Bioreduction of substituted a-tetralones promoted by Daucus carota root

ARTIGO

Bioreduction of substituted a-tetralones promoted by Daucus carota root^‡

Helena M. C. FerrazI, ^†; Graziela G. Bianco^I,*; Fernanda I. Bombonato^I; Leandro H. Andrade^I; André L. M. Porto^II

^IInstituto de Química, Universidade de São Paulo, CP 26077, 05513-970 São Paulo - SP, Brazil

^IIInstituto de Química de São Carlos, Universidade de São Paulo, CP 780, 13560-970 São Carlos - SP, Brazil

ABSTRACT

The bioreduction of a series of substituted a-tetralones, carried out using Daucus carota root (carrot), afforded the corresponding homochiral a-tetralols in variable conversions (9 to 90%) and excellent enantiomeric excesses. Two of the assayed a-tetralones were resistant to the bioreduction conditions. The absolute configurations of four a-tetralols were assigned as being (S), by comparison to the (S)-enantiomers obtained by kinetic resolution promoted by CALB-catalysed acetylation. Additionally, the new 5-methoxy-6-methyl-1-tetralone was synthesized in seven steps from 3-methylsalicylic acid.

Keywords: bioreduction; Daucus carota; a-tetralols.

INTRODUCTION

a-Tetralols are versatile intermediates in organic synthesis, being employed as building blocks and as catalysts ligands.^1-4 Therefore, many efforts have been dedicated to search for reactions that can furnish homochiral a-tetralols. There are several reports dealing with the asymmetric hydrogenation of the a-tetralone itself,^5-11 as well as with its bioreduction, using either isolated enzymes or microorganisms.^12-16 It is of note that substituted homochiral b-tetralols have been obtained by reacting a large variety of enzymes and microorganisms with the corresponding b-tetralones.^11,17-21 To our knowledge, however, there are no previous works dealing with the analogous substituted a-tetralones.

In a recent paper, we reported the enzymatic kinetic resolution of a series of a-tetralols, using the lipase B from Candida antarctica (CALB).²² The (S)-1-tetralols and their respective (R)-acetates were obtained in excellent enantiomeric excesses. The absolute configurations of the products were assigned by comparison of the optical rotation values to those of literature. These results are summarized in Scheme 1.

The Daucus carota root is frequently used to promote the bioreduction of a number of ketones, constituting an efficient way for the preparation of enantiomerically pure secondary alcohols.^{12, 23-30} To our knowledge, there is just one paper concerning the Daucus carota promoted bioreduction of two a-tetralones, namely the a-tetralone itself and the 6-methoxy-1-tetralone.¹²

Therefore, we decided to investigate the behaviour of a series of substituted a-tetralones towards the bioreduction with Daucus carota, aiming higher yields (theoretically 100%) than those earlier obtained using CALB in the kinetic resolution (theoretically 50%).²² Moreover, the a-tetralol derivatives could be useful model substrates in our studies concerning the synthesis of some natural products, such as the sesquiterpenes mutisianthol (I)^31,32 and jungianol (II),^33-35 and the lignane flossonol (III)³⁶ (Figure 1).

RESULTS AND DISCUSSION

A series of nine substituted a-tetralones, besides the a-tetralone itself (Figure 2) were employed as substrates for the bioreduction studies. The tetralones 1a-7a are commercially available, while the others (8a-10a) were synthesized as described in the next sections.

The a-tetralones 8a and 10a were prepared according to known procedures from 2-methyl-anisole, as depicted in Scheme 2.^{32, 37}

The a-tetralone 9a was synthesized in seven steps from 3-methylsalicylic acid (11), as summarized in Scheme 3. Although the 2-methoxy-3-methyl benzaldehyde (12) is commercially available, this compound was prepared in 3 steps from the acid 11, through known reactions.³⁸ Addition of the alkyllithium 13 to the aldehyde 12 afforded the intermediate 14, which was then submitted to hydrogenolysis under acidic conditions. These conditions promoted the concomitant deprotection of the silylether, furnishing the primary alcohol 15 in 85% yield from 12. Oxidation of 15 with Jones reagent, followed by intramolecular cyclization, led to the desired product 9a in 81% yield for the two steps.

The tetralones were initially submitted to reduction with sodium borohydride, to obtain the racemic patterns of the tetralols. Several of them (1b, 4b-8b) could not be analytically resolved by chiral gas chromatography, and therefore were acetylated using classical conditions. The results are shown in Scheme 4.

The a-tetralones 1a-10a were then submitted to the reaction with carrot, in a phosphate buffered aqueous medium, employing acetonitrile and ethanol for solubilization of the substrates. The erlenmeyers containing the reactional mixture were stirred at 32 ºC and 180 rpm during 4 days. In the first set of experiments (conditions A, Table 1), for 20 mg of the tetralones were used 10 g of carrot. In the second set (conditions B, Table 1) the amount of carrot was doubled.

The conversions of the a-tetralones to the a-tetralols in the conditions A were variable, ranging from 9 to 82%, while the enantiomeric excesses were very good for the majority of the obtained a-tetralols. Doubling the amount of carrot (conditions B) increased the conversion of six tetralones, namely 1a, 3a, 4a, 5a, 7a and 8a, but the enantiomeric excess was better just for the reduction of 7a. The tetralone 2a gave a high enatiomeric excess and conversion in the conditions A. However, it was surprising that in the conditions B these good results could not be reproduced. The tetralones 6a and 10a were resistant to both the reduction conditions.

A possible explanation for the lack of reactivity of the tetralone 6a would be the a-carbonylic position of the methyl group, which certainly causes a steric hindrance. It is of note that the difficulty of the analogous tetralol 6b in reacting with isolated enzymes^22,39 and microorganisms⁴⁰ was already observed. The tetralone 10a showed to be resistant also to chemical reduction, requiring 5 equivalents of sodium borohydride for the preparation of (±)-10b.³²

The chromatograms of the products obtained in the bioreduction of the a-tetralones 1a and 4a are presented in Figures 3 and 4, respectively.

We have assigned the (S)-configuration to the tetralols 1b, 2b, 4b and 5b, by comparison of the retention time in the GC analysis with those obtained previously for these tetralols.²² The (S) configuration agrees to Prelog's rule,⁴¹ which predict that hydrogen transfer to the prochiral ketone occurs to the face where the large group is in the right side (Figure 5a), in this case the Re-face (Figure 5b). Additionally, Yadav et al.¹² attributed the (S)-configuration to the a-tetralol (1b) and to the 6-methoxy-1-tetralol (3b) obtained by bioreduction mediated by carrot of the corresponding a-tetralones.

Finally, the bioreduction of the tetralone (±)-7a led to either the enantiomer of the cis isomer (90% ee) and of the trans isomer (97% ee). This result showed that the keto-reductase from carrot (probably pro-S enantioselective) was not sensitive to substituents at the 4-position, since a mixture of 1:1 (cis:trans) was obtained (Figure 6). It is noteworthy that Bégué et al. observed a similar behaviour when (±)-7a was submitted to bioreduction mediated by Rhodotorula rubra.⁴²

CONCLUSION

The Daucus carota-promoted bioreduction of eight substituted a-tetralones afforded the corresponding homochiral alcohols in conversions ranging from 9 to 90% and in very good enantiomeric excesses. Four of the a-tetralols thus obtained have the absolute configuration assigned as (S). This biotransformation may be an useful tool for the asymmetric synthesis of natural products with biological properties such as flossonol.³⁶

EXPERIMENTAL

General

All solvents and chemicals used were previously purified according to the usual methods. Column chromatography was performed using silica gel 200-400 mesh. ¹H and ¹³C NMR spectra were measured in CDCl₃ with TMS as the internal standards and recorded on Bruker and Varian spectrometers. IR spectra were measured on a Perkin-Elmer 1750-FT. Gas chromatography analyses were performed in a HP-6890 series II. Conversions and enantiomeric excesses were determined using a HP-6890 series II gas chromatograph equipped with a chiral capillary column AG100-2000 (packed with b-cyclodextrin (30 m x 0.32 mm x 0.25 µm) Agilent-HP). The carrier gas was hydrogen. GC-MS analyses were performed using Finnigan-MAT INCOS 50B and GC Varian 2400. Elemental analyses were performed using Perkin-Elmer 2400 apparatus. High-resolution mass spectra were performed on a Bruker Daltonics Microtof Eletrospray instrument. The carrot was bought in a local market. The racemic tetralols 1b, 2b, 4b-8b and acetates 1c, 4c-8c were prepared according to known procedures.²² The spectroscopic data of these compounds were identical to those earlier reported.²²

Preparation of the tetralone 9a

4-(triisopropylsililoxy)-1-(2-methoxy-3-methylphenyl)butane-1-ol (14)

To a two-necked flask, under nitrogen, was added metallic lithium (0.88 g, 0.13 mol) in small pieces that was washed with dry hexanes. After a few minutes under nitrogen, (3-bromopropoxy)triisopropylsilane (8.8 g, 30 mmol) was added in dry THF (100 mL). This solution was irradiated by ultrasound for 2 h. The grey solution of 13 was transferred by cannula to another two-necked flask equipped with a magnetic stirrer, ice bath and under nitrogen containing a solution of aldehyde 12 (3.0 g, 20 mmol) in dry Et₂O (100 mL). This mixture was stirred for 2 h at 0 ºC. The reaction was quenched with water and then extracted with EtOAc. The combined organic layers were washed with water, brine and then dried with anhydrous MgSO₄. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography [silica gel 200-400 mesh, eluent with a mixture of 7:3 hexanes: EtOAc] to afford 14 (6.6 g, 18 mmol, 90%) as a colorless oil. ¹H NMR (300 MHz) d: 1.04-1.15 (m, 21H), 1.60-1.97 (m, 4H), 2.29 (s, 3H), 3.75-3.79 (m, 5H), 5.02 (dd, J 7.7 and 4.8 Hz, 1H), 7.00-7.05 (m, 1H), 7.06-7.10 (m, 1H), 7.27-7.30 (m, 1H); ¹³C NMR (75 MHz) d: 12.0, 16.1, 18.0, 29.8, 35.7, 60.8, 63.6, 69.0, 124.2, 124.6, 130.2, 130.7, 137.7, 155.7; IR (film) n_máx/cm^-1: 3418; LRMS (EI) m/z (%):175 (M^+·, 100). Anal. calcd for C₂₁H₃₈O₃Si: C, 68.89; H, 10.45. Found: C, 68.76; H, 10.35.

4-(2-methoxy-3-methylphenyl)butan-1-ol (15)

To an autoclave system equipped with a magnetic stirrer were added 14 (7.2 g, 21 mmol), dry methanol (50 mL) and HClO₄ (1 mL). This mixture was stirred until completed homogenization and then 10% Pd/C (0.20 g) was added. The autoclave was purged three times with hydrogen gas and then pressurized at the 4 atm. After 16 h at the room temperature, the excess of hydrogen gas was released. The reactional mixture was filtered through silica gel column chromatography using CH₂Cl₂. The organic phase was washed with water, brine and then dried with anhydrous MgSO₄. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography [silica gel 200-400 mesh, eluent with a mixture of 1:1 hexanes: EtOAc] to afford 15 (3.9 g, 20 mmol, 94%) as a yellow oil. ¹H NMR (300 MHz) d: 1.58-1.74 (m, 1H), 2.29 (s, 3H), 3.63-3.68 (m, 2H), 3.65-3.70 (m, 2H), 3.73 (s, 3H), 6.92-6.97 (m, 1H), 7.01-7.03 (m, 2H); ¹³C NMR (75 MHz) d: 16.2, 26.9, 29.4, 32.5, 60.3, 62.8, 123.9, 127.8, 129.0, 130.9, 135.1, 156.7. IR (film) n_máx/cm^-1: 3363; LRMS (EI) m/z (%): 194 (M^+·, 46), 135 (85), 105 (100). HRMS [ESI (+)]: m/z calcd for [C₁₂H₁₈O₂ +Na]⁺ 217.1204, found 217.1203.

4-(2-methoxy-3-methylphenyl)butanoic acid (16)

To a two-necked flask equipped with a drying tube, magnetic stirrer and ice bath, acetone (50 mL) and 15 (1.4 g, 7.3 mmol) were added. The mixture was stirred until completed solubilization. The Jones reagent was slowly added until the brown color persists. After 2 h the reaction was quenched by addition of isopropylic alcohol and then extracted with EtOAc. The combined organic layers were washed with water, brine and then dried with anhydrous MgSO₄. After the solvent removal under reduced pressure, the desired product was purified by flash chromatography [silica gel 200-400 mesh, eluent with a mixture of 1:1 hexanes: EtOAc] to afford 16 (1.1 g, 6.9 mmol, 94%) as a yellow solid: mp: 54.9- 56.0 ºC; ¹H NMR (300 MHz) d: 1.91-2.01 (m, 2H), 2.29 (s, 3H), 2.40 (t, J 7.4 Hz, 2H); 2.69 (t, J 7.4 Hz, 2H), 3.72 (s, 3H), 6.92-6.97 (m, 1H), 7.01-7.05 (m, 2H); ¹³C NMR (75 MHz) d: 16.2, 25.6, 29.1, 33.6, 60.3, 124.0, 127.8, 129.4, 131.1, 156.8, 179.6; IR (film) n_máx/cm^-1: 1706; LRMS (EI) m/z (%): 208 (M^+·,42), 148 (50), 133 (70). Anal. calcd for C₁₂H₁₆O₃: C, 69.21; H, 7.74. Found: C, 68.76; H, 7.67.

3,4-dihydro-5-methoxy-6-methylnaphthalen-1(2H)-one (9a)

To a two-necked flask equipped with magnetic stirrer, oil bath, condenser and drying tube were added 16 (2.7 g, 13 mmol) and polyphosphoric acid (40 mL). The mixture was stirred at 65-75 ºC for 1 h. After that, the warm red solution was slowly poured into ice (16 g) and then was stirred for 20 min. The aqueous phase was extracted with Et₂O. The combined organic layers were washed with water, brine and then dried with anhydrous MgSO₄. After the solvent removal under reduced pressure, the desired product was purified by Kugelrohr distillation (horizontal distillation) (0.7 mmHg, 175 ºC) to afford the tetralone 9a (2.1 g, 11 mmol, 86%) as a yellow solid: mp: 57.9-58.5 ºC; ¹H NMR (300 MHz) d: 2.06-2.15 (m, 2H), 2.34 (s, 3H), 2.62 (t, J 6.1 Hz, 2H), 2.97 (t, J 6.1 Hz, 2H), 3.77 (s, 3H), 7.14 (dd, J 8.0 and 0.5 Hz, 1H), 7.75 (d, J 8.0 Hz, 1H); ¹³C NMR (75 MHz) d: 16.5, 22.9, 23.4, 38.8, 59.9, 122.8, 129.1, 132.3, 137.1, 137.5, 155.8, 198.0. IV (film) n_máx/cm^-1: 1682; LRMS (EI) m/z (%): 190 (M^+·,100), 175 (33), 134 (39); Anal. calcd for C₁₂H₁₄O₂: C, 75.76; H, 7.46. Found: C, 75.60; H, 7.20.

General procedure for reduction of the tetralones 1a-10a

Preparation of 1,2,3,4-tetrahydro-6-methoxynaphthalen-1-ol (3b)⁴³

To a solution of 1,2,3,4-tetrahydro-6-methoxynaphthalen-1-one (3a) (0.36 g, 2.0 mmol) in anhydrous MeOH (6 mL) at 0 ºC and under N₂, NaBH₄ (0.15 g, 4.0 mmol, 2 eq.) was portionwise added. The mixture was allowed to reach room temperature and then was stirred for 2 h. The reaction mixture was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by silica flash chromatography (hexanes:AcOEt, 7:3 as eluent), to give 3b as a colorless oil (0.32 g, 1.8 mmol, 90%); ¹H NMR (300 MHz) d: 1.68-2.03 (m, 5H), 2.63-2.84 (m, 2H), 3.78 (s, 3H), 4.72-4.74 (m, 1H), 6.61-6.62 (d, J 3 Hz, 1H), 6.76 (dd, J 9 Hz and J 3 Hz, 1H), 7.32 (d, J 9 Hz, 1H). The alcohol 3b is unstable and decomposed before fully characterization.

1,2,3,4-tetrahydro-5-methoxy-6-methylnaphthalen-1-ol (9b)

Using the general procedure described for 3b, the 1,2,3,4-tetrahydro-5-methoxy-6-methylnaphthalen-1-one (9a) (0.36g, 1.9 mmol) was converted into 9b (0.34 g, 1.8 mmol, 95%); ¹H NMR (300 MHz) d: 1.71-2.06 (m, 4H), 2.26 (s, 3H), 2.58-2.68 (m, 1H), 2.80-2.90 (m, 1H), 3.70 (s, 3H), 4.72-4.75 (m, 1H), 7.03 (dd, J 7.8 and 0.6 Hz, 1H), 7.11 (d, J 7.8 Hz, 1H); ¹³C NMR (75 MHz) d: 16.0, 18.3, 23.4, 31.9, 59.4, 68,0, 124.3, 128.8, 129.9, 130.5, 138.2, 156.0. IR (film) n_máx/cm^-1: 3237; LRMS (EI) m/z (%): 192 (M^+·, 100), 177 (74), 91 (75). Anal. calcd for C₁₂H₁₆O₂: C, 74.97; H, 8.39. Found: C, 74.68; H, 7.91.

1,2,3,4-tetrahydro-4,7-dimethyl-6-methoxynaphthalen-1-ol (10b)

Using the general procedure described for 3b, except for the amount of NaBH₄ (5 eq., 0.10 g, 2.7 mmol), 1,2,3,4-tetrahydro-4,7-dimethyl-6-methoxynaphthalen-1-one (10a) (0.11 g, 0.54 mmol) was converted into 10b (0.10 g, 0.51 mmol, 95%) as a colorless oil. The alcohol 10b is unstable and decomposed before fully characterization.

Control of the bioreduction of a-tetralones

Tetralones 1a-10a and the corresponding tetralols 1b-10b obtained from bioreduction were compared with the racemic mixtures previously analyzed. GC conditions: Injector: 250 ºC, Detector: 350 ºC, Oven: 120-180 º C (120 min), Rate: 0.5 ºC/min, flow: 1.4 mL/min; Pressure of H_2(g): 10 psi, Constant pressure, Split ratio 1:50. t_R=retention time (min).

General procedures for biorreduction of the tetralones 1a-10a with Daucus carota root

Conditions A: Tetralones 1a-10a (20 mg) were dissolved in a mixture of acetonitrile (0,5 mL) and ethanol (0,5 mL) and the solutions obtained were added to a suspension of freshly cut carrot root (10 g, thickness of 0,5 cm, previously sterilized by washing in 2% NaOCl) in 40 mL of phosphate buffer (0,1 M). The reaction mixtures were incubated in an orbital shaker (180 rpm) at 32 ºC for 4 days. A collected aliquot of the reactional mixture was centrifuged and the aqueous medium was extracted with EtOAc. The solvent was removed and the residual product was directly analyzed by GC. The results are summarized in Table 1.

Conditions B: identical, except for carrot (20 g) and buffer (80 mL).

Quiral-GC data

1a: t_R= 27.9 min; (R)-1c: t_R=35.09 min (minor); (S)-1c: t_R=35.63 min (major).

2a: t_R=65.2 min; (S)-2b: t_R=75.20 min (minor); (R)-2b: t_R=76.32 min (major).

3a: t_R=77.0 min; 3b: t_R=79.45 min (minor) and t_R=80.48 min (major)

4a: t_R=62.5 min; (R)-4c: t_R=72.67 min (minor); (S)-4c: t_R=73.34 min (major);

5a: t_R=59.9 min; (R)-5c: t_R=66.50 min (minor); (S)-5c: t_R=67.52 min (major);

(±)-7a: 35.0 and 35.7 min; cis-7c': t_R= 41.88 min (minor) and 43.60 (major); trans-7c: 42.28 min (minor) and 44.32 min (major)

8a: t_R=74.9 min; 8c: t_R= 80.00 min (minor) and 81.03 min (major).

9a: t_R=73.0 min; 9b: t_R=81.36 min (minor) and 82.35 min (major).

ACKNOWLEDGMENT

We are indebted to FAPESP, CAPES and CNPq, for financial support, and to Prof. Dr. L. F. Silva Jr., for fruitful discussions. We would like to thank M. V. Craveiro for the critical reading of the manuscript.

Recebido em 15/1/08; aceito em 27/2/08; publicado na web em 2/4/09

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†

in memorian, 1948-2007.

‡

This article is dedicated to Prof. Helena M. C. Ferraz

Publication Dates

• Publication in this collection
  16 June 2008
• Date of issue
  2008

History

• Accepted
  27 Feb 2008
• Received
  15 Jan 2008