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 (un 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.

Graphical Abstract

INTRODUCTION

Chiral recognition is one of the most significant topics in a variety of research fields, such as catalytic asymmetric chemistry and chiral pharmaceuticals, biology, and life science.¹ Among them, assignment of the absolute configuration of chiral molecules and determination of enantiomeric excess (ee) of chiral compounds are indispensable elements of structural characterization and practical applications because different enantiomers possess different optical properties, biological activities, and pharmacological (even toxic) effects.² For this purpose, a variety of techniques and methods, such as high-performance liquid chromatography,³ X-ray crystallography,⁴ circular dichroism (CD),⁵ vibrational CD,⁶ nuclear magnetic resonance (NMR),⁷ UV–vis, and fluorescence spectroscopy,⁸ have been developed and utilized separately or in tandem. Among these available techniques, the ¹H NMR technique has several obvious advantages, associated with simple and fast measurement, accurate and convenient application, and employment of a low amount of samples, as well as the availability of a ubiquitous NMR apparatus in nearly all chemical laboratories.⁹ Thus, the NMR technique has widely emerged as the commonly applied tool for the determination of absolute configuration and quantitative analysis of ee of chiral substrates.¹⁰ In the course of research on chiral recognition, on the one hand, effective chiral auxiliaries play a key role in chiral discriminating behavior between hosts and guests by NMR spectroscopy because the differentiation of chiral substrates relies on the generation of a pair of diastereomeric adducts by means of covalent bond formation or noncovalent interactions with chiral auxiliaries (chiral derivatizing agents and chiral solvating agents).¹¹ To explore chiral auxiliaries with sufficient sensitivity and high chiral discriminating performance, various chiral auxiliaries have been designed, synthesized, and screened through the continuous efforts of chemists.¹² On the other hand, chiral recognition of a variety of chiral substrates should be explored and investigated to further deepen and promote the development of chiral recognition and its related applications by ¹H NMR spectroscopy. In the past decades, chiral recognition of acyclic compounds, such as chiral amines,¹³ amino alcohols,¹⁴ alcohols,¹⁵ amino acids or their derivatives,¹⁶ carboxylic acids,¹⁷ and esters,¹⁸ has been frequently reported by means of ¹H NMR spectroscopy. In recent years, we have also reported some studies on chiral recognition of α-hydroxy acids, α-amino acid derivatives, dipeptide derivatives with two chiral centers, and tripeptide derivatives with three stereogenic centers as acyclic substrates in the presence of a series of tetraaza macrocyclic chiral solvating agents (TAMCSAs) by means of ¹H NMR spectroscopy. Based on these results, these TAMCSAs have been successfully established as a family of versatile and highly effective chiral solvating agents vis-à-vis the aforementioned acyclic compounds.¹⁹ Nevertheless, recognition of chiral cyclic substrates has rarely been investigated by ¹H NMR spectroscopy.²⁰ This is surprising, given the fact that enantiomerically pure cyclic products, including several chiral hydantoin derivatives, have been used to treat many human diseases, due to their powerful physiological and pharmacological activities.²¹ In this paper, we offer a significant solution to the challenging chiral recognition of hydantoin derivatives, as five-membered N,N-heterocyclic compounds, with the discovery of a panel of remarkable tetraaza macrocyclic chiral solvating agents (TAMCSAs) that enable the determination of enantiomeric purity by means of ¹H NMR spectroscopy.

RESULTS AND DISCUSSION

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.

Scheme 1.

Synthesis of TAMCSAs 1a–1c and Chiral Compounds 2a–2c

All products were characterized by ¹H NMR, ¹³C NMR, HRMS, and IR methods. Unfortunately, we were unable to obtain crystals of TAMCSAs 1a–1c, suitable for X-ray singlecrystal diffraction. Therefore, their nuclear overhauser effect spectroscopy (NOESY) spectra were measured for assignment of absolute configuration of the two newly generated chiral carbon atoms (ArCHNH) of TAMCSAs 1a–1c. Their spectra show that the two types of protons of the ArCHNH and COCHBn (phenylalanine moiety) groups of TAMCSAs 1a–1c are located on the same side of the macrocyclic framework, as determined by the NOESY correlated ¹H NMR signals between the two types of protons (ArCHNH and COCHBn). Based on the known absolute configuration (R) of COCHBn and the C₂-symmetric geometry, the absolute configuration of 5- and 6-carbon atoms (ArCHNH) of TAMCSAs 1a–1c is assigned as S and S-configurations (Scheme 1). Detailed NOESY spectra are available in the Supporting Information (Figures S5, S9, and S13).

As shown in Scheme 1, the multiple potential hydrogen bonding sites, such as amino, amide, and phenolic hydroxyl groups, featured in the molecular structure of TAMCSAs 1a–1c, are the most distinguished structural elements, along with a C₂-symmetry and a 12-membered cavity.

Meanwhile, the enantiomers of hydantoin derivatives G1–14, as five-membered N,N-heterocycles, were directly prepared from the corresponding l- and d-amino acids (5.5 mmol, 1.1 equiv) in NaOH solution (1 M, 5 mL) with p-tolyl isocyanate (5 mmol) and 3,5-bis(trifluoromethyl)phenyl isocyanate (5 mmol) in CH₃CN (2 mL) in 50–89% isolated yields according to the related literature,²⁴ respectively (Scheme 2).

Scheme 2.

Synthesis of Enantiomers of Hydantoin Derivatives 1–14^a

^aConditions: (i) NaOH, CH₃CN, 0 °C and (ii) 1,4-dioxane, rt; HCl, reflux.

The new products were characterized by the spectroscopic methods noted above and by ¹⁹F NMR spectroscopy (for new products containing CF₃ groups).

To explore the discrimination of enantiomers of hydantoin derivatives in the presence of TAMCSAs 1a–1c by ¹H NMR spectroscopy, two samples of (±)-G1 with TAMCSA 1a (1:1 molar ratio, [5 mM]) and (±)-G7 with TAMCSA 1c (1:1 molar ratio, [10 mM]) were prepared in CDCl₃ based on the solubility, and their ¹H NMR spectra were measured on a 400 MHz spectrometer at 25 °C. The results show that enantiomers of (±)-G1 and (±)-G7 were remarkably differentiated by the split protons of CONH and PhCH₃ groups, respectively. Especially, a maximum nonequivalent chemical shift value (ΔΔδ) of the NH proton (CONH) of (±)-G7 has been established as 1.031 ppm, which is a sufficiently large nonequivalent chemical shift value in the field of chiral recognition by ¹H NMR chiral solvating agents. Subsequently, the assignments of enantiomers were determined by adding (R)-G1 and (R)-G7 to their corresponding samples note above. The ¹H NMR spectra of (±)-G7 (a) and (±)-G7 in the presence of TAMCSA 1c (b), including partial expanded spectra and ΔΔδ values of the split protons of CONH and PhCH₃, are shown in Figure 1.

Figure 1.

¹H NMR spectra of (±)-G7 (a) and (±)-G7 in the presence of TAMCSA 1c (b) and their expanded spectra in CDCl₃ at 25 °C (400 MHz), [(±)-G7] = 10 mM. The marks “red ○”and “red ●” stand for (S)-G7 and (R)-G7, respectively.

Encouraged by these remarkable chiral discriminating results, we sought to further test and evaluate a range of chiral discriminating conditions, including concentration effects, the molar ratio of the host and guest, and a variety of deuterated solvents. In the end, CDCl₃ (in most cases) and a 1:1 molar ratio of the host/guest were adopted in this study. Different concentrations were used from 2.0 to 12.5 mM for obtaining clear ¹H NMR signals with as little overlapping and better baseline resolution peaks as possible. Detailed information is available (Table S1 and Figures S1 and S2).

Under optimized conditions, 40 samples of (±)-G1–14 were prepared in the presence of TAMCSAs 1a–1c in CDCl₃ or CDCl₃ containing 10% CD₃COCD₃ (three samples). Their ¹H NMR spectra were measured on a 400 or 600 MHz spectrometer at 25 °C, with the exception of (±)-G1 with TAMCSA 1a and (±)-G7 with TAMCSA 1c. The results indicate that the separated ¹H NMR signals of the multiple protons of (±)-G1–14 were detected in the presence of TAMCSAs 1a–1c. Subsequently, the assignments of enantiomers [(S)-GX (red ○) and (R)-GX (red ●), X = 1–7 and 9–13; (S,R)-GX (red ○) and (R,S)-GX (red ●), X = 8 and 14] were determined based on the aforementioned method. The ΔΔδ values and partial ¹H NMR spectra of the NH proton (CONH) of (±)-G1–14, as the representative protons, are summarized in Table 1.

Table 1.

Nonequivalent Chemical Shifts (ΔΔδ, ppm) and Partial ¹H NMR Spectra of the NH Proton (CONH) of (+)-G1–14 in the Presence of TAMCSAs 1a–1c in CDCl₃ (400 or 600 MHz) at 25 °C^a

^a5.0 mM.

^b7.5 mM.

^c10.0 mM.

^d6.0 mM.

^e4.0 mM.

^f12.5 mM.

^g2.0 mM.

^h3.0 mM.

ⁱ600 MHz.

^j10% CD₃COCD₃.

As shown Table 1, all of the ΔΔδ values of the split NH proton of (±)-G1–14 exceed 0.1 ppm (from 0.167 to 1.309 ppm) in the TAMCSAs 1a–1c. Furthermore, among them, a maximum ΔΔδ value was observed at 1.309 ppm, which is unprecedented for the separated ¹H NMR signal in the field of chiral recognition by CSAs. In addition, compared with the ΔΔδ values of the split proton of (±)-G2 and (±)-G3, and (±)-G7 and (±)-G8, the ΔΔδ values of the corresponding protons of the (±)-G11–14 with the 3,5-bis(trifluoromethyl)-phenyl group exhibited a clear tendency to become larger in most cases in the presence of the same chiral solvating agent, which may be the result of the electronic effect of the 3,5-bis(trifluoromethyl)phenyl substituent. Additional ΔΔδ values of other protons and the ¹H NMR spectra of (±)-G1–14 are shown in Table 2.

Table 2.

Nonequivalent Chemical Shifts (ΔΔδ, ppm) of Other Split Protons of (±)-G1–14 in the Presence of TAMCSAs 1a–1c in CDCl₃ (400 or 600 MHz) at 25 °C^a

guest/TAMCSA	proton	ΔΔδ	guest/TAMCSA	proton	ΔΔδ
(±)-G1/1a	PhCH	0.030	(±)-G9/1bb	4-PhCH2CH	0.024
(±)-G1/1bb	PhCH	0.041	(±)-G9/1ce	PhCH3	0.007
(±)-G1/1c	PhCH	0.029		4-PhCH2CH	0.052
(±)-G2/1a	PhCH2	0.091	(±)-G10/1ac	CH 2	0.070
		0.049		α-H(trp unit)	0.036
	PhCH2CH	0.042		ArH	0.012
(±)-G2/1bb	PhCH2	0.061		ArH	0.119
		0.040		C═CHNH	0.031
	PhCH2CH	0.031	(±)-G10/1bf	CH 2	0.051
(±)-G2/1cc	PhCH2	0.111		α-H(trp unit)	0.027
		0.054		ArH	0.067
	PhCH2CH	0.051		ArH	0.013
(±)-G3/1ac,i	CH 3	0.049	(±)-G10/1cb	CH 2	0.045
(±)-G3/1bb	CH 3	0.020		α-H(trp unit)	0.029
(±)-G3/1cd,i	CH 3	0.029		ArH	0.078
(±)-G4/1a	(CH3)2CHCH	0.014		C═CHNH	0.030
		0.042	(±)-G11/1ac	PhCH2	0.153
	(CH3)2CHCH	0.031			0.100
(±)-G4/1b	(CH3)2CHCH	0.007		PhCH2CH	0.086
		0.022		ArH	0.061
	(CH3)2CHCH	0.024		ArH	0.014
(±)-G4/1cb	(CH3)2CHCH	0.013	(±)-G11/1bb	PhCH2	0.095
		0.044			0.068
	(CH3)2CHCH	0.037		PhCH2CH	0.077
(±)-G5/1ae	CH 3	0.018		ArH	0.058
		0.007		ArH	0.012
	(CH3)2CHCH2CH	0.039	(±)-G11/1cc	PhCH2	0.154
(±)-G5/1bc	CH 3	0.022			0.087
		0.008		PhCH2CH	0.080
	(CH3)2CHCH2CH	0.059		ArH	0.061
(±)-G5/1c	CH 3	0.020		ArH	0.013
		0.008	(±)-G12/1ah	CH 3	0.034
	(CH3)2CHCH2CH	0.045		ArH	0.016
(±)-G6/1ab	SCH3	0.030	(±)-G12/1bd	CH 3	0.017
(±)-G6/1bb	SCH3	0.021		ArH	0.032
(±)-G6/1cb	SCH3	0.025	(±)-G12/1cb	CH 3	0.032
(±)-G7/1ac	PhCH3	0.038		ArH	0.019
(±)-G7/1bc	PhCH3	0.023	(±)-G13/1ab	ArH	0.026
(±)-G7/1cc	PhCH3	0.033		ArH	0.012
(±)-G8/1ab	CH 3	0.040	(±)-G13/1bb	ArH	0.014
	PhCH3	0.037		ArH	0.040
	CH3(OH)CHCH	0.027	(±)-G13/1cc	ArH	0.022
(±)-G8/1bf	CH 3	0.050		ArH	0.029
	PhCH3	0.025	(±)-G14/1ab,j	CH 3	0.024
	CH3(OH)CHCH	0.024		CH3(OH)CHCH	0.028
(±)-G8/1cb	CH 3	0.038	(±)-G14/1bb,j	CH 3	0.009
	PhCH3	0.035		CH3(OH)CHCH	0.022
	CH3(OH)CHCH	0.027	(±)-G14/1cj	CH 3	0.018
(±)-G9/1ag	PhCH3	0.005		CH3(OH)CHCH	0.021
	4-PhCH2CH	0.030

^a5.0 mM.

^b7.5 mM.

^c10.0 mM.

^d6.0 mM.

^e4.0 mM.

^f12.5 mM.

^g2.0 mM.

^h3.0 mM.

ⁱ600 MHz.

^jCDCl₃ (10% CD₃COCD₃).

Stimulated by the highly significant discriminating results noted above, we strongly desired to explore interactions between the host and guest and the possible mechanism of chiral discrimination. First, Job plots²⁵ of (±)-G1 with TAMCSA 1a were achieved by ¹H NMR titration experiments. The results show that a maximum value (X × Δδ_SR = 0.184 ppm, X × Δδ_S = 0.255 ppm, and X × Δδ_R = 0.071 ppm) of the NH proton (CONH) of (±)-G1 was observed at a molar fraction of X = 0.5. Meanwhile, a maximum value (X × Δδ_SR = 0.011 ppm, X × Δδ_S = 0.026 ppm, and X × Δδ_R = 0.015 ppm) of PhCH of (±)-G1 was also exhibited at a molar fraction of X = 0.5 (Figure 2). The two results suggest that a pair of diastereoisomeric complexes with 1:1 stoichiometry is established between (±)-G1 and TAMCSA 1a.

Figure 2.

Job plots for diastereoisomeric complexes of (S)-G1 and (R)-G1 with TAMCSA 1a. Δδ stands for the chemical shift change in NH (CONH) of (S)-G1 (red ●) and (R)-G1 (blue ●), and PhCH of (S)-G1 (green ▼) and (R)-G1 (red ▲) in the presence of TAMCSA 1a in CDCl₃ at 25 °C (400 MHz). X stands for the molar fraction of (±)-G1, (X = [(±)-G1]/[(±)-G1 + TAMCSA 1a]).

In addition, to further understand the chiral discriminating behavior between the guest and host, the geometries of enantiomers (S)-G1 and (R)-G1 with TAMCSA 1a were optimized using density functional theory (DFT) at the B3LYP/6-31G* level.²⁶ The continuum model (SMD) for chloroform was employed in all NMR calculations to simulate the effects of the solvent. All quantum chemical calculations were performed by the Gaussian 16 program package. The proposed models suggest that two pairs of hydrogen bonds between (S)-G1 and (R)-G1 with TAMCSA 1a have been established. The hydrogen bonding interactions, CONH⋯OCNH (1.845 Å) and NHCO⋯HOC₆H₄ (1.748 Å) between (S)-G1 and TAMCSA 1a and CONH⋯OCNH (1.884 Å) and NHCO⋯HOC₆H₄ (1.749 Å) between (R)-G1 and TAMCSA 1a, are shown in Figure 3.

Figure 3.

Proposed DFT models for the hydrogen bonding interactions between (S)-G1 (a) and (R)-G1 (b) with TAMCSA 1a.

Additionally, the corresponding chemical shifts and non-equivalent chemical shifts obtained by DFT/SMD calculations are shown in Table 3.

Table 3.

Observed and Calculated Chemical Shift Values (δ, ppm) and Nonequivalent Chemical Shift Values (Δδ, ppm) for the NH Proton (CONH) of (S)-G1 and (R)-G1 with TAMCSA 1a

	δ (S)-G1	δ (R)-G1	Δδa
obsd values	6.5995	6.1139	0.4856
calcd values	8.6570	8.1340	0.5230

^aΔδ=δ_(S)-G1 - δ_(R)-G1.

The Cartesian coordinates and total energies (hartree) of the complexes of (S)-G1 and (R)-G1 with TAMCSA 1a were obtained by means of B3LYP/6-31G* structural optimization (Tables S2–S6).

To further evaluate the intermolecular interaction between the host and guest, ¹H NMR titration of (S)-G2 and (R)-G2 with TAMCSA 1a was performed, and their association constants (K_a) were calculated by the nonlinear curve-fitting method and are shown in Table 4.²⁷

Table 4.

Association Constants (K_a, M⁻¹) of (S)-G2 and (R)-G2 with TAMCSA 1a in CDCl₃ (400 MHz)

guest	TAMCSA	Ka (M−1)	−ΔG° (kJ mol−1)
(S)-G2	1a	(3.98 ± 0.96) × 102	14.8 ± 4.4
(R)-G2	1a	(3.83 ± 1.50) × 102	14.7 ± 4.3

As shown in Table 4, it can be found that no significant differences between the association constants of (S)-G2 and (R)-G2 with TAMCSA 1a may result from the differences in the geometry of the diastereoisomeric complexes, rather than the thermodynamic factors.

A highly remarkable chiral discrimination has thus been established by the split ¹H NMR peaks of multiple protons of hydantoin derivatives, in conjunction with sufficiently enough nonequivalent chemical shift values. Based on these excellent discriminating results, we ventured to explore another research goal of chiral recognition, namely, its application in the determination of ee of chiral analytes. For this purpose, samples of G4 with different optical purities, containing (S)-G4% with 95.0, 90.0, 70.0, 50.0, 30.0, 5.0, and 0.0% ee, were prepared in the presence of TAMCSA 1a in CDCl₃, and their ¹H NMR spectra were recorded on a 400 MHz spectrometer at 25 °C. Their ee values were calculated based on the integration of the NH proton (CONH), featuring well-separated ¹H NMR signals and superior baseline resolution. The ee values for samples of high optical purity (up to 95% ee) were clearly elucidated by ¹H NMR spectra (Figure 4a). An excellent linear correlation between the theoretical (X) and observed (Y) % ee values was obtained (Figure 4c). To further verify this application, another set of samples of G10 with different optical purities containing (S)-G10% with 90.0, 70.0, 50.0, 30.0, 5.0, and 0.0% ee was prepared in the presence of TAMCSA 1c, and their ¹H NMR spectra were recorded on a 400 MHz spectrometer. Similar results (up to 90% ee) were obtained based on the aforementioned method and are shown in Figure 4b,d.

Figure 4.

Determination of ee of G4 and G10, ee (%) = {[(S)-GX – (R)-GX]/[(S)-GX + (R)-GX]} × 100%, (X = 4 and 10). Overlaid ¹H NMR spectra of the NH proton (CONH) of (S)-G4 (red ○) and (R)-G4 (red ●) in the presence of TAMCSAs 1a [5 mM] (a) and (S)-G10 (red ○) and (R)-G10 (red ●) in the presence of TAMCSAs 1c [7.5 mM] (b) in CDCl₃ at 25 °C (400 MHz). Linear correlation between the theoretical (X) and observed (Y) % values of G4 with TAMCSA 1a (c) and G10 with TAMCSA 1c (d).

CONCLUSIONS

In conclusion, chiral recognition has been established by means of unprecedented nonequivalent chemical shift values (up to 1.309 ppm) of chiral hydantoin derivatives, in the presence of TAMCSAs 1a–1c by ¹H NMR spectroscopy. In addition, better baseline resolution and clear ¹H NMR signals without overlapping peaks have been achieved. Their practical application in the determination of ee values has been established by accurate calculation of the integration area of the NH proton (CONH) of G4 (up to 95% ee) in the presence of TAMCSA 1a and G10 (up to 90% ee) in the presence of TAMCSA 1c. Meanwhile, the intermolecular interaction between guests and hosts has been investigated by Job plots, association constants (K_a), and quantum chemical calculations. Most importantly, this work is highlighting the impact of the discrimination of enantiomers of chiral heterocyclic compounds and determination of ee values with the assistance of highly effective chiral solvating agents by ¹H NMR spectroscopy.

EXPERIMENTAL SECTION

General Information.

¹H NMR spectra and ¹³C NMR were recorded on a Bruker Avance III spectrometer at 400 MHz and JEOL spectrometers at 400 and 600 MHz at 25 °C. The peak patterns are shown as the singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). HRMS spectra were acquired on AB SCIEX Triple TOF 5600+. IR spectra were obtained on a 360 Avatar FT-IR spectrometer as KBr pellets. Optical rotations were measured on a PerkinElmer model 343 and Autopol III polarimeter using the sodium D line at 589 nm. All the solvents were dried by the standard procedure prior to use.

Synthesis of TAMCSAs 1a–1c.

To a solution of chiral diimines 3a–3c (1 mmol) in dried DMF (60 mL) were added the activated zinc powder (0.65 g, 10 mmol) and MsOH (0.96 g, 10 mmol) in dried DMF (20 mL). The mixture was stirred for 23 h under a nitrogen atmosphere from −18 °C to rt. The reaction mixture was basified to pH = 10 with a saturated NaHCO₃ solution. The precipitate formed was filtered off and washed with CHCl₃. The organic layer was separated from the filtrate. The water layer was extracted with CHCl₃ (15 mL × 3). The combined organic phase was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel to afford TAMCSAs 1a–1c in 17–25% yields and chiral compounds 2a–2c in 17–19% yields.

(3R,5S,6S,8R,10aS, 14aS)-3,8-Dibenzyl-5,6-bis(2-hydroxy-5-methylphenyl)tetradecahydrobenzo[b][1, 4, 7, 10]-tetraazacydododecine-2,9-dione (TAMCSA 1a).

149 mg, 23% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1/2). mp 186–188 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+64.8$ (c 0.01, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.15–7.19 (m, 6H), 7.06–7.08 (m, 4H), 6.89 (dd, J = 8.20, 1.64 Hz, 2H), 6.81 (d, J = 8.12 Hz, 2H), 5.95 (s, 2H), 5.71 (d, J = 7.88 Hz, 2H), 4.32 (s, 2H), 3.68–3.73 (m, 2H), 3.28–3.32 (m, 2H), 2.93 (dd, J = 12.66, 9.78 Hz, 2H), 2.78 (dd, J = 12.68, 5.52 Hz, 2H), 2.01 (s, 6H), 1.62–1.64 (m, 2H), 1.24–1.27 (m, 2H), 1.11–1.16 (m, 2H), 0.90–0.96 (m, 2H). ¹³C{¹H}NMR (100 MHz, CDCl₃): δ 173.7, 152.7, 136.7, 129.3, 128.6, 128.4, 128.3, 128.1, 126.7, 125.2, 116.8, 67.0, 61.6, 52.7, 40.1, 31.5, 24.6, 20.4. IR (KBr, cm⁻¹): 3286, 2936, 1655, 1560, 1500, 1455, 1260, 700. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₄₀H₄₇N₄O₄, 647.3591; found, 647.3594.

(3R,5S,6S,8R,10aS, 14aS)-3,8-Dibenzyl-5,6-bis(2-hydroxy-3-methoxyphenyl)tetradecahydrobenzo[b][1, 4, 7, 10]-tetraazacyclododecine-2,9-dione (TAMCSA 1b).

115 mg, 17% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 2/3). mp 179–180 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+50.4$ (c 0.01, THF). ¹H NMR (400 MHz, CDCl₃): δ 7.12–7.19 (m, 6H), 7.08–7.10 (m, 4H), 6.71 (d, J = 8.04 Hz, 2H), 6.62 (t, J = 7.90 Hz, 2H), 6.37 (d, J = 7.28 Hz, 2H), 5.53 (br, 2H), 4.34 (s, 2H), 3.78 (s, 6H), 3.61–3.67 (m, 2H), 3.19–3.23 (m, 2H), 2.89–2.91 (m, 4H), 1.69 (br, 2H), 1.59–1.61 (m, 2H), 1.26–1.29 (m, 2H), 1.09–1.14 (m, 2H), 0.83–0.90 (m, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 174.0, 147.4, 145.4, 137.1, 129.4, 128.3, 126.6, 124.2, 120.7, 118.5, 110.6, 66.8, 63.0, 56.0, 52.9, 40.1, 31.7, 24.7. IR (KBr, cm⁻¹): 3300, 2938, 1661, 1631, 1450, 1406, 1238, 1076, 697. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₄₀H₄₇N₄O₆, 679.3490; found, 679.3465.

(3R,5S,6S,8R,10aS,14aS)-3,8-Dibenzyl-5,6-bis(2-hydroxy-4-methoxyphenyl)tetradecahydrobenzo[b][1, 4, 7, 10]-tetraazacyclododecine-2,9-dione (TAMCSA 1c).

170 mg, 25% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 2/3). mp 156–158 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+111.2$ (c 0.01, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.13–7.21 (m, 6H), 7.05–7.07 (m, 4H), 6.44 (s, 2H), 6.22–6.23 (m, 2H), 6.20–6.21 (m, 2H), 5.64 (s, 2H), 4.28 (s, 2H), 3.73 (s, 6H), 3.69–3.75 (m, 2H), 3.23–3.26 (m, 2H), 2.92 (dd, J = 12.36, 9.76 Hz, 2H), 2.82 (dd, J = 12.74, 5.54 Hz, 2H), 1.62–1.64 (m, 2H), 1.22–1.26 (m, 2H), 1.11–1.16 (m, 2H), 0.86–0.92 (m, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 174.1, 159.6, 156.4, 136.7, 129.3, 129.0, 128.3, 126.6, 117.5, 105.2, 102.2, 66.6, 61.6, 55.0, 52.6, 40.1, 31.4, 24.6. IR (KBr, cm⁻¹): 3297, 2936, 1660, 1617, 1511, 1455, 1161, 700. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₄₀H₄₇N₄O₆, 679.3490; found, 679.3488.

(2R,2′R)-N,N′-((1S,2S)-Cyclohexane-1,2-diyl)bis(2-((2-hydroxy-5-methylbenzyl)amino)-3-phenylpropanamide) (2a).

117 mg, 18% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1/1). mp 172–174 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+51.7$ (c 0.01, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.21–7.28 (m, 6H), 7.09–7.11 (m, 4H), 6.91 (dd, J = 8.16, 1.80 Hz, 2H), 6.70 (d, J = 8.12 Hz, 2H), 6.53 (d, J = 5.84 Hz, 2H), 6.49 (d, J = 1.6 Hz, 2H), 3.78 (d, J = 13.04 Hz, 2H), 3.50–3.53 (m, 2H), 3.46 (d, J = 13.04 Hz, 2H), 3.28 (t, J = 7.32 Hz, 2H), 2.98 (dd, J = 13.42, 7.02 Hz, 2H), 2.83 (dd, J = 13.4, 7.64 Hz, 2H), 2.09 (s, 6H), 1.79–1.82 (m, 2H), 1.64–1.66 (m, 5H), 1.19–1.24 (m, 2H), 0.90–0.98 (m, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 173.7, 154.6, 136.9, 129.5, 129.4, 129.1, 128.8, 128.6, 127.0, 122.9, 116.2, 63.6, 53.4, 50.5, 40.1, 31.9, 24.4, 20.3. IR (KBr, cm⁻¹): 3299, 2933, 1647, 1629, 1550, 1499, 1252, 817, 699. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₄₀H₄₉N₄O₄, 649.3748; found, 649.3750.

(2R,2′R)-N,N′-((1S,2S)-Cyclohexane-1,2-diyl)bis(2-((2-hydroxy-3-methoxybenzyl)amino)-3-phenylpropanamide) (2b).

129 mg, 19% yield as a white solid. R_f = 0.2 (ethyl acetate/petroleum ether = 2/3). mp 165—166 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+102.8$ (c 0.01, THF). ¹H NMR (400 MHz, CDCl₃): δ 7.42 (d, J = 6.56 Hz, 2H), 7.18–7.23 (m, 6H), 7.06–7.09 (m, 4H), 6.74 (dd, J = 8.16, 1.24 Hz, 2H), 6.63 (dd, J = 7.76, 7.92 Hz, 2H), 6.43 (dd, J = 7.60, 1.08 Hz, 2H), 3.85 (s, 6H), 3.81 (d, J = 12.84 Hz, 2H), 3.63—3.67 (m, 2H), 3.42 (d, J = 12.84 Hz, 2H), 3.29 (dd, J = 9.10, 5.30 Hz, 2H), 3.11 (dd, J = 13.70, 5.26 Hz, 2H), 2.65 (dd, J = 13.62, 9.18 Hz, 2H), 2.02–2.05 (m, 2H), 1.70–1.73 (m, 2H), 1.29–1.34 (m, 2H), 1.07–1.15 (m, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 173.9, 147.2, 145.2, 137.3, 129.0, 128.6, 126.8, 124.1, 121.7, 119.2, 110.6, 63.2, 56.0, 52.9, 49.3, 40.1, 32.2, 24.6. IR (KBr, cm⁻¹): 3292, 2940, 2860, 1641, 1530, 1481, 1456, 1269, 1240, 1074, 733, 696. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₄₀H₄₉N₄O₆, 681.3647; found, 681.3587.

(2R,2′R)-N,N′-((1S,2S)-Cyclohexane-1,2-diyl)bis(2-((2-hydroxy-4-methoxybenzyl)amino)-3-phenylpropanamide) (2c).

116 mg, 17% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1/1). mp 186–188 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+69.9$ (c 0.01, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.21–7.30 (m, 6H), 7.12–7.13 (m, 4H), 6.62 (d, J = 8.32 Hz, 2H), 6.38 (d, J = 2.48 Hz, 2H), 6.32 (d, J = 5.64 Hz, 2H), 6.23 (dd, J = 8.28, 2.52 Hz, 2H), 3.78 (d, J = 13.08 Hz, 2H), 3.72 (s, 6H), 3.46–3.49 (m, 4H), 3.27 (t, J = 7.32 Hz, 2H), 2.96 (dd, J = 13.42, 7.22 Hz, 2H), 2.87 (dd, J = 13.42, 7.42 Hz, 2H), 1.75–1.78 (m, 2H), 1.63–1.66 (m, 2H), 1.17–1.22 (m, 2H), 0.88–0.94 (m, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 173.6, 160.6, 158.3, 136.9, 129.4, 129.1, 128.8, 127.0, 115.2, 105.1, 102.3, 63.2, 55.2, 53.7, 50.0, 40.1, 31.8, 24.4. IR (KBr, cm⁻¹): 3330, 3303, 1633, 1535, 1508, 1204, 1160, 1106, 699. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₄₀H₄₉N₄O₆, 681.3647; found, 681.3659.

Synthesis of Enantiomrs of Hydantoin Derivatives G1–14.

To d- or l-amino acid (5.5 mmol, 1.1 equiv) in NaOH solution (1 M, 5 mL) was dropwise added the corresponding isocyanate (5 mmol) in CH₃CN (2 mL) at 0 °C. 1,4-Dioxane (5 mL) was added to the reaction solution after the mixture was stirred for 3 h. It was acidified to pH = 2 with concd hydrochloric acid after the reaction mixture was stirred for 8 h at room temperature. The mixture was stirred again for 10 h at 110 °C using a lab heating mantle. After cooling, the reaction mixture was extracted with EtOAc (10 mL × 3), and the combined organic phase was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel to afford the corresponding enantiomers of hydantoin derivatives G1–14 in 50–89% yields.

(S)-5-Phenyl-3-(p-tolyl)imidazolidine-2,4-dione ((S)-G1).

1.07 g, 85% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 2/3). mp 240–243 °C. $[\alpha {]}_{20}^{\mathrm{D}}=-5.4$ (c 0.01, DMSO). ¹H NMR (400 MHz, CDCl₃): δ 7.42–7.44 (m, 5H), 7.26 (s, 3H), 6.28 (s, 1H), 5.19 (s, 1H), 2.37 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 171.0, 157.0, 134.2, 129.8, 129.2, 128.6, 126.5, 126.1, 60.6, 21.2. IR (KBr, cm⁻¹): 2915, 1713, 1515, 1430, 1176, 810, 708. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₅N₂O₂, 267.1128; found, 267.1126.

(R)-5-Phenyl-3-(p-tolyl)imidazolidine-2,4-dione ((R)-G1).

1.10 g, 87% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 2:3). mp 242–246 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+5.6$ (c 0.01, DMSO). ¹H NMR (400 MHz, CDCl₃): δ 7.42–7.45 (m, 5H), 7.26 (s, 3H), 6.29 (s, 1H), 5.19 (s, 1H), 2.37 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 171.0, 156.9, 138.5, 134.2, 129.8, 129.2, 128.6, 126.5, 126.1, 60.6, 21.2. IR (KBr, cm⁻¹): 2915, 1713, 1515, 1425, 1176, 810, 708. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₅N₂O₂, 267.1128; found, 267.1126.

(R)-5-Benzyl-3-(p-tolyl)imidazolidine-2,4-dione ((R)-G2).

1.07 g, 80% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1:1). mp 119–120 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+194.7$ (c 0.01, CH₃OH). ¹H NMR (400 MHz, CDCl₃): δ 7.28–7.33 (m, 3H), 7.21–7.25 (m, 4H), 7.04 (d, J = 8.20 Hz, 2H), 6.33 (s, 1H), 4.35–4.38 (m, 1H), 3.05 (dd, J = 13.90, 3.82 Hz, 1H), 3.05 (dd, J = 13.86, 7.34 Hz, 1H), 2.36 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 172.2, 156.5, 138.5, 134.7, 129.8, 129.5, 128.8, 128.6, 127.5, 126.1, 58.1, 37.9, 21.2. IR (KBr, cm⁻¹): 3288, 1724, 1476, 1419, 1278, 1137, 894, 702. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₇N₂O₂, 281.1284; found, 281.1289.

(R)-5-Methyl-3-(p-tolyl)imidazolidine-2,4-dione ((R)-G3).

0.75 g, 79% yield as a white solid. R_f = 0.2 (ethyl acetate/petroleum ether = 1:1). mp 150–153 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+32.5$ (c 0.01, CH₃OH). ¹H NMR (400 MHz, CDCl₃): δ 7.27 (br, 4H), 6.33 (s, 1H), 4.21–4.23 (m, 1H), 2.38 (s, 3H), 1.54 (d, J = 6.36 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 173.7, 156.8, 138.5, 129.8, 128.7, 126.1, 52.9, 21.2, 17.8, IR (KBr, cm⁻¹): 3232, 1713, 1520, 1430, 1188, 815, 770. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₁H₁₃N₂O₂, 205.0971; found, 205.0973.

(R)-5-Isopropyl-3-(p-tolyl)imidazolidine-2,4-dione ((R)-G4).

0.93 g, 85% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 2:3). mp 170–173 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+96.6$ (c 0.01, CH₃OH). ¹H NMR (400 MHz, CDCl₃): δ 7.25 (br, 4H), 6.06 (br, 1H), 4.05–4.06 (m, 1H), 2.38 (s, 3H), 2.32–2.33 (m, 1H), 1.09 (d, J = 6.84 Hz, 3H), 1.01 (d, J = 6.64 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 166.8, 151.6, 132.6, 124.0, 123.0, 120.3, 56.4, 24.8, 15.4, 12.9, 10.2. IR (KBr, cm⁻¹): 3226, 1770, 1713, 1515, 1425, 1176, 787, 764. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₇N₂O₂, 233.1284; found, 233.1286.

(S)-5-Isobutyl-3-(p-tolyl)imidazolidine-2,4-dione ((S)-G5).

0.80 g, 69% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 2:3). mp 136–138 °C. $[\alpha {]}_{20}^{\mathrm{D}}=-78.3$ (c 0.01, CH₃OH). ¹H NMR (400 MHz, CDCl₃): δ 7.26 (br, 4H), 6.00 (br, 1H), 4.17–4.19 (m, 1H), 2.38 (s, 3H), 1.85–1.89 (m, 2H), 1.65–1.68 (m, 1H), 1.00 (2d, J = 6.68, 7.36 Hz, 6H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 173.5, 156.8, 138.3, 129.7, 128.8, 126.0, 55.7, 41.0, 25.1, 23.0, 21.7, 21.2. IR (KBr, cm⁻¹): 3254, 2955, 1719, 1515, 1413, 1170, 815, 753. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₉N₂O₂, 247.1441; found, 247.1438.

(R)-5-Isobutyl-3-(p-tolyl)imidazolidine-2,4-dione ((R)-G5).

0.87 g, 75% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 2:3). mp 136–138 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+78.5$ (c 0.01, CH₃OH). ¹H NMR (400 MHz, CDCl₃): δ 7.26 (br, 4H), 6.16 (br, 1H), 4.17–4.19 (m, 1H), 2.38 (s, 3H), 1.85–1.89 (m, 2H), 1.65–1.68 (m, 1H), 1.00 (2d, J = 7.12, 6.96 Hz, 6H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 173.5, 156.9, 138.3, 129.8, 128.8, 126.0, 55.7, 25.1, 23.0, 21.7, 21.2. IR (KBr, cm⁻¹): 3254, 2955, 1719, 1515, 1413, 1171, 821, 747. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₉N₂O₂, 247.1441; found, 247.1443.

(S)-5-(2-(Methylthio)ethyl)-3-(p-tolyl)imidazolidine-2,4-dione ((S)-G6).

0.99 g, 79% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1:1). mp 109–111 °C. $[\alpha {]}_{20}^{\mathrm{D}}=-53.9$ (c 0.01, CH₃OH). ¹H NMR (400 MHz, CDCl₃): δ 7.27 (br, 4H), 6.49 (br, 1H), 4.28–4.31 (m, 1H), 2.67–2.71 (m, 2H), 2.38 (s, 3H), 2.28–2.34 (m, 1H), 2.12 (s, 3H), 2.04–2.10 (m, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 172.8, 156.7, 138.4, 130.0, 128.7, 126.0, 56.3, 30.5, 30.1, 21.2, 15.3. IR (KBr, cm⁻¹): 3277, 2915, 1781, 1713, 1515, 1425, 1188, 815, 674. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₇N₂O₂S, 265.1005; found, 265.1007.

(R)-5-(2-(Methylthio)ethyl)-3-(p-tolyl)imidazolidine-2,4-dione ((R)-G6).

1.11 g, 89% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1:1). mp 107–108 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+54.2$ (c 0.01, CH₃OH). ¹H NMR (400 MHz, CDCl₃): δ 7.27 (br, 4H), 6.39 (br, 1H), 4.29–4.31 (m, 1H), 2.68–2.71 (m, 2H), 2.38 (s, 3H), 2.29–2.33 (m, 1H), 2.12 (s, 3H), 2.06–2.10 (m, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 172.8, 156.8, 138.4, 129.8, 128.7, 126.0, 56.3, 30.5, 30.1, 21.2, 15.3. IR (KBr, cm⁻¹): 3277, 2916, 1781, 1713, 1515, 1425, 1188, 821, 674. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₇N₂O₂S, 265.1005; found, 265.1003.

(S)-5-(Hydroxymethyl)-3-(p-tolyl)imidazolidine-2,4-dione ((S)-G7).

0.88 g, 85% yield as a white solid. R_f = 0.2 (ethyl acetate/petroleum ether = 8:1). mp 168–170 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+99.8$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 7.26 (br, 4H), 6.04 (br, 1H), 4.25–4.27 (m, 1H), 3.96–4.01 (m, 2H), 2.38 (s, 4H). ¹³C{¹H} NMR (100 MHz, CD₃OD): δ 172.8, 157.7, 138.1, 129.4, 129.2, 126.4, 60.4, 59.5, 19.8. IR (KBr, cm⁻¹): 3260, 2916, 1713, 1520, 1425, 1334, 1171, 776. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₁H₁₃N₂O₃, 221.0920; found, 221.0923.

(R)-5-(Hydroxymethyl)-3-(p-tolyl)imidazolidine-2,4-dione ((R)-G7).

0.89 g, 86% yield as a white solid. R_f = 0.2 (ethyl acetate/petroleum ether = 8:1). mp 168–170 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+98.7$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 7.26 (br, 4H), 6.18 (br, 1H), 4.24–4.26 (m, 1H), 3.94–4.00 (m, 2H), 2.50 (br, 1H), 2.38 (s, 3H). ¹³C{¹H} NMR (100 MHz, CD₃OD): δ 172.8, 157.7, 138.1, 129.4, 129.2, 126.4, 60.4, 59.5, 19.8. IR (KBr, cm⁻¹): 3328, 2921, 1775, 1713, 1521, 1425, 1176, 680. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₁H₁₃N₂O₃, 221.0920; found, 221.0919.

(S)-5-((R)-1-Hydroxyethyl)-3-(p-tolyl)imidazolidine-2,4-dione ((S,R)-G8).

0.87 g, 79% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 6:1). mp 176–178 °C. $[\alpha {]}_{20}^{\mathrm{D}}=-122.9$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 7.22–7.27 (m, 4H), 6.55 (s, 1H), 4.21 (br, 1H), 4.01–4.03 (m, 1H), 2.64 (br, 1H), 2.37 (s, 3H), 1.34 (d, J = 6.52 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CD₃OD): δ 173.0, 157.9, 138.1, 129.4, 129.2, 126.4, 66.3, 62.9, 19.8, 18.9. IR (KBr, cm⁻¹): 3305, 1781, 1719, 1515, 1425, 1182, 810. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₅N₂O₃, 235.1077; found, 235.1081.

(R)-5-((S)-1-Hydroxyethyl)-3-(p-tolyl)imidazolidine-2,4-dione ((R,S)-G8).

0.97 g, 88% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 6:1). mp 174–176 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+121.1$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 7.22–7.25 (m, 4H), 6.64 (s, 1H), 4.20 (br, 1H), 4.00–4.01 (m, 1H), 2.71–2.73 (m, 1H), 2.37 (s, 3H), 1.33 (d, J = 6.44 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CD₃OD): δ 173.0, 157.9, 138.1, 129.4, 129.2, 126.4, 66.3, 62.9, 19.8, 18.9. IR (KBr, cm⁻¹): 3305, 1781, 1719, 1515, 1425, 1182, 810. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₅N₂O₃, 235.1077; found, 235.1074.

(S)-5-(4-Hydroxybenzyl)-3-(p-tolyl)imidazolidine-2,4-dione ((S)-G9).

1.16 g, 82% yield as a white solid. R_f = 0.2 (ethyl acetate/petroleum ether = 1:1). mp 80–83 °C. $[\alpha {]}_{20}^{\mathrm{D}}=-158.0$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 7.22 (d, J = 8.08 Hz, 2H), 7.04–7.08 (m, 4H), 6.71 (d, J = 8.48 Hz, 2H), 6.03 (br, 1H), 5.48 (s, 1H), 4.35–4.38 (m, 1H), 3.18 (dd, J = 14.12, 4.04 Hz, 1H), 3.02 (dd, J = 14.12, 6.92 Hz, 1H), 2.35 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 172.8, 157.3, 155.3, 138.8, 130.8, 129.9, 128.3, 126.3, 125.7, 115.6, 58.3, 36.5, 21.1. IR (KBr, cm⁻¹): 3316, 1782, 1713, 1515, 1420, 1170, 815. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₇N₂O₃, 297.1233; found, 297.1236.

(R)-5-(4-Hydroxybenzyl)-3-(p-tolyl)imidazolidine-2,4-dione ((R)-G9).

1.17 g, 83% yield as a white solid. R_f = 0.2 (ethyl acetate/petroleum ether = 1:1). mp 82–84 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+158.8$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 7.21 (d, J = 8.00 Hz, 2H), 7.02–7.05 (m, 4H), 6.67 (d, J = 8.56 Hz, 2H), 6.27 (s, 1H), 5.82 (br, 1H), 4.34–4.38 (m, 1H), 3.14 (dd, J = 14.10, 4.14 Hz, 1H), 3.03 (dd, J = 14.12, 6.52 Hz, 1H), 2.34 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 172.8, 157.3, 155.3, 138.8, 130.8, 129.9, 128.3, 126.3, 125.7, 115.6, 58.3, 36.5, 21.1. IR (KBr, cm⁻¹): 3322, 1781, 1509, 1430, 1171, 815. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₇N₂O₃, 297.1233; found, 297.1237.

(S)-5-((1H-Indol-3-yl)methyl)-3-(p-tolyl)imidazolidine-2,4-dione((S)-G10).

1.28 g, 80% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 2:1). mp 92–95 °C. $[\alpha {]}_{20}^{\mathrm{D}}=-107.4$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 7.65 (d, J = 7.88 Hz, 1H), 7.36 (d, J = 8.12 Hz, 1H), 7.20–7.23 (m, 3H), 7.15 (t, J = 7.50 Hz, 1H), 7.04–7.06 (m, 3H), 5.75 (s, 1H), 4.42–4.45 (m, 1H), 3.49 (dd, J = 14.72, 3.76 Hz, 1H), 3.19 (dd, J = 14.68, 8.28 Hz, 1H), 2.35 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 172.7, 156.6, 138.4, 136.2, 129.7, 128.7, 127.0, 126.1, 123.4, 122.5, 119.9, 118.7, 111.4, 109.0, 57.7, 28.0, 21.2. IR (KBr, cm⁻¹): 3345, 1770, 1708, 1509, 1425, 1188, 815, 742. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₈N₃O₂, 320.1393; found, 320.1394.

(R)-5-((1 H-Indol-3-yl)methyl)-3-(p-tolyl)imidazolidine-2,4-dione ((R)-G10).

1.28 g, 80% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 2:1). mp 92–96 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+107.5$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 7.64 (d, J = 8.00 Hz, 1H), 7.35 (d, J = 8.04 Hz, 1H), 7.20–7.23 (m, 3H), 7.15 (t, J = 7.23 Hz, 1H), 7.02–7.05 (m, 3H), 5.84 (s, 1H), 4.41–4.44 (m, 1H), 3.47 (dd, J = 14.70, 3.70 Hz, 1H), 3.18 (dd, J = 14.70, 8.18 Hz, 1H), 2.35 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 172.8, 156.8, 138.4, 136.2, 129.7, 128.6, 127.0, 126.1, 123.5, 122.4, 119.8, 118.7, 111.4, 108.9, 57.7, 27.9, 21.1. IR (KBr, cm⁻¹): 3345, 1770, 1713, 1515, 1419, 1176, 810, 748. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₈N₃O₂, 320.1393; found, 320.1395.

(S)-5-Benzyl-3-(3,5-bis(trifluoromethyl)phenyl)imidazolidine-2,4-dione ((S)-G11).

1.11 g, 55% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1:4). mp 110–111 °C. $[\alpha {]}_{20}^{\mathrm{D}}=-101.2$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 7.85 (s, 1H), 7.78 (s, 2H), 7.30–7.36 (m, 3H), 7.24–7.26 (m, 2H), 5.82 (s, 1H), 4.47–4.49 (m, 1H), 3.35 (dd, J = 13.86, 3.10 Hz, 1H), 3.08 (dd, J = 13.94, 7.82 Hz, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 171.1, 154.9, 134.1, 132.9, 132.5 (q, J = 33.9 Hz), 129.4, 129.0, 127.9, 126.0–126.8 (m), 122.8 (q, J = 269.7 Hz), 121.7(5)-121.8 (m), 58.2, 38.1. ¹⁹F NMR (376 MHz, CDCl₃): δ −62.8. IR (KBr, cm⁻¹): 3299, 1790, 1726, 1476, 1418, 1279, 1184, 112, 895, 700. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₃N₂O₂F₆, 403.0875; found, 403.0879.

(R)-5-Benzyl-3-(3,5-bis(trifluoromethyl)phenyl)imidazolidine-2,4-dione ((R)-G11).

1.05 g, 52% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1:4). mp 110–111 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+99.5$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 7.85 (s, 1H), 7.77 (s, 2H), 7.30–7.38 (m, 3H), 7.24–7.26 (m, 2H), 5.89 (s, 1H), 4.47–4.50 (m, 1H), 3.34 (dd, J = 13.92, 3.72 Hz, 1H), 3.08 (dd, J = 13.96, 7.80 Hz, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 171.4, 155.6, 134.1, 132.9, 132.5 (q, J = 33.9 Hz), 129.6, 128.9, 127.9, 126.1–126.1(2) (m), 122.8 (q, J = 271.5 Hz), 121.8–121.9 (m), 58.2, 38.0. ¹⁹F NMR (376 MHz, CDCl₃): δ −62.8. IR (KBr, cm⁻¹): 3285, 1780, 1728, 1448, 1416, 1279, 1179, 1132, 895, 698. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₃N₂O₂F₆, 403.0875; found, 403.0880.

(S)-3-(3,5-Bis(trifluoromethyl)phenyl)-5-methylimidazolidine-2,4-dione ((S)-G12).

0.88 g, 54% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1:2). mp 90–91 °C. $[\alpha {]}_{20}^{\mathrm{D}}=-21.5$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 8.04 (s, 1H), 7.88 (s, 2H), 6.43 (br, 1H), 4.30–4.35 (m, 1H), 1.60 (d, J = 6.92 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 172.5, 155.0, 133.2, 132.5 (q, J = 33.9 Hz), 125.7–125.7(5) (m), 122.8 (q, J = 271.5 Hz), 121.5(5)–121.6 (m), 52.9, 17.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −62.8. IR (KBr, cm⁻¹): 3316, 1787, 1730, 1476, 1413, 1278, 1176, 1137, 894, 680; HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₂H₉N₂O₂F₆, 327.0562; found, 327.0559.

(R)-3-(3,5-Bis(trifluoromethyl)phenyl)-5-methylimidazolidine-2,4-dione ((R)-G12).

0.82 g, 50% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1:2). mp 90–92 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+22.5$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 8.03 (s, 1H), 7.88 (s, 2H), 6.48 (br, 1H), 4.30–4.35 (m, 1H), 1.60 (d, J = 6.96 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 172.6, 155.0, 133.2, 132.5 (q, J = 33.9 Hz), 125.7 (q, J = 3.4 Hz), 122.8 (q, J = 271.5 Hz), 121.5(5)–121.6 (m), 52.9, 17.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −62.8. IR (KBr, cm⁻¹): 3316, 1782, 1732, 1478, 1416, 1281, 1179, 1132, 893, 681. HRMS (ESI⁺-TOF) m/z: [M + H]+ calcd for C₁₂H₉N₂O₂F₆, 327.0562; found, 327.0556.

(S)-3-(3,5-Bis(trifluoromethyl)phenyl)-5-(hydroxymethyl)-imidazolidine-2,4-dione ((S)-G13).

0.91 g, 53% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 2:1). mp 134–136 °C. $[\alpha {]}_{20}^{\mathrm{D}}=-57.6$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 8.02 (s, 2H), 7.89 (s, 1H), 6.13 (br, 1H), 4.35–4.37 (m, 1H), 4.03–4.12 (m, 2H), 2.28 (br, 1H). ¹³C{¹H} NMR (100 MHz, CD₃OD): δ 171.8, 156.2, 134.2, 131.9 (q, J = 33.6 Hz), 126.1 (q, J = 3.9 Hz), 123.1 (q, J = 270.5 Hz), 120.6–120.8 (m), 60.3, 59.6. ¹⁹F NMR (376 MHz, CD₃OD): δ −64.4. IR (KBr, cm⁻¹): 3418, 3260, 1787, 1724, 1476, 1419, 1278, 1188, 1131, 1075, 685. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₂H₉N₂O₃F₆, 343.0511; found, 343.0509.

(R)-3-(3,5-Bis(trifluoromethyl)phenyl)-5-(hydroxymethyl)-imidazolidine-2,4-dione ((R)-G13).

0.92 g, 54% yield as a white solid. R^f = 0.3 (ethyl acetate/petroleum ether = 2:1). mp 132–133 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+57.8$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 8.02 (s, 2H), 7.88 (s, 1H), 6.21 (br, 1H), 4.36–4.38 (m, 1H), 4.04–4.14 (m, 2H), 2.28 (br, 1H). ¹³C{¹H} NMR (100 MHz, CD₃OD): δ 171.8, 156.2, 134.2, 131.9 (q, J = 33.7 Hz), 126.1 (q, J = 3.8 Hz), 123.1 (q, J = 270.5 Hz), 120.7 (q, J = 3.8 Hz), 60.3, 59.6. ¹⁹F NMR (376 MHz, CD₃OD): δ −64.3. IR (KBr, cm⁻¹): 3418, 3260, 1787, 1476, 1419, 1278, 1188, 1131, 1075, 889, 686. HRMS (ESI⁺-TOf) m/z: [M + H]⁺ calcd for C₁₂H₉N₂O₃F₆, 343.0511; found, 343.0512.

(S)-3-(3,5-Bis(trifluoromethyl)phenyl)-5-((R)-1-hydroxyethyl)-imidazolidine-2,4-dione ((S,R)-G14).

0.99 g, 56% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1:1). mp 178–180 °C. $[\alpha {]}_{20}^{\mathrm{D}}=-83.1$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 8.02 (s, 2H), 7.87 (s, 1H), 5.84 (s, 1H), 4.26–4.34 (m, 1H), 4.13–4.14 (m, 1H), 1.94 (d, J = 6.68 Hz, 1H), 1.45 (d, J = 6.48 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CD₃OD): δ 172.0, 156.4, 134.2, 131.9 (q, J = 33.6 Hz), 126.1 (q, J = 3.5 Hz), 123.1 (q, J = 270.5 Hz), 120.6–120.7 (m), 66.3, 63.0, 18.9. ¹⁹F NMR (376 MHz, CD₃OD): δ −64.3. IR (KBr, cm⁻¹): 3433, 3372, 1777, 1730, 1482, 1423, 1281, 1182, 1135, 1088, 890, 686; HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₁N₂O₃F₆, 357.0668; found, 357.0669.

(R)-3-(3,5-Bis(trifluoromethyl)phenyl)-5-((S)-1-hydroxyethyl)-imidazolidine-2,4-dione ((R,S)-G14).

1.02 g, 57% yield as a white solid. R_f = 0.3 (ethyl acetate/petroleum ether = 1:1). mp 172–174 °C. $[\alpha {]}_{20}^{\mathrm{D}}=+82.9$ (c 0.01, DMF). ¹H NMR (400 MHz, CDCl₃): δ 8.02 (s, 2H), 7.87 (s, 1H), 5.89 (s, 1H), 4.26–4.33 (m, 1H), 4.13–4.14 (m, 1H), 1.95 (d, J = 6.64 Hz, 1H), 1.45 (d, J = 6.48 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CD₃OD): δ 172.0, 156.4, 134.2, 131.9 (q, J = 33.6 Hz), 126.1–126.1(2) (m), 123.1 (q, J = 270.5 Hz), 120.6–120.7 (m), 66.3, 63.0, 18.9. ¹⁹F NMR (376 MHz, CD₃OD): δ −64.4. IR (KBr, cm⁻¹): 3373, 1775, 1730, 1481, 1425, 1278, 1182, 1131, 1086, 894, 680. HRMS (ESI⁺-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₁N₂O₃F₆, 357.0668; found, 357.0667.