A remarkable chiral recognition of racemic Mosher's acid salt by naturally derived chiral ionic liquids using ¹⁹F NMR spectroscopy

Abstract

A new class of D-xylose derived imidazolium-based chiral ionic liquids were designed and synthesized via simple tuning approaches. The developed chiral ionic liquids were tested for their chiral recognition properties with racemic Mosher's acid salt using ¹⁹F NMR spectroscopy. For the first time, we demonstrate the excellent enantioselective discrimination of the racemic salt using significantly less equivalents of carbohydrate derived chiral ionic liquids. We have determined the enantiomeric excess values of non-racemic mixtures of Mosher's acid salts using ¹⁹F NMR spectroscopy.

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In modern organic chemistry, ionic liquids (ILs) show significant applications due to their outstanding physical and chemical properties and they also display considerable effects on reaction kinetics, specificity, recyclability and catalyst recovery.¹ Among the variety of ILs reported, chiral ionic liquids (CILs) are of special interest because of their ability to influence the stereochemical outcome of a reaction by acting as either a chiral solvent or chiral catalyst.² CILs have shown good applications in asymmetric synthesis,³ chromatography⁴ and stereoselective polymerization.⁵ Based on the available literature, the majority of the CILs are derived from natural amino acids because they provide an essential source of chirality.⁶ Some of the CILs known for their chiral recognition ability have been used as NMR chiral shift reagents for the discrimination of racemates.⁷ Malhotra and co-workers were synthesized bis(ammonium) based CILs derived from isomannide that show good chiral recognition of racemic Mosher's acid salt.⁸

A major class of naturally occurring organic molecules in nature are carbohydrates, which are produced from various bio-renewable sources. Although numerous reports are available on the application of carbohydrate derivatives in achiral/chiral synthesis, the reports on carbohydrate derived chiral ionic liquids (CCILs) are rare.⁹ Recently, we reported the synthesis of D-ribose and D-galactose based CILs and their application in the Michael addition reaction, wherein they were used as recyclable chiral solvents, as well as chiral catalysts.¹⁰

Furthermore, a hydrophobic D-galactose based IL was utilized for the effective removal of Pb²⁺ ions from an aqueous solution.¹¹ In a continuation of our efforts to synthesize CCILs and study their applications in asymmetric transformations, we herein report the synthesis of novel imidazolium containing D-xylose derived CILs. The synthesized CCILs were studied for their chiral recognition properties using racemic Mosher's acid salt (Scheme 1).

Scheme 1 Chiral recognition of racemic Mosher's acid salt using D-xylose derived CILs.

The synthetic route used to prepare the CCILs presented in this study is a straightforward protocol starting from naturally occurring D-xylose, which is cheap and readily available (Scheme 2). The synthesis of the D-xylose based CIL began with an acid catalyzed protection of D-xylose 1 in dry acetone, followed by selective deprotection using 0.1 N HCl solution at room temperature, which resulted in (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol 3.¹²

Scheme 2 The synthetic routes used to prepare the D-xylose derived CCILs.

Reagents and conditions: (i) CuSO₄, H₂SO₄, Me₂CO, 24 h, rt (85%); (ii) HCl, H₂O, 3 h, rt (95%); (iii) p-TsCl, dry DCM, N-methyl imidazole, TEA, reflux (91%); (iv-a) TFA, MeOH, reflux, 10 h (93%); (iv-b) K₂CO₃, MeOH, 3 h, rt; (v) imidazole, Cs₂CO₃, DMF, 120 °C, overnight (90%); (vi) CH₃I, rt, 6 h (91%); LiX, H₂O, 24 h, rt (8–72%, 9–82%, 10–76%, 11–62%).

Then, compound 3 was converted to the ditosylated compound ((3aS,5S,6R,6aS)-2,2-dimethyl-5-((tosyloxy)methyl)tetrahydrofuro[2,3-d][1,3]dioxol-6-yl 4-methylbenzenesulfonate) 4 using p-TSCl and N-methylimidazole. The oxirane derivative of D-xylose ((1R,2R,5R)-2-(dimethoxymethyl)-3, 6-dioxabicyclo [3.1.0] hexane) 5 was synthesized from compound 4 via an acid promoted ring transposition followed by treatment with potassium carbonate in methanol at room temperature.¹³ The epoxide ring of compound 5 was opened by nucleophilic attack of imidazole in the presence of Cs₂CO₃ at 120 °C to produce (2R,3R,4S)-2-(dimethoxymethyl)-4-(1H-imidazol-1-yl) tetrahydrofuran-3-ol 6. Finally, compound 6 was quaternized using methyl iodide at room temperature, affording the target CCIL 7 (1-((3S,4R,5R)-5-(dimethoxymethyl)-4-hydroxytetrahydrofuran-3-yl)-3-methyl-1H-imidazol-3-ium iodide)¹⁴ in good overall yield (56%) starting from D-xylose. Furthermore, the iodo anion of compound 7 was exchanged with different fluorine containing anions via simple anion metathesis in an aqueous medium with very good yields. All the synthesized CCILs were liquids and stable at room temperature.

After the successful synthesis of the target CCILs (7–11, Scheme 2), the chiral discrimination ability was evaluated by studying the diastereomeric interaction between CCIL 7 (10 mg, 0.027 mmol) and racemic Mosher's acid silver salt (4.6 mg, 0.013 mmol) in CD₃CN (0.6 mL). The mixture was analyzed, using ¹⁹F NMR spectroscopy. Clear splitting of the CF₃ signal was observed (Fig. 1(a)), which indicated the excellent chiral discrimination properties on racemic Mosher's acid salt.¹⁵

Fig. 1 The partial ¹⁹F NMR (376.5 MHz) spectra of CCIL 7 and the racemic Mosher's acid salt complex. The splitting pattern of the CF₃ signal for (a) 2 equiv. of CCIL 7; (b) 4 equiv. of CCIL 7; and (c) 6 equiv. of CCIL 7.

Broad peaks for the CF₃ signals were observed when the experiments were performed using the remaining CCILs (8, 9, 10 and 11) under similar conditions. To get clear splitting, each CCIL was mixed with the racemic salt in dry acetonitrile, stirred for 10 min at room temperature, filtered and the filtrate distilled. The residual compound was dissolved in CDCl₃ and the ¹⁹F NMR spectrum was obtained. CCILs 8, 9 and 11 show very good splitting for the CF₃ signal of racemic Mosher's acid salt, while in the case of CCIL 10 no splitting was observed. The results are summarized in Table 1. Among all the CCILs studied, CCIL 7 showed excellent optical resolution properties using less equivalents (2 equiv.) in CD₃CN itself. Furthermore, we analyzed the splitting pattern of racemic Mosher's acid salt using CCIL 7 by ¹H and ¹³C NMR spectroscopy. In the ¹H NMR spectra, only a broad peak (OMe of Mosher's acid salt) was observed and no clear splitting was observed by ¹³C NMR spectroscopy.

Table 1 The Δδ values of the CF₃ signals of racemic Mosher's acid silver salt in the presence of 2 equiv. of CCILs (7–11)

Entry	CCIL	CCIL anion	Solvent	Chemical shift difference (Δδ)^R/S in ppm^a
a Recorded using ^19F NMR spectroscopy at 376.5 MHz.b NS: no splitting observed for the CF3 signal.
1	7	[I]	CD3CN	0.062
2	8	[PF6]	CDCl3	0.031
3	9	[Tf2N]	CDCl3	0.045
4^b	10	[OTf]	CDCl3	NS
5	11	[BF4]	CDCl3	0.047

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Furthermore, CCIL 7 was employed at varied concentrations with respect to the racemic salt and the details summarized in Table 2.¹⁶ From Table 2, it was evident that 2 equiv. (0.0450 mol L⁻¹) of CCIL was sufficient enough for the clear separation of the racemic mixture and an almost saturation point was reached while using 4 and 6 equiv. of CCIL 7 (Table 2 and Fig. 1). The concentration effect of CCIL 7 on the magnitude of the CF₃ signal splitting is represented in Fig. 2. The high splitting for the CF₃ signal of racemic Mosher's acid salt using CCILs has been rarely reported in the literature (except by Malhotra and co-workers in 2007).

Table 2 Δδ Values of CF₃ signals of racemic Mosher's acid silver salt in the presence of varied concentrations of CCIL 7

Entry	CCIL 7 (equiv.)	Racemic Mosher's silver salt (equiv.)	Chemical shift difference (Δδ)^R/S in ppm^a
a Recorded using ^19F NMR spectroscopy at 376.5 MHz.
1	1	1	0.017
2	2	1	0.062
3	4	1	0.074
4	6	1	0.075

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Fig. 2 The effect of the concentration of CCIL 7 on the signal splitting of the racemic Mosher's acid salt.

Because CCIL 7 has shown excellent chiral discrimination properties, it was used for the determination of the enantiomeric excess of non-racemic Mosher's acid salt mixtures. Two different ratios of non-racemic mixtures were prepared by adding (S)-Mosher's acid salt to racemic Mosher's acid salt ((R/S) = 1 : 2 and 1 : 4 approximately). The ee value can be determined by integration of the CF₃ signal observed by ¹⁹F NMR spectroscopy (Fig. 3).

Fig. 3 Determination of the ee values of non-racemic Mosher's acid salt by ¹⁹F NMR spectroscopy. (R/S) = 1 : 2 (a) and 1 : 4 (b) approximately.

In conclusion, novel D-xylose derived CILs have been synthesized via simple modifications starting from D-xylose in good overall yields. Their chiral recognition properties were studied using racemic and non-racemic Mosher's acid silver salts and excellent discrimination was observed with significantly less quantities of the CCILs. The high resolution properties of the CCILs for the racemic salt indicate their potential application as NMR chiral shift reagents for various racemic carboxylic acids. Further applications of these CCILs as a chiral solvent and chiral catalyst for various asymmetric transformations are currently underway in our laboratory.

Acknowledgements

Funding from DST/SR/FT/CS-93/2011 (FAST-TRACK-SCHEME), Govt. of India is gratefully acknowledged. We thank the DST-FIST and VIT-SIF for providing FT-NMR facilities and also special thanks to the VIT University for providing the RGEMS grant. We would like to extend our sincerest thanks to Dr V. Jayathirtha Rao (Head & Chief scientist, CFC-division) and Mr M. Sasikumar, CSIR-IICT-Hyderabad for their support.

Notes and references

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14. 1-((3S,4R,5R)-5-(dimethoxymethyl)-4-hydroxytetrahydrofuran-3-yl)-3-methyl-1H-imidazol-3-ium iodide (7): methyl iodide (598 mg/0.26 mL, 4.212 mmol) was added to a stirred solution of compound 6 (641 mg, 2.808 mmol) in dry acetonitrile (2 mL) and the resulting mixture was stirred at room temperature for 6 h. Upon completion of the reaction, the solvent was removed using vacuum distillation. The crude compound was dissolved in 50% methanol/chloroform and passed through neutral alumina to afford compound 7 as a colorless liquid in 91% yield. [α]²⁵_D = +88.8 (c 1, MeOH); ¹H NMR (400 MHz, chloroform-d) δ 9.84 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.17 (t, J = 2.0 Hz, 1H), 5.41 (d, J = 4.8 Hz, 1H), 4.61 (d, J = 4.8 Hz, 1H), 4.51 (d, J = 3.6 Hz, 1H), 4.30 (dd, J = 11.2, 4.8 Hz, 1H), 4.20 (d, J = 11.2 Hz, 1H), 4.00 (s, 3H), 3.98 (dd, J = 4.8, 3.2 Hz, 1H), 3.46 (s, 3H), 3.44 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) δ 137.50, 122.69, 121.37, 103.66, 85.67, 78.69, 70.92, 68.34, 55.99, 55.55, 36.91; HRMS (ESI) exact calculated mass for [M⁺] (C₁₁H₁₉O₄N₂) requires m/z 243.1339, found m/z 243.1336; LR-MS (ESI) ES⁺: 243.2, ES⁻: 126.9.
15. The racemic Mosher's acid silver salt (4.6 mg, 0.013 mmol) was mixed with CCIL 7 (10 mg, 0.027 mmol) in 0.6 mL of CD₃CN and stirred for 10 min at room temperature to exchange anions. The AgI precipitate formed was filtered and the filtrate was analyzed by ¹⁹F NMR spectroscopy (376.5 MHz). For CCILs 8–11, the racemic salt (1 equiv.) was mixed with each CIL (10 mg, 2 equiv.) separately in dry ACN and stirred for 10 min. The formed salts were filtered and the filtrate concentrated under reduced pressure using a rotary evaporator. The residual compound was dissolved in CDCl₃ and analyzed by ¹⁹F NMR spectroscopy.
16. The effect of CCIL 7 concentration: in another set of experiments, each different concentration of CCIL 7 (1 eq., 4 eq. and 6 eq.) was mixed with the racemic salt and the effect of the concentration of CCIL 7 was studied for chiral discrimination by ¹⁹F NMR spectroscopy.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra02792j

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