Discrimination of enantiomers of dipeptide derivatives with two chiral centers by tetraaza macrocyclic chiral solvating agents using¹H NMR spectroscopy

Abstract

1H NMR spectroscopy is often used to discriminate enantiomers of chiral analytes and determine their enantiomeric excess (ee) by various chiral auxiliaries. In reported research, these studies were mainly focused on chiral discriminantion of chiral analytes with only one chiral center. However, many chiral compounds possessing two or more chiral centers are often found in natural products, chiral drugs, products of asymmetric synthesis and biological systems. Therefore, it is necessary to investigate their chiral discrimination by effective chiral auxiliaries using 1H NMR spectroscopy. In this paper, a new class of tetraaza macrocyclic chiral solvating agents (TAMCSAs) with two amide (CONH), two amino (NH) and two phenolic hydroxyl (PhOH) groups has been designed and synthsized for chiral discrimination towards dipeptide derivatives with two chiral centers. These dipeptide derivatives are important chiral species because some of them are used as clinical drugs and special dietary supplements for treatment of human diseases, such as L-alanyl-L-glutamine and aspartame. The results show that these TAMCSAs have excellent chiral discriminating properties and offer multiple detection possibilities pertaining to 1H NMR signals of diagnostic split protons. The nonequivalent chemical shifts (up to 0.486 ppm) of various types of protons of these dipeptide derivatives were evaluated with the assistance of well-resolved 1H NMR signals in most cases. In addition, enantiomeric excesses (ee) of the dipeptide derivatives with different optical compositions have been calculated based on integration of well-separeted proton signals. At the same time, the possible chiral discriminating behaviors have been discussed by means of Job plots, ESI mass spectra and a proposed theoretical model of (±)-G1 with TAMCSA 1c. Additionally, the association constants of enantiomers of (±)-G5 with TAMCSA 1a were calculated by employing the nonlinear curve-fitting method.

Chiral discrimination of α-hydroxy acids and N-Ts-α-amino acids induced by tetraaza macrocyclic chiral solvating agents by using1H NMR spectroscopy

“…15 In our previous work, a new class of tetraaza macrocyclic chiral solvating agents (TAMCSAs) has been synthesized for chiral discrimination of dipeptide derivatives with two chiral centers by 1 H NMR spectroscopy (Figure 1). 16 Our results have established that TAMCSAs 1a – 1c possess excellent chiral discriminating abilities towards dipeptide derivatives. Their success may mainly result from the most outstanding feature of TAMCSAs 1a – 1d , which is the presence of two amide, two amino and two phenolic hydroxyl groups, as multiple potential hydrogen bonding interaction sites, along with an overall C 2 -symmetry and a well-defined reaction cavity.…”

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

“…However, chiral recognition of analytes with two or more stereogenic centers, which would be a challenging problem due to complicated stereogenic configurations, is rarely studied and reported. 8 Herein, a series of enantiomers of tripeptide derivatives possessing three stereogenic centers were synthesized and utilized to probe their chiral recognition by 1 H NMR spectroscopy.…”

“…4,7 In contrast, studies on enantiomeric discrimination of chiral analytes possessing two or more stereogenic centers have been rarely reported. 8 Nevertheless, these chiral analytes often exist in natural products, biological systems, chiral drugs, and products of catalytic asymmetric synthesis. 9 For example, it is well established that several oligopeptides or their derivatives, play a crucial role in the treatment of human diseases as clinical drugs or special dietary supplements, as exemplified by thyrotropin-releasing hormone (TRH) or its analogues, 10 and aspartame, 11 which have been used clinically for the treatment of spinocerebellar degeneration and disturbance of consciousness in humans, as well as in special dietary supplements, respectively.…”

“…Among them, NMR spectroscopy, as one of the most efficient analytical techniques, has been widely utilized for chiral recognition due to several advantages, including fast, accurate, and convenient application, as well as ubiquitous NMR instrumentation availability in nearly all chemical laboratories . So far, reported research relying on 1 H NMR spectroscopy largely implicates enantiomeric discrimination of chiral analytes with only one stereogenic center. , In contrast, studies on enantiomeric discrimination of chiral analytes possessing two or more stereogenic centers have been rarely reported . Nevertheless, these chiral analytes often exist in natural products, biological systems, chiral drugs, and products of catalytic asymmetric synthesis .…”

A New Chirally Organized Trifluoromethylanthrylmethanol Derivative and Its Application as Chiral Solvating Agent

“…The enantiomeric excess determination by NMR using a CSA is an easy, fast, and economically available methodology . Based on the formation of the corresponding diastereoisomeric complexes by addition of variable quantities of CSA to a chiral mixture, it allows determining the enantiomeric composition by the simple integration of the split signals.…”