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

Abstract

Enantiomers of a series of hydantoin derivatives were prepared from d- and l-amino acids with p-tolyl isocyanate and 3,5-bis­(trifluoromethyl)­phenyl isocyanate as guests for chiral recognition by 1H NMR spectroscopy. Meanwhile, several tetraaza macrocyclic compounds were synthesized as chiral solvating agents from d-phenylalanine and (1S,2S)-(+)-1,2-diaminocyclohexane. An uncommon enantiomeric discrimination has been successfully established for hydantoin derivatives, representatives of five-membered N,N-heterocycles, in the presence of tetraaza macrocyclic chiral solvating agents (TAMCSAs) 1a–1c by means of 1H NMR spectroscopy. Several unprecedented nonequivalent chemical shifts (up to 1.309 ppm) were observed in the split 1H NMR spectra. To evaluate practical applications in the determination of enantiomeric excess (ee), the ee values of samples with different optical purities (up to 95% ee) were accurately calculated by the integration of relevant proton peaks. To better understand the chiral discriminating behavior, Job plots of (±)-G1 with TAMCSA 1a were investigated. Furthermore, in order to further explore any underlying intermolecular hydrogen bonding interactions, theoretical calculations of the enantiomers of (S)-G1 and (R)-G1 with TAMCSA 1a were performed by means of the hybrid density functional theory (B3LYP/6-31G*) of the Gaussian 16 program.

Isohexide-Based Tunable Chiral Platforms as Amide- and Thiourea-Chiral Solvating Agents for the NMR Enantiodiscrimination of Derivatized Amino Acids

“…Enhanced acidity of thiourea function compared to amide one, together with potentiality of 3,5-bis(trifluoromethyl)phenyl moiety as a booster of enantiodiscriminating capabilities, suggested [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 33 ] the possibility of changing the aromatic moiety of the CSA preparing thiourea derivatives 8a – b with exo–exo and exo–endo stereochemistry, respectively. Preliminarily, their efficiency was compared using amino acid derivatives with free carboxylic functionalities, on considering the possibility of introducing suitable probes as N -3,5-dinitrobenzoyl ( N -DNB), N-trifluoroacetyl ( N -TFA) and N -acetyl ( N -Ac) groups for the detection of enantiodifferentiation as in the cases of 9a – b , 10a , and 11a, respectively.…”

“…Chiral amides [ 24 , 25 , 26 , 27 , 28 , 29 ] and especially chiral arylthioureas [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ] are known to exhibit excellent enantiodiscriminating capabilities when employed as CSAs for the NMR enantiodiscrimination of chiral carboxylic acids [ 30 , 31 , 32 , 33 , 34 , 35 ] and derivatives of amino acids [ 35 , 36 , 37 , 38 ].…”

Enantiomers Identification of Penicillamine by Chiral Mono-Schiff Base Macrocycles

“…丁传凡团队 [34] 基于环糊 精与青霉胺对映体之间的非共价相互作用能力差异, 采 用光谱耦合技术(IM-MS)对 D-和 L-Pen 的快速分析与识 别进行详细考察. 基于含手性 NH 功能基的环状有机分 子, 其骨架结构收敛, 能有效调控环缘上的 NH 功能基 与客体分子作用的空间取向, 在针对生物分子或药用有 机小分子的选择性识别作用及作用机制研究方面是一 类具有重要研究价值的人工受体分子 [35][36][37] .…”

A Tunable Cascade Reaction of Ureidomalonates and Alkenyl Azlactones for the Divergent Synthesis of Hydantoins with Distinct Functional Groups

“…The high medicinal potential of hydantoins provoked intensive studies on the development of efficient methods for their diversity- and complexity-oriented assembly . With respect to 3,5-substituted hydantoins, the catalytic approaches to them are still limited . In 2013, Miao and coauthors reported an I 2 -mediated one-pot synthesis of azetidines using amino malonate derivatives and enones as reaction partners, in which they conducted the addition of ureidomalonate to chalcone for the stereoselective synthesis of the 3,5,5-trisubstituted hydantoin (Scheme a) .…”