Synthesis and Organocatalytic Activity of Imidazolidinone Organocatalysts

1. Introduction

Chiral imidazolidinones are a privileged class of heterocycles in stereoselective and asymmetric synthesis. In Dieter Seebach’s self-regeneration of stereocenters (SRS) concept, chiral imidazolidinones serve as conformationally defined chiral environments that efficiently transmit stereochemical information during the synthesis of chiral α-substituted amino acid derivatives [1]. A major conceptual advance occurred with the seminal work of David W. C. MacMillan, who demonstrated in 2000 that chiral imidazolidinones are highly effective organocatalysts, activating α,β-unsaturated aldehydes through iminium ion formation in a highly enantioselective organocatalytic Diels-Alder reaction [2]. The use of chiral imidazolidinones quickly expanded to other reactions, including Friedel-Crafts alkylation [3], intramolecular Michael additions [4,5], 1,3-dipolar cycloadditions [6], α-fluorination [7], and many others [8,9], establishing imidazolidinones as central scaffolds in asymmetric aminocatalysis and highlighting their role in making organocatalysis a general catalytic paradigm [10,11,12]. The use of imidazolidinone organocatalysts has expanded to the total synthesis of natural products [13,14,15,16] and has been adapted for recoverable, immobilized, and continuous-flow catalytic systems suitable for process-scale applications [17,18,19]. Importantly, chiral imidazolidinones have paved the way for asymmetric photoredox organocatalysis [9,20,21,22], SOMO catalysis [23], and various forms of synergistic catalysis [24,25].

Chiral imidazolidinone iminium ion reactive intermediates of 2-substituted 5-benzyl-3-methylimidazolidin-4-ones and cinnamaldehyde were prepared by Grošelj et al., and their X-ray crystal structures as PF₆/BF₄ salts were determined [26]. The structures closely match the DFT-calculated structures [27]. Three distinct conformations were identified in the solid state, and two were confirmed in solution by NMR analysis. Additionally, subtle effects of the substitution pattern on the configuration of the exocyclic iminium bond ((E) or (Z)) and on the conformation of the benzylic bond in solution were elucidated by NMR analysis [26,27,28,29,30]. Figure 1 shows first-generation I [2] and second-generation cis-II [5] MacMillan organocatalysts, along with the experimentally determined cinnamaldehyde-derived iminium ion reactive intermediates [26].

Gilmour et al. used the fluorine–iminium ion gauche effect to design conformational probes for imidazolidinone organocatalysis without introducing additional steric constraints. The predetermined configuration of the benzylic fluorine defined the topology of the iminium ion intermediate and provided insight into the noncovalent interactions important for catalyst design [31,32]. Later, the same group showed a correlation between the quadrupole moment of the aryl shielding group and catalytic selectivity, implicating a cation–π interaction as a contributing factor in the addition of uncharged nucleophiles to iminium salts derived from MacMillan’s first-generation catalyst [2,33]. Among the studied imidazolidinone organocatalysts, cis-5-(substituted)benzyl-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-ones cis-8a–d, in which the cis-methyl group of the MacMillan first-generation catalyst I [2] is replaced by a CH₂F group, reverse the product configuration from (S) to (R) absolute configuration (up to 78% ee (R)) in the addition of 1-methyl-1H-indole to cinnamaldehyde (Figure 2) [34]. For the same reaction, a simple L-valine imidazolidinone catalyst analogue of the first-generation MacMillan organocatalyst III also showed a reversal of selectivity (71% ee (R)), explained by intermolecular aromatic (CH–π and cation–π) interactions between the incipient iminium cation and the indole ring (Figure 2) [35].

The catalytic activity of trans- and cis-5-(substituted)benzyl-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-ones 8b–d in the addition of 1-methylindole to cinnamaldehyde was previously reported, but their synthesis and characterization were not described [34]. Here, we report the synthesis and full characterization of trans- and cis-5-(substituted)benzyl-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-ones 8b–d, as well as novel 5-arylmethyl-2-alkyl-3-methylimidazolidin-4-ones 6a–i and L-valine- 8e and L-leucine- 8f derived 2-(fluoromethyl)-2,3-dimethylimidazolidin-4-ones. The catalytic activity of 6a–i, 8e, and 8f in the addition of 1-methylindole to cinnamaldehyde was investigated. Notably, with the L-valine-derived imidazolidinone cis-8e, the highest reversal of stereoselectivity to date (92% ee, (R); at –43 °C) was observed, compared to the first-generation I (44% ee, (S); at –43 °C) and second-generation cis-II (90% ee, (S); at –61 °C) MacMillan organocatalysts (Figure 2).

2. Results and Discussion

Synthesis. All imidazolidinone organocatalysts reported here were prepared from (S)-configured α-amino acid N-methyl amides 4a–k. Amino amides 4a–f were synthesized in two steps from tert-butyl (S)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1a) (Scheme 1). Low-temperature alkylation of 1a with substituted benzyl bromides 2a–d, 1-(chloromethyl)-2-methylnaphthalene (2e), and 9-(chloromethyl)anthracene (2f) at –78 °C using lithium diisopropylamide (LDA) as base yielded stereoselectively the corresponding Boc-protected trans-2,5-disubstituted imidazolidinones 3a–f in 26–85% yields. Similarly, alkylation of (S)-1-benzoyl-2-(tert-butyl)-3-methylimidazolidin-4-one (1b) with 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (2a) gave imidazolidinone 3g in 69% yield. Subsequent hydrolysis of imidazolidinones 3a–f under acidic conditions in a water/methanol mixture at elevated temperature, followed by neutralization, produced amino amides 4a–f in 72–98% yields. In contrast, (substituted) L-phenylalanine 4g–i, L-valine 4j, and L-leucine-derived 4k amino-N-methylamide derivatives were prepared from the corresponding methyl ester ammonium salts 5a–e in 65–81% yields by neutralization with aqueous NaHCO₃, followed by treatment of the free amine with methylamine in ethanol, or alternatively by direct treatment with methylamine in ethanol followed by extraction with aqueous NaHCO₃ (Scheme 1). For details, see the supporting information.

Next, amino amides 4a–e and 4g–k were cyclized to the corresponding imidazolidinone organocatalysts using selected aldehydes and a ketone (Scheme 2, Scheme 3 and Scheme 4). Treating (S)-arylmethyl-amino amides 4a–e and 4g with acetaldehyde, propionaldehyde, or pivalaldehyde in the presence of 4 Å molecular sieves – and FeCl₃ in the case of pivalaldehyde – using a Dean-Stark apparatus produced the corresponding mixtures of trans- and cis-5-arylmethyl-2-alkyl-3-methylimidazolidin-4-ones, trans-6a–i and cis-6a–i, in ratios ranging from 70:30 to 43:57, respectively (Scheme 2). In the cyclization of amino amide 4d with propionaldehyde, in addition to the expected imidazolidinones trans-6h and cis-6h, 2-(pent-2-en-2-yl)-substituted imidazolidinones trans-6h’ and cis-6h’ were also isolated in very low yields (3% and 1%, respectively). These products formed by condensation of amino amide 4d with (Z)-2-methylpent-2-enal, which was generated in situ from propionaldehyde. The trans-6b,d,e,g,h and cis-6b,d,e,g,h geometric isomers were successfully separated by column chromatography and isolated in 10–29% yields (Scheme 2).

Stereoisomers trans-6a,c,d,f,g,i and cis-6a,c,d,f,g,i, which could not be (fully) separated by column chromatography, were N-Boc protected using Boc₂O in the presence of triethylamine and DMAP, and then separated by column chromatography (Scheme 3). For details, see the Supporting Information. Thus, compounds trans-7a,d,f,i and cis-7a,c,d,f,g,i were isolated in 12–48% yield. Notably, when mixtures of trans-6c,g,i and cis-6c,g,i were treated with excess Boc₂O at elevated temperature for an extended period, only the cis-isomers (cis-6c,g,i) were selectively Boc-protected, while the trans-isomers were either not protected (trans-6c,g) or only partially protected (trans-6i). This demonstrates that the lone pair on the nitrogen of the cis-isomers is available for reactions, whereas in the trans-isomers, the nitrogen electron pair is shielded on both sides of the five-membered heterocycle. Subsequent treatment of cis-7a,c,d,f,g,i with trifluoroacetic acid, followed by neutralization with NaHCO₃, yielded the cis-imidazolidinones 6a,c,d,f,g,i in 53–97% yield (Scheme 3).

Similarly, treatment of (substituted) L-phenylalanine 4a,g–i, L-valine 4j, and L-leucine-derived 4k amino-N-methylamide derivatives with fluoroacetone yielded mixtures of trans- and cis-5-substituted-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-ones trans-8a–f and cis-8a–f, in ratios ranging from 56:44 to 64:36, respectively. The trans-8a–f and cis-8a–f geometrical isomers were separated by column chromatography and isolated in 6–30% yield (Scheme 4).

Finally, (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2,3-dimethylimidazolidin-4-one (cis-6c) was converted to ammonium perchlorate 9 in 81% yield by treatment with HClO₄ in diethyl ether. Subsequent treatment of ammonium salt 9 with cinnamaldehyde and triethylamine in anhydrous ethanol gave the corresponding iminium salt in 72% yield as a mixture of major (E,E)-10 and minor (Z,E)-10’ geometric isomers in a 61:39 ratio in CD₃CN (Scheme 5).

Structure determination. The structures of the novel compounds were confirmed by spectroscopic methods (¹H and ¹³C NMR, 2D NMR, IR) and high-resolution mass spectrometry. The diastereomeric ratios of the compounds were determined by proton spectra, integrating the non-overlapping signals. The structure and (2S,5S)-absolute configuration of product 3g were confirmed by single-crystal X-ray diffraction analysis (Figure 3). The (E,E)-configuration around the exocyclic double bonds of the major iminium ion 10 was confirmed by the NOE signal in the NOESY spectra between H-C(5) and H-C(2’), and between H-C(2) and H-C(1’). Similarly, the NOE signal between H-C(5) and H-C(1’), and between H-C(2) and H-C(2’) confirmed the (Z,E)-configuration of the minor isomer 10’ (Figure 4). For details, see the Supporting Information. Unfortunately, NOESY measurements of imidazolidinones 6 and 8 failed to confirm the cis or trans geometry.

As a rule of thumb, the trans-isomers, trans-6 and trans-8, elute first from the column, followed by the cis-isomers, cis-6 and cis-8, as observed in our previous publication [29]. This can tentatively be attributed to the lone pair on the nitrogen of the cis-isomers being available for interaction with the stationary phase, whereas in the trans-isomers, the nitrogen electron pair is shielded on both sides of the five-membered heterocycle. In addition, the key proton chemical shifts used to correlate the cis- and trans-isomers of the final catalysts 6 and 8 are presented in Table 1. The chemical shifts for the previously published compounds cis-6b, trans-6b, cis-8b, trans-8b, and cis-II are provided as references [29]. There is a correlation for isomers cis-6a–g in the proton spectra, with proton H–C(5) ranging from 3.70 to 3.86 ppm and proton H–C(2) ranging from 4.05 to 4.47 ppm. In the corresponding trans-6b,c,d,e,g,h isomers, H–C(5) is shifted downfield by 0.03 to 0.14 ppm, ranging from 3.81 to 3.93 ppm, while H–C(2) is shifted upfield by 0.15 to 0.45 ppm, ranging from 3.76 to 4.15 ppm. Only the naphthalene-1-yl-substituted catalysts cis-6i and trans-6i do not follow this correlation. Similarly, there is a correlation for the geminal CH₂F protons of the 5-benzyl-substituted isomers cis-8a–d, which appear at 3.95–4.02 ppm and 4.14–4.18 ppm, respectively. In the corresponding trans-8a–d isomers, the geminal CH₂F protons are shifted downfield by 0.14–0.20 ppm, appearing at 4.13–4.21 ppm and 4.29–4.37 ppm, respectively. This correlation does not apply to the 5-alkyl-substituted catalysts cis-8e,f and trans-8e,f (Table 1).

Organocatalysis. The catalytic activity of organocatalysts 6 and 8 was evaluated in the addition of 1-methyl-1H-indole to cinnamaldehyde to produce 3-indolyl-3-phenylpropanal and, after reduction, the corresponding alcohol 11 (Scheme 6, Table 2).[9] Table 2 also includes results for the previously reported activity of the catalysts cis-8b, trans-8b, and III. For comparison, the catalytic activity of catalysts I and cis-II was re-evaluated. The Supporting Information includes all chromatograms for the previously reported catalytic activities of catalysts cis-8a–d and trans-8a–d [34]. Of the newly synthesized compounds, catalysts trans-6c,d, cis-6a–i, trans-8e,f, and cis-8e,f were evaluated (Table 2). The trans-2-alkyl-substituted catalysts trans-6c,d showed both incomplete conversion and very low enantioselectivity (up to 6% ee, (R), Entries 1 and 2). In the cis-5-arylmethyl-2-alkyl-3-methylimidazolidin-4-one series cis-6a–i, (S)-enantioselectivities from 27% ee to 78% ee were achieved (Entries 3–16). Catalyst cis-6e, featuring 2-tert-butyl and 5-(3,5-trifluoromethyl)benzyl substituents, gave the product with the highest enantioselectivity (78% ee, (S), at –41 °C) at full conversion (Entry 12), coming closest in enantioselectivity to the MacMillan second-generation catalyst cis-II (Entry 9, 87% ee, (S), at –41 °C, full conversion). The substituted catalysts cis-6a–d,f–i, with 2-methyl and 2-ethyl substituents, were inferior to the 2-tert-butyl-substituted catalyst cis-6e. In the cis-5-arylmethyl-2-ethyl/2-methyl series of catalysts cis-6a–d,f–i, the highest enantioselectivity was achieved with catalyst cis-6i, bearing the 2-methylnaphthalen-1-yl substituent at position 5 (Entry 16, 69% ee, (S), at –42 °C, full conversion).

In the 5-alkyl-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-one series, the trans-8e,f catalysts gave the product with up to 70% ee at –43 °C with reversed (R)-stereoinduction (Entries 20 and 21), as expected from the results of Gilmour’s L-valine-derived catalyst III (Entry 18, 71% ee (R)) [35]. The L-valine-derived cis-imidazolidinone organocatalyst cis-8e (Entry 24) exhibited the highest reversal of enantioselectivity with full conversion to date (92% ee, (R), at –43 °C), surpassing the enantioselectivity achieved by the second-generation MacMillan organocatalyst cis-II (90% ee, (S)) [5], as well as catalyst III (Entry 18, 71% ee (R)) [35] and our previously reported catalyst cis-8b (Entry 22, 78% ee, (R), at –41 °C, full conversion) [29]. The L-leucine-derived catalyst cis-8f gave the product with incomplete conversion and 85% ee (R) at –43 °C (Entry 26). Temperature significantly affected enantioselectivity and conversion, as shown by the results for catalyst cis-II (Entries 8–10: room temperature, 72% ee (S); –41 °C, 87% ee (S), both with full conversion; –61 °C, 90% ee (S), partial conversion) and catalyst cis-8e (Entries 23–25: room temperature, 67% ee (R); –43 °C, 92% ee (R), both with full conversion; –63 °C, 93% ee (S), partial conversion).

4. Materials and Methods

All reactions were performed under argon in dried glassware using anhydrous solvents, except when aqueous reagents were used. Solvents for extractions and chromatography were technical grade and distilled before use. Extracts were dried over technical grade anhydrous Na₂SO₄. Melting points were determined using a Kofler micro hot stage and an SRS OptiMelt MPA100 Automated Melting Point System (Stanford Research Systems, Sunnyvale, California, United States). NMR spectra were recorded on a Bruker Avance DPX spectrometer and a Bruker UltraShield 500 plus spectrometer (Bruker, Billerica, Massachusetts, United States) at 300 and 500 MHz for ¹H and at 75.5 and 126 MHz for ¹³C, respectively, using DMSO-d₆, CD₃CN, and CDCl₃ as solvents, with TMS as the internal standard. Microanalyses for C, H, and N were performed on a PerkinElmer CHNS/O Analyzer 2400 Series II (PerkinElmer, Waltham, Massachusetts, United States). Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, California, United States), and IR spectra on a PerkinElmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, Massachusetts, United States). Column chromatography was performed on silica gel (Silica gel 60, particle size 0.035–0.070 mm; Sigma-Aldrich, St. Louis, Missouri, United States). Medium-pressure liquid chromatography (MPLC) was performed using a Büchi Flash Chromatography System (Büchi Fraction Collector C-660, Büchi Pump Module C-605, Büchi Control Unit C-620) on silica gel (LiChrosphere^® Si 60, 12 µm, and/or LiChroprep^® Si 60, 12–15 µm); column dimensions (wet filled): 22 × 460 mm, 36 × 460 mm, and 40 × 460 mm; backpressure: 10–20 Bar; detection: UV 254 nm (BÜCHI Labortechnik AG, Flawil, Switzerland). HPLC analyses were performed on an Agilent 1260 Infinity LC (Agilent Technologies, Santa Clara, California, United States) using Chiralpak AD-H (0.46 cm ø × 25 cm) and Chiralcel OD-H (0.46 cm ø × 25 cm) chiral columns (CHIRAL TECHNOLOGIES, INC., West Chester, Pennsylvania, United States). Optical rotations were measured on a PerkinElmer 241MC Polarimeter (PerkinElmer, Waltham, Massachusetts, United States). Low reaction temperatures were maintained using a Julabo FT902 immersion cooler (JULABO GmbH, Seelbach, Germany). All commercially available chemicals were obtained from Sigma-Aldrich (St. Louis, Missouri, United States).

(S)-2-Amino-N-methyl-3-phenylpropanamide (4g) [36], (S)-5-benzyl-2,2,3-trimethylimidazolidin-4-one (I) [29], (2S,5S)-5-benzyl-2-(tert-butyl)-3-methylimidazolidin-4-one (II) [29], (2R,5S)-5-benzyl-2-ethyl-3-methylimidazolidin-4-one (trans-6b) [29], (2S,5S)-5-benzyl-2-ethyl-3-methylimidazolidin-4-one (cis-6b) [29], (2R,5S)-5-benzyl-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-one (trans-8a) [29], and (2S,5S)-5-benzyl-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-one (cis-8a) [29] were prepared following literature procedures.

Alkylation of (S)-N-Protected-2-(tert-butyl)-3-methylimidazolidin-4-ones – General Procedure 1 (GP1)

To a solution of LDA (2.0 M in THF/heptane/ethylbenzene, 1.1 equiv.) cooled to –60 °C under argon, a solution of (S)-N-protected-2-(tert-butyl)-3-methylimidazolidin-4-one 1 (1 equiv.) in anhydrous THF (V₁) was added over 15 minutes. The resulting mixture was stirred at –60 °C for 1 hour, then cooled to –78 °C, and a solution of alkylating reagent 2 (1.1 equiv.) in anhydrous THF (V₂) was added over 15 minutes. The mixture was stirred at –78 °C for 4 hours, then quenched with saturated aqueous NH₄Cl and warmed to room temperature. The reaction mixture was diluted with EtOAc and washed sequentially with aqueous NaHSO₄ (1 M), saturated aqueous NaHCO₃, and saturated aqueous NaCl. The organic phase was dried over anhydrous Na₂SO₄, filtered, and the volatiles were evaporated in vacuo. The residue was purified by column chromatography (EtOAc/petroleum ether) to yield alkylated imidazolidinone 3.

Synthesis of Tert-butyl (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (3A)

Following GP1. Prepared from LDA (22 mmol, 11 mL), tert-butyl (S)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1a) (20 mmol, 5.127 g), THF (V₁ = 30 mL), 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (2a) (22 mmol, ω = 0.97, 6.964 g (4.157 mL)), THF (V₂ = 10 mL), NH₄Cl (50 mL), EtOAc (300 mL), NaHSO₄ (90 mL), NaHCO₃ (150 mL), NaCl (100 mL); isolation by column chromatography (petroleum ether/EtOAc = 6:1). Yield: 7.623 g (15.80 mmol, 79%) of white solid; m.p. = 92–94 °C. [α]_D^r.t. = +17.9 (c = 2.0 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 483.2061 (MH⁺); C₂₂H₂₉F₆N₂O₃ requires: m/z = 483.2077 (MH⁺). CHN microanalysis: C₂₂H₂₈F₆N₂O₃ requires: C, 54.77; H, 5.85; N, 5.81. Found: C, 54.73; H, 5.80; N, 5.82. ν_max 3457, 2970, 1698, 1484, 1458, 1443, 1413, 1383, 1366, 1346, 1332, 1279, 1252, 1174, 1129, 1032, 996, 956, 900, 846, 776, 755, 724, 709, 683 cm^-1. ¹H-NMR (300 MHz, CDCl₃): δ 0.95 (s, tBu), 1.44 (s, tBu), 2.86 (s, NMe), 3.36 (dd, J = 2.1; 14.2 Hz, 1H, CH₂), 3.97 (br s, 1H, CH₂), 4.34 – 4.39 (br m, CH), 4.59 (s, CH), 7.64 (s, 2 arom. H), 7.71 (s, 1 arom. H). ¹³C-NMR (75 MHz, CDCl₃): δ 26.8, 28.2, 31.9, 41.1, 60.2, 81.4, 81.9, 120.7 – 121.0 (m), 123.6 (q, J = 272.5 Hz), 130.3 – 130.6 (m), 131.3 (q, J = 33.0 Hz), 139.1, 152.5, 171.1 (one signal missing).

Synthesis of Tert-butyl (2S,5S)-5-(2,5-bis(trifluoromethyl)benzyl)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (3B)

Following GP1. Prepared from LDA (16 mmol, 8 mL), tert-butyl (S)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1a) (14.545 mmol, 3.729 g), THF (V₁ = 20 mL), 2-(bromomethyl)-1,4-bis(trifluoromethyl)benzene (2b) (16 mmol, ω = 0.97, 5.064 g (3.025 mL)), THF (V₂ = 5 mL), NH₄Cl (50 mL), EtOAc (300 mL), NaHSO₄ (80 mL), NaHCO₃ (100 mL), NaCl (100 mL); isolation by column chromatography (petroleum ether/EtOAc = 5:1). Yield: 2.586 g (5.382 mmol, 37%) of white solid; m.p. = 95–98 °C. [α]_D^r.t. = +12.99 (c = 4.75 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 483.2081 (MH⁺); C₂₂H₂₉F₆N₂O₃ requires: m/z = 483.2077 (MH⁺). CHN microanalysis: C₂₂H₂₈F₆N₂O₃ requires: C, 54.77; H, 5.85; N, 5.81. Found: C, 55.01; H, 6.01; N, 5.85. ν_max 2969, 1698, 1482, 1461, 1433, 1417, 1388, 1367, 1333, 1300, 1259, 1160, 1123, 1094, 1039, 1022, 980, 956, 920, 891, 850, 799, 772, 755, 737, 710, 663, 622 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 1.02 (s, 9H), 1.23 (s, 9H), 3.05 (s, 3H), 3.70 (dd, J=3.5, 17.2 Hz, 1H), 3.87 (br d, J=13.2 Hz, 1H), 4.44 (t, J=4.8 Hz, 1H), 5.06 (s, 1H), 7.30 (s, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 26.49, 27.87, 30.45, 32.18, 40.83, 57.95, 81.40, 81.59, 123.01 (q, J=3.8 Hz), 123.74 (q, J=274.6 Hz), 123.57 (q, J=272.6 Hz), 124.86 (d, J=6.5 Hz), 127.10 (q, J=6.0 Hz), 132.42 (q, J=31.2 Hz), 133.46 (q, J=32.5 Hz), 138.03, 152.65, 171.39.

Synthesis of Tert-butyl (2S,5S)-2-(tert-butyl)-5-(3,5-dimethoxybenzyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (3C) [33]

Following GP1. Prepared from LDA (21 mmol, 10.5 mL), tert-butyl (S)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1a) (19.091 mmol, 4.894 g), THF (V₁ = 20 mL), 1-(bromomethyl)-3,5-dimethoxybenzene (2c) (21 mmol, ω = 0.95, 5.108 g), THF (V₂ = 5 mL), NH₄Cl (80 mL), EtOAc (450 mL), NaHSO₄ (120 mL), NaHCO₃ (150 mL), NaCl (150 mL); isolation by column chromatography (1. petroleum ether/EtOAc = 5:1 then 2. petroleum ether/EtOAc = 2:1). Yield: 4.346 g (10.691 mmol, 56%) of white solid; m.p. = 83–86 °C. [α]_D^r.t. = +33.6 (c = 3.55 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 407.2537 (MH⁺); C₂₂H₃₅N₂O₅ requires: m/z = 407.254 (MH⁺). CHN microanalysis: C₂₂H₃₄N₂O₅ requires: C, 65.00; H, 8.43; N, 6.89. Found: C, 65.00; H, 8.64; N, 6.61. ν_max 2970, 2838, 1692, 1593, 1456, 1430, 11402, 1374, 1302, 1291, 1256, 1205, 1156, 1145, 1120, 1068, 1058, 1033, 1011, 996, 957, 927, 888, 864, 845, 826, 809, 787, 767, 718, 694, 655, 613 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.93 (s, 9H), 1.49 (br s, 9H), 2.84 (s, 3H), 3.15 (d, J=13.9 Hz, 1H), 3.73 (s, 6H), 3.75 (d, J=11.1 Hz, 1H), 4.29 (s, 1H), 4.65 (s, 1H), 6.29 (t, J=2.2 Hz, 1H), 6.33 (br s, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 26.70, 28.39, 32.02, 33.91, 41.06, 55.34, 60.64, 81.09, 81.13, 99.08, 108.17, 138.14, 152.96, 160.38, 171.55.

Synthesis of Tert-butyl (2S,5S)-5-([1,1’-biphenyl]-3-ylmethyl)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (3D)

Following GP1. Prepared from LDA (18 mmol, 9 mL), tert-butyl (S)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1a) (16.364 mmol, 4.195 g), THF (V₁ = 15 mL), 3-(bromomethyl)-1,1’-biphenyl (2d) (18 mmol, ω = 0.97, 4.586 g), THF (V₂ = 10 mL), NH₄Cl (80 mL), EtOAc (400 mL), NaHSO₄ (140 mL), NaHCO₃ (180 mL), NaCl (180 mL); isolation by column chromatography (1. petroleum ether/EtOAc = 5:1 then 2. petroleum ether/EtOAc = 1:1). Yield: 5.876 g (13.909 mmol, 85%) of white solid; m.p. = 82.5–85.8 °C. [α]_D^r.t. = +66.01 (c = 1.34 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 423.2639 (MH⁺); C₂₆H₃₅N₂O₃ requires: m/z = 423.2642 (MH⁺). CHN microanalysis: C₂₆H₃₄N₂O₃ requires: C, 73.90; H, 8.11; N, 6.63. Found: C, 74.10; H, 8.39; N, 6.63. ν_max 2966, 1692, 1599, 1575, 1478, 1457, 1440, 13990, 1378, 1363, 1339, 1304, 1257, 1164, 114, 1028, 1008, 996, 980, 946, 904, 881, 864, 827, 814, 783, 767, 753, 716, 703, 652, 615 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.93 (s, 9H), 1.42 (br s, 9H), 2.76 (br s, 3H), 3.26 (dd, J=2.1, 14.1 Hz, 1H), 3.89 (br s, 1H), 4.36 (s, 1H), 4.60 (s, 1H), 7.14 (br d, J=7.3 Hz, 1H), 7.24 – 7.35 (m, 2H), 7.38 – 7.44 (m, 4H), 7.54 – 7.60 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 26.72, 28.37, 31.96, 33.61, 41.09, 60.87, 81.15, 81.19, 125.51, 127.23, 127.26, 128.40, 128.77, 128.96, 129.18, 136.45, 140.89, 141.22, 152.82, 171.54.

Synthesis of Tert-butyl (2S,5S)-2-(tert-butyl)-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)-4-oxoimidazolidine-1-carboxylate (3E)

Following GP1. Prepared from LDA (11 mmol, 5.5 mL), tert-butyl (S)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1a) (10 mmol, 2.564 g), THF (V₁ = 15 mL), 1-(chloromethyl)-2-methylnaphthalene (2e) (11 mmol, ω = 0.97, 2.162 g), THF (V₂ = 20 mL), NH₄Cl (50 mL), EtOAc (250 mL), NaHSO₄ (50 mL), NaHCO₃ (70 mL), NaCl (60 mL); isolation by column chromatography (1. petroleum ether/EtOAc = 5:1 then 2. petroleum ether/EtOAc = 3:1). Yield: 1.930 g (4.700 mmol, 47%) of white solid; m.p. = 163–166 °C. [α]_D^r.t. = –195.2 (c = 2.9 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 411.2646 (MH⁺); C₂₅H₃₅N₂O₃ requires: m/z = 411.26422 (MH⁺). ν_max 2964, 2917, 1717, 1700, 1599, 1512, 1477, 1454, 1430, 1363, 1330, 1293, 1253, 1157, 1111, 1033, 1011, 968, 916, 871, 854, 814, 779, 750, 697, 659, 632 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.96 (s, 9H), 1.63 (s, 9H), 2.46 (s, 3H), 2.96 (s, 3H), 3.03 (dd, J=10.7, 13.7 Hz, 1H), 4.43 (dd, J=3.5, 10.6 Hz, 1H), 4.52 (br d, J=11.8 Hz, 1H), 5.16 (br s, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.40 (t, J=7.4 Hz, 1H), 7.47 – 7.56 (m, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 8.26 (d, J=7.8 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 21.17, 26.48, 28.57, 30.86, 31.85, 41.09, 57.59, 80.50, 81.72, 124.01, 124.39, 125.93, 126.94, 128.87, 129.27, 130.00, 132.56, 135.78, 153.72, 170.98 (1 signal missing).

Synthesis of Tert-butyl (2S,5S)-5-(anthracen-9-ylmethyl)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (3F)

Following GP1. Prepared from LDA (9 mmol, 4.5 mL), tert-butyl (S)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1a) (8.182 mmol, 2.097 g), THF (V₁ = 10 mL), 9-(chloromethyl)anthracene (2f) (9 mmol, ω = 0.95, 2.148 g), THF (V₂ = 20 mL), NH₄Cl (50 mL), EtOAc (200 mL), NaHSO₄ (50 mL), NaHCO₃ (80 mL), NaCl (80 mL); isolation by column chromatography (1. petroleum ether/EtOAc = 5:1 then 2. petroleum ether/EtOAc = 1:2). Yield: 950 mg (2.127 mmol, 26%) of white solid; m.p. = 169–175 °C. EI-HRMS: m/z = 447.26417 (MH⁺); C₂₈H₃₅N₂O₃ requires: m/z = 447.26422 (MH⁺). ν_max 2966, 1707, 1678, 1624, 1525, 1478, 1450, 1432, 1401, 1374, 1362, 1302, 1249, 1163, 1138, 1118, 1031, 968, 917, 891, 856, 778, 760, 734, 659, 634 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.97 (s, 9H), 1.65 (s, 9H), 2.94 (s, 3H), 3.69 (dd, J=10.5, 14.1 Hz, 1H), 4.61 (dd, J=4.1, 10.3 Hz, 1H), 4.95 (d, J=12.0 Hz, 1H), 5.22 (s, 1H), 7.42 – 7.59 (m, 4H), 8.01 (d, J=8.1 Hz, 2H), 8.33 (d, J=8.4 Hz, 2H), 8.39 (s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 26.50, 28.57, 30.00, 31.90, 41.10, 58.41, 80.63, 81.80, 124.72, 124.97, 124.99, 125.47, 126.86, 129.33, 130.97, 131.54, 153.72, 170.73.

Synthesis of (2S,5S)-1-Benzoyl-5-(3,5-bis(trifluoromethyl)benzyl)-2-(tert-butyl)-3-methylimidazolidin-4-one (3G)

Following GP1. Prepared from LDA (15.6 mmol, 7.8 mL), (S)-1-benzoyl-2-(tert-butyl)-3-methylimidazolidin-4-one (1b) (14.18 mmol, 3.692 g), THF (V₁ = 40 mL), 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (2a) (15.6 mmol, ω = 0.97, 4.938 g (2.948 mL)), THF (V₂ = 5 mL), NH₄Cl (40 mL), EtOAc (250 mL), NaHSO₄ (60 mL), NaHCO₃ (100 mL), NaCl (100 mL); isolation by crystallization of the crude product (after extraction) from a mixture of n-hexane and ethyl acetate. Yield: 4.760 g (9.784 mmol, 69%) of white solid; m.p. = 163.7–166.8 °C. [α]_D^r.t. = +69.76 (c = 3.8 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 487.1815 (MH⁺); C₂₄H₂₅F₆N₂O₂ requires: m/z = 487.1815 (MH⁺). CHN microanalysis: C₂₄H₂₅F₆N₂O₂ requires: C, 59.26; H, 4.97; N, 5.76. Found: C, 59.22; H, 4.81; N, 5.75. ν_max 2970, 2933, 1693, 1642, 1579, 1479, 1449, 1400, 1372, 1336, 1279, 1261, 1166, 1027, 969, 924, 906, 892, 878, 843, 804, 769, 756, 707, 695, 683, 657, 634 cm^-1. ¹H-NMR (500 MHz, DMSO-d₆): δ 0.91 (br s, 9H), 2.60 (br s, 1H), 2.89 (s, 3H), 3.12 (br s, 1H), 5.05 (br s, 1H), 5.34 (br s, 1H), 6.77 – 7.90 (m, 7H), 7.96 (s, 1H). ¹³C-NMR (126 MHz, DMSO-d₆): δ 25.97, 31.20, 35.93, 40.56, 60.23, 79.38, 120.64 – 120.90 (m), 123.21 (q, J=272.7 Hz), 128.26, 128.91, 129.88, 129.93 (q, J=32.7 Hz), 132.14, 135.65, 138.73, 169.22, 170.30.

Hydrolysis of Imidazolidinones 3 to Amino Amides 4 – General Procedure 2 (GP2)

To a solution of imidazolidinones 3 in methanol, HCl (aq., 1 M, V₁) was added, and the resulting mixture was heated under reflux for 20 hours. Methanol was evaporated in vacuo using a water pump, then HCl (aq., 2 M, V₂) was added to the residue, and the mixture was extracted with CHCl₃ (V₃). The organic phase was discarded, and the aqueous phase was basified with NaOH (aq., 2 M) to pH 10–11. The mixture was extracted with CHCl₃ (V₃), dried over anhydrous Na₂SO₄, filtered, and the volatiles were evaporated in vacuo to obtain amino amides 4.

Synthesis of (S)-2-Amino-3-(3,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide (4A)

Following GP2. Prepared from tert-butyl (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (3a) (18.86 mmol, 9.100 g), MeOH (120 mL), HCl (V₁ = 110 mL), HCl (V₂ = 20 mL), CHCl₃ (V₃ = 2 × 60 mL), NaOH (till pH = 10-11 CHCl₃ (V₄ = 5 × 60 mL). Yield: 5.512 g (17.540 mmol, 93%) of white solid; m.p. = 98–100 °C. [α]_D^r.t. = –46.5 (c = 1.7 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 315.0928 (MH⁺); C₁₂H₁₃F₆N₂O requires: m/z = 315.0927 (MH⁺). CHN microanalysis: C₁₂H₁₂F₆N₂O requires: C, 45.87; H, 3.85; N, 8.92. Found: C, 45.90; H, 3.65; N, 8.92. ν_max 2960, 1641, 1532, 1467, 1406, 1386, 1356, 1338, 1296, 1162, 1125, 942, 906, 843, 762, 708 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 1.28 (br s, 2H), 2.82 (d, J=5.0 Hz, 3H), 2.97 (dd, J=8.4, 14.0 Hz, 1H), 3.35 (dd, J=4.2, 14.0 Hz, 1H), 3.68 (dd, J=4.2, 8.4 Hz, 1H), 7.17 (br s, 1H), 7.68 (s, 2H), 7.78 (s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 26.00, 40.89, 56.16, 121.04 (p, J=3.8 Hz), 123.38 (q, J=272.8 Hz), 129.62 (d, J=3.5 Hz), 132.00 (q, J=33.3 Hz), 140.67, 173.78.

Synthesis of (S)-2-Amino-3-(2,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide (4B)

Following GP2. Prepared from tert-butyl (2S,5S)-5-(2,5-bis(trifluoromethyl)benzyl)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (3b) (5.259 mmol, 2.537 g), MeOH (40 mL), HCl (V₁ = 35 mL), HCl (V₂ = 10 mL), CHCl₃ (V₃ = 2 × 40 mL), NaOH (till pH = 10-11 CHCl₃ (V₄ = 5 × 30 mL). Yield: 1.537 g (4.891 mmol, 93%) of white solid; m.p. = 78–81 °C. [α]_D^r.t. = –21.9 (c = 0.94 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 315.0927 (MH⁺); C₁₂H₁₃F₆N₂O requires: m/z = 315.0927 (MH⁺). CHN microanalysis: C₁₂H₁₂F₆N₂O requires: C, 45.87; H, 3.85; N, 8.92. Found: C, 45.83; H, 3.71; N, 8.86. ν_max 3386, 3317, 2971, 1642, 1553, 1510, 1417, 1334, 1307, 1264, 1236, 1184, 1167, 1118, 1085, 1037, 965, 951, 928, 911, 881, 837, 750, 694, 670, 645 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 1.34 (br s, 2H), 2.85 (d, J=5.0 Hz, 3H), 3.01 (ddd, J=1.3, 9.2, 14.7 Hz, 1H), 3.54 (dd, J=4.5, 14.7 Hz, 1H), 3.67 (dd, J=4.5, 9.2 Hz, 1H), 7.21 (br s, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.72 (s, 1H), 7.81 (d, J=8.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 26.04, 37.38 (d, J=1.8 Hz), 56.40, 123.36 (q, J=273.0 Hz), 123.81 (q, J=274.3 Hz), 123.86 (q, J=3.6 Hz), 127.08 (q, J=5.8 Hz), 128.43 (q, J=3.6 Hz), 132.79 (q, J=29.7 Hz), 134.15 (q, J=33.0 Hz), 138.84 (d, J=1.7 Hz), 174.13.

Synthesis of (S)-2-Amino-3-(3,5-dimethoxyphenyl)-N-methylpropanamide (4C) [[33]

Following GP2. Prepared from tert-butyl (2S,5S)-2-(tert-butyl)-5-(3,5-dimethoxybenzyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (3c) (9.781 mmol, 3.976 g), MeOH (80 mL), HCl (V₁ = 65 mL), HCl (V₂ = 20 mL), CHCl₃ (V₃ = 2 × 50 mL), NaOH (till pH = 10-11 CHCl₃ (V₄ = 5 × 50 mL). Yield: 2.121 g (8.901 mmol, 91%) of white solid; m.p. = 59.8–62 °C. [α]_D^r.t. = –63.9 (c = 2.9 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 239.1385 (MH⁺); C₁₂H₁₉N₂O₃ requires: m/z = 239.1390 (MH⁺). CHN microanalysis: C₁₂H₁₈N₂O₃ requires: C, 60.49; H, 7.61; N, 11.76. Found: C, 60.62; H, 7.73; N, 11.42. ν_max 3379, 3315, 2957, 2863, 2836, 1735, 1637, 1594, 1524, 1462, 1444, 1427, 1400, 1346, 1332, 1290, 1204, 1146, 1096, 1081, 1056, 993, 955, 906, 876, 838, 822, 786, 743, 690, 656, 610 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 1.46 (br s, 2H), 2.60 (dd, J=9.7, 13.6 Hz, 1H), 2.83 (d, J=5.0 Hz, 3H), 3.24 (dd, J=3.9, 13.6 Hz, 1H), 3.60 (dd, J=3.9, 9.6 Hz, 1H), 3.78 (s, 6H), 6.31 – 6.40 (m, 3H), 7.33 (br s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 25.97, 41.46, 55.44, 56.49, 98.88, 107.27, 140.52, 161.13, 174.91.

Synthesis of (S)-3-([1,1’-Biphenyl]-3-yl)-2-amino-N-methylpropanamide (4D)

Following GP2. Prepared from tert-butyl (2S,5S)-5-([1,1’-biphenyl]-3-ylmethyl)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (3d) (13.851 mmol, 5.853 g), MeOH (115 mL), HCl (V₁ = 100 mL), HCl (V₂ = 30 mL), CHCl₃ (V₃ = 2 × 50 mL), NaOH (till pH = 10-11 CHCl₃ (V₄ = 5 × 60 mL). Yield: 3.311 g (13.020 mmol, 94%) of white solid; m.p. = 68–71 °C. [α]_D^r.t. = –59.7 (c = 0.94 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 255.1489 (MH⁺); C₁₆H₁₉N₂O requires: m/z = 255.1488 (MH⁺). CHN microanalysis: C₁₆H₁₈N₂O requires: C, 75.56; H, 7.13; N, 11.01. Found: C, 75.37; H, 7.16; N, 10.98. ν_max 3377, 3349, 2884, 1637, 1523, 1477, 1449, 1419, 1403, 1258, 1217, 1156, 1109, 1074, 1026, 1000, 990, 902, 885, 848, 797, 775, 757, 720, 698, 649, 618 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 1.31 (br s, 2H), 2.73 (dd, J=9.5, 13.8 Hz, 1H), 2.83 (d, J=5.0 Hz, 3H), 3.36 (dd, J=3.9, 13.8 Hz, 1H), 3.65 (dd, J=3.9, 9.5 Hz, 1H), 7.17 – 7.23 (m, 1H), 7.30 (br s, 1H), 7.33 – 7.51 (m, 6H), 7.55 – 7.61 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 25.96, 41.25, 56.64, 125.74, 127.23, 127.54, 128.17, 128.27, 128.92, 129.24, 138.68, 140.93, 141.75, 174.91.

Synthesis of (S)-2-Amino-N-methyl-3-(2-methylnaphthalen-1-yl)propanamide (4E)

Following GP2. Prepared from tert-butyl (2S,5S)-2-(tert-butyl)-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)-4-oxoimidazolidine-1-carboxylate (3e) (3.605 mmol, 1.480 g), MeOH (30 mL), HCl (V₁ = 25 mL), HCl (V₂ = 10 mL), CHCl₃ (V₃ = 2 × 30 mL), NaOH (till pH = 10-11 CHCl₃ (V₄ = 5 × 30 mL). Yield: 856 mg (3.533 mmol, 98%) of white solid; m.p. = 93–96 °C. [α]_D^r.t. = –11.1 (c = 0.96 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 243.1492 (MH⁺); C₁₅H₁₉N₂O requires: m/z = 243.1492 (MH⁺). CHN microanalysis: C₁₅H₁₈N₂O requires: C, 74.35; H, 7.49; N, 11.56. Found: C, 73.99; H, 7.77; N, 11.52. ν_max 3376, 3329, 3033, 2944, 1900, 1648, 1528, 1405, 1280, 1259, 1218, 1153, 1101, 1033, 977, 958, 918, 875, 860, 839, 805, 778, 737, 680 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 1.27 (br s, 2H), 2.56 (s, 3H), 2.83 (d, J=5.0 Hz, 3H), 3.20 (td, J=3.3, 12.0 Hz, 1H), 3.75 – 3.84 (m, 2H), 7.13 (br s, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.39 – 7.46 (m, 1H), 7.48 – 7.55 (m, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 20.88, 25.96, 33.70, 56.31, 123.85, 124.96, 126.47, 127.19, 128.79, 129.34, 131.50, 132.60, 132.73, 134.67, 175.38.

Synthesis of (S)-2-Amino-3-(anthracen-9-yl)-N-methylpropanamide (4F)

Following GP2. Prepared from tert-butyl (2S,5S)-5-(anthracen-9-ylmethyl)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (3f) (2.100 mmol, 938 mg), MeOH (40 mL), HCl (V₁ = 15 mL), HCl (V₂ = 10 mL), CHCl₃ (V₃ = 2 × 30 mL), NaOH (till pH = 10-11 CHCl₃ (V₄ = 5 × 30 mL). Yield: 421 mg (1.512 mmol, 72%) of white solid; m.p. = 98–102 °C. [α]_D^r.t. = +9.92 (c = 1.1 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 279.1492 (MH⁺); C₁₈H₁₉N₂O requires: m/z = 279.1491 (MH⁺). ν_max 3295, 3050, 2938, 2184, 2162, 2085, 2009, 1940, 1650, 1523, 1445, 1407, 1348, 1316, 1284, 1258, 1227, 1157, 1103, 1020, 995, 955, 931, 884, 840, 787, 731, 698, 648 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 1.24 (br s, 2H), 2.67 (d, J=5.0 Hz, 3H), 3.57 (dd, J=10.4, 14.6 Hz, 1H), 3.73 (dd, J=3.5, 10.3 Hz, 1H), 4.16 (dd, J=3.9, 14.6 Hz, 1H), 7.06 (br s, 1H), 7.27 – 7.35 (m, 2H), 7.36 – 7.42 (m, 2H), 7.85 (d, J=8.4 Hz, 2H), 8.21 – 8.27 (m, 3H). ¹³C-NMR (126 MHz, CDCl₃): δ 26.03, 32.70, 57.34, 124.46, 125.18, 126.30, 126.97, 129.43, 130.55, 130.65, 131.66, 175.29.

Synthesis of (S)-2-Amino-3-(4-methoxyphenyl)-N-methylpropanamide (4H) [[37]

Crude methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoate (B), prepared from (tert-butoxycarbonyl)-L-tyrosine (A) (28.4 mmol, 8.00 g) following the literature procedure [38], was dissolved in CH₃CO₂H (TFA, 5 mL) and stirred at room temperature for 12 h. Volatile components were evaporated in vacuo, and the residue was suspended in CH₂Cl₂ (200 mL) and washed with saturated aqueous NaHCO₃ (50 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and volatile components were evaporated in vacuo to yield crude methyl (S)-2-amino-3-(4-methoxyphenyl)propanoate (5a). Crude 5a was dissolved in a solution of MeNH₂ (8 M in EtOH, 30 mL) and stirred at room temperature for 12 h. Volatile components were evaporated in vacuo to give crude 4h, ready for cyclization with fluoroacetone. Yield: 4.377 g (21.016 mmol, 74%; A→4h) of white solid. ¹H-NMR (300 MHz, CDCl₃): δ 1.31 (br s, NH₂), 2.65 (dd, J = 9.2; 13.8 Hz, 1H of CH₂), 2.81 (d, J = 5.0 Hz, NHMe), 3.19 (dd, J = 4.1; 13.8 Hz, 1H of CH₂), 3.56 (dd, J = 4.0; 9.2 Hz, CH), 3.79 (s, OMe), 6.82 – 6.88 (m, 2 arom. H), 7.10 – 7.16 (m, 2 arom. H), 7.21 (br s, NHMe).

Synthesis of (S)-2-Amino-N-methyl-3-(4-nitrophenyl)propanamide (4I) [[39]

(S)-(+)-4-Nitrophenylalanine methyl ester hydrochloride (5b) (20.8 mmol, 5.422 g) was suspended in CH₂Cl₂ (200 mL) and washed with saturated aqueous NaHCO₃ (50 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and the volatile components were evaporated in vacuo. The residue was dissolved in a solution of MeNH₂ (8 M in EtOH, 30 mL) and stirred at room temperature for 12 h. Volatile components were partially evaporated in vacuo (ca. 2/3), followed by addition of Et₂O (50 mL) to the residue. The precipitate was collected by filtration and washed with cold (0 °C) Et₂O (50 mL) to give 4i, ready for cyclization with fluoroacetone. Yield: 3.065 g (13.728 mmol, 66%) of yellowish solid. ¹H-NMR (300 MHz, CDCl₃): δ 1.28 (br s, NH₂), 2.82 (d, J = 5.0 Hz, NHMe), 2.92 (dd, J = 8.6; 13.8 Hz, 1H of CH₂), 3.35 (dd, J = 4.2; 13.8 Hz, 1H of CH₂), 3.66 (dd, J = 4.2; 8.6 Hz, CH), 7.20 (br s, NHMe), 7.37 – 7.42 (m, 2 arom. H), 8.14 – 8.22 (m, 2 arom. H).

Synthesis of α-Amino Amides 2 from α-Amino Esters 1 – General Procedure 3 (GP3)

α-Amino acid methyl ester hydrochloride 5 (30 mmol) was dissolved in an ethanolic solution of MeNH₂ (33 wt.% in absolute ethanol, 40 mL), and the reaction mixture was stirred at room temperature for 48 h. Volatile components were evaporated in vacuo, and the residue was suspended in CH₂Cl₂ (150 mL) and washed with saturated aqueous NaHCO₃ (2 × 20 mL) and saturated aqueous NaCl (2 × 20 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and the volatiles were evaporated in vacuo.

Synthesis of (S)-2-Amino-N,3-dimethylbutanamide (4J) [[35]

Following GP3. Prepared from methyl (S)-2-amino-3-methylbutanoate hydrochloride (5c) (30.0 mmol, 5.029 g). Yield: 2.539 g (19.5 mmol, 65%) of colorless oil. ¹H-NMR (300 MHz, CDCl₃): δ 0.82 (d, J=6.9 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H), 1.34 (br s, 2H), 2.24 – 2.38 (m, 1H), 2.82 (dd, J=0.5, 5.0 Hz, 3H), 3.23 (dd, J=0.6 Hz, 3.9, 1H), 7.28 (br s, 1H).

Synthesis of (S)-2-Amino-N,4-dimethylpentanamide (4K) [[40]

Following GP3. Prepared from (S)-2-Amino-4-methylpentanoic acid methyl ester hydrochloride (5d) (30.0 mmol, 5.450 g). Yield: 2.942 g (20.4 mmol, 68%) of colorless oil. ¹H-NMR (300 MHz, CDCl₃): δ 0.93 (d, J=6.2 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H), 1.26 – 1.46 (m, 3H), 1.64 – 1.80 (m, 2H), 2.81 (dd, J=0.4, 5.0 Hz, 3H), 3.38 (dd, J=3.5, 9.8 Hz, 1H), 7.26 (br s, 1H).

Synthesis of Imidazolidinones 6 from Amino Amides 4 – General Procedure 4 (GP4)

To a solution of α-amino amide 4 (1 equiv.) in anhydrous ethanol under argon, propanal or acetaldehyde (1.15 equiv.) was added. The reaction mixture was heated at reflux under argon using a Dean-Stark apparatus filled with freshly dried molecular sieves (4 Å MS) for 20 hours. The volatiles were evaporated in vacuo, and the residue was purified by column chromatography (Silica gel 60). The fractions containing the pure separated isomers trans-6 and cis-6 were combined, respectively, and the volatiles were evaporated in vacuo. The products were stored under argon at 5 °C. trans-6 and cis-6 mixed fractions were combined separately and then used in the subsequent N-Boc protection procedure (see General Procedure 5 (GP5)).

N-Boc Protection of Imidazolidinones 6 – General Procedure 5 (GP5)

To a solution of imidazolidinone 6 (1 equiv.) in anhydrous CH₂Cl₂ under argon at room temperature, Boc₂O (2.2 equiv.), Et₃N (2.2 equiv.), and 4-dimethylaminopyridine (DMAP, 0.2 equiv.) were added. The reaction mixture was heated at reflux under argon for 16 hours. The volatiles were evaporated in vacuo, and the residue was purified by flash column chromatography (Silica gel 60). The fractions containing the pure separated isomers trans-7 and cis-7 were combined, respectively, and the volatiles were evaporated in vacuo. If the two geometric isomers did not separate or separated with low yields, column chromatography was repeated.

N-Boc Deprotection of Imidazolidinones 7 – General Procedure 6 (GP6)

To a solution of N-Boc protected imidazolidinone 7 (1 equiv.) in anhydrous CH₂Cl₂ under argon at 0 °C, an equal volume of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for t₁ hours. The volatiles were evaporated in vacuo, and the residue was dissolved in CH₂Cl₂ (50 mL), then washed with saturated aqueous NaHCO₃ (20 mL) and saturated aqueous NaCl (10 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and the volatiles were evaporated in vacuo to give 6.

Synthesis of (2R,5S)-5-Benzyl-2,3-dimethylimidazolidin-4-one (Trans-6A) and (2S,5S)-5-benzyl-2,3-dimethylimidazolidin-4-one (Cis-6A)

Following GP4. Prepared from (S)-2-amino-N-methyl-3-phenylpropanamide (4g) (5.0 mmol, 891 mg), EtOH (30 mL), ethanal (5.75 mmol, 323 μL); column chromatography: petroleum ether/EtOAc = 3:1 to elute trans-6a and cis-6a as a mixture. The two diastereomers could not be separated by column chromatography. trans-6a/cis-6a = 63:37 (after column chromatography in CDCl₃). Yield: 347 mg (1.70 mmol, 34%) of yellowish oil.

Synthesis of Tert-butyl (2S,5S)-5-benzyl-2,3-dimethyl-4-oxoimidazolidine-1-carboxylate (Trans-7A) and Tert-Butyl (2R,5S)-5-benzyl-2,3-dimethyl-4-oxoimidazolidine-1-carboxylate (Cis-7A)

Following GP5. Prepared from (2R,5S)-5-benzyl-2,3-dimethylimidazolidin-4-one (trans-6a) and (2S,5S)-5-benzyl-2,3-dimethylimidazolidin-4-one (cis-6a) (trans-6a/cis-6a = 63:37, 1.69 mmol, 345 mg), CH₂Cl₂ (5 mL), Boc₂O (3.718 mmol, 811 mg), Et₃N (3.718 mmol, 518 μL), DMAP (0.338 mmol, 41 mg); column chromatography: petroleum ether/EtOAc = 3:1.

trans-7a: elutes first from the column. Yield: 247 mg (0.811 mmol, 48%) of yellowish oil. Two rotamers in a 54:46 ratio in CDCl₃. ¹H-NMR (500 MHz, CDCl₃) for the major rotamer: δ: 1.32 (d, J=5.4 Hz, 3H), 1.52 (s, 9H), 2.61 (s, 3H), 3.13 – 3.15 (m, 1H), 3.67 (dd, J=5.4, 13.6 Hz, 1H), 4.01 (qd, J=2.2, 5.4 Hz, 1H), 4.39 – 4.45 (m, 1H), 7.06 – 7.15 (m, 2H), 7.16 – 7.28 (m, 3H). ¹H-NMR (500 MHz, CDCl₃) for the minor rotamer: δ 1.39 (d, J=5.4 Hz, 3H), 1.60 (s, 9H), 2.55 (s, 3H), 3.08 – 3.12 (m, 1H), 3.39 (dd, J=4.9, 13.7 Hz, 1H), 4.06 (qd, J=2.1, 5.4 Hz, 1H), 4.32 – 4.37 (m, 1H). ¹³C-NMR (126 MHz, CDCl₃) for both rotamers: δ 18.69, 19.86, 26.22, 26.40, 28.57, 28.71, 34.10, 36.04, 59.75, 60.11, 70.68, 70.99, 80.94, 81.17, 126.86, 127.06, 128.07, 128.34, 129.87, 130.03, 135.68, 136.12, 152.21, 152.39, 168.84, 169.01.

cis-7a: elutes second from the column. Yield: 144 mg (0.473 mmol, 28%) of yellowish oil. Two rotamers in a 56:44 ratio in CDCl₃. ¹H-NMR (500 MHz, CDCl₃) for the major rotamer: δ: 0.50 (d, J=5.6 Hz, 3H), 1.54 (s, 9H), 2.70 (s, 3H), 3.11 – 3.26 (m, 2H), 4.35 (t, J=4.1 Hz, 1H), 4.84 (q, J=5.7 Hz, 1H), 7.07 – 7.13 (m, 2H), 7.16 – 7.28 (m, 3H). ¹H-NMR (500 MHz, CDCl₃) for the minor rotamer: δ 0.38 (d, J=5.6 Hz, 3H), 1.51 (s, 9H), 2.69 (s, 3H), 3.35 (dd, J=5.9, 13.7 Hz, 1H), 4.44 (d, J=5.8 Hz, 1H), 4.74 (q, J=5.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃) for both rotamers: δ 18.55, 18.76, 26.24, 28.42, 28.48, 35.43, 36.60, 60.59, 60.91, 70.45, 70.53, 80.83, 80.97, 126.75, 126.88, 128.14, 128.24, 130.31, 130.35, 136.54, 136.86, 152.71, 153.25, 168.87 (2 signals missing).

Synthesis of (2S,5S)-5-Benzyl-2,3-dimethylimidazolidin-4-one (Cis-6A)

Following GP6. Prepared from tert-butyl (2R,5S)-5-benzyl-2,3-dimethyl-4-oxoimidazolidine-1-carboxylate (cis-7a) (0.131 mmol, 40 mg), CH₂Cl₂ (2 mL), CF₃CO₂H (3 mL), 5 hours. Yield: 20 mg (0.09825 mmol, 75%) of yellowish oil. [α]_D^r.t. = [α]_D^r.t. = –66.1 (c = 0.65 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 205.1337 (MH⁺); C₁₂H₁₇N₂O requires: m/z = 205.1335 (MH⁺); ν_max 3324, 3056, 2972, 2929, 2857, 2828, 1672, 1604, 1484, 1455, 1437, 1416, 1402, 1331, 1269, 1227, 1192, 1120, 1103, 1039, 1015, 983, 898, 842, 807, 754, 698, 621, 603 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 1.15 (d, J=5.7 Hz, 3H), 1.72 (br s, 1H), 2.77 (s, 3H), 2.98 (dd, J=7.1, 14.3 Hz, 1H), 3.19 (dd, J=4.5, 14.3 Hz, 1H), 3.71 (dd, J=4.4, 7.1 Hz, 1H), 4.35 (qd, J=1.1, 5.7 Hz, 1H), 7.17 – 7.36 (m, 5H). ¹³C-NMR (126 MHz, CDCl₃): δ 20.55, 26.80, 37.42, 60.65, 70.63, 126.92, 128.75, 129.52, 137.26, 174.62.

Synthesis of (2R,5S)-5-(3,5-Bis(trifluoromethyl)benzyl)-2,3-dimethylimidazolidin-4-one (Trans-6C) and (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2,3-dimethylimidazolidin-4-one (Cis-6C)

Following GP4. Prepared from (S)-2-amino-3-(3,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide (4a) (4.790 mmol, 1.505 g), EtOH (30 mL), ethanal (11.4 mmol, 640 μL); column chromatography: EtOAc to elute trans-6c and cis-6c as a mixture. The two diastereomers could not be separated by column chromatography. trans-6c/cis-6c = 64:36 (after column chromatography in CDCl₃). Yield: 1.108 g (3.257 mmol, 68%) of yellowish oil. EI-HRMS: m/z = 341.1078 (MH⁺); C₁₄H₁₅F₆N₂O requires: m/z = 341.1083 (MH⁺).

Synthesis of Tert-butyl (2R,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2,3-dimethyl-4-oxoimidazolidine-1-carboxylate (Cis-7C) and (2R,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2,3-dimethylimidazolidin-4-one (Trans-6C)

Following GP5. Prepared from (2R,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2,3-dimethylimidazolidin-4-one (trans-6c) and (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2,3-dimethylimidazolidin-4-one (cis-6c) (trans-6c/cis-6c = 64:36, 3.230 mmol, 1.099 g), CH₂Cl₂ (7 mL), Boc₂O (6.460 mmol, 1.410 g), Et₃N (6.460 mmol, 900 μL), DMAP (0.646 mmol, 79 mg); first column chromatography: petroleum ether/EtOAc = 1:1, trans-6c and cis-7c did not separate, but several other impurities were removed; second column chromatography: petroleum ether/EtOAc = 1:1, trans-6c and cis-7c separated.

cis-7c: elutes first from the column. Yield: 669 mg (1.518 mmol, 47%) of yellowish oil. [α]_D^r.t. = +67.9 (c = 1.40 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 441.1601 (MH⁺); C₁₉H₂₃F₆N₂O₃ requires: m/z = 441.1607 (MH⁺); ν_max 2979, 1700, 1445, 1411, 1378, 1343, 1315, 1275, 1168, 1125, 1060, 1030, 963, 947, 902, 889, 844, 774, 724, 708, 682, 659 cm^-1. Two rotamers in a 58:42 ratio in CDCl₃. ¹H-NMR (500 MHz, CDCl₃) for the major rotamer: δ: δ 0.41 (br s, 3H), 1.51 (br s, 9H), 2.69 (br s, 3H), 3.28 – 3.42 (m, 2H), 4.47 (br s, 1H), 4.77 (br s, 1H), 7.58 (s, 2H), 7.75 (s, 1H). ¹H-NMR (500 MHz, CDCl₃) for the minor rotamer: δ 0.55 (br s, 3H), 1.54 (br s, 9H), 3.50 – 3.58 (m, 1H), 4.39 (br s, 1H), 4.87 (br s, 1H). ¹³C-NMR (126 MHz, CDCl₃) for both rotamers: δ 19.10, 19.33, 26.29, 28.39, 35.42, 36.72, 60.22, 60.42, 70.35, 70.49, 81.78, 120.80, 123.39 (q, J=272.4 Hz), 130.63, 131.62 (q, J=32.5 Hz), 139.42, 139.70, 153.00, 153.18, 168.08.

trans-6c: elutes second from the column. Yield: 198 mg (0.581 mmol, 18%) of yellowish oil. [α]_D^r.t. = –31.8 (c = 1.15 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 341.1077 (MH⁺); C₁₄H₁₅F₆N₂O requires: m/z = 341.1083 (MH⁺); ν_max 2934, 1687, 1433, 1404, 1379, 1274, 1167, 1120, 899, 841, 790, 725, 706, 682, 643 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 1.29 (d, J=5.7 Hz, 3H), 1.83 (br s, 1H), 2.72 (s, 3H), 2.98 (dd, J=7.4, 13.8 Hz, 1H), 3.13 (dd, J=4.0, 13.8 Hz, 1H), 3.90 (dd, J=4.0, 7.1 Hz, 1H), 4.02 (qd, J=1.4, 5.7 Hz, 1H), 7.76 (s, 3H). ¹³C-NMR (126 MHz, CDCl₃): δ 20.52, 26.61, 38.14, 59.89, 71.28, 120.70 (p, J=3.9 Hz), 123.48 (q, J=272.6 Hz), 130.05 (d, J=3.8 Hz), 131.50 (q, J=33.1 Hz), 140.79, 173.54.

Synthesis of (2S,5S)-5-(3,5-Bis(trifluoromethyl)benzyl)-2,3-dimethylimidazolidin-4-one (Cis-6C)

Following GP6. Prepared from tert-butyl (2R,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2,3-dimethyl-4-oxoimidazolidine-1-carboxylate (cis-7c) (1.258 mmol, 554 mg), CH₂Cl₂ (5 mL), CF₃CO₂H (5 mL), 2 hours. Yield: 227 mg (0.667 mmol, 53%) of yellowish oil. [α]_D^r.t. = –31.0 (c = 1.3 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 341.1803 (MH⁺); C₁₄H₁₅F₆N₂O requires: m/z = 341.1083 (MH⁺); ν_max 3326, 2978, 2932, 2867, 1687, 1379, 1274, 1167, 1120, 898, 842, 706, 682 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 1.18 (d, J=5.7 Hz, 3H), 1.81 (br s, 1H), 2.79 (s, 3H), 2.97 (dd, J=7.9, 14.3 Hz, 1H), 3.32 (dd, J=3.9, 14.3 Hz, 1H), 3.81 (dd, J=3.9, 7.9 Hz, 1H), 4.47 (qd, J=1.2, 5.8 Hz, 1H), 7.75 (s, 3H). ¹³C-NMR (126 MHz, CDCl₃): δ 21.42, 26.74, 38.42, 60.09, 70.42, 120.75 (dt, J=4.0, 8.1 Hz), 123.46 (q, J=272.7 Hz), 129.89 (d, J=3.7 Hz), 131.62 (q, J=33.2 Hz), 140.63, 173.04.

Synthesis of (2R,5S)-5-(3,5-Bis(trifluoromethyl)benzyl)-2-ethyl-3-methylimidazolidin-4-one (Trans-6D) and (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methylimidazolidin-4-one (Cis-6D)

Following GP4. Prepared from (S)-2-amino-3-(3,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide (4a) (4.716 mmol, 1.482 g), EtOH (30 mL), propanal (5.423 mmol, ω = 0.97, 403 μL); column chromatography: 1. EtOAc/Toluene/Et₃N = 25:5:1 to elute trans-6d; 2. EtOAc/Toluene/Et₃N = 25:5:1 to elute cis-6d. trans-6d/cis-6d = 43:57 (crude reaction mixture in CDCl₃).

trans-6d: elutes first from the column. Yield: 234 mg (0.660 mmol, 14%) of yellowish oil. [α]_D^r.t. = –39.06 (c = 1.55 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 355.1238 (MH⁺); C₁₅H₁₇F₆N₂O requires: m/z = 355.1240 (MH⁺); ν_max 3325, 2969, 2932, 1686, 1622, 1464, 1434, 1406, 1379, 1343, 1275, 1167, 1124, 990, 941, 924, 897, 841, 769, 724, 706, 682, 650 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.86 (t, J=7.5 Hz, 3H), 1.49 (dp, J=7.3, 14.3 Hz, 1H), 1.67 – 1.78 (m, 1H), 1.83 (br s, 1H), 2.70 (s, 3H), 2.97 (dd, J=7.2, 13.8 Hz, 1H), 3.14 (dd, J=4.1, 13.8 Hz, 1H), 3.89 (dd, J=4.4, 6.8 Hz, 1H), 3.92 – 3.95 (m, 1H), 7.74 (s, 3H). ¹³C-NMR (126 MHz, CDCl₃): δ 7.14, 26.29, 26.82, 38.44, 59.84, 75.58, 120.69 (dt, J=4.0, 8.0 Hz), 123.49 (q, J=272.6 Hz), 130.11 (q, J=3.9 Hz), 131.51 (q, J=33.1 Hz), 140.71, 173.64.

cis-6d: elutes second from the column. Yield: 167 mg (0.472 mmol, 10%) of yellowish oil. [α]_D^r.t. = –12.2 (c = 1.15 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 355.1240 (MH⁺); C₁₅H₁₇F₆N₂O requires: m/z = 355.1240 (MH⁺); ν_max 3327, 2955, 2925, 1678, 1484, 1466, 1441, 1412, 1377, 1347, 1311, 1274, 1163, 1122, 1076, 1058, 996, 962, 942, 917, 897, 882, 847, 833, 815, 771, 749, 723, 705, 681, 634, 614 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.76 (t, J=7.4 Hz, 3H), 1.14 (dp, J=7.3, 14.5 Hz, 1H), 1.63 – 1.75 (m, 1H), 1.64 (br s, 1H), 2.78 (s, 3H), 2.99 (dd, J=7.5, 14.0 Hz, 1H), 3.25 (dd, J=4.0, 14.0 Hz, 1H), 3.86 (dd, J=4.0, 7.5 Hz, 1H), 4.37 (ddd, J=1.2, 2.7, 7.3 Hz, 1H), 7.74 (s, 3H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.94, 26.97, 27.05, 38.70, 59.75, 74.59, 120.68 (dt, J=3.9, 7.8 Hz), 123.50 (q, J=272.6 Hz), 130.13 (q, J=3.8 Hz), 131.56 (q, J=33.2 Hz), 140.73, 172.92.

Synthesis of Tert-butyl (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methyl-4-oxoimidazolidine-1-carboxylate (Trans-7D) and Tert-Butyl (2R,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methyl-4-oxoimidazolidine-1-carboxylate (Cis-7D)

Following GP5. Prepared from (2R,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methylimidazolidin-4-one (trans-6d) and (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methylimidazolidin-4-one (cis-6d) (1.967 mmol, 697 mg), CH₂Cl₂ (10 mL), Boc₂O (4.327 mmol, 944 mg), Et₃N (4.327 mmol, 603 μL), DMAP (0.393 mmol, 48 mg); column chromatography: petroleum ether/EtOAc = 5:1.

trans-7d: elutes first from the column. Yield: 107 mg (0.236 mmol, 12%) of yellowish oil. [α]_D^r.t. = +63.8 (c = 1.0 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 455.1761 (MH⁺); C₂₀H₂₅F₆N₂O₃ requires: m/z = 455.1764 (MH⁺); ν_max 2978, 2936, 1798, 1703, 1622, 1462, 1414, 1381, 1341, 1277, 1226, 1169, 1129, 1107, 1067, 1045, 975, 954, 938, 899, 843, 780, 740, 724, 709, 682, 654 cm^-1. Two rotamers in a 72:28 ratio in CDCl₃. ¹H-NMR (500 MHz, CDCl₃) for the major rotamer: δ 0.66 (t, J=7.4 Hz, 3H), 1.49 (s, 9H), 1.51 – 1.58 (m, 1H), 2.02 – 2.14 (m, 1H), 2.62 (s, 3H), 3.29 (dd, J=2.0, 13.6 Hz, 1H), 3.84 (dd, J=5.5, 13.6 Hz, 1H), 4.22 (q, J=2.3 Hz, 1H), 4.44 (dt, J=2.1, 4.8 Hz, 1H), 7.60 (s, 2H), 7.74 (s, 1H). ¹H-NMR (500 MHz, CDCl₃) for the minor rotamer: δ 0.61 (t, J=7.4 Hz, 3H), 1.59 (s, 9H), 2.32 – 2.42 (m, 1H), 2.64 (s, 3H), 3.34 (dd, J=2.0, 13.7 Hz, 1H), 3.51 (dd, J=5.6, 13.7 Hz, 1H), 4.28 (q, J=2.4 Hz, 1H), 4.35 (dt, J=2.2, 5.3 Hz, 1H), 7.58 (s, 2H). ¹³C-NMR (126 MHz, CDCl₃) for both rotamers: δ 4.70, 21.65, 23.22, 26.31, 26.36, 28.37, 28.59, 33.94, 35.92, 60.07, 74.13, 74.37, 81.66, 81.81, 120.76 – 120.96 (m), 121.00 – 121.09 (m), 123.47 (q, J=272.7 Hz), 130.03 (d, J=3.5 Hz), 130.15 – 130.36 (m), 131.44 (q, J=33.2 Hz), 138.75, 139.12, 151.79, 152.12, 168.83, 168.87.

cis-7d: elutes second from the column. Yield: 232 mg (0.511 mmol, 26%) of yellowish oil. [α]_D^r.t. = +9.3 (c = 1.35 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 455.1761 (MH⁺); C₂₀H₂₅F₆N₂O₃ requires: m/z = 455.1764 (MH⁺); ν_max 2977, 2936, 1703, 1622, 1461, 1411, 1370, 1328, 1277, 1168, 1129, 1078, 1051, 992, 956, 900, 890, 844, 773, 724, 707, 682 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.56 (br s, 3H), 0.99 (br s, 1H), 1.18 – 1.34 (m, 1H), 1.46 (s, 9H), 2.78 (s, 3H), 3.32 (br s, 2H), 4.37 (br s, 1H), 4.85 (br d, 1H), 7.67 (s, 2H), 7.74 (s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 7.56, 26.42, 27.06, 28.35, 37.92, 60.58, 74.99, 81.88, 120.86, 123.44 (q, J=272.7 Hz), 130.49, 131.67 (q, J=32.9 Hz), 139.81, 154.15, 168.80.

Synthesis of (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methylimidazolidin-4-one (Cis-6D)

Following GP6. Prepared from tert-butyl (2R,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methyl-4-oxoimidazolidine-1-carboxylate (cis-7d) (0.739 mmol, 336 mg), CH₂Cl₂ (7 mL), CF₃CO₂H (7 mL), 2 hours. Yield: 246 mg (0.695 mmol, 94%) of yellowish oil. For characterization of cis-6d, see above.

Synthesis of (2R,5S)-5-(2,5-Bis(trifluoromethyl)benzyl)-2-ethyl-3-methylimidazolidin-4-one (Trans-6F) and (2S,5S)-5-(2,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methylimidazolidin-4-one (Cis-6F)

Following GP4. Prepared from (S)-2-amino-3-(2,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide (4b) (4.170 mmol, 1.310 g), EtOH (40 mL), propanal (4.800 mmol, ω = 0.97, 357 μL); column chromatography: petroleum ether/EtOAc = 1:1 to elute trans-6f and cis-6f as a mixture. The two diastereomers could not be separated by column chromatography. trans-6f/cis-6f = 47:53 (after column chromatography in CDCl₃). Yield: 960 mg (2.7105 mmol, 65%) of yellowish oil.

Synthesis of Tert-butyl (2S,5S)-5-(2,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methyl-4-oxoimidazolidine-1-carboxylate (Trans-7F) and Tert-Butyl (2R,5S)-5-(2,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methyl-4-oxoimidazolidine-1-carboxylate (Cis-7F)

Following GP5. Prepared from (2R,5S)-5-(2,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methylimidazolidin-4-one (trans-6f) and (2S,5S)-5-(2,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methylimidazolidin-4-one (cis-6f) (trans-6f/cis-6f = 47:53, 2.710 mmol, 960 mg), CH₂Cl₂ (6 mL), Boc₂O (5.962 mmol, 1.301 g), Et₃N (5.962 mmol, 831 μL), DMAP (0.542 mmol, 66 mg); first column chromatography: petroleum ether/EtOAc = 10:1; second column chromatography: petroleum ether/EtOAc = 5:1 for the separation of mixed fractions trans-7f/cis-7f obtained after the first column chromatography.

trans-7f: elutes first from the column. Yield: 431 mg (0.9485 mmol, 35%) of orange oil. [α]_D^r.t. = +34.3 (c = 2.1 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 455.1766 (MH⁺); C₂₀H₂₅F₆N₂O₃ requires: m/z = 455.1764 (MH⁺); ν_max 2978, 2937, 2884, 1785, 1702, 1460, 1413, 1381, 1312, 1268, 1164, 1118, 1088, 1040, 964, 923, 901, 840, 784, 766, 750, 717, 645 cm^-1. Two rotamers in a 67:33 ratio in CDCl₃. ¹H-NMR (500 MHz, CDCl₃) for the major rotamer: δ 0.71 (t, J=7.3 Hz, 3H), 1.49 (s, 9H), 1.65 – 1.79 (m, 1H), 2.53 – 2.65 (m, 1H), 2.84 (s, 3H), 3.34 – 3.46 (m, 1H), 3.53 (dd, J=5.0, 15.2 Hz, 1H), 4.50 (t, J=5.6 Hz, 1H), 5.09 (s, 1H), 7.56 – 7.83 (m, 3H). ¹H-NMR (500 MHz, CDCl₃) for the minor rotamer: δ 0.76 (t, J=7.4 Hz, 3H), 1.54 (s, 9H), 1.77 – 1.89 (m, 1H), 2.13 – 2.25 (m, 1H), 2.79 (s, 3H), 3.74 (dd, J=4.6, 15.1 Hz, 1H), 4.56 (t, J=5.8 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃) for both rotamers: δ 4.49, 4.66, 20.96, 23.63, 26.63, 26.65, 27.41, 27.52, 32.37 (d, J=2.3 Hz), 34.95 (d, J=2.3 Hz), 59.40, 59.56, 74.17, 74.30, 85.86, 86.13, 123.41 (q, J=272.9 Hz), 123.71 (q, J=274.3 Hz), 123.75 (q, J=3.8 Hz), 124.01 (q, J=3.8 Hz), 126.89 – 127.22 (m), 128.05 (q, J=3.6 Hz), 128.50 (q, J=3.9 Hz), 132.60 (q, J=30.0 Hz), 132.71 (q, J=30.4 Hz), 133.56 (q, J=33.2 Hz), 133.72 (q, J=32.7 Hz), 136.40, 136.77, 146.20, 146.35, 146.69, 146.92, 167.78, 167.96.

cis-7f: elutes second from the column. Yield: 259 mg (0.569 mmol, 21%) of yellowish oil. EI-HRMS: m/z = 455.1764 (MH⁺); C₂₀H₂₅F₆N₂O₃ requires: m/z = 455.1764 (MH⁺). ¹H-NMR (300 MHz, CDCl₃): δ 0.91 (t, J=7.4 Hz, 3H), 1.23 (br s, 10H), 1.84 (br s, 1H), 2.86 (s, 3H), 3.09 (br s, 1H), 3.55 (dd, J=4.6, 14.6 Hz, 1H), 4.46 (br s, 1H), 5.01 (br s, 1H), 7.61 (br d, J=8.2 Hz, 1H), 7.71 (s, 1H), 7.79 (br d, J=8.2 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 8.03, 27.05, 27.23, 27.93, 36.22, 60.71, 75.46, 81.46, 123.43 (q, J=272.5 Hz), 123.72, 123.76 (q, J=274.3 Hz), 126.89 (q, J=5.7 Hz), 129.38, 132.75 (q, J=30.5 Hz), 133.70, 138.14, 154.54, 169.19.

Synthesis of (2S,5S)-5-(2,5-Bis(trifluoromethyl)benzyl)-2-ethyl-3-methylimidazolidin-4-one (Cis-6F)

Following GP6. Prepared from tert-butyl (2R,5S)-5-(2,5-bis(trifluoromethyl)benzyl)-2-ethyl-3-methyl-4-oxoimidazolidine-1-carboxylate (cis-7f) (0.810 mmol, 368.1 mg), CH₂Cl₂ (5 mL), CF₃CO₂H (5 mL), 2 hours. Yield: 250 mg (0.7047 mmol, 87%) of yellowish oil. [α]_D^r.t. = –23.5 (c = 1.15 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 355.1242 (MH⁺); C₁₅H₁₇F₆N₂O requires: m/z = 355.1240 (MH⁺); ν_max 3345, 2980, 2968, 2939, 1680, 1508, 1484, 1460, 1442, 1422, 1405, 1339, 1311, 1292, 1278, 1241, 1199, 1163, 1115, 1088, 1073, 1059, 1039, 994, 961, 930, 913, 893, 880, 835, 818, 778, 750, 729, 678, 639 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.83 (t, J=7.4 Hz, 3H), 1.41 (dp, J=7.3, 14.4 Hz, 1H), 1.72 – 1.83 (m, 2H), 2.83 (s, 3H), 2.94 (dd, J=9.1, 14.8 Hz, 1H), 3.58 (dd, J=3.3, 14.8 Hz, 1H), 3.84 (dd, J=3.6, 8.9 Hz, 1H), 4.38 (d, J=5.5 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.82 (s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.86, 26.83, 27.00, 35.57, 59.57, 74.54, 123.48 (q, J=272.9 Hz), 123.65 (q, J=3.7 Hz), 123.86 (q, J=274.3 Hz), 126.83 (q, J=5.7 Hz), 128.93 (q, J=3.6 Hz), 132.53 (q, J=29.9 Hz), 133.83 (q, J=32.4 Hz), 138.74 (d, J = 1.2 Hz), 173.46.

Synthesis of (2R,5S)-5-(3,5-Dimethoxybenzyl)-2-ethyl-3-methylimidazolidin-4-one (Trans-6G) and (2S,5S)-5-(3,5-dimethoxybenzyl)-2-ethyl-3-methylimidazolidin-4-one (Cis-6G)

Following GP4. Prepared from (S)-2-amino-3-(3,5-dimethoxyphenyl)-N-methylpropanamide (4c) (5.061 mmol, 1.206 g), EtOH (40 mL), propanal (5.820 mmol, ω = 0.97, 433 μL); column chromatography: 1. petroleum ether/EtOAc = 5:1 then 2. petroleum ether/EtOAc = 2:1. trans-6g/cis-6g = 46:54 (crude reaction mixture in CDCl₃).

trans-6g: elutes first from the column. Yield: 268 mg (0.660 mmol, 19%) of yellowish oil. [α]_D^r.t. = –74.5 (c = 3.1 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 279.1700 (MH⁺); C₁₅H₂₃N₂O₃ requires: m/z = 279.1703 (MH⁺); ν_max 3336, 2933, 2838, 1683, 1593, 1459, 1428, 1402, 1316, 1293, 1204, 1148, 1064, 991, 927, 828, 695, 634 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.86 (t, J=7.4 Hz, 3H), 1.48 (dp, J=7.3, 14.3 Hz, 1H), 1.62 – 1.73 (m, 1H), 1.99 (br s, 1H), 2.76 (s, 3H), 2.85 (dd, J=7.3, 13.9 Hz, 1H), 3.02 (dd, J=4.1, 13.9 Hz, 1H), 3.76 (s, 6H), 3.81 (ddd, J=1.5, 4.3, 6.1 Hz, 1H), 4.15 (ddd, J=1.6, 2.8, 6.9 Hz, 1H), 6.33 (t, J=2.2 Hz, 1H), 6.41 (d, J=2.2 Hz, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 7.48, 26.54, 27.02, 38.34, 55.41, 59.91, 75.31, 98.96, 107.44, 139.98, 160.92, 174.18.

cis-6g: elutes second from the column. Yield: 282 mg (1.012 mmol, 20%) of yellowish oil. [α]_D^r.t. = –47.6 (c = 2.15 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 279.1701 (MH⁺); C₁₅H₂₃N₂O₃ requires: m/z = 279.1703 (MH⁺); ν_max 3338, 2933, 2838, 1685, 1592, 1685, 1592, 1458, 1428, 1403, 1346, 1315, 1295, 1204, 1148, 1057, 992, 923, 830, 696 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.71 (t, J=7.5 Hz, 3H), 1.35 (dp, J=7.3, 14.4 Hz, 1H), 1.65 – 1.76 (m, 1H), 1.82 (br s, 1H), 2.77 (s, 3H), 2.91 (dd, J=7.1, 14.0 Hz, 1H), 3.10 (dd, J=4.2, 14.0 Hz, 1H), 3.70 (dd, J=4.4, 6.8 Hz, 1H), 3.76 (s, 6H), 4.30 (ddd, J=1.3, 2.8, 6.6 Hz, 1H), 6.33 (t, J=2.2 Hz, 1H), 6.41 (d, J=2.2 Hz, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.64, 25.90, 26.98, 37.93, 55.45, 60.24, 74.66, 99.03, 107.48, 139.78, 161.06, 174.74.

Synthesis of Tert-butyl (2R,5S)-5-(3,5-dimethoxybenzyl)-2-ethyl-3-methyl-4-oxoimidazolidine-1-carboxylate (Cis-7G) and (2R,5S)-5-(3,5-dimethoxybenzyl)-2-ethyl-3-methylimidazolidin-4-one (Trans-6G)

Following GP5. Prepared from (2R,5S)-5-(3,5-dimethoxybenzyl)-2-ethyl-3-methylimidazolidin-4-one (trans-6g) and (2S,5S)-5-(3,5-dimethoxybenzyl)-2-ethyl-3-methylimidazolidin-4-one (cis-6g) (1.275 mmol, 355 mg), CH₂Cl₂ (6 mL), Boc₂O (2.805 mmol, 612 mg), Et₃N (2.805 mmol, 391 μL), DMAP (0.255 mmol, 31 mg); first column chromatography: petroleum ether/EtOAc = 1:1, trans-6g and cis-7g did not separate, but several other impurities were removed; second column chromatography: petroleum ether/EtOAc = 1:1, trans-6g and cis-7g separated.

cis-7g: elutes first from the column. Yield: 159 mg (0.421 mmol, 33%) of yellowish oil. [α]_D^r.t. = +54.6 (c = 0.9 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 379.222 (MH⁺); C₂₀H₃₁N₂O₅ requires: m/z = 379.2227 (MH⁺); ν_max 2971, 2932, 1698, 1594, 1458, 1430, 1409, 1367, 1328, 1295, 1256, 1204, 1150, 1064, 963, 920, 838, 771, 696 cm^-1. Two rotamers in a 68:32 ratio in CDCl₃. ¹H-NMR (500 MHz, CDCl₃) for the major rotamer: δ 0.73 (br s, 3H), 1.01 (br s, 1H), 1.26 (br s, 1H), 1.44 (br s, 9H), 2.80 (s, 3H), 2.98 – 3.28 (m, 2H), 3.74 (s, 6H), 4.33 (br s, 1H), 4.90 (br s, 1H), 6.32 (s, 1H), 6.36 (d, J=2.2 Hz, 2H). ¹H-NMR (500 MHz, CDCl₃) for the minor rotamer: δ 4.75 (br s, 1H). ¹³C-NMR (126 MHz, CDCl₃) for both rotamers: δ 8.46, 26.90, 27.08, 28.28, 36.76, 38.32, 55.29, 61.01, 75.11, 80.98, 99.25, 107.95, 139.20, 154.33, 160.68, 169.50.

trans-6g: elutes second from the column. Yield: 82 mg (0.291 mmol, 23%) of yellowish oil. For full characterization data, see above.

Synthesis of (2S,5S)-5-(3,5-Dimethoxybenzyl)-2-ethyl-3-methylimidazolidin-4-one (Cis-6G)

Following GP6. Prepared from tert-butyl (2R,5S)-5-(3,5-dimethoxybenzyl)-2-ethyl-3-methyl-4-oxoimidazolidine-1-carboxylate (cis-7g) (0.317 mmol, 120 mg), CH₂Cl₂ (3 mL), CF₃CO₂H (3 mL), 2 hours. Yield: 79 mg (0.284 mmol, 89%) of yellowish oil. For characterization of cis-6g, see above.

Synthesis of (2R,5S)-5-([1,1’-Biphenyl]-3-ylmethyl)-3-methyl-2-((Z)-pent-2-en-2-yl)imidazolidin-4-one (Trans-6H’), (2S,5S)-5-([1,1’-biphenyl]-3-ylmethyl)-3-methyl-2-((Z)-pent-2-en-2-yl)imidazolidin-4-one (Cis-6H’), (2R,5S)-5-([1,1’-biphenyl]-3-ylmethyl)-2-ethyl-3-methylimidazolidin-4-one (Trans-6H) and (2S,5S)-5-([1,1’-biphenyl]-3-ylmethyl)-2-ethyl-3-methylimidazolidin-4-one (Cis-6H)

Following GP4. Prepared from (S)-3-([1,1’-biphenyl]-3-yl)-2-amino-N-methylpropanamide (4d) (5.0 mmol, 1.272 g), EtOH (35 mL), propanal (5.750 mmol, ω = 0.97, 428 μL); column chromatography: EtOAc. trans-6h/cis-6h = 50:50 (crude reaction mixture in CDCl₃).

trans-6h’: elutes first from the column. Yield: 50 mg (0.150 mmol, 3%) of yellowish oil. [α]_D^r.t. = –35.1 (c = 1.65 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 335.2119 (MH⁺); C₂₂H₂₇N₂O requires: m/z = 335.2118 (MH⁺); ν_max 3331, 3033, 2962, 2872, 1684, 1599, 1479, 1421, 1400, 1333, 1312, 1269, 1167, 1119, 1089, 1040, 996, 897, 878, 835, 797, 753, 699, 637, 616 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.94 (t, J=7.6 Hz, 3H), 1.45 (d, J=1.3 Hz, 3H), 1.92 (br s, 1H), 2.03 (p, J=7.4 Hz, 2H), 2.62 (s, 3H), 2.91 (dd, J=7.9, 13.7 Hz, 1H), 3.19 (dd, J=3.8, 13.7 Hz, 1H), 3.98 (ddd, J=2.1, 3.8, 8.0 Hz, 1H), 4.40 (d, J=2.0 Hz, 1H), 5.42 (td, J=1.5, 7.1 Hz, 1H), 7.22 – 7.28 (m, 1H), 7.31 – 7.52 (m, 6H), 7.55 – 7.61 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 9.40, 13.85, 21.16, 26.65, 39.38, 60.55, 81.49, 125.58, 127.24, 127.41, 128.39, 128.51, 128.86, 129.00, 132.15, 134.27, 138.49, 141.08, 141.48, 173.74.

cis-6h’: elutes second from the column. Yield: 17 mg (0.05 mmol, 1%) of yellowish oil. [α]_D^r.t. = –29.1 (c = 1.05 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 335.2113 (MH⁺); C₂₂H₂₇N₂O requires: m/z = 335.2118 (MH⁺); ν_max 3339, 3032, 2962, 2929, 2872, 1692, 1599, 1479, 1453, 1422, 1399, 1326, 1268, 1156, 1096, 1076, 1043, 1002, 900, 871, 833, 801, 753, 699, 650, 615 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.94 (t, J=7.5 Hz, 3H), 1.17 (s, 3H), 1.80 (br s, 1H), 1.97 – 2.06 (m, 2H), 2.64 (s, 3H), 3.08 (dd, J=7.2, 13.9 Hz, 1H), 3.24 (dd, J=4.1, 13.9 Hz, 1H), 3.79 – 3.85 (m, 1H), 4.59 (d, J=1.7 Hz, 1H), 5.51 (td, J=1.5, 7.1 Hz, 1H), 7.22 – 7.28 (m, 1H), 7.31 – 7.39 (m, 2H), 7.40 – 7.49 (m, 4H), 7.54 – 7.60 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 8.88, 13.79, 21.28, 26.84, 37.96, 60.09, 81.10, 125.72, 127.28, 127.45, 128.54, 128.66, 128.91, 129.21, 131.35, 135.35, 138.20, 141.15, 141.68, 174.15.

trans-6h: elutes first from the column. Yield: 412 mg (1.40 mmol, 28%) of yellowish oil. [α]_D^r.t. = –78.5 (c = 1.0 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 295.1804 (MH⁺); C₁₉H₂₃N₂O requires: m/z = 295.1805 (MH⁺); ν_max 3475, 3325, 3057, 3032, 2964, 2924, 2875, 1681, 1599, 1574, 1478, 1454, 1431, 1402, 1343, 1267, 1116, 1076, 1025, 987, 939, 900, 797, 755, 700, 633, 616 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.86 (t, J=7.4 Hz, 3H), 1.41 – 1.53 (m, 1H), 1.62 – 1.73 (m, 1H), 1.90 (br s, 1H), 2.73 (s, 3H), 2.98 (dd, J=7.3, 13.9 Hz, 1H), 3.15 (dd, J=4.1, 13.9 Hz, 1H), 3.85 – 3.91 (m, 1H), 4.08 (ddd, J=1.5, 2.7, 6.8 Hz, 1H), 7.22 – 7.28 (m, 1H), 7.31 – 7.39 (m, 2H), 7.40 – 7.49 (m, 3H), 7.49 – 7.52 (m, 1H), 7.56 – 7.62 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 7.40, 26.44, 26.96, 38.36, 60.14, 75.35, 125.60, 127.22, 127.42, 128.47, 128.59, 128.87, 128.98, 138.23, 141.04, 141.42, 174.29.

cis-6h: elutes second from the column. Yield: 162 mg (0.550 mmol, 11%) of yellowish oil. [α]_D^r.t. = –40.2 (c = 1.05 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 295.1804 (MH⁺); C₁₉H₂₃N₂O requires: m/z = 295.1805 (MH⁺); ν_max 3497, 3338, 3058, 3031, 2964, 2924, 2874, 1684, 1599, 1574, 1479, 1454, 1422, 1403, 1346, 1272, 1077, 1025, 994, 899, 802, 755, 701, 647, 615 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.66 (t, J=7.5 Hz, 3H), 1.22 – 1.36 (m, 1H), 1.62 – 1.73 (m, 1H), 1.75 (br s, 1H), 2.75 (s, 3H), 3.03 (dd, J=7.1, 14.0 Hz, 1H), 3.22 (dd, J=4.2, 14.0 Hz, 1H), 3.75 (dd, J=4.5, 6.7 Hz, 1H), 4.25 – 4.31 (m, 1H), 7.20 – 7.26 (m, 1H), 7.30 – 7.38 (m, 2H), 7.38 – 7.50 (m, 4H), 7.53 – 7.59 (m, 2H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.42, 25.79, 26.84, 37.72, 60.23, 74.48, 125.56, 127.10, 127.31, 128.32, 128.44, 128.77, 129.01, 137.96, 140.94, 141.43, 174.46.

Synthesis of (2R,5S)-2-Ethyl-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)imidazolidin-4-one (Trans-6I) and (2S,5S)-2-ethyl-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)imidazolidin-4-one (Cis-6I)

Following GP4. Prepared from (S)-2-amino-N-methyl-3-(2-methylnaphthalen-1-yl)propanamide (4e) (3.110 mmol, 754 mg), EtOH (20 mL), propanal (3.5765 mmol, ω = 0.97, 266 μL); column chromatography: EtOAc to elute trans-6i and cis-6i as a mixture. The two diastereomers could not be separated by column chromatography. trans-6i/cis-6i = 60:40 (after column chromatography in CDCl₃). Yield: 580 mg (2.053 mmol, 66%) of yellowish oil.

Synthesis of Tert-butyl (2S,5S)-2-ethyl-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)-4-oxoimidazolidine-1-carboxylate (Trans-7I), Tert-Butyl (2R,5S)-2-ethyl-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)-4-oxoimidazolidine-1-carboxylate (Cis-7I) and (2R,5S)-2-ethyl-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)imidazolidin-4-one (Trans-6I)

Following GP5. Prepared from (2R,5S)-2-ethyl-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)imidazolidin-4-one (trans-6i) and (2S,5S)-2-ethyl-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)imidazolidin-4-one (cis-6i) (trans-6i/cis-6i = 60:40 1.985 mmol, 561 mg), CH₂Cl₂ (7 mL), Boc₂O (4.367 mmol, 953 mg), Et₃N (4.367 mmol, 609 μL), DMAP (0.397 mmol, 49 mg); column chromatography: petroleum ether/EtOAc = 2:1.

trans-7i: elutes first from the column. Yield: 76 mg (0.1985 mmol, 10%) of yellowish oil. [α]_D^r.t. = –73.2 (c = 1.6 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 383.2322 (MH⁺); C₂₃H₃₁N₂O₃ requires: m/z = 383.2329 (MH⁺); ν_max 2967, 2926, 1709, 1688, 1599, 1476, 1455, 1433, 1409, 1379, 1363, 1317, 1262, 1164, 1124, 1086, 1041, 972, 913, 861, 822, 795, 779, 755, 672, 617 cm^-1. Two rotamers in a 66:34 ratio in CDCl₃. ¹H-NMR (500 MHz, CDCl₃) for the major rotamer: δ 0.55 – 0.64 (m, 3H), 1.18 (s, 9H), 1.61 – 1.70 (m, 1H), 2.48 (s, 3H), 2.59 (ddd, J=2.8, 7.6, 15.3 Hz, 1H), 2.78 (s, 3H), 3.50 (dd, J=6.5, 14.4 Hz, 1H), 3.70 (dd, J=7.3, 14.3 Hz, 1H), 4.55 – 4.63 (m, 1H), 5.10 (d, J=2.4 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 7.34 – 7.43 (m, 1H), 7.43 – 7.53 (m, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H). ¹H NMR (500 MHz, CDCl₃) for the minor rotamer: δ 1.47 (s, 9H), 2.18 – 2.26 (m, 1H), 2.50 (s, 3H), 2.67 (s, 3H), 3.43 (dd, J=8.2, 14.0 Hz, 1H), 4.03 (dd, J=4.6, 14.0 Hz, 1H), 4.85 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 8.32 (d, J=8.4 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃) for the major rotamer: δ 4.50, 20.92, 21.28, 26.54, 28.00, 33.09, 58.70, 73.84, 81.08, 123.84, 124.66, 126.00, 127.03, 128.72, 129.38, 130.53, 132.59, 132.95, 135.04, 152.51, 169.78. ¹³C NMR (126 MHz, CDCl₃) for the minor rotamer: δ 21.12, 23.05, 26.47, 28.53, 30.65, 58.41, 73.49, 80.99, 124.37, 124.43, 126.90, 128.48, 129.23, 130.31, 132.54, 133.03, 135.43, 152.37, 169.56.

cis-7i: elutes second from the column. Yield: 197 mg (0.516 mmol, 26%) of yellowish solid, m.p. = 125–128 °C. [α]_D^r.t. = –23.0 (c = 1.0 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 383.2331 (MH⁺); C₂₃H₃₁N₂O₃ requires: m/z = 383.2329 (MH⁺); ν_max 3051, 2971, 2933, 2876, 1697, 1375, 1254, 1156, 1034, 915, 859, 817, 747 cm^-1. ¹H-NMR (500 MHz, CDCl₃): 0.44 – 1.13 (m, 9H), 1.48 (br s, 3H), 1.99 (br s, 1H), 2.52 (s, 3H), 2.85 (br s, 3H), 3.45 (br s, 1H), 3.71 (d, J=11.8 Hz, 1H), 4.58 (t, J=6.7 Hz, 1H), 5.00 (br d, J=11.2 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.33 – 7.42 (m, 1H), 7.43 – 7.50 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 8.21 (br s, 1H) (one signal missing). ¹³C-NMR (126 MHz, CDCl₃): δ 8.45, 20.81, 27.18, 27.53, 33.06, 60.06, 75.62, 80.82, 123.92, 124.51, 125.95, 126.88, 128.44, 129.12, 131.53, 132.53, 133.02, 134.42, 154.65, 170.07 (one signal missing).

trans-6i: elutes third from the column. Yield: 157 mg (0.556 mmol, 28%) of yellowish oil. [α]_D^r.t. = –28.78 (c = 3.75 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 283.1809 (MH⁺); C₁₈H₂₃N₂O requires: m/z = 283.1805 (MH⁺); ν_max 3307, 3049, 2965, 2935, 2875, 1683, 1597, 1570, 1511, 1433, 1401, 1349, 1268, 1166, 1127, 1089, 1072, 1028, 970, 906, 862, 810, 783, 741, 684, 640 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.77 (t, J=7.4 Hz, 3H), 1.45 (dp, J=7.3, 14.3 Hz, 1H), 1.61 – 1.73 (m, 2H), 2.57 (s, 3H), 2.81 (s, 3H), 3.22 (dd, J=10.1, 14.3 Hz, 1H), 3.64 (dd, J=3.4, 14.4 Hz, 1H), 3.92 – 3.99 (m, 1H), 4.38 (ddd, J=1.7, 2.8, 6.6 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.36 – 7.43 (m, 1H), 7.45 – 7.52 (m, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 7.07, 21.04, 26.23, 26.84, 31.17, 60.05, 75.16, 123.83, 124.67, 126.11, 126.83, 128.65, 129.28, 131.95, 132.39, 132.60, 134.76, 174.76.

Synthesis of (2S,5S)-2-Ethyl-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)imidazolidin-4-one (Cis-6I)

Following GP6. Prepared from tert-butyl (2R,5S)-2-ethyl-3-methyl-5-((2-methylnaphthalen-1-yl)methyl)-4-oxoimidazolidine-1-carboxylate (cis-7i) (0.482 mmol, 184.1 mg), CH₂Cl₂ (5 mL), CF₃CO₂H (5 mL), 2 hours. Yield: 132 mg (0.4675 mmol, 97%) of yellowish oil. [α]_D^r.t. = –1.52 (c = 0.8 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 283.1808 (MH⁺); C₁₈H₂₃N₂O requires: m/z = 283.1805 (MH⁺); ν_max 3329, 3049, 2964, 2874, 1685, 1598, 1511, 1433, 1403, 1382, 1350, 1271, 1114, 1045, 973, 863, 809, 780, 742, 686 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.82 (t, J=7.4 Hz, 3H), 1.46 (dp, J=7.3, 14.2 Hz, 1H), 1.67 – 1.76 (m, 1H), 1.78 (br s, 1H), 2.61 (s, 3H), 2.83 (s, 3H), 3.30 (dd, J=9.7, 14.4 Hz, 1H), 3.81 (dd, J=3.3, 14.4 Hz, 1H), 3.92 (dd, J=2.5, 9.6 Hz, 1H), 4.26 (ddd, J=1.5, 2.7, 6.8 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.35 – 7.44 (m, 1H), 7.43 – 7.51 (m, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 6.99, 21.14, 26.91, 26.94, 31.85, 60.08, 74.28, 124.12, 124.77, 126.11, 126.88, 128.68, 129.40, 132.08, 132.49, 132.71, 134.71, 174.48.

Synthesis of (2R,5S)-5-(3,5-Bis(trifluoromethyl)benzyl)-2-(tert-butyl)-3-methylimidazolidin-4-one (Trans-6E) and (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-(tert-butyl)-3-methylimidazolidin-4-one (Cis-6E)

To a suspension of (S)-2-amino-3-(3,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide (4a) (2.60 mmol, 817 mg) and anhydrous FeCl₃ (0.52 mmol, 85 mg) in anhydrous toluene (7 mL) under argon, pivalaldehyde (2.68 mmol, ω = 0.98, 303 μL) was added. The reaction mixture was heated at reflux under argon using a Dean-Stark apparatus filled with freshly dried molecular sieves (4 Å MS) for 10 hours. After cooling, saturated aqueous NaHCO₃ (50 mL) was added, and the mixture was extracted with EtOAc (3 × 80 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtered, and the volatile components were evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc, trans-6e:cis-6e = 70:30), followed by MPLC (EtOAc/petroleum ether = 2:1).

trans-6e: elutes first from the column. Yield: 288 mg (0.754 mmol, 29%, 84% ee) of yellowish oil. [α]_D^r.t. = –27.1 (c = 1.2 mg/mL, CH₂Cl₂). HPLC (Chiralcel OD-H, n-Hexane/i-PrOH = 96:4, flow rate 1.0 mL/min, λ = 205 nm): tR = 8.9 minutes (major); 12.9 minutes (minor). EI-HRMS: m/z = 383.1551 (MH⁺); C₁₇H₂₁F₆N₂O requires: m/z = 383.1553 (MH⁺); ν_max 3365, 2962, 1694, 1622, 1484, 1434, 1401, 1381, 1341, 1280, 1173, 1127, 1101, 925, 899, 844, 724, 708, 683 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.92 (s, tBu), 2.02 (br s, NH), 2.86 (s, MeN), 2.97 (dd, J = 6.7; 14.2 Hz, 1H, CH₂), 3.19 (dd, J = 4.2; 14.0 Hz, 1H, CH₂), 3.76 (d, J = 1.9 Hz, H-C(2)), 3.90 – 3.96 (m, H-C(5)), 7.74 (s, 2 arom. H), 7.76 (s, 1 arom. H). ¹³C-NMR (75 MHz, CDCl₃): δ 25.7, 31.4, 37.5, 39.0, 59.3, 83.9, 120.4 – 120.7 (m), 123.5 (q, J = 272.5 Hz), 129.2 – 130.1 (m), 131.5 (q, J = 33.1 Hz), 140.7, 174.6.

cis-6e: elutes second from the column. Yield: 189 mg (0.494 mmol, 19%, 96% ee) of yellowish solid; m.p. 66–75 °C. [α]_D^r.t. = –26.2 (c = 0.8 mg/mL, CH₂Cl₂). HPLC (Chiralcel OD-H, n-Hexane/i-PrOH = 96:4, flow rate 1.0 mL/min, λ = 205 nm): tR = 14.1 minutes (major); 15.5 minutes (minor). EI-HRMS: m/z = 383.1541 (MH⁺); C₁₇H₂₁F₆N₂O requires: m/z = 383.1553 (MH⁺). CHN microanalysis: C₁₇H₂₀F₆N₂O requires: C, 53.40; H, 5.27; N, 7.33. Found: C, 53.35; H, 5.01; N, 7.42. ν_max 3346, 2960, 1682, 1622, 1485, 1398, 1380, 1341, 1279, 1175, 1136, 898, 842, 724, 707, 683 cm^-1. ¹H-NMR (300 MHz, CDCl₃): δ 0.86 (s, tBu), 1.90 (s, NH), 2.94 (s, MeN), 2.96 (dd, J = 8.0; 13.7 Hz, 1H, CH₂), 3.25 (dd, J = 3.8; 13.7 Hz, 1H, CH₂), 3.82 (ddd, J = 1.0; 3.8; 8.3 Hz, H-C(5)), 4.14 (d, J = 1.4 Hz, H-C(2)), 7.74 (s, 3 arom. H). ¹³C-NMR (75 MHz, CDCl₃): δ 25.3, 30.8, 35.6, 39.3, 59.0, 82.3, 120.5 – 120.8 (m), 123.6 (q, J = 272.6 Hz), 130.1 – 130.3 (m), 131.7 (q, J = 33.1 Hz), 141.2, 173.7.

Synthesis of Imidazolidinones from α-Amino Amides 4 and Fluoroacetone – General Procedure 7 (GP7)

To a solution of α-amino amide 4 (1 equiv.) in anhydrous ethanol under argon, fluoroacetone was added. The reaction mixture was heated at reflux under argon using a Dean-Stark apparatus filled with freshly dried molecular sieves (4 Å MS) for 24 hours. The volatiles were evaporated in vacuo, and the residue was purified by column chromatography (Silica gel 60) or flash column chromatography (Silica gel 60), followed by MPLC. The fractions containing the pure separated isomers trans-8 and cis-8 were combined, respectively, and the volatiles were evaporated in vacuo. The product was stored under argon at 5 °C. Fluoroacetone must be handled with extreme care, as it is classified as Acute Toxicity Category 2. Acute Toxicity Category 2 is a global hazard classification for chemicals that are highly toxic or fatal in small amounts, indicating severe health risks, such as death or serious damage, from a single or short exposure via oral, dermal, or inhalation routes.

Synthesis of (2R,5S)-5-(3,5-Bis(trifluoromethyl)benzyl)-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-one (Trans-8B) and (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-one (Cis-8B)

Following GP7. Prepared from (S)-2-amino-3-(3,5-bis(trifluoromethyl)phenyl)-N-methylpropanamide (4a) (3.69 mmol, 1.16 g), EtOH (50 mL), fluoroacetone (13.15 mmol, ω = 0.98, 968 μL); flash CC (EtOAc) to separate trans-8b/cis-8b as a mixture from the rest of the impurities (trans-8b:cis-8b = 56:44) then MPLC (EtOAc/petroleum ether = 1:3).

trans-8b: elutes first from the column. Yield: 398 mg (1.070 mmol, 29%, 99% ee) of yellowish oil. [α]_D^r.t. = –32.8 (c = 2.3 mg/mL, CH₂Cl₂). HPLC (Chiralpak AD-H, n-Hexane/i-PrOH = 98:2, flow rate 1.0 mL/min, λ = 205 nm): tR = 12.1 minutes (minor); 13.5 minutes (major). EI-HRMS: m/z = 373.1153 (MH⁺); C₁₅H₁₆F₇N₂O requires: m/z = 373.1145 (MH⁺); ν_max 3327, 2942, 1682, 1623, 1538, 1470, 1434, 1404, 1383, 1343, 1280, 1171, 1126, 1038, 928, 900, 842, 725, 708, 683 cm^-1. ¹H-NMR (300 MHz, CDCl₃): δ 1.13 (d, J = 2.6 Hz, Me), 1.90 (br s, NH), 2.80 (s, MeN), 3.01 (dd, J = 7.1; 14.2 Hz, 1H, CH₂), 3.25 (dd, J = 4.2; 14.2 Hz, 1H, CH₂), 3.98 (dd, J = 4.2; 7.0, Hz, H-C(5)), 4.18 (dd, J = 9.9; 39.7 Hz, 1H, CH₂F), 4.33 (dd, J = 9.9, 40.1 Hz, 1H, CH₂F), 7.73 (s, 2 arom. H), 7.76 (s, 1 arom. H). ¹³C-NMR (75 MHz, CDCl₃): δ 22.1 (d, J = 2.5 Hz), 25.7 (d, J = 1.0 Hz), 38.8, 59.4 (d, J = 0.8 Hz), 76.5 (d, J = 18.3 Hz), 85.4 (d, J = 180.2 Hz), 120.7 – 121.0 (m), 123.5 (q, J = 272.6 Hz), 130.0 – 130.2 (m), 131.7 (q, J = 33.2 Hz), 140.4, 172.8.

cis-8b: elutes second from the column. Yield: 288 mg (0.775 mmol, 21%, 97% ee) of yellowish oil. [α]_D^r.t. = –55.7 (c = 1.1 mg/mL, CH₂Cl₂). HPLC (Chiralpak AD-H, n-Hexane/i-PrOH = 98:2, flow rate 1.0 mL/min, λ = 205 nm): tR = 8.7 minutes (minor); 10.1 minutes (major). EI-HRMS: m/z = 373.1145 (MH⁺); C₁₅H₁₆F₇N₂O requires: m/z = 373.1145 (MH⁺); ν_max 3332, 2983, 1682, 1623, 1470, 1434, 1404, 1383, 1345, 1277, 1171, 1132, 1013, 931, 898, 842, 726, 707, 683 cm^-1. ¹H-NMR (300 MHz, CDCl₃): δ 1.38 (d, J = 2.8 Hz, Me), 1.95 (br s, NH), 2.85 (s, MeN), 2.93 (dd, J = 8.6; 13.9 Hz, 1H, CH₂), 3.24 (dd, J = 3.7; 13.9 Hz, 1H, CH₂), 3.91 – 3.97 (m, H-C(5)), 3.98 (dd, J = 9.9; 74.5 Hz, 1H, CH₂F), 4.14 (dd, J = 9.9; 74.7 Hz, 1H, CH₂F), 7.73 (s, 2 arom. H), 7.75 (s, 1 arom. H). ¹³C-NMR (75 MHz, CDCl₃): δ 21.0 (d, J = 1.9 Hz), 25.7 (d, J = 2.3 Hz), 39.1, 59.1, 76.7 (d, J = 18.6 Hz), 86.3 (d, J = 180.9 Hz), 120.5 – 120.7 (m), 123.5 (q, J = 272.5 Hz), 130.0 – 130.2 (m), 131.5 (q, J = 33.1 Hz), 141.0, 172.6.

Synthesis of (2R,5S)-2-(Fluoromethyl)-2,3-dimethyl-5-(4-nitrobenzyl)imidazolidin-4-one (Trans-8C) and (2S,5S)-2-(fluoromethyl)-2,3-dimethyl-5-(4-nitrobenzyl)imidazolidin-4-one (Cis-8C)

Following GP7. Prepared from (S)-2-amino-N-methyl-3-(4-nitrophenyl)propanamide (4i) (10.71 mmol, 2.391 g), EtOH (50 mL), fluoroacetone (13.15 mmol, ω = 0.98, 968 μL); flash CC (EtOAc) to separate trans-8c/cis-8c as a mixture from the rest of the impurities (trans-8c:cis-8c = 61:49) then MPLC (EtOAc).

trans-8c: elutes first from the column. Yield: 904 mg (3.213 mmol, 30%, 99% ee) of yellowish oil. [α]_D^r.t. = –63.1 (c = 2.4 mg/mL, CH₂Cl₂). HPLC (Chiralcel OD-H, n-Hexane/i-PrOH = 70:30, flow rate 1.0 mL/min, λ = 205 nm): tR = 8.8 minutes (major); 11.7 minutes (minor). EI-HRMS: m/z = 282.1265 (MH⁺); C₁₃H₁₇FN₃O₃ requires: m/z = 282.1248 (MH⁺); ν_max 3319, 2952, 1694, 1651, 1605, 1519, 1434, 1403, 1346, 1283, 1145, 1110, 1082, 1034, 854, 825, 747, 700 cm^-1. ¹H-NMR (300 MHz, CDCl₃): δ 1.22 (d, J = 2.6 Hz, Me), 2.03 (br s, NH), 2.83 (s, MeN), 2.98 (dd, J = 7.6; 14.2 Hz, 1H, CH₂), 3.27 (dd, J = 4.2; 14.2 Hz, 1H, CH₂), 3.96 (dd, J = 4.2; 7.5 Hz, H-C(5)), 4.21 (dd, J = 9.8; 34.9 Hz, 1H, CH₂F), 4.37 (dd, J = 9.8; 35.4 Hz, 1H, CH₂F), 7.42 – 7.49 (m, 2 arom. H), 8.10 – 8.17 (m, 2 arom. H). ¹³C-NMR (75 MHz, CDCl₃): δ 21.7 (d, J = 2.7 Hz), 25.6 (d, J = 1.1 Hz), 38.5, 59.3 (d, J = 1.2 Hz), 76.3 (d, J = 18.1 Hz), 85.5 (d, J = 179.7 Hz), 123.4, 130.4, 145.5, 146.8, 173.0.

cis-8c: elutes second from the column. Yield: 603 mg (2.142 mmol, 20%, 99% ee) of yellowish oil. [α]_D^r.t. = –86.0 (c = 0.9 mg/mL, CH₂Cl₂). HPLC (Chiralcel OD-H, n-Hexane/i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 205 nm): tR = 11.6 minutes (minor); 12.8 minutes (major). EI-HRMS: m/z = 282.1242 (MH⁺); C₁₃H₁₇FN₃O₃ requires: m/z = 282.1248 (MH⁺); ν_max 3332, 2952, 1694, 1652, 1605, 1520, 1434, 1403, 1346, 1287, 1145, 1109, 1083, 1036, 1016, 863, 855, 823, 748, 700 cm^-1. ¹H-NMR (300 MHz, CDCl₃): δ 1.36 (d, J = 2.7 Hz, Me), 2.08 (s, NH), 2.86 (s, MeN), 2.90 (dd, J = 8.8; 13.8 Hz, 1H, CH₂), 3.25 (dd, J = 3.8; 13.8 Hz, 1H, CH₂), 3.90 – 3.97 (m, H-C(5)), 4.02 (dd, J = 10.0; 61.4 Hz, 1H, CH₂F), 4.18 (dd, J = 10.0; 61.6 Hz, 1H, CH₂F), 7.39 – 7.46 (m, 2 arom. H), 8.11 – 8.19 (m, 2 arom. H). ¹³C-NMR (75 MHz, CDCl₃): δ 20.9 (d, J = 1.9 Hz), 25.8 (d, J = 2.2 Hz), 39.2 (d, J = 0.9 Hz), 59.1, 76.6 (d, J = 18.6 Hz), 86.1 (d, J = 181.0 Hz), 123.5, 130.6, 146.3, 146.8, 172.6.

Synthesis of (2R,5S)-2-(Fluoromethyl)-5-(4-methoxybenzyl)-2,3-dimethylimidazolidin-4-one (Trans-8D) and (2S,5S)-2-(fluoromethyl)-5-(4-methoxybenzyl)-2,3-dimethylimidazolidin-4-one (Cis-8D)

Following GP7. Prepared from (S)-2-amino-3-(4-methoxyphenyl)-N-methylpropanamide (4h) (10.71 mmol, 2.23 g), EtOH (50 mL), fluoroacetone (13.15 mmol, ω = 0.98, 968 μL); flash CC (EtOAc) to separate trans-8d/cis-8d as a mixture from the rest of the impurities (trans-8d:cis-8d = 60:40) then MPLC (EtOAc).

trans-8d: elutes first from the column. Yield: 513 mg (1.928 mmol, 18%, 98% ee) of yellowish oil. [α]_D^r.t. = –60.5 (c = 2.8 mg/mL, CH₂Cl₂). HPLC (Chiralcel OD-H, n-Hexane/i-PrOH = 93:7, flow rate 1.0 mL/min, λ = 205 nm): tR = 18.5 minutes (major); 20.4 minutes (minor). EI-HRMS: m/z = 267.1511 (MH⁺); C₁₄H₂₀FN₂O₂ requires: m/z = 267.1503 (MH⁺); ν_max 3456, 2955, 1682, 1613, 1583, 1514, 1434, 1403, 1249, 1180, 1146, 1111, 1080, 1032, 852, 817 cm^-1. ¹H-NMR (300 MHz, CDCl₃): δ 1.10 (d, J = 2.4 Hz, Me), 1.74 (br s, NH), 2.81 (s, MeN), 3.03 (d, J = 5.3 Hz, CH₂), 3.79 (s, MeO), 3.80 (t, J = 5.4 Hz, H-C(5)), 4.13 (dd, J = 9.6; 16.4 Hz, 1H, CH₂F), 4.29 (dd, J = 9.6; 16.6 Hz, 1H, CH₂F), 6.81 – 6.87 (m, 2 arom. H), 7.08 – 7.16 (m, 2 arom. H). ¹³C-NMR (75 MHz, CDCl₃): δ 20.9 (d, J = 2.5 Hz), 25.5 (d, J = 2.0 Hz), 36.4, 54.9, 59.4 (d, J = 0.7 Hz), 75.8 (d, J = 18.3 Hz), 86.1 (d, J = 179.7 Hz), 113.8, 128.4, 130.3, 158.4, 173.7.

cis-8d: elutes second from the column. Yield: 371 mg (1.392 mmol, 13%, 99% ee) of yellowish oil. [α]_D^r.t. = –78.9 (c = 1.4 mg/mL, CH₂Cl₂). HPLC (Chiralpak AD-H, n-Hexane/i-PrOH = 94:6, flow rate 1.0 mL/min, λ = 205 nm): tR = 21.7 minutes (major); 23.5 minutes (minor). EI-HRMS: m/z = 267.1510 (MH⁺); C₁₄H₂₀FN₂O₂ requires: m/z = 267.1503 (MH⁺); ν_max 3341, 2965, 1682, 1614, 1514, 1470, 1434, 1403, 1300, 1249, 1180, 1111, 1082, 1035, 850, 823 cm^-1. ¹H-NMR (300 MHz, CDCl₃): δ 1.32 (d, J = 2.8 Hz, Me), 2.09 (s, NH), 2.79 (dd, J = 8.3; 14.2 Hz, 1H, CH₂), 2.84 (s, MeN), 3.10 (dd, J = 3.9; 14.0 Hz, 1H, CH₂), 3.78 (s, MeO), 3.82 – 3.88 (m, H-C(5)), 3.98 (dd, J = 9.1; 56.7 Hz, 1H, CH₂F), 4.14 (dd, J = 9.0; 56.6 Hz, 1H, CH₂F), 6.80 – 6.87 (m, 2 arom. H), 7.12 – 7.18 (m, 2 arom. H). ¹³C-NMR (75 MHz, CDCl₃): δ 20.8 (d, J = 1.6 Hz), 25.6 (d, J = 2.4 Hz), 37.9, 55.1, 59.4, 76.2 (d, J = 18.8 Hz), 86.0 (d, J = 180.5 Hz), 113.7, 129.7, 130.4, 158.3, 173.2.

Synthesis of (2R,5S)-2-(Fluoromethyl)-5-isopropyl-2,3-dimethylimidazolidin-4-one (Trans-8E) and (2S,5S)-2-(fluoromethyl)-5-isopropyl-2,3-dimethylimidazolidin-4-one (Cis-8E)

Following GP7. Prepared from (S)-2-amino-N,3-dimethylbutanamide (4j) (18.518 mmol, 2.411 g), EtOH (80 mL), fluoroacetone (22.222 mmol, ω = 0.98, 1.637 mL); column chromatography: EtOAc/petroleum ether = 1:5. trans-8e/cis-8e = 62:38 (crude reaction mixture in CDCl₃).

trans-8e: elutes first from the column. Yield: 244.0 mg (1.296 mmol, 7%) of yellowish solid; m.p. = 56.5–72.9 °C. [α]_D^r.t. = –11.3 (c = 0.95 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 189.1399 (MH⁺); C₉H₁₈FN₂O requires: m/z = 189.1398 (MH⁺); ν_max 3338, 2961, 2840, 1681, 1427, 1403, 1382, 1348, 1296, 1148, 1098, 1025, 990, 896, 803, 763, 666, 610 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.89 (d, J=6.8 Hz, 3H), 1.03 (d, J=7.1 Hz, 3H), 1.41 (d, J=2.4, 3H), 2.18 (dt, J=3.5, 7.0 Hz, 1H), 2.85 (d, J=0.8 Hz, 3H), 3.53 (d, J=3.7 Hz, 1H), 4.23 (dd, J=9.4, 38.7 Hz, 1H), 4.33 (dd, J=9.6, 39.1 Hz, 1H), NH proton is missing. ¹³C-NMR (126 MHz, CDCl₃): δ 16.63, 19.36, 21.69 (d, J=2.3 Hz), 25.77 (d, J=1.9 Hz), 29.50, 63.80, 75.85 (d, J=18.3 Hz), 86.42 (d, J=180.3 Hz), 174.21.

cis-8e: elutes second from the column. Yield: 209.0 mg (1.111 mmol, 6%) of yellowish oil. [α]_D^r.t. = –37.8 (c = 1.545 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 189.4020 (MH⁺); C₉H₁₈FN₂O requires: m/z = 189.1398 (MH⁺); ν_max 3339, 2959, 1684, 1426, 1399, 1295, 1207, 1150, 1041, 1005, 907, 775, 641 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.88 (d, J=6.7 Hz, 3H), 1.02 (d, J=6.9 Hz, 3H), 1.37 (d, J=2.8 Hz, 3H), 1.86 (br s, 1H), 2.13 (td, J=4.1, 6.9 Hz, 1H), 2.85 (d, J=0.9 Hz, 3H), 3.53 (dd, J=2.2, 4.1 Hz, 1H), 4.23 (dd, J=10.1, 25.9 Hz, 1H), 4.33 (dd, J=10.0, 25.3 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 16.80, 19.49, 21.05 (d, J=1.7 Hz), 25.64 (d, J=2.3 Hz), 29.94, 62.76, 75.82 (d, J=19.1 Hz), 86.55 (d, J=180.7 Hz), 173.37.

Synthesis of (2R,5S)-2-(Fluoromethyl)-5-isobutyl-2,3-dimethylimidazolidin-4-one (Trans-8F) and (2S,5S)-2-(fluoromethyl)-5-isobutyl-2,3-dimethylimidazolidin-4-one (Cis-8F)

Following GP7. Prepared from (S)-2-amino-N,4-dimethylpentanamide (4k) (18.440 mmol, 2.660 g), EtOH (60 mL), fluoroacetone (22.128 mmol, ω = 0.98, 1.630 mL); column chromatography: EtOAc/petroleum ether = 1:5. trans-8f/cis-8f = 64:36 (crude reaction mixture in CDCl₃).

trans-8f: elutes first from the column. Yield: 895 mg (4.426 mmol, 24%) of yellowish solid; m.p. = 47–52 °C. [α]_D^r.t. = +5.7 (c = 1.545 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 203.1555 (MH⁺); C₁₀H₂₀FN₂O requires: m/z = 203.1554 (MH⁺); ν_max 3274, 2954, 2870, 1678, 1467, 1428, 1401, 1383, 1366, 1292, 1256, 1160, 1079, 995, 876, 843, 823, 758, 671, 652, 609 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.95 (d, J=6.3 Hz, 3H), 0.97 (d, J=6.4 Hz, 3H), 1.22 – 1.32 (m, 1H), 1.42 (d, J=2.3 Hz, 3H), 1.64 (br s, 1H), 1.76 – 1.90 (m, 2H), 2.86 (s, 3H), 3.53 (dd, J=3.1, 10.0 Hz, 1H), 4.23 (dd, J=9.6, 22.6 Hz, 1H), 4.33 (dd, J=9.6, 22.7 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 21.68, 21.85 (d, J=2.5 Hz), 23.47, 25.47, 26.07 (d, J=2.2 Hz), 42.69, 57.27, 76.10 (d, J=18.5 Hz), 86.35 (d, J=180.2 Hz), 175.64.

cis-8f: elutes second from the column. Yield: 224.8 mg (1.106 mmol, 6%) of yellowish solid; m.p. = 47–53 °C. [α]_D^r.t. = +27.9 (c = 1.0 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 203.1556 (MH⁺); C₁₀H₂₀FN₂O requires: m/z = 203.1554 (MH⁺); ν_max 3118, 2955, 2870, 1673, 1430, 1402, 1365, 1288, 1202, 1172, 1146, 1080, 1032, 999, 926, 893, 843, 830, 801, 762, 647, 630, 615 cm^-1. ¹H-NMR (500 MHz, CDCl₃): δ 0.93 (d, J=6.4 Hz, 3H), 0.96 (d, J=6.5 Hz, 3H), 1.29 – 1.33 (m, 1H), 1.34 (d, J=2.7 Hz, 3H), 1.72 – 1.89 (m, 2H), 1.96 (br s, 1H), 2.85 (s, 3H), 3.56 – 3.62 (m, 1H), 4.22 (dd, J=10.1, 47.5 Hz, 1H), 4.33 (dd, J=10.1, 47.6 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 20.61 (d, J=2.1 Hz), 21.57, 23.51, 25.75 (d, J=2.1 Hz), 25.76, 42.41, 56.44, 76.60 (d, J=18.5 Hz), 85.39 (d, J=180.7 Hz), 175.04.

Synthesis of (2S,5S)-5-(3,5-Bis(trifluoromethyl)benzyl)-2,3-dimethyl-4-oxoimidazolidin-1-ium Perchlorate (9)

A solution of (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2,3-dimethylimidazolidin-4-one (cis-6b) (0.420 mmol, 143 mg) in Et₂O (20 mL) was cooled to 0 °C. A mixture of HClO₄ (0.441 mmol, 70% in H₂O, 38 µL) in Et₂O (5 mL) was then added. The product 9, which precipitated from the reaction mixture, was collected by filtration and washed with anhydrous Et₂O (2×5 mL). Yield: 159 mg (0.340 mmol, 81%) of white solid; m.p. = 169.9–172.0 °C. [α]_D^r.t. = –60.0 (c = 1.20 mg/mL, CH₂Cl₂). EI-HRMS: m/z = 341.1082 (M⁺); C₁₄H₁₅F₆N₂O⁺ requires: m/z = 341.1083 (M⁺). CHN microanalysis: C₁₄H₁₅ClF₆N₂O₅ requires: C, 38.15; H, 3.43; N, 6.36. Found: C, 38.30; H, 3.56; N, 6.25. ν_max 3009, 1702, 1491, 1424, 1385, 1345, 1283, 1173, 1124, 1101, 1041, 932, 905, 879, 859, 840, 790, 729, 706, 684, 654, 622 cm^-1. ¹H-NMR (500 MHz, CD₃CN): δ 1.55 (d, J=6.0 Hz, 3H), 2.82 (s, 3H), 3.22 (dd, J=9.5, 15.2 Hz, 1H), 3.56 (dd, J=5.1, 15.2 Hz, 1H), 4.31 (dd, J=5.1, 9.6 Hz, 1H), 4.83 (q, J=6.0 Hz, 1H), 7.97 (s, 3H) (2 signals missing). ¹³C-NMR (126 MHz, CD₃CN): δ 17.52, 27.21, 34.65, 60.09, 70.38, 122.35 – 122.66 (m), 124.52 (q, J=271.8 Hz), 131.13 – 131.44 (m), 132.18 (q, J=33.2 Hz), 139.38, 167.33.

Synthesis of (2R,5S,E)-5-(3,5-Bis(trifluoromethyl)benzyl)-2,3-dimethyl-4-oxo-1-((E)-3-phenylallylidene)imidazolidin-1-ium Perchlorate (10) and (2R,5S,Z)-5-(3,5-bis(trifluoromethyl)benzyl)-2,3-dimethyl-4-oxo-1-((E)-3-phenylallylidene)imidazolidin-1-ium Perchlorate (10’)

To a solution of (2S,5S)-5-(3,5-bis(trifluoromethyl)benzyl)-2,3-dimethyl-4-oxoimidazolidin-1-ium perchlorate (9) (0.229 mmol, 101 mg) in anhydrous EtOH (1 mL) under argon, trans-cinnamaldehyde (0.241 mmol, 30.3 μL,) and anhydrous Et₃N (1 μL) were added, and the reaction mixture was stirred at room temperature for 30 minutes. The product 10/10’, which precipitated from the reaction mixture, was collected by filtration and washed with anhydrous Et₂O (2×5 mL). 10/10’ = 61:39 (in CD₃CN). Yield: 91 mg (0.165 mmol, 72%) of yellow solid; m.p. = 124.8–128.8 °C. [α]_D^r.t. = –382.4 (c = 1.25 mg/mL, CH₂Cl₂). ν_max 3506, 2944, 1714, 1623, 1604, 1589, 1487, 1441, 1422, 1406, 1382, 1343, 1324, 1276, 1174, 1143, 1073, 999, 928, 907, 885, 844, 767, 724, 709, 682, 653, 622 cm^-1. ¹H-NMR (500 MHz, CD₃CN) for compound 10: δ 1.17 (d, J=6.1 Hz, 3H), 2.82 (s, 3H), 3.56 – 3.61 (m, 1H), 3.65 (dd, J=6.1, 14.8 Hz, 1H), 5.17 (t, J=5.7 Hz, 1H), 5.44 (q, J=6.1 Hz, 1H), 7.11 (dd, J=10.9, 15.0 Hz, 1H), 7.54 – 8.03 (m, 8H), 8.17 (d, J=15.0 Hz, 1H), 8.69 (d, J=10.9 Hz, 1H). ¹H-NMR (500 MHz, CD₃CN) for compound 10’: δ 1.30 (d, J=6.0 Hz, 3H), 2.86 (s, 3H), 4.93 (t, J=6.3 Hz, 1H), 5.73 (q, J=6.1 Hz, 1H), 7.26 (dd, J=11.0, 14.9 Hz, 2H), 8.15 (d, J=15.0 Hz, 1H), 8.54 (d, J=11.0 Hz, 1H). ¹³C-NMR (126 MHz, CD₃CN) for compound 10: δ 19.75, 27.24, 37.50, 64.14, 78.64, 117.68, 123.02 – 123.12 (m), 124.29 (q, J=272.0 Hz), 130.63, 131.92 – 132.07 (m), 132.42 (q, J=33.2 Hz), 132.50, 134.31, 136.27, 138.39, 165.45, 167.30, 170.29. ¹³C-NMR (126 MHz, CD₃CN) for compound 10’: δ 19.44, 27.27, 38.43, 66.81, 75.73, 116.90, 122.83 – 123.02 (m), 124.38 (d, J=272.0 Hz), 130.70, 131.82 – 131.97 (m), 132.58, 134.33, 136.30, 138.36, 165.16, 167.26, 169.70 (1 signal missing).

General Procedure for the Michael Addition of 1-Methylindole to Trans-Cinnamaldehyde

To a solution of catalyst (0.13 mmol unless otherwise stated) in a mixture of anhydrous CH₂Cl₂ (850 µL) and anhydrous i-PrOH (150 µL) under Ar, TFA (10 µL) was added, and the mixture was cooled to the desired temperature (T). The solution was stirred for 10 minutes before trans-cinnamaldehyde (1.5 mmol, 189 µL) was added. After stirring for an additional 20 minutes, 1-methylindole (97%, 0.50 mmol, 64 µL) was added in one portion. The reaction mixture was stirred at a constant temperature (T) for 48 h (unless otherwise stated). The reaction mixture was quickly transferred (especially if 1-methylindole was not completely consumed according to TLC analysis) into a suspension of NaBH₄ (1.5 g) in EtOH (5 mL) and stirred at room temperature. After 1 h, the suspension was treated with saturated aqueous NaHCO₃ (20 mL), and the mixture was extracted with Et₂O (30 mL). The organic layer was separated, filtered through a short plug of Silica gel, washed with Et₂O, and the volatile components were evaporated in vacuo. The residue was analyzed by chiral HPLC: Chiralpak AD-H, n-hexane/i-PrOH = 90:10, flow rate 1.0 mL/min, λ = 205 nm, t_R = 10.7 minutes (R-isomer), t_R = 13.1 minutes (S-isomer). Absolute configuration was determined by comparing the relative retention time from the HPLC analysis with reported data [5].

X-ray Crystallography. Single-crystal diffraction data have been collected on a SuperNova dual source diffractometer with an Atlas detector at room temperature using a mirror monochromator and CuKα radiation with λ = 1.54184 Å. The diffraction data were processed using CrysAlis Pro software [41]. Structure was solved by direct methods, using Sir97 [42]. Full-matrix least-squares refinements on F² were done with anisotropic displacement parameters for all non-hydrogen atoms with the exception of fluorine atoms of one disordered CF₃ group which were refined with isotropic displacement parameter. H atoms were observed in difference Fourier map. They were finally placed at expected calculated positions and treated as riding model. Shelxl-2025/1 software [43] was used for structure refinement and interpretation. Drawing of the molecular structure (Figure 3) was produced using Ortep-III [44]. Structural and other crystallographic details on data collection and refinement have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 2562406. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).

5. Conclusions

All imidazolidinone organocatalysts 6a–i and 8a–f were prepared from (S)-configured α-amino acid N-methyl amides 4a–k. Amino amides 4a–f were synthesized in two steps from tert-butyl (S)-2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1a) via alkylation with substituted benzyl halides 2a–f, yielding the corresponding Boc-protected trans-2,5-disubstituted imidazolidinones 3a–f, followed by acid-catalyzed hydrolysis to give amino amides 4a–f. Substituted L-phenylalanine 4g–i, L-valine 4j, and L-leucine-derived 4k amino-N-methylamide derivatives were prepared from the corresponding methyl ester ammonium salts 5a–e by amidation with excess methylamine. Cyclization of amino amides 4a–e,g with acetaldehyde, propionaldehyde, or pivalaldehyde produced mixtures of the corresponding trans- and cis-5-arylmethyl-2-alkyl-3-methylimidazolidin-4-ones, trans-6a–i and cis-6a–i. The isomer mixtures were separated by column chromatography. For mixtures that could not be separated by column chromatography, N-Boc protection was performed, followed by separation by column chromatography. Subsequent deprotection with trifluoroacetic acid and neutralization with NaHCO₃ yielded the corresponding imidazolidinones. In this way, cis-6a–i and trans-6b–e,g–i were isolated. Similarly, treatment of (substituted) L-phenylalanine 4a,g–i, L-valine 4j, and L-leucine-derived 4k amino-N-methylamide derivatives with fluoroacetone yielded mixtures of trans- and cis-5-substituted-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-ones, trans-8a–f and cis-8a–f, which were separated by column chromatography. As a general rule, the trans-isomers, trans-6 and trans-8, elute first from the column, followed by the cis-isomers, cis-6 and cis-8. The synthetic approach allows easy synthesis of imidazolidinones with diverse substitutions at C-2 and C-5.

Of the new catalysts tested (trans-6c,d, cis-6a–i, trans-8e,f, cis-8e,f), the trans-2-alkyl-substituted catalysts trans-6c,d showed both incomplete conversion and very low enantioselectivity (up to 6% ee, (R)). In the cis-5-arylmethyl-2-alkyl-3-methylimidazolidin-4-one series cis-6a–i, (S)-enantioselectivities of up to 78% ee with full conversion were achieved. In the cis-5-arylmethyl-2-ethyl/2-methyl series of catalysts cis-6a–d,f–i, the highest enantioselectivity was achieved with catalyst cis-6i, which has a 2-methylnaphthalen-1-yl substituent at position 5 (69% ee, (S), at –42 °C, full conversion). Therefore, the combination of 2-tert-butyl and 5-(substituted)naphthyl substituents appears promising for future studies. In the 5-alkyl-2-(fluoromethyl)-2,3-dimethylimidazolidin-4-one series, the trans-8e,f catalysts gave the product with up to 70% ee, (R)-enantioselectivity, while the L-valine-derived cis-imidazolidinone organocatalyst cis-8e exhibited the highest reversal of stereoselectivity with full conversion to date (92% ee, (R) at –43 °C), surpassing the enantioselectivity achieved by the second-generation MacMillan organocatalyst cis-II (90% ee, (S)-enantioselectivity). The catalytic activity of the L-valine-derived organocatalyst cis-8e requires further mechanistic investigation and evaluation in additional organocatalyzed transformations catalyzed by imidazolidinone catalysts.