1. A new amino acid derivative with a masked side-chain aldehyde and its use in peptide synthesis and chemoselective ligation
J C Spetzler, T Hoeg-Jensen J Pept Sci. 2001 Oct;7(10):537-51. doi: 10.1002/psc.349.
A new amino acid derivative with a diol side-chain, L-2-amino-4,5-dihydroxy-pentanoic acid (Adi), has been prepared from L-allylglycine by suitable protection, for use in peptide synthesis, as Fmoc-L-Adi(Trt)2. This building block enables the introduction of a side-chain aldehyde at any position in a given peptide sequence without use of specialized side-chain protection schemes. The aldehyde is revealed by mild oxidation with sodium periodate, circumventing the problematic release of reactive peptidic aldehydes in TFA solution. Peptides with aldehyde side-chains are useful for chemo-selective ligation, reacting selectively with oxyamines to yield oxime links, while all other peptide functions can be left unprotected. The utility of the new building block has been demonstrated by the synthesis of peptide dimers and a cyclo-peptide.
2. Preparative Method for Asymmetric Synthesis of ( S)-2-Amino-4,4,4-trifluorobutanoic Acid
Jianlin Han, Ryosuke Takeda, Xinyi Liu, Hiroyuki Konno, Hidenori Abe, Takahiro Hiramatsu, Hiroki Moriwaki, Vadim A Soloshonok Molecules. 2019 Dec 10;24(24):4521. doi: 10.3390/molecules24244521.
Enantiomerically pure derivatives of 2-amino-4,4,4-trifluorobutanoic acid are in great demand as bioisostere of leucine moiety in the drug design. Here, we disclose a method specifically developed for large-scale (>150 g) preparation of the target (S)-N-Fmoc-2-amino-4,4,4-trifluorobutanoic acid. The method employs a recyclable chiral auxiliary to form the corresponding Ni(II) complex with glycine Schiff base, which is alkylated with CF3-CH2-I under basic conditions. The resultant alkylated Ni(II) complex is disassembled to reclaim the chiral auxiliary and 2-amino-4,4,4-trifluorobutanoic acid, which is in situ converted to the N-Fmoc derivative. The whole procedure was reproduced several times for consecutive preparation of over 300 g of the target (S)-N-Fmoc-2-amino-4,4,4-trifluorobutanoic acid.
3. Helix formation and capping energetics of arginine analogs with varying side chain length
Richard P Cheng, et al. Amino Acids. 2012 Jul;43(1):195-206. doi: 10.1007/s00726-011-1064-2. Epub 2011 Sep 16.
Arginine (Arg) has been used for recognizing negatively charged biological molecules, cell penetration, and oligosaccharide mass signal enhancement. The versatility of Arg has inspired the need to develop Arg analogs and to research the structural effects of incorporating Arg analogs. Accordingly, we investigated the effect of Arg side chain length on helix formation by studying 12 Ala-based peptides containing the Arg analogs (S)-2-amino-6-guanidino-hexanoic acid (Agh), (S)-2-amino-4-guanidinobutyric acid (Agb), and (S)-2-amino-3-guanidinopropionic acid (Agp). Solid phase guanidinylation with orthogonal protection strategies was necessary to synthesize Agb- and Agp-containing peptides using Fmoc-based chemistry. The fraction helix for the peptides was determined by circular dichroism spectroscopy, and used to derive the statistical mechanical parameters and energetics for N-capping, C-capping, and helix propagation (propensity). All four Arg analogs were unfavorable for N-capping. The C-cap parameter followed the trend AgpAgh, highlighting the uniqueness of the Arg side chain length in helix formation. Molecular mechanics calculations and a survey on protein structures were consistent with the experimental results. Furthermore, calculations and survey both showed that the g- conformation for the χ1 dihedral was present for the first two residues at the N-terminus of helices, but not favored in the center or C-terminus of helices due to sterics. These results should serve as the foundation for developing Arg-related bioactive compounds and technologies.
