1. Direct conversion of resin-bound peptides to C-terminal esters
Rushia A Turner, Robert J Weber, R Scott Lokey Org Lett. 2010 Apr 16;12(8):1852-5. doi: 10.1021/ol100471k.
A mild and effective method was developed to convert peptides immobilized on the 2-chlorotrityl and Wang resins directly to C-terminal esters. After conventional Fmoc peptide synthesis, treatment with anhydrous HCl (0.2-3 M) in a variety of alcohols was shown to produce the corresponding peptide esters in good yield and purity. Under the mildest conditions investigated, acid-sensitive protection groups such as N-Boc, trityl, tert-butyl ether, tert-butyl ester, and Pbf remain intact.
2. Rapid total synthesis of cyclic lipodepsipeptides as a premise to investigate their self-assembly and biological activity
Matthias De Vleeschouwer, Davy Sinnaeve, Jos Van den Begin, Tom Coenye, José C Martins, Annemieke Madder Chemistry. 2014 Jun 16;20(25):7766-75. doi: 10.1002/chem.201402066. Epub 2014 May 9.
A rapid and efficient total synthesis is reported for the cyclic lipodepsipeptide pseudodesmin A. This member of the Pseudomonas viscosin group is active against Gram-positive bacteria and features self-assembling properties. A conserved serine residue within the lactone macrocycle is exploited for initial immobilization on 2-chlorotrityl chloride resin through ether formation with the side-chain alcohol. Subsequent elongation proceeds through Fmoc solid-phase peptide synthesis, including automated incorporation of the enantioselectively synthesized (R)-3-hydroxydecanoic acid lipid tail. Following esterification to generate the incipient lactone bond, the macrocycle is formed by on-resin head-to-tail macrolactamization and cleaved from the resin to give the desired compound in good purity. The short and efficient synthesis route allows rapid generation of analogues by facile variation of both the peptide and lipid moieties with good control of epimerization while maximizing automation. Synthesis of the pseudodesmin A enantiomer yields identical self-assembly and biological activity to that observed for the natural compound, showing that activity is not mediated by chiral interactions. A D-Asn8 analogue developed en route retains self-assembly, but loses activity. The synthesis strategy should be generally applicable for the rapid generation of analogues from various cyclic lipodepsipeptide groups, allowing an investigation of their self-assembling properties and structure-activity relationships.
3. The effect of peptide length on the cleavage kinetics of 2-chlorotrityl resin-bound ethers
László Kocsis, Ferenc Ruff, György Orosz J Pept Sci. 2006 Jun;12(6):428-36. doi: 10.1002/psc.745.
Different characteristics of cleavage kinetics of resin-bound amino alcohols and their peptide derivatives were observed in acid containing protic and aprotic solvent mixtures. The hydrolysis reactions are hindered by steric crowding around the cleaving C--O bond and accelerated by the special solvation effect of CF(3)CH(2)OH on the peptide chain as well as the increase of the strength and concentration of the acid. In trifluoroacetic acid containing mixtures, trifluoroacetylation of the peptide alcohols was detected. The appearance of O-trifluoroacetyl serine and threonine derivatives is detected in cleavage mixtures containing trifluoroacetic acid in anhydrous solvent.
