Synthesis of Tripeptide Derivatives with Three Stereogenic Centers and Chiral Recognition Probed by Tetraaza Macrocyclic Chiral Solvating Agents Derived from d-Phenylalanine and (1S,2S)-(+)-1,2-Diaminocyclohexane via ¹H NMR Spectroscopy


Enantiomers of a series of tripeptide derivatives with three stereogenic centers (±)-G1-G9 have been prepared from d- and l-α-amino acids as guests for chiral recognition by ¹H NMR spectroscopy. In the meantime, a family of tetraaza macrocyclic chiral solvating agents (TAMCSAs) 1a-1d has been synthesized from d-phenylalanine and (1S,2S)-(+)-1,2-diaminocyclohexane. Discrimination of enantiomers of (±)-G1-G9 was carried out in the presence of TAMCSAs 1a-1d by ¹H NMR spectroscopy. The results indicate that enantiomers of (±)-G1-G9 can be effectively discriminated in the presence of TAMCSAs 1a-1d by 1H NMR signals of multiple protons exhibiting nonequivalent chemical shifts (ΔΔδ) up to 0.616 ppm. Furthermore, enantiomers of (±)-G1-G9 were easily assigned by comparing ¹H NMR signals of the split corresponding protons with those attributed to a single enantiomer. Different optical purities (ee up to 90%) of G1 were clearly observed and calculated in the presence of TAMCSAs 1a-1d, respectively. Intermolecular hydrogen bonding interactions were demonstrated through theoretical calculations of enantiomers of (±)-G1 with TAMCSA 1a by means of the hybrid functional theory with the standard basis sets of 3-21G of the Gaussian 03 program.




The authors are grateful for the financial support from the Beijing Municipal Commission of Education and the National Natural Science Foundation of China (91441108). Work in the Missouri Lab (P.S.) is supported by the National Institute of General Medical Science of the National Institutes of Health (R15GM117508).

Keywords and Phrases

Amino acids; Enantiomers; Hydrogen bonds; Nuclear magnetic resonance spectroscopy

International Standard Serial Number (ISSN)

0022-3263; 1520-6904

Document Type

Article - Journal

Document Version


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© 2018 American Chemical Society (ACS), All rights reserved.

Publication Date

01 Nov 2018

PubMed ID