WOS: 000246883000005A chemoenzymatic synthesis of 2-bromo-6-hydroxy-3-methoxy-2-cyclohexen-1-one starting from cyclohexane-1,3-dione is reported. Manganese (III) acetate-mediated acetoxylation followed by the enzyme-mediated hydrolysis of alpha'-acetoxy enone affords hydroxy-enone 5 and enone 4 with high enantiomeric excesses in good yields

Karaaslan, Emine Ozgul

Toka, Yasemin

TURKISH JOURNAL OF CHEMISTRY

Kırıkkale Üniversitesi Akademik Arşiv Sistemi

Turk J Chem31 (2007) , 149 – 153.c© TÜBİTAKChemoenzymatic Synthesis of2-Bromo-6-Hydroxy-3-Methoxy-2-Cyclohexen-1-oneEmine ÖZGÜL KARAASLAN∗, Yasemin TOKADepartment of Chemistry, Faculty of Arts and Science, Kırıkkale University,71400 Kırıkkale-TURKEYe-mail: eozgul@gmail.comReceived 06.09.2006A chemoenzymatic synthesis of 2-bromo-6-hydroxy-3-methoxy-2-cyclohexen-1-one starting from cyclo-hexane-1,3-dione is reported. Manganese(III) acetate-mediated acetoxylation followed by the enzyme-mediated hydrolysis of α′-acetoxy enone affords hydroxy-enone 5 and acetoxy enone 4 with high enan-tiomeric excesses in good yields.Key Words: Chemoenzymatic synthesis, cyclic polyoxo cyclohexenones, manganese(III) acetate, ace-toxylation.IntroductionThe synthesis of optically active cyclic enones like 4 and 5 is of significant importance since they areimportant structural units in many biologically active compounds and are important synthons for theasymmetric synthesis of natural products.1−7OOCH3BrRO4, R=Ac5, R=H*Several studies have been reported on the racemic and asymmetric synthesis of various hydroxy cyclicenones;8−13 however, there is no work on the synthesis of 2-bromo-6-hydroxy-3-methoxy-2-cyclohexen-1-oneto the best of our knowledge. We describe herein an efficient chemoenzymatic route to the 4-step synthesisof 2-bromo-6-hydroxy-3-methoxy-2-cyclohexen-1-one and 6-acetoxy-2-bromo-3-methoxy-2-cyclohexen-1-one,starting from cyclohexane-1,3-dione and using Mn(OAc)3 methodology.∗Corresponding author149Chemoenzymatic Synthesis of, E. ÖZGÜL KARAASLAN, Y. TOKAIn the literature, there are several papers about the Mn(OAc)3 mediated direct acetoxylation andacyloxylation of enones and aromatic ketones followed by the enzymatic and fungus mediated resolution ofacyloxy enones to obtain enantiomerically pure α-hydroxy ketones.14−20 Since chiral 2-bromo-6-hydroxy-3-methoxy-2-cyclohexen-1-one has a multi-functional nature, it can take part in several stereoselectivetransformations and this led us to explore a chemoenzymatic method for obtaining it in its enantiomericallypure forms.ExperimentalAll reagents were of commercial quality and reagent quality solvents were used without further purification.NMR spectra were recorded on a Bruker DPX 400. Column chromatography was conducted on silica gel 60(mesh size 40-63 µm). Enantiomeric excesses were determined by HPLC analysis using a ThermoQuest (TSP)LC-MS equipped with an appropriate chiral column. GC/MS spectra were recorded on a ThermoQuest(TSP) Trace GC-2000 Series equipped with ThermoQuest Finnigan Multi Mass (EI, 70 eV).Synthesis of 3-methoxy-2-cyclohexen-1-one (2). 1.0 M TiCl4 solution in CH2Cl2 (0.50 mL,0.50 mmol) was added at room temperature to a well-stirred solution of the cyclohexane-1,3-dione (2.0 g,17.8 mmol) in methanol (35 mL). The reaction mixture was then stirred for an additional 30 min. Afterthat, the mixture was filtered, concentrated and purified by flash column chromatography (3:1, EtOAc /n-Hexane) to afford the desired product as a yellow oily liquid (1.91 g, 15.1 mmol, 85%). 1H-NMR (400MHz, CDCl3) δ 1.97 (p, J = 6.39 Hz, 2H, CH2), 2.31 (t, J = 6.47 Hz, 2H, CH2), 2.39 (t, J = 6.22 Hz, 2H,CH2), 3.68 (s, 3H, OCH3), 5.33 (s, 1H, CH); 13C-NMR (100 MHz, CDCl3) δ 21.2, 28.7, 36.6, 55.4, 102.2,178.2, 198.9. Spectroscopic data agree with the literature.21Synthesis of 2-bromo-3-methoxy-2-cyclohexen-1-one (3). A solution of 3-methoxy-2-cyclohexen-1-one (1.9 g, 15.1 mmol) in dichloroethane (10 mL), maintained between 5 and 10 ◦C, was treated with NBS(2.7 g, 15.1 mmol) in portions over 0.5 h. After 0.5 h the mixture was filtered and the filtrate evaporated.The residue was dissolved in toluene (40 mL) and rapidly washed with cold water (2 x 20 mL). The organiclayer was dried over MgSO4 and evaporated to 5 mL, cooled to 0 ◦C and the product was filtered off as awhite crystal (2.47 g, 12.1 mmol, 80%). 1H-NMR (400 MHz, CDCl3) δ 2.06 (p, J = 6.43 Hz, 2H, CH2),2.52 (t, J = 6.42 Hz, 2H, CH2), 2.71 (t, J = 5.97 Hz, 2H, CH2), 3.95 (s, 3H, OCH3); 13C-NMR (100 MHz,CDCl3) δ 20.4, 26.7, 36.6, 56.3, 102.9, 172.3, 190.6. Spectroscopic data agree with the literature.22Synthesis of (±)-6-acetoxy-2-bromo-3-methoxy-2-cyclohexen-1-one (rac-4). A solution of2-bromo-3-methoxy-2-cyclohexen-1-one (2.5 g, 12.1 mmol), Mn(OAc)3 (9.7 g, 36.2 mmol) and benzene (120mL) was heated under reflux for 52 h. After cooling, the reaction mixture was first filtered and then washedwith sat. NaHCO3 solution. The mixture was then dried over MgSO4, concentrated and purified by flashcolumn chromatography (1:1, EtOAc / n-Hexane) to yield the desired product as a red oily liquid (2.38 g,9.03 mmol, 75%).General procedure for the enzyme-catalyzed hydrolysis of (±)-6-acetoxy-2-bromo-3-methoxy-2-cyclohexen-1-one. Lipase (200-300 mg) was dissolved in 30 mL of potassium phosphatebuffer (20 mM, pH 7.0) and added to a solution of the rac-4 (1 mmol) in DMSO (3 mL) and the reactionmixture left to stir at room temperature. The reaction was monitored by TLC and when maximum con-version was reached the reaction was terminated by filtration. The unreacted acetate 4 and the product 5150Chemoenzymatic Synthesis of, E. ÖZGÜL KARAASLAN, Y. TOKAwere separated by flash column chromatography (2:1, EtOAc / n-Hexane).6-Acetoxy-2-bromo-3-methoxy-2-cyclohexen-1-one (4). Red oily liquid (118 mg, 0.45 mmol,45%). 1H-NMR (400 MHz, CDCl3) δ 2.07 (m, 1H, H-5), 2.24 (m, 1H, H-5), 2.10 (s, 3H, CH3), 2.68 (m,1H, H-4), 2.82 (m, 1H, H-4), 3.90 (s, 3H, OCH3), 5.25 (dd, J = 7.58, 4.97 Hz, 1H, H-6); 13C-NMR (100MHz, CDCl3) δ 20.7, 24.8, 25.9, 56.4, 71.7, 101.2, 169.5, 171.3, 185.5; GC/MS (m/z) 264 (M+), 220, 192,183, 160, 141, 123, 111, 97, 80, 68, 52, 43, 42.2-Bromo-6-hydroxy-3-methoxy-2-cyclohexen-1-one (5). White solid (90.6 mg, 0.41 mmol,41%). 1H-NMR (400 MHz, CDCl3) δ 1.82 (ddd, J = 5.42, 5.36, 5.24 Hz, 1H, H-5), 2.39 (m, 1H, H-5), 2.62(m, 1H, H-4), 2.80 (m, 1H, H-4), 3.63 (s, 1H, OH), 3.92 (s, 3H, OCH3), 4.03 (dd, J = 5.45, 5.06 Hz, 1H,H-6); 13C-NMR (100 MHz, CDCl3) δ 25.2, 28.4, 56.3, 71.3, 99.2, 172.5, 192.1; GC/MS (m/z) 222 (M+),220, 179, 178, 175, 149, 97, 81, 69, 68, 67.Results and DiscussionCommercially available cyclohexane-1,3-dione (1) was converted to the 3-methoxy-2-cyclohexen-1-one (2)and then to the 2-bromo-3-methoxy-2-cyclohexen-1-one (3) using procedures reported in the literature.21,22Then, oxidation of the enone 3 with 3 equivalents of manganese(III) acetate in benzene was performed toobtain the α′-acetoxy enone rac-4 in 75% yield after purification by column chromatography (Scheme 1).OOTiCl4MeOH, rtOOCH3NBSOOCH3BrOOCH3BrMn(OAc)3benzene, refluxOO1 2 3 rac-4Scheme 1Lipase type enzymes are used extensively for the synthesis of enantiomerically pure compounds viathe resolution of racemic mixtures. The high stereoselectivity in organic media and their low cost makethem very useful catalysts for enantioselective resolution.In connection with published studies related to biocatalyst-mediated reactions, we tested severalenzymes for screening the enantioselective hydrolysis of the acetoxy enone rac-4 (Scheme 2). The hydrolysisof rac-4 was investigated using 4 readily available enzymes: PLE (Pig Liver Esterase), Amano PS, CCL(Candida Cylindracea Lipase), and PPL (Porcine Pancreatic Lipase). Only Amono PS showed activity, with50% conversion within 4 h. PLE, CCL and PPL did not show any activity toward the substrate. Carefulmonitoring of the reaction with TLC furnished the acetoxy enone (99% ee, 45% yield) and hydroxy enone(96% ee, 41% yield). Ee values were determined by HPLC analysis using a chiral column (Chiralcell OBcolumn, UV detection at 254 nm, eluent: Hexane/2-propanol = 60:40, flow 0.5 mL.min−1 (Figures 1-3).OOCH3BrOOrac-4enzymeDMSO, buffer(pH=7)OOCH3BrOO(R/S)-4OOCH3BrHO(R/S)-5** +Scheme 2151Chemoenzymatic Synthesis of, E. ÖZGÜL KARAASLAN, Y. TOKA4020040200mAUmAU0 20 40 60 80 100 120Minutes59.39739.055Retention TimeUV1000-254nmFigure 1. HPLC chromatogram of racemic α′-acetoxy-2-bromo-3-methoxy-2-cyclohexen-1-one.3210mAUmAU0 20 40 60 80 100 120Minutes59.70339.815Retention TimeUV1000-254nm 3210Figure 2. HPLC chromatogram of chiral α′-acetoxy-2-bromo-3-methoxy-2-cyclohexen-1-one.2001000mAUmAU0 20 40 60 80 100 120Minutes21.4277.725Retention TimeUV1000-254nm 2001000Figure 3. HPLC chromatogram of chiral α′-hydroxy-2-bromo-3-methoxy-2-cyclohexen-1-one.In a typical experiment for enzymatic hydrolysis, the racemic acetoxy enone 4 was dissolved in DMSO,a phosphate buffer (pH 7.0) then added and the mixture stirred at room temperature in the presence of theenzyme. The reaction was monitored by TLC analysis. When approximately 50% conversion was attained,the crude product was separated by flash column chromatography to provide acetoxy enone 4 and hydroxyenone 5.The results show that manganese(III) acetate-mediated acetoxylation of an enone followed by enzyme-mediated hydrolysis of the acetoxy group provides hydroxy enone 5 and acetoxy enone 4 with high enan-tiomeric excesses in good chemical yields. Thus, highly functionalized, polyoxygenated chiral enones, 4 and5, with potential applications as synthetic intermediates have been successfully synthesized.AcknowledgmentsWe are grateful for the financial support from Kırıkkale University (BAP 03/03-06-09).152Chemoenzymatic Synthesis of, E. ÖZGÜL KARAASLAN, Y. TOKAReferences1. J. Wang and T.R.R. Pettus, Tetrahedron Lett. 45, 5895-99 (2004).2. X. Xu and Y. Zhu, Tetrahedron Lett. 50, 9173-76 (1995).3. G. Liu and Z. Wang, Chem. Commun. 1129-30 (1999).4. R. Noyori and M. Suzuki, Angew. Chem., Int. Ed. Engl. 123, 847-76 (1984).5. P.W. Collins and S.W. Djuric, Chem. Rev. 93, 1533-64 (1993).6. P.P.M.A. Dols, A.J.H. Klunder and B. Zwanenburg, Tetrahedron 50, 8515-38 (1994).7. F.A. Davies and B.C. Chen, Chem. Rev. 92, 919-34 (1992).8. L. Canonica, A. Corbella, G. Jommi, F. Pelizzoni and C. Scolastico, Tetrahedron Lett. 26, 3031-34 (1966).9. M.E. Ochoa, M.S. Arias, R. Aguilar, F. Delgado and J. Tamariz, Tetrahedron 55, 14535-46 (1999).10. 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Chemoenzymatic synthesis of 2-brorno-6-hydroxy-3-methoxy-2-cyclohexen-1-one

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