Histidine-based copper tetrapeptides as enantioselective catalysts for aldol reactions

Abstract

Copper(II)-peptides are widely used as industrial catalysts such as in the aerobic oxidation of organic molecules, formation of new C-H bonds and in the azide-alkyne cycloaddition reaction. The length of peptides and the effect of adding copper metal into peptides were questioned in their field of applications. Five novel histidine-based tetrapeptides with the sequences HAAD (P1), HAFD (P2), HAVD (P3), AGHD (P4) and PGHD (P5) were synthesized using the solid phase peptide scheme and analysed with high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) with percentage purities as high as 99.5%. All the peptides were positively charged (+1) and the molecular weight calculated from m/z values of MS results coincided with the theoretical molecular weight of the peptides. Copper(II)-peptides derived from these peptides and copper(II) acetate monohydrate (CuP1-CuP5) in a 1 : 2 ratio was synthesised, purified and characterised by ultravioletvisible spectroscopy (UV-Vis), ultraviolet-fluorescence spectroscopy (fluorescence) and fourier transform infrared spectroscopy (FTIR), circular dichroism spectroscopy (CD) and optical rotation polarimetry. It provided the necessary information on the secondary structure and the successful binding of copper(II) to the specific amino acids, hence leading to the putative geometry of copper(II)-peptides and the difference in the chirality of amino acids, peptides and copper(II)-peptides. The catalytic activities of the synthesised complexes were evaluated. CuP1 & CuP3 catalysed both the asymmetric aldol reactions with high enantioselectivity of p-nitrobenzaldehyde with cyclohexanone (% ee ¼ 87. 3 & 80.3, respectively) and of p-anisaldehyde with cyclohexanone (% ee ¼ 95.5 & 90.9, respectively).

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“…The sharp melting points observed indicate that these compounds were pure. The PLOS ONE yields of copper(II)-peptides synthesized in this work are comparable to those previously reported for tetrapeptides used as catalysts for aldol reactions [14].…”

“…The peptide sequences were modified using PEP-FOLD (https://bioserv.rpbs.univ-paris-diderot.fr/ services/PEP-FOLD/) and Lomets (https://zhanglab.ccmb.med.umich.edu/LOMETS/) and the resulting pdb was viewed using PyMOL. The general synthesis of Tp which followed procedures reported in our previous work [14] is given in the (S1 Scheme in S1 File).…”

“…The copper(II)-peptides (Table 1) were synthesized using copper(II) acetate and copper(II) sulphate following procedures outlined in our previously reported work [14]. Aqueous copper (II) solution (1.6 mmol, 5 mL) was added dropwise to the pre-prepared peptide aqueous solution (0.8 mmol, 5 mL).…”

“…Peptides of longer chain are favoured for copper(II) binding compared to di-and tri-peptides as it needs to bind to more than one-metal binding amino acid such as histidine, aspartic acid, glutamic acid, cysteine and methionine to increase the stability of the complex [12]. Copper(II)peptides have been used as catalysts in asymmetric reactions and have been reported to have good catalytic activity [14]. Up to now, there have not been any copper-peptides reported as catalyst for oxidation reactions.…”

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“…[ 23 ] Comparison to the UV–visible spectrum of copper(II)acetate, the UV–visible spectrum of microstructures (Figure 1a), prepared from 1:1 ratio of Cu 2+ to palmitic acid, shows a blue shifted absorbance with the absorption maximum at 298 nm with a rather pronounced shoulder peak at 450 nm, confirming the successful conjugation of Cu 2+ to the new ligand, palmitic acid. [ 23,24 ] Agreeing with these results, the similar shifts in the absorption bands for MLCT transitions were observed in Cu(II)‐conjugated peptides. [ 24 ] As shown in Figure 1b,c, the similar trends in the peak shifts for MLCT bands at 302 nm and 400 to 500 nm were observed for all the microstructures made from different stoichiometric ratios of two precursors.…”