conditions.…”

Efficient total syntheses and biological activities of two teixobactin analogues

“…Next, (d) arginine was coupled via an amide bond, the Fmoc protecting group is removed and (e) the N-terminus is protected via a trityl protecting group 15 (combining cleavage and deprotection in a single step) to facilitate the cleavage and cyclisation as described in reactions (h and i). (f) The Alloc group protecting the N-terminus of the threonine is then removed 16 and (g) the peptide chain is built via standard solid phase peptide synthesis (SPPS). Partial cleavage was performed using 2 : 5 : 93 TFA : TIS : DCM followed by cyclisation using 1-[bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]-pyridinium 3-oxid hexafluorophosphate (HATU) as a coupling reagent and DIPEA as a base in DMF for 1 h. The protecting groups are then cleaved off using 95 : 2.5 : 2.5 TFA : TIS : H 2 O yielding the desired peptide (22% recovery, refer ESI, † S10).…”