Evaluation of lipases in the desymmetrization of meso-exo-3,5-dihydroxymethylenetricyclo[5.2.1.0(2,6)]decane and the synthesis of chiral derivatives

ARTICLE

Evaluation of lipases in the desymmetrization of meso-exo-3,5-dihydroxymethylenetricyclo[5.2.1.0 ^2,6]decane and the synthesis of chiral derivatives

Valentim E. U. Costa^*; Adriana R. Pohlmann; Marli L. T. de Sordi

Instituto de Química, Universidade Federal do Rio Grande do Sul, Av.Bento Gonçalves, 9500, 91501-970 Porto Alegre-RS, Brazil

ABSTRACT

meso-exo-3,5-dihydroxymethylenetricyclo[5.2.1.0 ^2,6]decane was efficiently desymmetrized by the lipase from Pseudomonascepacia (PS–C 'Amano' II) in vinyl acetate in high yields (93%) and with excellent enantiomeric excesses (ee > 99% by chiral GC). Chiral synthons for asymmetric synthesis were synthesized from this enantiopure compound.

Keywords: lipases, enzymatic catalysis, desymmetrization, chiral compounds

RESUMO

A dessimetrização mais eficiente do composto meso-exo-3,5-dihidroximetilenotriciclo[5.2.1.0 ^2,6]decano foi com a lipase da Pseudomonas cepacia (PS–C 'Amano' II) em acetato de vinila, quando obteve-se alto rendimento químico (93%) e excelente excesso enantiomérico (ee > 99%), determinado por cromatografia gasosa em coluna quiral. Desse sistema quiral, foram preparados derivados enantiopuros com potenciais aplicações como intermediários sintéticos.

Introduction

Bicyclic amino alcohol derivatives are stereochemically constrained compounds and are interesting systems used as chiral auxiliaries,^1-5 as well as synthetic intermediates and chiral ligands for asymmetric synthesis.^1,6-8 Optically active amino alcohols are constituents of many biologically and pharmacologically important compounds such as adrenaline, b-adrenergic receptor blockers and local anaesthetics.⁹ The abundance and crystallinity of (+)-camphor have attracted considerable interest to the synthesis of enantiomerically pure derivatives including 3-endo-amino-2-endo-bornanol,¹⁰ exo,exo-amino alcohol,¹¹anti-(+)-camphorquinone-3-oxime¹² and bridgehead-substituted 2-norbornanones and 2-norbonanoximes.¹³

The desymmetrization of an meso compound by reaction with a suitable enantiomerically pure reagent provides a versatile approach to the preparation chiral synthons for asymmetric synthesis.¹⁴ Desymmetrization of meso-compounds or prochiral diols and diacetates in the presence of lipase has become a practical approach for the preparation of chiral compounds due to its high specificity and reproducibility.⁹

Optically active aminooxy alcohols would appear to be very interesting building blocks in the search for novel biologically active compounds and the synthesis of such optically active derivatives by using a lipase-catalyzed acetylation has been described.⁹

The goal of our research group over the last few years has been the study and application of constrained polycyclic compounds, from both a conformational and stereochemical viewpoint,¹⁵ as well as in terms of their reactivity and enantiomeric resolution.¹⁶

In this work we report the evaluation of various lipases for the desymmetrization of meso-exo-3,5-dihydroxymethylenetricyclo[5.2.1.0 ^2,6]decane in vinyl acetate and the preparation of derivatives as chiral building blocks, carrying functional groups in flexible chains on appropriate positions of the tricyclic framework.

Results and Discussion

The symmetric starting material endo,exo-tetracyclo[6.2.1.1^3,6.0 ^2,7]dodec-4-ene, (1), was prepared easily by the Diels-Alder reaction between norbornene and dicyclopentadiene according to known procedure.¹⁷

The treatment of the resulting adduct 1 with KMnO₄ and NaIO₄ at room temperature over 5 h gave the respective dicarboxylic acid 2 in 83% yield,¹⁸ while the use of RuCl₃.3H₂O (cat.), NaIO_4, CCl₄-CH₃CN-H₂ O provided yields around 85%.¹⁹ This meso diacid was then reduced with lithium aluminium hydride in tetrahydrofuran to give the meso-diol 3 in 78% yield (Scheme 1).

The lipase-catalysed transesterification reaction with vinyl acetate at 23-26^oC was used to afford the kinetic desymmetrization of meso-diol 3 (Scheme 2).

Catalytic desymmetrization reaction of meso-diol 3 mediated by lipase from Pseudomonas cepacia supplied in three different preparations were evaluated: powder (Lipase PS "Amano"), immobilized on ceramic particles chemically modified with methacrylic groups (Lipase PS–C "Amano" II) and immobilized on diatomaceous earth (Lipase PS–D "Amano" I). The same reaction mediated by lipase from Candida rugosa (AY Amano 30) and lipase from Porcine pancreatic (PPL) supplied as a powder were also evaluated.

The AY Amano 30 lipase (from Candida rugosa supplied as a powder) gave only the racemic monoacetate (±)–4 while all the other lipases produced exclusively monoacetate (+)–4 with high enantiomeric excesses (ee > 99%). However, the Amano PS – C II lipase was found to be the best catalyst, giving the highest yields (93%) and the most favorable reaction time (Table 1).

After reaction, the acetoxy alcohol (+)–4 was purified by filtration over Celite with ethyl acetate. The enantiomeric excess (ee%) of the separated acetate was determined by gas chromatography on a Beta-Dex^TM 120 chiral column.

The oxidation of the acetoxy alcohol (+)–4 with pyridinium chlorotrioxochromate (PCC) gave the respective enantiomerically pure acetoxy aldehyde (-)-5 in 88% yield with an [a]_D²⁰ = - 16 (c =2, CH₂Cl₂); as this aldehyde is unstable we prepared directly its oxime derivative and, consequently, the elemental analysis was made of its oxime. The acetoxy oxime derivative (+)-6 was obtained from the reaction of the aldehyde (-)-5 with hydroxylamine chloride/sodium acetate in a 65-85% yield. The acetoxy oxime (+)-6 is a conformer mixture determined by ¹H NMR (60:40) and it had a specific rotation of [a]_D²⁰ = + 24 (2, CH₂Cl₂).

In order to obtain the protected amino alcohol 7 the oxime (+)-6 was reduced with nickel chloride hexahydrate and sodium borohydride in methanol. However, direct extraction and purification of the chiral amino-alcohol afforded poor yields, and to overcome this, in situ acetylation of the reaction product was carried out, producing the protected amino alcohol (-)-7 in a 77% yield ([a]_D²⁰ = - 10 (1, CH₂Cl₂)). The acetyl group of the amide function has two preferential conformers because it is possible to observe in ¹³C-NMR double signals for the methyl and carbonyl groups.

Conclusion

The Amano PS – C II lipase was found to be the best catalyst, giving highest yields and the best reaction rate in the desymmetrization reaction of meso-exo-3,5-dihydroxymethylenetricyclo[5.2.1.0 ^2,6]decane, (3) in vinyl acetate. Chiral derivatives, in non-racemic form, have been prepared, carrying functional groups on flexible chains in appropriate positions of this tricyclic framework. This constitutes an effective and convenient synthetic approach for the preparation of new chiral auxiliaries, synthons and building blocks.

Experimental

General

Melting points were determined on an Electrothermal IA9000 apparatus and are presented without correction. Infrared spectra were recorded using a Mattson 3020 FTIR spectrometer. Mass spectra were acquired on an HP 5988A spectrometer. NMR spectra were recorded on a Varian VXR-200 spectrometer at a magnetic field of 4.7 T at 22 ^oC. Chemical shifts are expressed as d(ppm) relative to TMS as internal standard and the J values are given in Hz. Elemental analyses were recorded on a Perkin – Elmer 2400 CHN elemental analyzer. The products were analyzed by GC on a Shimadzu GC – 17A Gas Chromatograph equipped with an FID detector. Optical rotations were recorded on a Perkin – Elmer 341 polarimeter using the sodium D line or mercury 365 nm line with a 0.1 dm cell at a temperature of 20 ^oC. Lipase PS "Amano" (Lot. LPSAX10508), PS – C "Amano" I (Lot. IPSAX08531K), PS – C "Amano" II (Lot. ILPSAX01520K), PS – D "Amano" I (Lot. ILPSAX02520K), AK "Amano" 20 (Lot. LAKX09510) from Pseudomonas and lipase AY Amano 30 (Lot. LAYY0450102S), were kindly provided by Amano Enzyme U.S.A. Co. Vinyl acetate was distilled from hydroquinone just before use. All enzymatic resolutions were carried out at 20 ^oC under anhydrous conditions on a Mistral Multi-Mixer apparatus. GC parameters for achiral analysis. injector 250 ºC; detector 300 ºC; oven 100 ºC for 5 min then 10 ºC min^-1 until 300 ºC; column pressure 15 kPa; column flow 9.5 mL min^-1; linear velocity 84.7 cm s^-1; total flow 200 mL; split ratio 1:20; column DB1 15 m x 0.53 mm (internal diameter).

GC parameters for chiral analysis. injector 250 ºC; detector 300 ºC; oven 150 ºC for 10 min then 5 ºC min^-1 until 200 ºC; column pressure 138 kPa; column flow 2.7 mL min^-1; linear velocity 75.5 cm s^-1; total flow 35 mL; split ratio 1:10; column b- cyclodextrin 30 m x 0.25 mm (internal diameter).

exo-Tricyclo[5.2.1.0^2,6]decan-3,5-dioic acid, (2)

To a solution of 1 (2.0 g, 4.5 mmol) in t-butanol (50 mL) was added an aqueous solution (150 mL) of NaIO₄ (10.0 g, 46.7 mmol), KMnO₄ (5.2 g, 32.9 mmol), and K₂CO₃ (10.0 g, 72.4 mmol). The medium was adjusted to pH 8 by the addition of a 3 mol L^-1 NaOH aqueous solution and the reaction underwent magnetic stirring at room temperature. After 5 h, the medium was acidified with concentrated HCl to pH 1 and sodium bisulfite was added. The mixture was extracted with ethyl acetate (3 x 40 mL), and the combined organic layers were extracted with 3 mol L^-1 NaOH aqueous solution (3 x 40 mL). Then, the dicarboxylate aqueous solution was acidified (concentrated HCl) to pH 3-4 and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over MgSO₄, filtered and evaporated under reduced pressure, giving 2.3 g of diacid 2 (82% yield). Elemental analysis: Found: C, 64.17; H, 7.18%; Calcd. for C₁₂H₁₆O₄: C, 64.28; H, 7.14%; mp 224° C; IR (KBr) n_max/ cm^-1: 3000, 1711; ¹H NMR (CD₃OD, 300 MHz): d 1.0-1.5 (m, 6H, tricyclic moiety), 1.8 (m, 1H, tricyclic moiety), 2.2-2.6 (m, 5H, tricyclic moiety), 3.1 (m, 2H, CH-3 and CH-5), 9.9 (s, 2H, COOH); ¹³C NMR (CD₃OD, 75 MHz): d 30.0 (CH₂), 33.0 (CH₂), 36.5 (CH₂), 41.0 (CH), 49.0 (CH), 51.8 (CH), 177.0 (COOH).

meso-endo,exo-3,5-dihydroxymethylenetricyclo[5.2.1.0 ^2,6]decane, (3)

To a suspension of LiAlH₄ (1.0 g, 27.2 mmol) in dry THF (50 mL) under argon was added a solution of diacid 2 (1.0 g, 4.46 mmol) in dry THF (10 mL). The reaction was carried out during 6 h with magnetic stirring at room temperature. Then, the mixture was added of distilled water (3 mL) and 30% (m/V) NaOH aqueous solution (10 mL). The precipitate was removed by filtration, and the filtrate was dried over anhydrous NaSO₄, filtered and evaporated under reduce pressure. The pure diol 3 (0.680 g, 3.5 mmol) was obtained in 78% of yield. Elemental analysis: Found: C, 72.02; H, 10.82%; Calcd. for C₁₂H₂₀O₂: C, 72.36; H, 10.20%; IR (KBr) n_max/ cm^-1: 3280, 1021; ¹H NMR (CDCl₃, 200 MHz): d 1.8-2.5 and 0.9-1.4 (m, 14H, tricyclic moiety and 2 H, OH), 3.7 (dd, J 13.0 Hz and J 7.6 Hz, 4H, 2 x CH₂-OH); ¹³C NMR ((CD₃)₂CO, 75 MHz): d 30.0 (CH2), 36.8 (CH2), 37.8 (CH2), 38.2 (CH), 47.0 (CH), 51.4 (CH), 64.0 (CH2O).

3-Hydroxymethylene-5-acetomethylenetricyclo[5.2.1.0 ^2,6]decane, [(±)-4]

The racemic standard (±)-4 was prepared to carry out the chiral chromatographic analyses. The meso-diol 3 (0.140 g, 0.71 mmol) and 0.550 g of silica gel (60, 70-230 mesh) were shaken. To this mixture sufficient acetic anhydride was added to cover the solid. After 2 h, the reaction was quenched by the addition of distilled water (20 mL). The mixture was neutralised with an aqueous solution of NaHCO₃ and extracted with ethyl acetate (3 x 40 mL). The combined organic phases were dried over MgSO₄, filtered and evaporated under reduce pressure. The GC analysis of crude product showed 3 peaks: A, 27%; B, 56% and C, 17%. The peaks A and B were the meso-diol 3 and the monoacetate (±)-4 respectively. Column chromatography (silica gel 60, 70-230 mesh; cyclohexane/ethyl acetate 3:1) of crude product gave the monoacetate (±)-4 in 47% yield. Elemental analysis: Found: C,70.07; H,9.31%; Calcd. for C₁₄H₂₂O₃: C,70.58; H,9.24%; IR (neat) n_max/ cm^-1: 3460, 1740, 1243, 1033; ¹H NMR (CDCl₃, 200 MHz): d 4.1 (m, 2H, CH₂-OAc), 3.7 (m, 2H, CH₂-OH), 3.3 (bs, 2H, CH-3 and CH-5), 2.2 (m, 2H, tricyclic moiety), 2.1 (s, 3H, CH₃), 1.7-1.9 (m, 2H, tricyclic moiety), 1.4 (m, 3H, tricyclic moiety), 0.9-1.3 (m, 5H, tricyclic moiety, and 1 H, OH); ¹³C NMR (CDCl₃, 50 MHz): d 20.9 (CH₃), 29.5 (2 CH₂), 35.2 (CH₂), 36.5 (CH₂), 36.7 (CH), 36.8 (CH), 41.4 (CH), 45.2 (CH), 49.6 (CH), 49.8 (CH), 65.2 (CH₂-OH), 66.2 (CH₂-OAc), 171.3 (CO).

3-Hydroxymethylene-5-acetomethylenetricyclo[5.2.1.0 ^2,6]decane, [(+)-4]

The general procedure for enzyme catalytic reactions (Table 1) was carried out as described for PS-C "Amano" II: to a solution of diol 3 (0.250 g, 1.27 mmol) in vinyl acetate (20 mL) was added the lipase (0.050 g). The reaction was stirred during 1.5 h at room temperature. The mixture was filtered over Celite, using ethyl acetate (30 mL). Then, the filtrate was evaporated under reduce pressure to give the product (+)-4 (0.265 g; 1.11 mmol, 88%). [a]_D²⁰ +1 (c = 2, CH₂Cl₂); the physical data are described above to racemic compound.

5-Acetomethylenetricyclo[5.2.1.0^2,7 ]decane-3-carbaldehyde, [(-)-5]

To a solution of product (+)-4 (0.100 g, 0.42 mmol) in CH₂Cl₂ (15 mL) was added pyridinium chlorotrioxochromate (PCC, 0.250 g, 1.16 mmol). After 4 h under magnetic stirring at room temperature, ethyl ether (10 mL) was added and a black precipitate was formed, which was filtered off with a small column fitted with silica gel 60 (70-230 mesh), and eluted with ethyl ether. The filtrate was evaporated under reduce pressure to give a colourless oil corresponding to aldehyde (-)-5 (0.087 g; 0.36 mmol, 88%), which was used immediately to avoided oxidation. [a]_D²⁰ -16 (c = 2, CH₂Cl₂); Elemental analysis: data were obtained from its stable oxime derivative; ¹H NMR (CDCl₃, 200 MHz): d 1.0 – 2.8 (m, 13H, tricyclic moiety), 2.1 (s, 3H, CH₃ ), 3.0 (ddd, J 9.77 Hz, J 9.44 Hz, J 1.52 Hz, 1H, CH-CHO), 4.2 (dd, J 7.47 Hz and J 4.80 Hz, 2H, CH2-OAc), 9.8 (d, J 1.53 Hz, 1H), ¹³C NMR (CDCl₃, 50 MHz): d 20.9 (CH₃), 29.1 (CH₂), ), 29.5 (CH₂), 29.6 (CH₂), 31.1 (CH₂), 36.6 (CH), 38.4 (CH), 41.4 (CH), 49.8 (CH), 49.8 (CH), 55.3 (CH), 65.1 (CH₂O), 171.2 (AcCO), 202.9 (CHO).

3-acetomethylene-5-oximemethylenetricyclo[5.2.1.0 ^2,6]decane, [(+)-6]

To a solution of acetoaldehyde (-)-5 (0.450 g, 1.89 mmol) in methanol was added sodium acetate (0.200 g; 2.0 mmol) and NH₂OH.HCl (0.138 g; 2.0 mmol). The mixture was stirred at room temperature for 18h, water was added (20 cm³) and then extracted with ethyl acetate (3 x 20 cm³). The organic layer was washed with NaHCO₃ solution (10%; m/v), dried over MgSO₄, filtered and evaporated in vacuo, affording the oxime (+)-6 (0.405 g; 0.123 mmol) with 85% of yield. [a]_D²⁰ + 24 (c = 2, CH₂Cl₂); Elemental analysis: Found: C, 68.20; H, 8.64; N, 5.26%; Calcd. for C₁₄H₂₁NO₃: C, 68.18; H, 8.33; N, 5.30%; IR (CHCl₃ film) n_max./cm^-1: 3388 (N-OH), 1739 (C=O); ¹ H NMR (200 MHz, CDCl₃) d 0.9 – 3.0 (m, 14H), 2.1 (s) and 2.2 (s) (3H), 4.2 (m, 2H), 6.8 (d, J 6.4Hz, 1H) and 7.52 (d, J 7.0Hz) (1H), 8.7 (s, 1H, OH); ¹³ C NMR (75 MHz, CDCl₃) d 20.9 (CH₃), 29.2 (CH₂), 29.6 (CH₂), 35.2 (CH₂), 36.1 (CH₂), 36.9 (CH₂), 38.0 (CH), 41.9 (CH), 42.8 (CH), 49.5 and 50.0 (CH), 51.2 and 51.8 (CH), 65.2 and 65.3 (CH₂), 153 (C=N), 171.2 and 171.3 (C=O).

3-acetomethylene-5-acetoamidomethylenetricyclo[5.2.1.0 ^2,6]decane, [(-)-7]

To a solution of hydroxy oxime (+)-6 (0.310 g; 1.11mmol) in methanol (10mL), nickel (II) chloride hexahydrate (0.47 g; 1.96 mmol) was added under magnetic stirring. After nickel dissolution, the solution was cooled to –78 °C. Powdered sodium borohydride (0.390 g; 10.2 mmol) was added in small portions under efficient stirring. The solution turned blue, and was stirred for an additional 12 h when the colour changed to black. The methanol was removed and acetic anhydride (10 mL) was added and the solution refluxed for 90 min. The excess anhydride was removed by distillation. The residue was neutralized with a solution of saturated potassium carbonate until pH 9–10 and extracted three times with chloroform, yielding, after solvent evaporation, a yellow oil corresponding to the compound (-)-7 (238 mg; 0.85 mmol, 77%). [a]_D²⁰ - 10 (c = 1, CH₂Cl₂); Elemental analysis: Found: C, 66.85; H, 8.85; N, 4.65%; Calcd. for C₁₆H₂₅NO₄.1/2H ₂O: C, 66.67; H, 9.02; N, 4.86%; IR (CHCl₃ film) n_max./cm^-1 3297 (N-H), 1739 (C=O; ester), 1650 (C=O; amide); ¹ H NMR (200 MHz, CDCl₃) d 1.02 (m, tricyclic moiety, 4H), 1.22 (m, tricyclic moiety, 1H), 1.42 (m, tricyclic moiety, 2H), 1.78 (m, tricyclic moiety, 1H), 1.90 – 2.40 (m, tricyclic moiety, 6H), 1.98 and 2.03 (2s, 3H, CH₃ amide), 2.05 (s, 3H, CH₃ ester), 3.26 – 3.34 (m, 2H, CH₂-NH), 4.06 – 4.15 (m, 2H, CH₂O), 5.8 (bs, 1H, NH); ¹³ C NMR (75 MHz, CDCl₃) d 20.70 and 20.85 (CH3 amide), 22.93 (CH3 ester), 29.30 (CH2), 29.39 (CH2), 36.11 (CH2), 36.42 (CH2), 36.68 (CH), 36.76 (CH), 40.85 (CH2), 41.25 (CH), 42.21 (CH), 49.78 (CH), 49.81 (CH), 65.20 (CH2), 170.66 (CO, ester), 171.24 and 175.60 (CO, amide).

Acknowlegments

We thank CNPq and FAPERGS for financial support. CNPq for fellowship to V.E.U.C. and A.R.P. and CAPES for scholarship to M.L.T.S. Special thanks to Dr. John Spencer for reviewing this text. The authors are indebted to Amano Enzyme USA Co. Ltd. for kindly providing the 'Amano' lipases used in this work.

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Received: July 24, 2002

Published on the web: October 28, 2003

Publication Dates

• Publication in this collection
  25 May 2004
• Date of issue
  Feb 2004

History

• Received
  24 July 2002
• Accepted
  28 Oct 2003