Synthesis of Chiral Ethyl 5-(Acetoxyimino)-2,7,7-trimethyl-4-(1-naphthyl)-5,6,7,8-tetrahydroquinoline-3-carboxylate via Lipase-Catalyzed Hydrolysis

Abstract

Novel racemic polyhydroquinoline derivatives were synthesized by a one-pot approach via a modified Hantzsch reaction and then by aromatization. The optical resolution was carried out by using lipase l-2 in MTBE containing one equivalent of butanol. This method allows the preparation of (+)-7 (>99% ee) and (-)-8 (99% ee) in 50% yield, respectively. The E value is up to 1175.

Key words

pyridine derivatives - oxime - axial chirality - hydrolysis - synthesis - asymmetric Hantzsch reaction

References and Notes

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12

Analytical-grade solvents and all chemicals were purchased from TCI Ltd. The ^¹H NMR and ^¹³C NMR spectra were measured with a JNM-ECS400 NMR spectrometer (400 MHz), JNM-ECS600 (600 MHz), Varian Mercury 200 (200 MHz), and Varian UNITY-INOVA 500 (500 MHz), respectively, in CHCl₃-d ₃ or DMSO solutions, and the chemical shifts are given relative to the residual solvent signal or TMS as internal standard. Mass spectra were recorded on a JOEL JMS-AX505HA and Shimadzu GCMS-QP5000 with GC-17A, respectively. The melting point was determined by MFB-595-030G digital thermometer apparatus. The IR spectra were recorded on a HORIBA FT-710 spectrometer. The UV/Vis spectra were recorded on a Hitachi U-2010 UV/Visible Spectrophotometer. The CD spectra were recorded on a JASCO J-720 spectrometer (L = 1 mm). Optical rotations were measured on a JASCO DIP-370 Digital Polarimeter.

13

General One-Pot Procedure
To a mixture of MeOH (30 mL) and toluene (30 mL), ethyl acetoactate (5.20 g, 40 mmol), 1-naphthaldehyde (6.24 g, 40 mmol), dimedone (5.60 g, 40 mmol), and NH₄OAc (3.24 g, 42 mmol) were added. The mixture was heated to reflux under stirring for 24 h. The resulting solution was worked up by azeotropic distillation to separate off all toluene, to which then H₂O (3 mL) was added. The resulting solvent was kept refluxing for another 24 h and then allowed to cool to r.t. The crystals were formed and filtered to give the product.

14

Synthesis of Ethyl 2,7,7-trimethyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylate (5)
Using the one-pot procedure, the light yellow crystals were formed and filtered to give the title compound with a yield of 96%; slight yellow solid; crystallized from EtOH; MS (FAB⁺): m/z = 390 [MH⁺]; mp 194.0-195.7 ˚C. IR (KBr):
ν = 3324 (NH), 1697 (CO) cm^-¹. ^¹H NMR (400 MHz, DMSO): δ = 9.11 (s, 1 H, NH), 8.63-8.61 (d, J = 8.61 Hz, 1 H, HAr), 7.76-7.74 (d, J = 8.15 Hz, 1 H, HAr), 7.63-7.61 (d, 1 H, HAr), 7.50-7.46 (dd, J = 7.25, 7.70 Hz, 1 H, HAr), 7.42-7.38 (dd, J = 7.25, 7.25 Hz, 1 H, HAr), 7.33 (s, 1 H, HAr), 5.60 (s, 1 H, OH), 3.81-3.62 (qq, qq, 2 H, CH₂), 2.46-2.42 (d, J = 17.22 Hz, 1 H, CH₂), 2.31-2.27 (d, J = 13.59 Hz, 1 H, CH₂), 2.12-2.08 (d, J = 16.31 Hz, 1 H, CH₂), 1.85-1.81 (d, J = 15.86 Hz, 1 H, CH₂), 2.27 (s, 3 H, CH₃), 0.97 (s, 3 H, CH₃), 0.82-0.79 (t, J = 6.80, 7.02 Hz, 3 H, CH₃), 0.76 (s, 3 H, CH₃) ppm.

15

Synthesis of Ethyl 2,7,7-Trimethyl-4-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate (6)
To a solvent of 5 and DME (30 mL) was added 2 N HNO₃ aq. The mixture was heated to reflux under stirring for 12 h. Then, H₂O and EtOH were added to the resulting solution. The light yellow crystals were formed and filtered to give the title compound with a yield of 98%; slight yellow solid; crystallized from EtOH; MS (FAB⁺): m/z = 388 [MH⁺]; mp 187.5-190.7 ˚C. IR (KBr): n = 1733 (CO) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): d = 7.85-7.83 (d, J = 8.70 Hz, 1 H, H_Ar), 7.47-7.43 (dd, J = 6.87, 8.24 Hz, 1 H, H_Ar), 7.44-7.40 (dd, J = 6.87, 8.24 Hz, 1 H, H_Ar), 7.34-7.30 (td, J = 0.92, 0.92, 0.92, 8.24, 6.87, 7.56 Hz, 1 H, H_Ar), 7.25-7.21 (t, J = 8.24, 8.70, 8.47 Hz, 1 H, H_Ar), 7.16-7.14 (d, J = 6.87, 1 H, H_Ar), 3.70-3.65 (q, J = 7.33, 14.20 Hz, 1 H, H_Ar), 3.14-3.14 (d, J = 2.75 Hz, 2 H, CH₂), 2.65 (s, 3 H, CH₃), 2.39-2.37 (d, J = 5.95 Hz, 2 H, CH₂), 1.13 (s, 3 H, CH₃), 1.10 (s, 3 H, CH₃), 0.42-0.39 (t, J = 6.87, 7.33 Hz, 3 H, CH₃) ppm.

16

Synthesis of ( E )-Ethyl 5-(Hydroxyimino)-2,7,7-trimethyl-4-(naphthalen-1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxylate (7)
Compound 6 was treated with NH₂OH˙HCl in a mixture of EtOH and pyridine at reflux temperature for 2 d and gave the title compound with a yield of 96%; white solid; crystallized from EtOH; MS (FAB⁺): m/z = 403 [MH⁺]. mp 227.0-227.8 ˚C. IR (KBr): ν = 3448 (OH), 1776 (C=O), 1546 (C=N), 1020, 891 (NO) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.85-7.82 (dd, J = 1.36, 7.25 Hz, 1 H, H_Ar), 7.46-7.40 (m, 2 H, H_Ar), 7.34-7.29 (m, 1 H, H_Ar), 7.23-7.21 (d, J = 8.15 Hz, 1 H, H_Ar), 7.16-7.13 (dd, J = 0.91, 1.36, 7.02 Hz, 1 H, H_Ar), 3.70-3.65 (q, J = 7.25, 6.80, 14.27 Hz, 2 H, CH₂), 3.14-3.14 (d, J = 2.27 Hz, 2 H, CH₂), 2.65 (s, 3 H, CH₃), 2.39-2.37 (d, J = 5.89 Hz, 2 H, CH₂), 1.13 (s, 3 H,CH₃), 1.10 (s, 3 H,CH₃), 0.43-0.40 (t, J = 6.80, 7.25 Hz, 3 H, CH₃) ppm.

17

Synthesis of ( E )-Ethyl 5-(Acetoxyimino)-2,7,7-trimethyl-4-(naphthalen-1-yl)-5,6,7,8-tetrahydroquinoline-3-carboxylate (8)
Acetylation of 7 (0.497 g, 1.2 mmol) was performed with AcCl (0.16 g, 2.0 mmol) catalyzed by N,N-dimethyl-4-aminopyridine (DMAP, 0.10 g, 0.8 mmol) in dry toluene (20 mL) and dry pyridine (10 mL). The reaction mixture was stirred for 2 d. The resulting solvent was diluted with CHCl₃. The organic phase was separated and washed with 10% HCl, sat. aq NaHCO₃, brine, and dried over MgSO₄. After filtration and evaporation the residue was chromatographed on SiO₂ (1% MeOH in CHCl₃, v/v) to afford 1 (0.44 g, 0.99 mmol) in 83% yield as red solid (mp 188.3-190.1 ˚C). MS (FAB⁺): m/z = 445 [MH⁺]. IR (KBr): ν = 3448 (OH), 1768 (C=O), 1546 (C=N), 1020, 891 (NO) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.82-7.80 (d, J = 8.15 Hz, 1 H, H_Ar), 7.79-7.77 (d, J = 8.15 Hz, 1 H, H_Ar), 7.47-7.43 (dd, J = 6.80, 8.15 Hz, 1 H, H_Ar), 7.44-7.41 (m, J = 3.17, 2.27, 7.70 Hz, 1 H, H_Ar), 7.36-7.36 (d, J = 3.62 Hz, 1 H, H_Ar), 7.35 (s, 1 H, H_Ar), 7.23-7.21 (J = 6.80 Hz, 1 H, H_Ar), 2.96-2.96 (d, J = 2.27 Hz, 2 H, CH₂), 2.66 (s, 2 H, CH₂), 2.61 (s, 3 H, CH₃), 1.11 (s, 3 H, CH₃), 1.07 (s, 3 H, CH₃), 0.44-0.41 (t, J = 7.25, 6.80, 7.02 Hz, 3 H, CH₃).

18

Enzymatic Hydrolysis of (±)-8
In a typical experiment, lipase (40 mg) and n-BuOH (0.045 mmol) were added to a solution of O-acetyl ketoxime (±)-1 (20 mg, 0.045 mmol) and 2′-acetonaphthone (1.0 mg, standard substance) in MTBE (5 mL) and the resulting mixture was stirred at 30 ˚C. The reaction was monitored periodically using HPLC (column, GL Sciences Inertsil ODS-80TM; mobile phase, MeCN-H₂O = 8:2; flow rate, 0.8 mL/min; UV detection at 254 nm). Upon completion, the reaction was terminated by removing the lipase via filtration. The lipase portion was washed with MTBE (15 mL). The filtrate and wash were combined, evaporated at 30 ˚C, and the resulting crude residue was purified using silica gel column chromatography with a mixture of CHCl₃ and MeOH (100:1, v:v) as the eluent to yield the corresponding chiral O-acetyl ketoxime 8 and ketoxime 7.

19

The ee values were determined using chiral HPLC column (Daicel ChiralPAK IC; mobile phase, hexane-EtOH-TFA = 50:50:0.1; flow rate, 0.7 mL/min; UV detection at 254 nm).

20

The E values were calculated according to the literature (ref. [²²] ).

21

ROD and CD Spectra
Optical rotation of optical enantiomer (+)-7: [α]_D ^²² +110.73 (c 0.41, MeOH); optical rotation of optical enantiomer (-)-8: [α]_D ^²6 -109.33 (c 0.675, MeOH).