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

Abstract

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.

Chiral Recognition of Hydantoin Derivatives Enabled by Tetraaza Macrocyclic Chiral Solvating Agents Using 1H NMR Spectroscopy

“…TAMCSAs 1a−1c were synthesized by intramolecular reductive coupling reaction of enantiopure diimines 3a−3c (1 mmol), which were prepared according to our previously reported synthetic procedure, 22 with a dilute suspension (60 mL of dried DMF) of the activated Zn powder (0.65 g, 10 mmol) and MsOH (0.96 g, 10 mmol) in dried DMF (20 mL) for chiral recognition as chiral auxiliaries (Scheme 1). 23 Meanwhile, chiral compounds 2a−2c were also obtained as intramolecular reductive products in 17−19% isolated yields.…”

Recognition in the Domain of Molecular Chirality: From Noncovalent Interactions to Separation of Enantiomers

“…976,977 C 2 -symmetrical bisthioureas 978 and a strong HB donor, selenourea, 979 were also reported for NMR spectroscopic chiral recognition of αamino acids and tertiary alcohols, respectively. Various other classes of CSA have been utilized in recent years; among them are tetraaza macrocycles for enantiodifferentiation of α-amino acids and small peptides, 980,981 tyrosinemodified pillar [5]arenes for enantiomeric identification chiral aromatic amines, 982 and chiral squaramides 983 and Kagan's amides 984 with high versatility towards different classes of chiral compounds. In recent years, chiral liquid crystals have been also used for NMR enantiotopic discrimination owing to the effect of magnetically induced anisotropic interactions.…”

Recent advances of the ionic chiral selectors for chiral resolution by chromatography, spectroscopy and electrochemistry

“…In NMR, choosing an appropriate chiral solvating agent (CSAs) or enantiopure chiral derivatizing agent is important to form noncovalent interactions with the testing samples for chiral recognition. It can generate the diastereomeric complexes with enough chemical shift [109][110][111][112]. Different from chromatography, fluorescence spectroscopy, and electrochemical analysis, it has none specific conditions to the isomers, like, stability, ultraviolet absorption, or others.…”