1. Chemoselective Disulfide Formation by Thiol-Disulfide Interchange in SIT-Protected Cysteinyl Peptides
Amit Chakraborty, Fernando Albericio, Beatriz G de la Torre J Org Chem. 2022 Jan 7;87(1):708-712. doi: 10.1021/acs.joc.1c02705. Epub 2021 Dec 15.
Chemoselective disulfide formation is accomplished through a thiol-disulfide interchange approach using sec-isoamyl mercaptan (SIT) as an alkyl sulfenyl-protecting group of one of the Cys residues involved in the pairing. SIT has a dual and unique characteristic, acting as a masking group during the synthesis and directing disulfide formation in the presence of a free thiol. This novel approach is illustrated by the synthesis of several peptides of biological interest.
2. Epimerization-Free Preparation of C-Terminal Cys Peptide Acid by Fmoc SPPS Using Pseudoproline-Type Protecting Group
Shugo Tsuda, Shun Masuda, Taku Yoshiya J Org Chem. 2020 Feb 7;85(3):1674-1679. doi: 10.1021/acs.joc.9b02344. Epub 2019 Oct 31.
Preparation of C-terminal Cys-containing peptide acid by Fmoc solid-phase peptide synthesis (SPPS) is difficult due to base-mediated epimerization at Cys. In this paper, use of a C-terminal pseudoproline structure and Trt(2-Cl) resin achieved epimerization-free direct preparation of the C-terminal Cys-containing peptide acid by Fmoc SPPS. Additionally, the C-terminal Cys(ΨDmp,Hpro)-containing protected peptide segment was applied to an epimerization-free segment condensation reaction.
3. An unnatural amino acid that induces beta-sheet folding and interaction in peptides
James S Nowick, Kit S Lam, Tatyana V Khasanova, William E Kemnitzer, Santanu Maitra, Hao T Mee, Ruiwu Liu J Am Chem Soc. 2002 May 8;124(18):4972-3. doi: 10.1021/ja025699i.
This paper introduces a unique amino acid that can readily be incorporated into peptides to make them fold into beta-sheetlike structures that dimerize through beta-sheet interactions. This new amino acid, Orn(i-PrCO-Hao), consists of an ornithine residue with the beta-strand-mimicking amino acid Hao [J. Am. Chem. Soc. 2000, 122, 7654-7661] attached to its side chain. When Orn(i-PrCO-Hao) is incorporated into a peptide, or appended to its N-terminus, the Hao group hydrogen bonds to the three subsequent residues to form a beta-sheetlike structure. The amino acid Orn(i-PrCO-Hao) is readily used in peptide synthesis as its Fmoc derivative, Fmoc-Orn(i-PrCO-Hao)-OH (3). Fmoc-Orn(i-PrCO-Hao)-OH behaves like a regular amino acid in peptide synthesis and was uneventfully incorporated into the peptide o-anisoyl-Val-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe (4) through standard automated Fmoc solid-phase peptide synthesis, with DIC and HOAt as the coupling agent for Fmoc-Orn(i-PrCO-Hao)-OH and o-anisic acid and HATU as the coupling agent for all other couplings. A second synthetic strategy was developed to facilitate the preparation of peptides with N-terminal Orn(i-PrCO-Hao) residues, which avoids the need for the preparation of Fmoc-Orn(i-PrCO-Hao)-OH. In this strategy, Boc-Orn(Fmoc)-OH is used as the penultimate amino acid in the peptide synthesis, and i-PrCO-Hao-OH (2) is used as the final amino acid. N-Terminal Orn(i-PrCO-Hao) peptide H-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe.TFA (5) was prepared in a fashion similar to that for 4, using DIC and HOAt as the coupling agent for i-PrCO-Hao-OH and HATU as the coupling agent for all other couplings. 1H NMR transverse-ROESY, coupling constant, and chemical shift studies establish that peptide 4 forms a dimeric beta-sheetlike structure in CDCl3 solution. The 1H NMR studies also suggest that the ornithine unit adopts a well-defined turn conformation. Analogous 1H NMR studies of peptide 5 indicate that this TFA salt folds but does not dimerize in CD3OD solution. Collectively, these synthetic and spectroscopic studies establish that the amino acid Orn(i-PrCO-Hao) induces beta-sheet structure and interactions in peptides in suitable organic solvents. Unlike the Hao amino acid, which acts as a prosthetic to replace three residues of the peptide strand, the Orn(i-PrCO-Hao) amino acid acts as a splint that helps enforce a beta-sheetlike structure without replacing the residues and their side chains. This feature of Orn(i-PrCO-Hao) is important, because it allows the creation of beta-sheet structure with minimal perturbation of the peptide sequence.
