Green Synthesis of (R)-Terbutaline for Recyclable Catalytic Asymmetric Transfer Hydrogenation in Ionic Liquids

Abstract

We synthesize optically active (R)-terbutaline 2, which is an anti-asthmatic drug, through recyclable catalytic asymmetric transfer hydrogenation (RCATH). Various chloroketones 4 were prepared and RCATH was performed on them. The products exhibit moderate to high enantioselectivity. In particular, the hydrogenation of acyl substituted substrates 4c yields chiral secondary alcohols 5c in good yield and enantioselectivity. Furthermore, (R)-terbutaline 2 can be synthesized in one step from the resulting secondary alcohol 5 without racemization.

Ionic liquids are ionic compounds that have the liquid form at temperatures below 100°C, or even at room temperature. They are non-volatile and non-flammable. Moreover, they exhibit (1) stability for reaction reagents such as acids or bases; (2) solubility for organic, inorganic, and metal compounds; and (3) recyclability after a work-up process. Ionic liquids have been attracting attention recently as environmentally friendly solvents.^1–4) For example, an asymmetric acylation of an allylic alcohol using an enzymatic reaction in an ionic liquid has been reported⁵⁾ as well as a reaction system in which the ion liquid can be repeatedly used as a catalyst container, with high catalyst activity, and as a reaction solvent.⁶⁾

Catalytic transfer hydrogenation (CTH) is a reduction reaction involving the exchange of hydrogen atoms between organic compounds such as 2-propanol or formic acid in the presence of catalysis agents.^7–9) It has several advantages such as (1) the absence of an explosive or flammable hydrogen source, (2) mild reaction conditions, and (3) avoidance of harmful by-products. Catalytic asymmetric transfer hydrogenation (CATH), in particular, is a very useful method for obtaining optically active secondary alcohols from prochiral ketones. CATH has many advantages in terms of safety and convenience over conventional hydrogenation because it uses 2-propanol or formic acid as a hydrogen source.^10,11)

In previous work, we showed that recyclable CATH (RCATH) can be performed in an ionic liquid [bmim][PF₆] using an ionic chiral ligand and the Ru(II) catalyst. We prepared several types of ionic ligands, including pyridinium, benzimidazolium, or imidazolium derivatives. Furthermore, by examining the length of the carbon chains and an imidazolium part, we developed chiral ligand 1, which was most suitable for RCATH^12,13) (Fig. 1). Because they can recycle a catalyst and a reaction solvent in RCATH, optically active organic compounds and pharmaceutical products can be synthesized by this method that is inexpensive and environmentally benign.

Fig. 1. Ligand 1

The β-agonist, which is used as a catecholamine-related pharmaceutical drug for asthma treatment, is generally used in the racemic form, although its pharmacologically active compounds are (R)-isomers in many cases (for example, terbutaline 2 and salbutamol 3).^14–18) Terbutaline 2 is used in the racemic form in clinical practice even today. However, (R)-isomer (eutomer) is about 1000 times more active than (S)-isomer (distomer)¹⁹⁾ (Fig. 2). So far, asymmetric synthesis of (R)-2 was reported using an enzyme for asymmetric induction in 7–9 steps from the starting material.^20–22)

Fig. 2. Eutomer of Terbutaline 2 and Salbutamol 3

Based on this background, we attempted the effective asymmetric synthesis of (R)-terbutaline ((R)-2) using chiral ionic ligand 1 and Ru(II) in [bmim][PF₆], which showed the best results in RCATH reaction conditions toward prochiral ketone as reported in previous paper.^12,13)

Results and Discussion

The synthesis of (R)-2 follows the procedure presented in Chart 1. Secondary alcohol 5 was prepared from chloroketone 4 using the complex of Ru(II) and chiral ligand 1 for RCATH.^12,13) Aminoalcohol 6 was synthesized by amination of 5, and the deprotection of 6 then generates (R)-2. In this way, we performed RCATH from 4 to secondary alcohol 5 and obtained the optically active compounds.

To investigate the yield, enantioselectivity, and recycle efficiency of RCATH, various chloroketones 4 were synthesized and CATH was performed one time.

Chart 1. Synthesis of (R)-2

O-Alkyl chloroketones (4a, b) and O-acyl chloroketones (4c–e) were prepared from the corresponding benzoic acid 10 through treatment with SOCl₂ and Arndt–Eistert synthesis with 87–42% yields.²³⁾ Carbamate protected chloroketone (4f) was prepared by the chlorination of methyl ketone 12 using N-chlorosuccinimide with 78% yield.²⁴⁾ Carbonate protected chloroketone (4g) was synthesized through deprotection of 4d and the Boc-protection approach with an overall yield of 67% (Chart 2).

Chart 2. Synthesis of Chloroketone 4

First, CATH was conducted using several substrates of 4 to examine their reactivity (Table 1). As a result, as expected, secondary alcohol 5 was obtained in moderate to high yield through CATH of substrates of 4 and (R)-isomer is mainly produced.²⁵⁾ The difference in enantioselectivity using different protecting groups is clear. These results suggest that the decrease in the electron density of the aromatic ring in the substrate by the electron withdrawing protecting group gave better enantioselectivity. We confirmed that the CATH of benzoyl derivative 4d produces formic ester 14d in addition to the desired compound 5d.

Table 1. CATH of Several Chloroketone 4

On the basis of the results of CATH, we chose chloroketones 4b and e as the substrates for the preparation of the precursor of (R)-terbutaline and examine RCATH (Table 2).

Table 2. RCATH of Chloroketones 4b, c, e

RCATH proceeded as intended, and it was possible to recycle, while maintaining the enantioselectivity, using any substrate. Under the reaction conditions, using 12 eq. formic acid as the hydrogen source, the catalytic activity did not decrease even after the 3rd cycle, affording 5b and e in 63–69% yields (70–75% enantiomeric excess (ee)) and in 81–82% yields (88–90% ee), respectively. However, when the recycling reaction of 5b and e was complete, the yield decreases in either of the substrate after the 4th cycle. In addition, formic ester 14e was detected as a by-product. This is because formic acid as a non-nucleophilic hydrogen source is gradually accumulated in the reaction mixture, and its concentration is affected by the nucleophilic substitution of HCOO⁻ to the primary alkyl chloride 4. Next, we reduced formic acid as a hydrogen source by half (6 eq.) and performed RCATH (Table 2). When it was compared to 4e, although tiny amounts of by-products are detected in the 7th cycle, the recycling efficiency was improved (70% yield, 89% ee in the 6th cycle). Then, these reaction conditions were applied to O-acetyl chloroketone 4c, which is considered to be able to easily synthesize terbutaline 2, affording a good result similar to 4e (57% yield, 91% ee in the 6th cycle).

We further synthesized (R)-terbutaline ((R)-2) from the secondary alcohol 5 obtained in RCATH. Compound 5b was reacted with t-BuNH₂ in the presence of NaOH, and aminoalcohol 6b was isolated in 82% yield. The reaction proceeded without the loss of the ee of substrate (R)-5b. On the other hand, it is reported that on using a 2 steps deprotection method of the allyl group in (R)-6b, (R)-2 is obtained without decreasing the ee of secondary alcohol.²⁰⁾ Therefore, formal asymmetric synthesis of (R)-2 is achieved here from 4b (Chart 3).

Chart 3. Synthesis of (R)-Terbutaline 2 from 5b

Furthermore, we introduced a t-butyl amino group and deprotected the acyl groups in a one step reaction to give (R)-2. When we attempted to react using compound 5e with t-BuNH₂, the compound (R)-2 is not obtained and the starting material 5e was mainly recovered because deprotection does not occur. In contrast, acetyl compound 5c was also reacted with t-BuNH₂, and (R)-2 is obtained in one step in 75% yield without any loss of ee of substrate 5c (Chart 4). From these results, we obtained (R)-2 in 3 steps from the starting material 10c.

Chart 4. Synthesis of (R)-Terbutaline 5c from e

Experimental

General

NMR spectra were obtained using a JEOL ECA-500 (¹H: 500 MHz, ¹³C: 125 MHz) or JEOL JNM-ECP400 (¹H: 400 MHz, ¹³C: 100 MHz) with tetramethylsilane (TMS) as the standard for ¹H-, ¹³C-NMR analyses. The chemical shifts were expressed in ppm. Mass spectra were obtained using a JEOL MStation JMS-700 spectrometer. IR spectra were obtained using an IRAffinity-1 spectrometer (Shimadzu, Kyoto, Japan). Elemental analyses were performed using a PERKIN ELMER series II CHNS/O Analyzer 2400. Silica gel (Merck Art. 7734) and silica gel 60 PF₂₅₄ (Nacalai Tesque Inc., Kyoto, Japan) were used for column chromatography and preparative thin layer chromatography (PTLC). Optical rotations were measured with a Jasco P-1020 Polarimeter in a 1 cm cell after purification of the major enantiomer from the reaction mixture. Ee were determined by chiral HPLC. All reagents and starting materials were purchased from commercial sources and used without further purification, unless otherwise indicated.

(R)-Terbutaline (2)

A mixture of 5c (10 mg, 0.037 mmol, 91% ee) was added to t-BuNH₂ (3 mL) at room temperature. After stirring for 19 h at 45°C in a sealed vessel, the reaction mixture was cooled to room temperature and evaporated. Next, the crude product was extracted in CHCl₃ and decanted to obtain compound (R)-2 (yield=75%, ee=91%). Yield and ee determinations were based on HPLC analysis [HPLC condition: Shodex ORpak CDBS-453 (4.6 mm i.d.×150 mm) ((1.1% CH₃COOH+0.2 M NaCl)aq. : CH₃CN=70 : 30, flow rate; 1.0 mL/min, detected at 275 nm)]: t_R (min)=R: 10.2 min, S: 11.6 min.

The chromatographic data were in good agreement with previous reports in the literature.²¹⁾

1-[3,5-Bis(2-propenyloxy)phenyl]-2-chloro-ethanone (4b)

A mixture of compound 10b (1171 mg, 5 mmol) and SOCl₂ (3.7 mL, 50 mmol) was refluxed for 2 h and excess SOCl₂ was removed under reduced pressure with toluene three times. The resulting acid chloride was dissolved in Et₂O (5 mL) and added dropwise with stirring to a solution composed of TMSCHN₂ in Et₂O (2.0 M, 5 mL, 10 mmol) and triethylamine (1.4 mL, 10 mmol) at 0°C. The reaction mixture was warmed to room temperature, and stirred for 1 h. The reaction mixture was then extracted with saturated NaHCO₃ aq. and Et₂O. The organic layer was dried over MgSO₄, filtered and evaporated. Next, the residue was added to conc. HCl (10 mL) and the resultant suspension was stirred at 0°C for 30 min. H₂O (10 mL) was added to the reaction mixture and the product was extracted with Et₂O. The organic layer was dried over MgSO₄, filtered, and evaporated. The crude product was purified by column chromatography (n-hexane : AcOEt=10 : 1) to give compound 4b. Yield: 940 mg (71%). Yellow oil. ¹H-NMR (CDCl₃) δ: 4.56 (4H, dt, J=5.5 and 1.5 Hz, 2×CH₂O), 4.67 (2H, s, CH₂Cl), 5.32 (2H, ddd, J=10.6, 2.7 and 1.5 Hz, 2×CH=CH_cisH_trans), 5.43 (2H, ddd, J=17.2, 3.1 and 1.6 Hz, 2×CH=CH_cisH_trans), 6.04 (2H, ddt, J=17.2, 10.6 and 5.3 Hz, 2×CH=CH₂), 6.72 (1H, t, J=2.3 Hz, 4-Ar-H), 7.08 (2H, d, J=2.4 Hz, 2,6-Ar-H). ¹³C-NMR (CDCl₃) δ: 46.1, 69.1, 107.2, 107.4, 118.2, 132.5, 135.9, 159.9, 190.6. IR (CHCl₃) cm⁻¹: 3500, 3090, 2910, 2850, 1699, 1680, 1590, 1439, 1348, 1300, 1163. High resolution (HR)-MS electron ionization (EI) m/z: Found, 266.0709 (Calcd for C₁₄H₁₅ClO₃: 266.0710). MS (EI) m/z (rel. int. %): 266 (M⁺, 27), 231 (100), 217 (54), 189 (34), 149 (41), 107 (26), 91 (47).

1-[3,5-Bis(benzooyloxy)phenyl]-2-chloro-ethanone (4d)

Compound 4d was synthesized from 10d (322 mg, 0.89 mmol) in the same manner as described for the synthesis of 4b. Yield: 305 mg (87%). White solid (recryst. from n-hexane/AcOEt). Melting point (mp) 101.0–105.2°C. ¹H-NMR (CDCl₃) δ: 4.70 (2H, s, CH₂Cl), 7.50 (1H, t, J=2.0 Hz, 4-Ar-H), 7.54 (4H, tt, J=7.0 and 1.5 Hz, 2×m-Bz-H), 7.67 (2H, tt, J=7.5 and 1.5 Hz, 2×p-Bz-H), 7.77 (2H, d, J=2.2 Hz, 2,6-Ar-H), 8.21 (4H, dt, J=7.0 and 1.5 Hz, o-Bz-H). ¹³C-NMR (CDCl₃) δ: 45.7, 119.4, 121.5, 128.8, 130.3, 134.1, 136.2, 151.9, 164.6, 189.4. IR (CHCl₃) cm⁻¹: 1742, 1713, 1599, 1441, 1312, 1258, 1244, 1132, 1061, 907, 789, 708. MS (EI) m/z (rel. int. %): 394 (M⁺, 2), 360 (1), 345 (1), 105 (100), 77 (23). Anal. Calcd for C₂₂H₁₅ClO₅: C, 66.93; H, 3.83. Found: C, 66.93; H, 3.77.

1-[3,5-Bis(pivaloxy)phenyl]-2-chloro-ethanone (4e)

Compound 4e was synthesized from 10e (676 mg, 2.1 mmol) in the same manner as described for synthesis of 4b. Yield: 469 mg (63%). White solid (recryst. from n-hexane/AcOEt). Mp 121.1–123.4°C. ¹H-NMR (CDCl₃) δ: 1.37 (18H, s, 2×t-Bu), 4.66 (2H, s, CH₂Cl), 7.14 (1H, t, J=2.0 Hz, 4-Ar-H), 7.53 (2H, d, J=2.2 Hz, 2,6-Ar-H). ¹³C-NMR (CDCl₃) δ: 27.1, 39.3, 45.8, 118.9, 121.1, 136.0, 152.0, 176.4, 189.5. IR (CHCl₃) cm⁻¹: 1753, 1713, 1593, 1441, 1314, 1267, 1207, 1128, 1101, 1030, 912, 789, 727. MS (EI) m/z (rel. int. %): 354 (M⁺, 17), 320 (2), 305 (7), 270 (8), 186 (7), 137 (11), 85 (59), 57 (100). Anal. Calcd for C₁₈H₂₃ClO₅: C, 60.93; H, 6.53. Found: C, 61.01; H, 6.77.

1-[3,5-Bis(tert-butoxycarbonyloxy)phenyl]-2-chloro-ethanone (4g)

A mixture of di-tert-butyl dicarbonate (655 mg, 3 mmol) and N,N-dimethyl-4-aminopyridine (DMAP) (catalytic amount) in CHCl₃ (5 mL) was added to compound 13 (187 mg, 1 mmol) at room temperature. After stirring for 1 h, the product was extracted with AcOEt. The organic layer was dried over MgSO₄, filtered, and evaporated. The crude product was purified by column chromatography (n-hexane : AcOEt=10 : 1) to give compound 4g. Yield: 271 mg (70%). White solid (recryst. from n-hexane/AcOEt). Mp 113.0–115.8°C. ¹H-NMR (CDCl₃) δ: 1.56 (18H, s, 2×Boc), 4.65 (2H, s, CH₂Cl), 7.36 (1H, t, J=2.1 Hz, 4-Ar-H), 7.65 (2H, d, J=1.9 Hz, 2,6-Ar-H). ¹³C-NMR (CDCl₃) δ: 27.7, 45.7, 84.5, 118.6, 120.3, 135.9, 150.9, 151.9, 189.3. IR (CHCl₃) cm⁻¹: 1761, 1715, 1595, 1506, 1456, 1371, 1252, 1207, 1130, 853, 791, 725, 665. MS (EI) m/z (rel. int. %): 386 (M⁺, 1), 271 (1), 227 (8), 186 (38), 137 (48), 57 (100). Anal. Calcd for C₁₈H₂₃ClO₇: C, 55.89; H, 5.99. Found: C, 55.66; H, 6.07.

Typical Procedure of CATH

The corresponding chloroketone 4 (0.5 mmol) was added to a solution of ionic ligand 2 (8.8 mg, 0.012 mmol) and [RuCl₂(benzene)]₂ (2.5 mg, 0.005 mmol) in [bmim][PF₆] (0.5 mL) with stirring under N₂, followed by the addition of a formic acid–triethylamine azeotropic mixture (108°C boiling point/29 mmHg; Table 1: 0.5 mL). The reaction mixture was stirred at room temperature for 24 h. Next, n-hexane : AcOEt at 2 : 1 (1.5 mL), 1 : 1 (1.5 mL), and 1 : 2 (1.5 mL) was added to the reaction mixture and the mixture was stirred for 5 min. Subsequently the solution was quiescent and the supernatant (organic solution) was decanted. The organic solution was extracted with H₂O. The organic layer was dried over MgSO₄, filtered, and evaporated. The crude product was purified by column chromatography and PTLC to give compound 5.

Typical Procedure of RCATH

The corresponding chloroketone 4 (0.5 mmol) was added to a solution of ionic ligand 2 (8.8 mg, 0.012 mmol) and [RuCl₂(benzene)]₂ (2.5 mg, 0.005 mmol) in [bmim][PF₆] (0.5 mL) with stirring under N₂, followed by addition of a formic acid–triethylamine azeotropic mixture (108°C boiling point/29 mmHg; Table 2: 0.5 or 0.25 mL). The reaction mixture was stirred at room temperature for 24 h. Next, n-hexane : AcOEt at 2 : 1 (1.5 mL), 1 : 1 (1.5 mL), and 1 : 2 (1.5 mL) was added to the reaction mixture and the mixture was stirred for 5 min. Subsequently the solution was quiescent and the supernatant (organic solution) was decanted. And the residual IL phase was dried in vacuo for 30 min. Chloroketone 4 (0.5 mmol) and formic acid–triethylamine azeotropic mixture (Table 2: 0.5 or 0.25 mL) were added to the remaining IL solution, and the next cycle of the reaction was started. The organic solution was extracted with H₂O. The organic layer was dried over MgSO₄, filtered, and evaporated. The crude product was purified by column chromatography and PTLC to give compound 5.

(R)-2-Chloro-1-(3,5-dimethoxyphenyl)ethanol (5a)

Yield: 45 mg (63%). Colorless oil. [α]_D²³=−34.8 (c=1.0, CHCl₃). (95.42% ee) ¹H-NMR (CDCl₃) δ: 2.65 (1H, d, J=2.9 Hz, OH), 3.63 (1H, dd, J=11.0 and 8.8 Hz, CHHCl), 3.73 (1H, dd, J=11.0 and 3.3 Hz, CHHCl), 3.79 (6H, s, OCH₃), 4.83 (1H, dt, J=8.8 and 2.5 Hz, ArCH(OH)), 6.41 (1H, t, J=2.4 Hz, 4-Ar-H), 6.54 (2H, d, J=2.6 Hz, 2,6-Ar-H). ¹³C-NMR (CDCl₃) δ: 50.8, 55.4, 74.1, 100.4, 104.0, 142.4, 161.1. IR (CHCl₃) cm⁻¹: 3584, 1597, 1462, 1429, 1339, 1298, 1206, 1157, 1065, 924, 839, 725, 665. MS (EI) m/z (rel. int. %): 216 (M⁺, 50), 167 (100), 139 (66), 124 (14), 107 (5), 77 (6). Anal. Calcd for C₁₀H₁₃ClO₃·1/10 H₂O: C, 54.98; H, 6.09. Found: C, 55.02; H, 6.20. Ee was calculated by the basis of HPLC [HPLC condition: DAICEL chiralcel OD column (n-hexane : i-PrOH=80 : 20, flow rate; 1.0 mL/min, detected at 254 nm)]: t_R (min)=S: 6.2 min, R: 7.6 min.

(R)-2-Chloro-1-[3,5-bis(allyloxy)phenyl]ethanol (5b)

Yield: 93 mg (69%). Colorless oil. [α]_D²⁶=−21.6 (c=1.0, CH₃OH). (64.3% ee) ¹H-NMR (CDCl₃) δ: 2.79 (1H, d, J=3.3 Hz, OH), 3.60 (1H, dd, J=11.2 and 8.8 Hz, CHHCl), 3.70 (1H, dd, J=11.2 and 3.3 Hz, CHHCl), 4.50 (4H, dt, J=5.3 and 1.5 Hz, 2×CH₂O), 4.79 (1H, dt, J=8.8 and 3.1 Hz, ArCH(OH)), 5.28 (2H, ddd, J=10.4, 2.7 and 1.5 Hz, 2×CH=CH_cisH_trans), 5.40 (2H, ddd, J=17.2, 3.3 and 1.6 Hz, 2×CH=CH_cisH_trans), 6.03 (2H, ddt, J=17.4, 10.6 and 5.5 Hz, 2×CH=CH₂), 6.44 (1H, t, J=2.3 Hz, 4-Ar-H), 6.54 (2H, d, J=2.2 Hz, 2,6-Ar-H). ¹³C-NMR (CDCl₃) δ: 50.7, 68.8, 74.0, 101.6, 104.9, 117.8, 132.9, 142.3, 159.8. IR (CHCl₃) cm⁻¹: 3550, 3350, 3090, 3000, 2960, 1593, 1445, 1419, 1280, 1160, 1046. HR-MS (EI) m/z: Found, 268.0861 (Calcd for C₁₄H₁₇ClO₃: 268.0866). MS (EI) m/z (rel. int. %): 268 (M⁺, 50), 233 (100), 215 (50), 191 (51), 173 (54), 135 (19). Ee was calculated by the basis of HPLC [HPLC condition: DAICEL chiralcel OD column (n-hexane : i-PrOH=95 : 5, flow rate; 1.0 mL/min, detected at 254 nm)]: t_R (min)=S: 11.6 min, R: 15.4 min.

(R)-2-Chloro-1-[3,5-bis(acetyloxy)phenyl]ethanol (5c)

Yield: 98 mg (72%). White solid (recryst. from n-hexane/AcOEt). Mp 38.1–40.4°C. [α]_D²⁴=−27.4 (c=0.6, CHCl₃). (>99% ee) ¹H-NMR (CDCl₃) δ: 2.28 (6H, s, 2×CH₃), 2.66 (1H, d, J=3.6 Hz, OH), 3.61 (1H, dd, J=11.0 and 8.4 Hz, CHHCl), 3.75 (1H, dd, J=11.4 and 3.7 Hz, CHHCl), 4.90 (1H, dt, J=8.7 and 3.3 Hz, ArCH(OH)), 6.90 (1H, t, J=2.2 Hz, 4-Ar-H), 7.04 (2H, d, J=1.8 Hz, 2,6-Ar-H). ¹³C-NMR (CDCl₃) δ: 21.0, 50.2, 73.1, 115.2, 116.7, 142.7, 151.1, 169.0. IR (CHCl₃) cm⁻¹: 3603, 1769, 1601, 1454, 1369, 1225, 1206, 1125, 1022, 903, 725. MS (EI) m/z (rel. int. %): 272 (M⁺, 23), 230 (68), 188 (88), 139 (100), 111 (50), 93 (7). Anal. Calcd for C₁₂H₁₃ClO₅·1/3H₂O: C, 51.72; H, 4.94. Found: C, 51.97; H, 4.97.

(R)-2-Chloro-1-[3,5-bis(benzoyloxy)phenyl]ethanol (5d)

Yield: 101 mg (51%). White solid (recryst. from n-hexane/AcOEt). Mp 97.8–100.0°C. [α]_D²⁶=−14.2 (c=0.6, CHCl₃). (78.0% ee) ¹H-NMR (CDCl₃) δ: 2.75 (1H, d, J=3.3 Hz, OH), 3.68 (1H, dd, J=11.4 and 8.8 Hz, CHHCl), 3.81 (1H, dd, J=11.3 and 3.3 Hz, CHHCl), 4.97 (1H, dt, J=8.5 and 3.3 Hz, ArCH(OH)), 7.18 (1H, t, J=2.2 Hz, 4-Ar-H), 7.24 (2H, d, J=1.8 Hz, 2,6-Ar-H), 7.51 (4H, t, J=7.9 Hz, 2×m-Bz-H), 7.65 (2H, t, J=7.3 Hz, 2×p-Bz-H), 8.19 (4H, d, J=7.0 Hz, 2×o-Bz-H). ¹³C-NMR (CDCl₃) δ: 50.5, 73.3, 115.7, 117.0, 128.7, 129.2, 130.2, 133.8, 142.7, 151.6, 164.7. IR (CHCl₃) cm⁻¹: 3564, 1740, 1599, 1456, 1260, 1246, 1130, 1063, 899, 789, 708. MS (EI) m/z (rel. int. %): 396 (M⁺, 11), 347 (1), 292 (1), 105 (100), 77 (19). Anal. Calcd for C₁₀H₁₃ClO₃: C, 66.59; H, 4.32. Found: C, 66.45; H, 4.32. Ee was calculated by the basis of HPLC [HPLC condition: DAICEL chiralcel OD column (n-hexane : i-PrOH=95 : 5, flow rate; 1.0 mL/min, detected at 254 nm)]: t_R (min)=S: 22.8 min, R: 25.4 min.

(R)-2-Chloro-1-[3,5-bis(pivaloxy)phenyl]ethanol (5e)

Yield: 166 mg (93%). White solid (recryst. from n-hexane/AcOEt). Mp 66.7–69.7°C. [α]_D²⁵=−22.0 (c=1.0, CHCl₃). (94.44% ee) ¹H-NMR (CDCl₃) δ: 1.34 (18H, s, 2×t-Bu), 2.69 (1H, d, J=3.0 Hz, OH), 3.62 (1H, dd, J=11.4 and 8.8 Hz, CHHCl), 3.76 (1H, dd, J=11.4 and 3.3 Hz, CHHCl), 4.90 (1H, dt, J=8.8 and 2.2 Hz, ArCH(OH)), 6.84 (1H, t, J=2.2 Hz, 4-Ar-H), 7.00 (2H, d, J=2.2 Hz, 2,6-Ar-H). ¹³C-NMR (CDCl₃) δ: 27.0, 39.1, 50.3, 73.2, 115.1, 116.4, 142.5, 151.6, 176.6. IR (CHCl₃) cm⁻¹: 3586, 1749, 1599, 1456, 1396, 1273, 1223, 1207, 1126, 1105, 1032, 908, 777, 685. MS (EI) m/z (rel. int. %): 356 (M⁺, 36), 272 (47), 188 (27), 139 (19), 85 (47), 57 (100). Anal. Calcd for C₁₈H₂₅ClO₃: C, 60.59; H, 7.06. Found: C, 60.39; H, 7.30. Ee was calculated by the basis of HPLC [HPLC condition: DAICEL chiralcel OD column (n-hexane : i-PrOH=95 : 5, flow rate; 1.0 mL/min, detected at 254 nm)]: t_R (min)=R: 5.8 min, S: 8.5 min.

(R)-2-Chloro-1-[3,5-bis(dimethylcarbamoyloxy)phenyl]ethanol (5f)

Yield: 140 mg (85%). Ee was calculated by the basis of HPLC/[HPLC condition: DAICEL chiralcel OD column (n-hexane : i-PrOH=85 : 15, flow rate; 1.0 mL/min, detected at 254 nm)]: t_R (min)=R: 11.0 min, S: 15.6 min.

The spectral data matched the previous reports in the literature.²²⁾

(R)-2-Chloro-1-[3,5-bis(tert-butoxycarbonyloxy)phenyl]ethanol (5g)

Yield: 143 mg (74%). Colorless oil. [α]_D²³=−16.7 (c=1.0, CHCl₃). (75.57% ee) ¹H-NMR (CDCl₃) δ: 1.55 (18H, s, 2×t-Boc), 2.70 (1H, d, J=3.3 Hz, OH), 3.62 (1H, dd, J=11.4 and 8.8 Hz, CHHCl), 3.75 (1H, dd, J=11.3 and 3.3 Hz, CHHCl), 4.90 (1H, dt, J=8.8 and 3.3 Hz, ArCH(OH)), 7.04 (1H, t, J=2.2 Hz, 4-Ar-H), 7.12 (2H, d, J=2.2 Hz, 2,6-Ar-H). ¹³C-NMR (CDCl₃) δ: 27.7, 50.4, 73.3, 84.0, 114.6, 116.2, 142.3, 151.2, 151.6. IR (CHCl₃) cm⁻¹: 3603, 1759, 1601, 1456, 1371, 1273, 1271, 1252, 1153, 1130, 1057, 945, 852, 787, 671. MS (EI) m/z (rel. int. %): 388 (M⁺, 2), 317 (3), 288 (58), 232 (40), 171 (40), 139 (65), 111 (22), 57 (100). Anal. Calcd for C₁₈H₂₅ClO₇·2/3H₂O: C, 53.93; H, 6.62. Found: C, 53.95; H, 6.60. Ee was calculated by the basis of HPLC/[HPLC condition: DAICEL chiralcel OD column (n-hexane : i-PrOH=95 : 5, flow rate; 1.0 mL/min, detected at 254 nm)]: t_R (min)=R: 7.1 min, S: 10.7 min.

(R)-1-[3,5-Bis-(allyloxy)phenyl]-2-(tert-butylamino)ethanol (6b)

A mixture of (R)-5b (269 mg, 1 mmol, 75% ee) in CH₃OH (2.5 mL) was added t-BuNH₂ (1.1 mg, 10 mmol) at room temperature. After stirring for 0.5 h at 45°C, the reaction mixture was cooled to room temperature and NaOH (40 mg, 1 mmol) was added. After stirring for 2 h at 80°C, the reaction mixture was added to H₂O (5 mL), and then extracted with Et₂O. The organic layer was dried over Na₂SO₄, filtered, and evaporated. The crude product was purified by column chromatography (FUJI SILYSIA NH silica gel; n-hexane : AcOEt=1 : 1) to give compound 6b. Yield: 249 mg (82%). Colorless oil. [α]_D²⁰=−11.4 (c=1.0, MeOH). ¹H-NMR (CDCl₃) δ: 1.10 (9H, s, t-Bu), 2.59 (1H, dd, J=11.9 and 8.4 Hz, CHHN), 2.60 (1H, s, NH), 2.88 (1H, dd, J=11.7 and 3.7 Hz, CHHCl), 4.51–4.54 (5H, m, ArCH(OH), 2×CH₂O), 5.28 (2H, ddd, J=10.4, 2.7 and 1.5 Hz, 2×CH=CH_cisH_trans), 5.40 (2H, ddd, J=17.2, 3.1 and 1.5 Hz, 2×CH=CH_cisH_trans), 6.05 (2H, ddt, J=17.2, 10.6 and 5.3 Hz, 2×CH=CH₂), 6.41 (1H, t, J=2.3 Hz, 4-Ar-H), 6.56 (2H, d, J=2.4 Hz, 2,6-Ar-H). ¹³C-NMR (CDCl₃) δ: 29.0, 50.0, 50.3, 68.8, 72.0, 100.6, 104.5, 117.6, 133.2, 145.6, 159.6. IR (CHCl₃) cm⁻¹: 3400, 2939, 1593, 1444, 1418, 1360, 1285, 1159, 1031. HR-MS (EI) m/z: Found, 305.2000 (Calcd for C₁₈H₂₇NO₃: 305.1991). MS (EI) m/z (rel. int. %): 305 (M⁺, 1), 272 (1), 220 (8), 86 (100), 70 (9), 57 (23).

3,5-Bis(pivaloyyloxy)benzoic Acid (10e)

Compound 9 (1541 g, 10 mmol) was dissolved in water (39 mL) and isopropanol (15 mL), and then K₂CO₃ (6910 mg, 50 mmol) was added. The mixture was maintained under an inert argon atmosphere and cooled to 0°C. The temperature was maintained between 0 and 5°C during the addition of pivaloyl chloride (3.0 mL, 24 mmol) to the stirred reaction mixture. After stirring for 5 h, the reaction mixture was added to a solution of HCl (6 M, 15 mL) while maintaining the reaction mixture in a cool environment during the addition. The solid was collected by filtration, washed with generous amounts of cold water, and dried in a vacuum oven to give compound 10e. Yield: 2416 mg (75%). White solid (recryst. from n-hexane/AcOEt). Mp 153.2–156.0°C. ¹H-NMR (CD₃OD) δ: 1.36 (18H, s, 2×t-Bu), 7.10 (1H, t, J=2.2 Hz, 4-Ar-H), 7.57 (2H, d, J=2.2 Hz, 2.6-Ar-H). ¹³C-NMR (CD₃OD) δ: 27.4, 40.1, 121.05, 121.14, 153.0, 167.8, 178.0. IR (CHCl₃) cm⁻¹: 3748, 1749, 1732, 1597, 1396, 1271, 1223, 1207, 1126, 1101, 1032, 912, 789, 725. MS (EI) m/z (rel. int. %): 322 (M⁺, 9), 238 (9), 154 (24), 85 (47), 57 (100), 44 (9). Anal. Calcd for C₁₇H₂₂O₆: C, 63.34; H, 6.88. Found: C, 63.46; H, 7.02.

1-[3,5-Bis(benzoyloxy)phenyl]-2-formyloxy-ethanone (14d)

White solid (recryst. from n-hexane/AcOEt). Mp 58.2–61.2°C. ¹H-NMR (CDCl₃) δ: 5.43 (2H, s, CH₂O), 7.51 (1H, t, J=2.3 Hz, 4-Ar-H), 7.54 (4H, tt, J=7.7 and 1.6 Hz, 2×m-Bz-H), 7.61 (2H, tt, J=7.5 and 1.4 Hz, 2×p-Bz-H), 7.73 (2H, d, J=2.2 Hz, 2,6-Ar-H), 8.21 (4H, dt, J=8.2 and 1.7 Hz, o-Bz-H), 8.24 (1H, s, CHO). ¹³C-NMR (CDCl₃) δ: 65.3, 118.7, 121.5, 128.74, 128.74, 130.3, 134.1, 135.8, 151.9, 159.8, 164.5, 189.5. IR (CHCl₃) cm⁻¹: 3028, 1740, 1713, 1599, 1441, 1258, 1244, 1132, 1024, 708, 665. MS (EI) m/z (rel. int. %): 404 (M⁺, 35), 345 (26), 105 (100), 77 (82). Anal. Calcd for C₂₃H₁₆O₇·1/4H₂O: C, 67.56; H, 4.07. Found: C, 67.79; H, 4.12.

1-[3,5-Bis(pivaloxy)phenyl]-2-formyloxy-ethanone (14e)

White solid (recryst. from n-hexane/AcOEt). Mp 75.5–78.4°C. ¹H-NMR (CDCl₃) δ: 1.37 (18H, s, t-Bu), 5.38 (2H, s, CH₂O), 7.15 (1H, t, J=2.2 Hz, 4-Ar-H), 7.49 (2H, d, J=2.2 Hz, 2,6-Ar-H), 8.23 (1H, s, CHO). ¹³C-NMR (CDCl₃) δ: 27.1, 39.2, 65.3, 118.2, 121.1, 135.6, 152.0, 159.8, 176.4, 189.6. IR (CHCl₃) cm⁻¹: 3026, 2980, 2359, 2340, 1753, 1694, 1595, 1206, 1128. MS (EI) m/z (rel. int. %): 364 (M⁺, 32), 305 (23), 280 (28), 221 (7), 196 (22), 137 (37), 85 (76), 57 (100). Anal. Calcd for C₁₉H₂₄O₇: C, 62.63; H, 6.64. Found: C, 62.55; H, 6.78.

Conclusion

In conclusion, we synthesized optically active (R)-terbutaline 2 using a newly developed RCATH. In carrying out RCATH, we examined several substrate–protection groups. As a result, substrate 4c, which had an acetyl group as the protecting group, was formed both in improved yield and better enantioselectivity than when using other derivatives 4. We considered that the decrease in the electron density of the aromatic ring in the substrate with the electron withdrawing protecting group gave better enantioselectivity to provide optically active secondary alcohol. Successively, RCATH of substrate 4c was performed and examined in terms of the hydrogen source. As a result, it was possible to develop a useful reaction system as a recycle reaction up to the 6th cycle. (R)-2 was synthesized from the resulting secondary alcohol 5 in one step, without reduction in ee.

Acknowledgments

We would like to thank the staff of the Instrument Analysis Center of Mukogawa Women’s University for the NMR and MS measurements and elemental analyses. A part of this work was financially supported by a Grant-in-Aid for Scientific Research (C) (Research project number: 23590031) from Japan Society for the Promotion of Science (JSPS).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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