Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives

The new chiral ligands I–III based on derivatives of imidazolidin-4-one were synthesised and characterised. The catalytic activity and enantioselectivity of their corresponding copper(II) complexes were studied in asymmetric Henry reactions. It was found that the enantioselectivity of these catalysts is overall very high and depends on the relative configuration of the ligand used; cis-configuration of ligand affords the nitroaldols with major enantiomer S- (up to 97% ee), whereas the application of ligands with trans-configuration led to nitroaldols with major R-enantiomer (up to 96% ee). The “proline-type” ligand IV was also tested in asymmetric aldol reactions. Under the optimised reaction conditions, aldol products with enantioselectivities of up to 91% ee were obtained.

Scheme 1.The synthesis of the ligands I-III.
To obtain the corresponding bis(imidazolidine-4-one) derivatives in satisfactory yields and to avoid the appearance of mono(imidazolidine-4-one) derivative intermediates in the crude product mixture, it was necessary to explore the appropriate reaction conditions.Key to the successful synthesis was the use of an excess of the 2-aminoamide reagent (3 equiv; 1.5 equiv to each carbonyl group) and an elevated reaction temperature of 80 °C.For this reason, the initially used solvent (MeOH) [1] needed to be replaced by n-BuOH.The reaction time was extended to 120 h, under an inert argon atmosphere, to ensure complete conversion to ligands Ia-c while simultaneously preventing the formation of mono(imidazolidine-4-one) intermediates and avoiding any undesirable oxidation to imidazoline-4-one derivative.This approach led to the high-yield production of ligands Ia-c (Figure 1), with the diastereomers

S3
being formed in a ratio of 1:2:1 (Ia:Ib:Ic).The final isolation of each diastereomer was achieved by careful column chromatography on silica using a mixture of acetone, AcOEt, and MeOH (13/7/1) as the eluent.Multiple fractionation stages were necessary to effectively separate the mixture into distinct components.
Figure 1 The relative configuration at imidazolidine-4-one rings of ligands Ia-c.
Inspired by the methodology outlined in reference [1] for the synthesis of a bidentate ligand (R 1 = Me; R 2 = iPr), and similar to the process used for the preparation of ligands Ia-c, ligands IIac were synthesised through a reaction between 2,6-diacetylpyridine and (S)-2-amino-2,3dimethylbutanamide (3 equiv).A notable adaptation in this synthesis was the employment of ortho-dichlorobenzene as the solvent, enabling the reaction to proceed efficiently at the elevated temperature of 140 °C.TLC was used to monitor the reaction, with the disappearance of mono-(imidazolidine-4-one) derivatives observed after 96 h.The subsequent chromatographic separation (SiO2; AcOEt/MeOH (20/1) yielded the individual diastereomers trans-trans (IIa), cis-trans (IIb), and cis-cis (IIc) in a ratio of 2:3:1, achieving an overall yield of 70%.
Building upon the methodologies employed for the earlier ligands and following the procedures outlined in reference [1]  of the desired products.The individual epimers IIIa and IIIb (in the ratio of 3:4) were then effectively separated using column chromatography (SiO2; acetone), ensuring the purity of the final compounds.
Following the established synthetic pathway detailed in references [2,3], compound IV was initially prepared starting from N-Boc-prolinol.The process involved synthesising (S)-2-(N-Boc-pyrrolidine-2-yl)-1H-imidazole.However, the deprotection step, traditionally conducted under conditions such as TFA/DCM [2] and BF3•Et2O [3], resulted in the formation of numerous undesired by-products.To address this issue, we modified the method by replacing the Boc protecting group with a CBz group (Scheme 2).This alteration allowed for the successful oxidation of N-CBz-prolinol via Swern oxidation, yielding the corresponding aldehyde with high efficiency (75%) [4].Subsequently, this aldehyde was converted to the imidazole derivative, following the original protocol, with a yield of 48% [2,3].The final step involved hydrogenolysis for the deprotection of the pyrrolidine moiety, resulting in the formation of ligand IV as a pale-yellow oil.Notably, no racemisation was observed throughout the reaction process.
Scheme 2. The synthesis of the ligand IV.

Experimental procedures 2.1. General procedures
The starting chemicals and solvents were obtained from TCI Chemicals or Fluorochem and used without further purification.(S)-2-Amino-2,3-dimethylbutanamide was prepared according to the method described previously [5].Column chromatography was performed Hydrogenations were performed in pressure vessel Berghof BR-100.To evaluate the effectiveness of the catalysts, the values of Turnover Number (TON) and Turnover Frequency (TOF) related to the production of the major stereoisomer were calculated using the following equations:   being stirred for an additional 20 min, TEA (9.4 mL; 67 mmol, 4 equiv) was added, the reaction mixture was gradually heated at 0 °C and stirred for 2 h.After the addition of DCM (75 mL), the mixture was washed with a saturated solution of NaHCO3 (75 mL) and brine (75 mL).The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give 2.92 g (75%) of aldehyde as a yellow oil, which was introduced into the next step without further purification. 1
The organic layer was dried over Na2SO4 and evaporated under reduced pressure.
using 60 Å (60-200 μm) silica gel.TLC was performed on aluminium-backed silica gel plates (Merck DC, Alufolien Kieselgel 60 F254) with spots visualised by UV light.The melting point temperatures are uncorrected.The IR spectra were measured at room temperature using Thermo Scientific Nicolet iS50 FT-IR Spectrometer with ATR technique, the resolution was 4 cm -1 , FT-IR data are presented in cm -1 . 1 H NMR spectra were recorded on a Bruker Avance 400 instrument (400.13MHz for 1H) or Bruker Ascend 500 instrument (500.13MHz for 1 H).Chemical shifts  were referenced to the residual peak of CDCl3 at 7.26 ppm or MeOD-d4 at 3.31 ppm.The 13 C NMR spectra were calibrated with respect to the middle signal in the triplet of CDCl3 ( = 77.23 ppm).High-resolution mass spectra were measured on the Thermo Fisher Scientific MALDI LTQ Orbitrap instrument.The used matrix was a 0.2 M solution of 2,5dihydroxybenzoic acid (DHB) in MeCN/H2O (95:5).Spectra were calibrated with respect to the used matrix.The optical rotation was measured on a Perkin-Elmer 341 instrument; the concentration c was given in g/100 mL.HPLC analyses were performed on the Watrex HPLC instrument with UV-Vis DAD (200-800 nm) SYKAM 3240 and with chiral Daicel columns Chilacel OD-H, Chiralpak AD-H, Chiralpak IA and Chiralpak AS-H (250 mm × 4.6 mm).

Summarisation of the results of catalytic experiments
The conversion was determined by1H NMR analysis of the crude product.
a b The enantiomeric excess was determined by chiral HPLC.