Synthesis of Novel Pseudo-Enantiomeric Phase-Transfer Catalysts from Cinchona Alkaloids and Application to the Hydrolytic Dynamic Kinetic Resolution of Racemic 3-Phenyl-2-oxetanone

Abstract

Naturally occurring Cinchona alkaloids such as quinidine (QD)/cinchonine (CN) and their diastereomers, quinine (QN)/cinchonidine (CD), have been recognized as pseudo-enantiomeric pairs. Utilizing these pseudo-enantiomeric alkaloids as chiral resources provides complementary enantioselectivity in many asymmetric reactions. During the screening of Cinchona alkaloid phase-transfer catalysts (PTCs) in the hydrolytic dynamic kinetic resolution of racemic 3-phenyl-2-oxetanone (1) to tropic acid (2), we found that the introduction of a 4-trifluoromethylphenyl group at the vinyl terminus of BnQN significantly reduced the enantioselectivity to 41% enantiomeric excess (ee). The optimized structure of tetrahedral intermediates (TI, PTC + 1 + OH⁻) of hydrolysis obtained by density functional theory (DFT) calculations shows that the orientation of the quinoline and benzene rings of QD class PTC are nearly parallel to each other and to construct a greatly extended π-electron cloud surface, allowing good π–π interaction with the benzene ring of 1.

Introduction

Naturally occurring optically active Cinchona alkaloids such as quinidine (QD)/cinchonine (CN) and their diastereomers, quinine (QN)/cinchonidine (CD), have been recognized as pseudo-enantiomeric pairs.¹⁾ Fortunately for synthetic organic chemists, using pseudo-enantiomeric alkaloids as chiral resources provides complementary enantioselectivity in many asymmetric reactions^2–7) (Fig. 1).

Fig. 1. Structures of Pseudo-Enantiomeric Cinchona Alkaloids

Recently, we reported the hydrolytic dynamic kinetic resolution of racemic 3-phenyl-2-oxetanone (rac-1, tropic acid β-lactone) to tropic acid (2) catalyzed by the Cinchona alkaloid class of chiral quaternary ammonium phase-transfer catalysts (PTCs) under non-aqueous condition using water-free basic anion exchange resin (R₄N⁺OH⁻) as the hydroxide ion donor⁸⁾ (Table 1).

Table 1. Hydrolytic Kinetic Resolution of 3-Phenyl-2-oxetanone (1) by Chiral PTCs

Entry	PTC	Yield (%)	% ee	R/S of 2
1	3	71	72	S
2	5	85	81	S
3	6	52	74	S
4	4	85	66	R
5	7	86	64	R
6	8	77	62	R

The chiral PTC-catalyzed hydrolysis of rac-1 illustrated that the relatively higher enantioselectivity was observed when BnQD and BnCN were used instead of their pseudo-enantiomeric BnQN and BnCD. We assumed that the diastereomeric structural difference was responsible for this phenomenon, which has also been observed in other reactions.⁹⁾ However, at that time, it was not clear how the relative stereochemistry between the C-3, C-8, and C-9 carbon would improve or worsen the enantioselectivity in asymmetric hydrolysis.

Results and Discussion

Although the observed difference in enantioselectivity between pseudo-enantiomeric PTCs was not large, we attempted to clarify the reason for the difference between the pseudo-enantiomers, BnQD (5) and BnQN (7). Therefore, we designed and synthesized unprecedented pseudo-enantiomeric pairs of CF₃BnQD (6)/CF₃BnQN (8), 4-CH₃PhBnQD (10)/4-CH₃PhBnQN (14), and 4-CF₃PhBnQD (12)/4-CF₃PhBnQN (16). The introduction of a trifluoromethyl (CF₃) group at C-2′ of QD/QN was performed by late-stage nucleophilic trifluoromethylation.¹⁰⁾ The benzylidene analogs (ArBnQD/ArBnQN), such as 10/14 and 12/16, originally synthesized by Morgan et al. for a structure–activity relationship study of antiplasmodial activity in QN-resistant and QN-sensitive strains, were synthesized from QD/QN by the Heck reaction according to their reported procedures¹¹⁾ (Chart 1).

Chart 1. Synthesis of Novel PTCs Derived from QD/QN

The results of the hydrolytic kinetic resolution of rac-1 by chiral PTCs are listed in Table 2.⁸⁾ The QD class PTC preferentially hydrolyzed (S)-1, and the QN class PTC hydrolyzed (R)-1 in all entries. The energy differences (E_TI^S − E_TI^R) between the tetrahedral intermediates (TI) obtained by density functional theory (DFT) calculations (ωB97XRV, 6-311 + G**, C-PCM dielectric = 8.82 (CH₂Cl₂)) showed enantiomer preferences similar to all experimental results. Unfortunately, the enantioselectivity of entries 2–4 and 6–8 was lower than that of the original catalysts. Quinidine-derived catalysts 5, 6, 10, and 12 retained relatively moderate enantioselectivity compared to quinine-derived catalysts 7, 8, 14, and 16. The introduction of a trifluoromethyl group at the quinoline 2-position resulted in only a slight decrease in the asymmetric yield, and arylation of the vinyl terminus of the catalyst resulted in a loss of enantioselectivity. Comparing the relative enantioselectivities of QD-derived PTCs and QN-derived PTCs, the loss of asymmetric yield was more pronounced for the 16 deteriorating from 68 to 41% enantiomeric excess (ee). We have previously found that the presence of a C-9 OH group is essential for enantioselective hydrolysis.⁸⁾ Therefore, high selectivity is unlikely to be achieved if a favorable orientation of 1 and the PTC is not possible. The optimized structure of tetrahedral intermediates (TI, PTC + 1 + OH⁻) of hydrolysis obtained by DFT calculations shows that the orientation of the quinoline and benzene rings of QD class PTC are nearly parallel to each other and to construct a greatly extended π-electron cloud surface, which allows good π–π interaction with the benzene ring of 1. Conversely, QN class PTCs do not retain good π–π interactions between the two aromatic rings of the PTC and the benzene ring of 1 (Fig. 2).

Table 2. Hydrolytic Kinetic Resolution of 3-Phenyl-2-oxetanone (1) by Novel Chiral PTCs

Entry	PTC	% ee	% yield	R/S of 2	PTC + (R)-1 + OH− (ETIR)	PTC + (S)-1 + OH− (ETIS)	ΔΕTI = ETIS − ETIR
					kcal/mol
1	5	81	85	S	−1180669.52	−1180671.33	−1.81
2	6	74	52	S	−1392172.26	−1392174.28	−2.02
3	10	57	65	S	−1350329.80	−1350331.01	−1.21
4	12	68	82	S	−1537161.88	−1537162.55	−0.67
5	7	64	86	R	−1180662.93	−1180661.15	1.78
6	8	62	77	R	−1392166.18	−1392164.03	2.15
7	14	57	93	R	−1350322.86	−1350322.34	0.52
8	16	41	49	R	−1537154.62	−1537154.54	0.08

Fig. 2. Optimized Structures of the Tetrahedral Intermediate of Hydrolysis (12 + (R)-1 + OH⁻, 12 + (S)-1 + OH⁻, 16 + (R)-1 + OH⁻ and 16 + (S)-1 + OH⁻) by Density Functional Theory Calculations (RWB97XRV, 6-311 + G**, C-PCM Dielectric = 8.82, Dichloromethane)

In conclusion, we synthesized a novel pseudo-enantiomeric PTC and investigated the hydrolytic dynamic kinetic resolution of 1. The enantioselectivity between the pseudo-enantiomers tended to be higher for the QD-derived class than for the QN-derived class; however, contrary to our expectations, we could not improve the asymmetric yield. However, we believe these results are useful because introducing an aryl substituent at the vinyl terminus may provide crucial guidelines for immobilizing cinchona alkaloid-derived PTC on resins.

Experimental

General Experimental Procedures

Materials were purchased from commercial suppliers and used directly without further purification unless otherwise noted. The strongly basic anion exchange resin (OH⁻ form) was prepared from Dowex-1^® × 8 (Cl⁻) or equivalent (CAS Registry Number 69011-19-4) purchased from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan).

¹H-NMR spectra were recorded on a JEOL JNM-ECA500 (495.1 MHz) spectrometer (JEOL, Tokyo, Japan), and chemical shifts were reported in parts per million δ downfield from internal tetramethylsilane (TMS). ¹³C-NMR spectra were recorded on a JEOL JNM-ECA500 (124.5 MHz) spectrometer. ¹⁹F-NMR spectra were recorded on a JEOL JNM-ECA500 (465.9 MHz) spectrometer, and chemical shifts were reported in parts per million δ downfield from internal hexafluorobenzene (δ: −164.9 ppm). IR spectra were obtained using a JASCO FT/IR-4100 spectrometer. Specific rotation was measured using a JASCO P1020 polarimeter. High-resolution mass spectra (electrospray ionization (ESI), positive and negative) were recorded using a JEOL JMS-T100TD mass spectrometer. Melting points (m.p.) were recorded using BÜCHI melting point apparatus B-540.

The products were isolated using silica gel flash column chromatography (Fuji Silysia Chemical, Aichi, Japan). Chiral HPLC was performed on a JASCO HPLC system using Daicel CHIRALPAK IC (4.6 × 250 mm) and HPLC grade solvents purchased from FUJIFILM Wako Pure Chemical Corporation.

General Procedure of the Enantioselective Hydrolysis of rac-1 Using Resin (R₄N⁺OH⁻) under Non-biphasic Condition

A strongly basic anion exchange resin (8% cross-linked, Cl⁻ form, 30 g) washed three times with distilled water was filled in to glass column, then, an aqueous NaOH solution (5 g/45 mL) was passed through it over 10 min followed by complete washing by distilled water until the eluent became phenolphthalein negative. The wet resin was collected on a glass filter and washed with anhydrous tetrahydrofuran (THF) (10 × 20 mL) by suction, then it was dried in vacuo to complete dryness. The resin (5 g) prepared as above, PTC (0.0500 mmol, 10 mol%) and CH₂Cl₂ (16 mL) were placed in a glass test tube and cooled to 0 °C. Then, rac-1¹²⁾ (74.1 mg, 0.500 mmol)/CH₂Cl₂ (4 mL) was added and stirred vigorously. The reaction was monitored by TLC. After completion of the reaction, the resin was washed with CH₂Cl₂ (50 mL) and charged into glass column. Then, aqueous 1 mol/L HCl and methanol (100 mL) were passed through the column and aqueous HCl eluent and methanol eluent were collected separately. The extract from aqueous HCl with ethyl acetate (3 × 50 mL) and the evaporated residue of methanol eluent were combined, and washed with brine, dried over anhydrous MgSO₄, concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate : HCO₂H = 100 : 1) to give 2 as colorless solid. The enantiomeric ratio was determined by chiral HPLC (Daicel IC, t-butyl methyl ether : trifluoroacetic acid (TFA) = 100 : 0.1, flow rate = 1.0 mL/min). ¹H-NMR (CDCl₃, 495.1 MHz) δ: 7.38–7.26 (5H, m), 4.15 (1H, dd, J = 8.5, 10.5 Hz), 3.92–3.85 (2H, m).

Acknowledgments

This work was funded by the Sasakawa Scientific Research Grant from The Japan Science Society. The financial support to M. K. by the Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan is greatly acknowledged.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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