Reinvestigation of the Absolute Configurations of Chiral Î²

Article pubs.acs.org/JAFC

Reinvestigation of the Absolute Configurations of Chiral β‑Mercaptoalkanones Using Vibrational Circular Dichroism and 1H NMR Analysis Christiane Kiske,† Svenja Nörenberg,† Miriam Ecker,† Xingyue Ma,† Tohru Taniguchi,‡ Kenji Monde,‡ Wolfgang Eisenreich,§ and Karl-Heinz Engel*,† †

Lehrstuhl für Allgemeine Lebensmitteltechnologie, Technische Universität München, Maximus-von-Imhof-Forum 2, D-85354 Freising-Weihenstephan, Germany ‡ Frontier Research Center for Post-Genome Science and Technology, Faculty of Advanced Life Science, Hokkaido University, Kita 21 Nishi 11, Sapporo 001-0021, Japan § Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstraße 4, D-85747 Garching, Germany S Supporting Information *

ABSTRACT: The absolute configurations of chiral β-mercaptoalkanones were previously assigned on the basis of the 1H NMR anisotropy method using (S)-2-methoxy-2-(1-naphthyl)propionic acid ((S)-MαNP) as the chiral auxiliary. This study presents a reinvestigation of the configurations of 4-mercapto-2-pentanone 1, 4-mercapto-2-heptanone 2, and 2-mercapto-4-heptanone 3. Enantiomers of 1, 2, and 3 were obtained by lipase-catalyzed hydrolyses of the respective acetylthioalkanones. Upon derivatization with (S)-MαNP, the configurations of the reaction products were deduced based on the order of the HPLC elution of the diastereoisomeric thioesters, assuming that the sector rule previously developed for secondary alcohols is also valid for thiols. In addition, the configurations were experimentally determined by vibrational circular dichroism (VCD) and 1H NMR analyses after esterification with (R)-hydratropic acid (HTA) and 2-methoxy-2-phenylacetic acid (MPA). The assignments of the configurations using VCD and NMR analyses of HTA- and MPA-thioesters were in agreement. However, they were opposite to those deduced for (S)-MαNP thioesters via the sector rule. Consequently, the formerly assigned configurations of βmercaptoalkanones deduced via investigation of (S)-MαNP-derivatives have to be revised. KEYWORDS: 4-mercapto-2-alkanones, 2-mercapto-4-alkanones, absolute configuration, lipase, VCD, 1H NMR spectroscopy

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INTRODUCTION Sulfur-containing volatiles are important flavor compounds in foods and beverages due to their low odor thresholds and distinct odor qualities.1−4 β-Mercaptoalkanones are representatives of naturally occurring polyfunctional thiols; for example, 4-mercapto-2-heptanone and 2-mercapto-4-heptanone have been isolated from cooked red bell pepper, and the C5homologue 4-mercapto-2-pentanone has been reported in aged cheddar cheese.5−7 Wakabayashi et al.8 previously determined the absolute configurations of 4-mercapto-2-alkanones by using the 1H HMR anisotropy method in combination with enzymecatalyzed kinetic resolutions of the corresponding 4-acetylthio-2-alkanones. To this end, the mercaptoalkanones were reacted with (S)-2-methoxy-2-(1-naphthyl)propionic acid ((S)MαNP); the resulting diastereoisomeric derivatives were separated via HPLC, and the configurations were assigned by applying the sector rule as described earlier for secondary alcohols.9−11 On the basis of these results, the relationship between the chain lengths and the odor thresholds and odor qualities of the enantiomers of 4-mercapto-2-alkanones and 4acetylthio-2-alkanones has been investigated.12 Nörenberg et al.13 also used the approach to determine the influence of the stereochemistry on the sensory properties of 4-mercapto-2heptanol and its acetyl derivatives. © 2016 American Chemical Society

Vibrational circular dichroism (VCD) has been described as useful tool for the determination of the absolute configurations of flavor compounds.14,15 A preliminary test of the suitability of this technique to determine the configurations of the enantiomers of 2-mercapto-4-heptanone indicated that the results were inconsistent with those obtained by applying the assignment via (S)-MαNP derivatives as reported by Wakabayashi et al.8 This prompted us to perform a thorough reinvestigation of the assignments of the configurations of βmercaptoalkanones using the C5-compound 4-mercapto-2pentanone 1, the C7-representative 4-mercapto-2-heptanone 2, and its positional isomer 2-mercapto-4-heptanone 3 as examples (Figure 1). The assignments of the configurations based on the 1H NMR anisotropy method using (S)-MαNP as the chiral auxiliary should be compared to the results obtained by applying VCD and by investigation of the respective diastereoisomeric thioesters of (R)-hydratropic acid and 2methoxy-2-phenylacetic acid.16,17 Received: Revised: Accepted: Published: 8563

August 16, 2016 October 25, 2016 October 25, 2016 October 25, 2016 DOI: 10.1021/acs.jafc.6b03670 J. Agric. Food Chem. 2016, 64, 8563−8571

Article

Journal of Agricultural and Food Chemistry

sulfate, and the solvent was evaporated. The crude product was purified by column chromatography on silica gel by elution with a mixture of n-hexane/Et2O 3/1 (v/v) for 1 and 4/1 (v/v) for 2 and 3; the obtained fractions were checked by TLC. 1: yield: 54.0%, purity: 96.7% (by GC). 2: yield: 62.8%, purity: 97.0% (by GC). 3: yield: 79.3%, purity: 91.6% (by GC). LRI: 1568 (DB-WAX), 1076 (DB-1). Mass spectrometric and NMR data were in accordance with those reported by Naef et al.5 (R)-2-Heptanethiol. The synthesis was performed according to Simian et al.18 starting from p-toluenesulfonyl chloride (1.1 equiv) and (S)-2-heptanol (3 mmol). The resulting 2-(p-toluenesulfonyl)heptane (yield: 96.1%) was used for the synthesis of 2-(acetylthio)heptane without further purification. The reaction of 2-(p-toluenesulfonyl)heptane (5.3 mmol) and potassium thioacetate (13.3 mmol, 2.5 equiv) yielded 2-(acetylthio)heptane (66.0%; purity: 58.5% (by GC)). The reduction of this intermediate (0.92 mmol) with lithium aluminum hydride (4.5 equiv) in dry Et2O resulted in (R)-2-heptanethiol (yield: 83.7%, purity: 80.9% (by GC); LRI: 1147 on DB WAX). Mass spectrometric and NMR data were in accordance with those previously reported.19 Lipase-Catalyzed Kinetic Resolutions. Preparation of enantiomerically enriched 1 and 3 by enzyme-catalyzed hydrolysis of the respective acetylthioalkanones 4 and 6 was carried out as follows: the acetylthioalkanone (425 mg) was mixed with 25 mL of 50 mM potassium phosphate buffer (pH 7.4); CAL-B* (500 mg) was added, and the mixture was stirred magnetically with a Teflon stir bar at RT. After defined reaction times, the mixture was filtered and extracted with Et2O (3 × 15 mL). The combined organic layers were dried with sodium sulfate and filtered, and the solvent was removed under reduced pressure. The enantiomerically enriched mercaptoalkanone resulting from hydrolysis of the acetylthioalkanone (enantiomer E1) was separated from the remaining substrate via column chromatography on silica gel by elution with a mixture of n-hexane/Et2O 3/1 (v/v) for 1 and 4/1 (v/v) for 3; the obtained fractions were checked by TLC. To obtain the opposite enantiomer of the mercaptoalkanone (enantiomer E2), the remaining acetylthioalkanone substrate was reacted with 10 mL of acidified methanol (pH 1−2) under reflux for 24 h. The reaction mixture was cooled to RT, diluted with 30 mL of Et2O, and washed with water (3 × 10 mL). After being dried with sodium sulfate, the solvent was removed under reduced pressure to yield the mercaptoalkanone enantiomer. The preparation of enantiomerically enriched 2 by enzymecatalyzed kinetic resolution was carried out as follows: 5 (425 mg) was mixed with 25 mL of 50 mM potassium phosphate buffer (pH 7.4); either PPL or ANL (500 mg) was added, and the mixture was stirred magnetically with a Teflon stir bar at RT. After defined reaction times, the mixture was filtered and extracted with Et2O (3 × 15 mL). The reaction mixture with PPL was additionally centrifuged (20 000 rpm, 5 min) before filtration. The combined organic layers were dried with sodium sulfate and filtered, and the solvent was removed under reduced pressure. After chromatography on silica gel by elution with a mixture of n-hexane/Et2O 4/1 (v/v), the enantiomers were obtained by reaction of the remaining substrate with 10 mL of acidified

Figure 1. Structures of investigated mercaptoalkanones 1−3 and the respective acetylthioalkanones 4−6.

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MATERIALS AND METHODS

Chemicals. 3-Penten-2-one, ethyl butyrylacetate, p-toluenesulfonyl chloride, lithium aluminum hydride, (S)- and (R)-2-heptanol, 4(dimethylamino)pyridine (DMAP), N,N′-dicyclohexylcarbodiimide (DCC), (R)-(−)-2-methoxy-2-phenylacetic acid ((R)-MPA), lipases from Candida antarctica (B lipase, adsorbed on a macroporous acrylic resin, CAL-B*), porcine pancreas (Type II, PPL), Aspergillus niger (ANL), and deuterochloroform (CDCl3) were purchased from SigmaAldrich (Steinheim, Germany). Thioacetic acid and acetaldehyde were obtained from Merck Schuchardt OHG (Hohenbrunn, Germany), and 3-hepten-2-one and (S)-(+)-2-methoxy-2-phenylacetic acid ((S)MPA) were obtained from Alfa Aesar (Karlsruhe, Germany). Spotassium thioacetate, (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid ((S)-MαNP), (R)-(−)-2-methoxy-2-(1-naphthyl)propionic acid ((R)-MαNP), and (R)-(−)-2-phenylpropionic acid ((R)-HTA) were purchased from TCI Europe (Zwijndrecht, Belgium). Silica gel (NormaSil60, 40−63 μm) was purchased from VWR Chemicals (Leuven, Belgium). Syntheses. Acetylthioalkanones. 4-Acetylthio-2-pentanone 4 and 4-acetylthio-2-heptanone 5 were synthesized by Michael-type addition of thioacetic acid (1.1 equiv) to the respective alkenone (10−20 mmol) as previously described.8,12 The crude products were purified by column chromatography on silica gel by elution with a mixture of nhexane/Et2O 3/1 (v/v) for 4 and 4/1 (v/v) for 5; the obtained fractions were checked by TLC. 4: yield: 94.5%, purity: 91.0% (by GC). 5: yield: 102.3%, purity: 94.5% (by GC). Chromatographic and mass spectrometric data were in accordance with those reported by Wakabayashi et al.8,12 For the synthesis of 2-acetylthio-4-heptanone 6, 2-hepten-4-one was synthesized according to the procedure described by Naef et al.5 starting from 78.23 mmol ethyl butyrylacetate. The obtained product (yield: 44.5%, purity: 57.4% (by GC)) was used for the subsequent addition of thioacetic acid as described above. 6: yield: 89.6%, purity: 95.5% (by GC); linear retention index (LRI): 1918 (DB-WAX), 1315 (DB-1). Mass spectrometric data corresponded to those published by Naef et al.5 Mercaptoalkanones. Fifteen milliliters of methanol (MeOH) acidified with 2.5 mL of 2N sulfuric acid (H2SO4, pH 1−2) was added to acetylthioalkanone, and the mixture was stirred for 24 h at 83 °C under reflux. After the mixture was cooled to room temperature (RT, 25 °C) and diethyl ether (70 mL, Et2O) was added, the organic phase was washed with water (3 × 20 mL) and dried over sodium

Table 1. Preparation of Mercaptoalkanone Enantiomers via Lipase-Catalyzed Hydrolysis of Acetylthioalkanones starting compounda

obtained enantiomerb

configurationc, optical rotation

lipased

reaction time (h)

conversione (%)

eef (%)

puritye (%)

yieldg (%)

4

1-E1 1-E2 2-E2 2-E2 3-E1 3-E2

(R)-(−) (S)-(+) (R)h (S)-(+) (R)-(−) (S)-(+)

CAL-B* CAL-B* PPL ANL CAL-B* CAL-B*

1 8 8 16 0.5 4

18 60 86 83 44 61

91.2 92.6 92.5 84.3 94.0 88.3

98.3 95.2 96.0 98.0 93.0 96.8

17.9 5.4 0.9 3.1 9.5 4.8

5 6

a

425 mg. bNumbering refers to the enantiomers obtained either as direct hydrolysis product (E1) or via the remaining substrate (E2). Configurations were determined via VCD and 1H NMR analysis of HTA and MPA thioesters; for optical rotations, see Materials and Methods. d 500 mg. eDetermined via GC (DBWAX). fEnantiomeric excess determined via GC (chiral stationary phases). gMolar yields. hOptical rotation not determined due to low yield. c

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DOI: 10.1021/acs.jafc.6b03670 J. Agric. Food Chem. 2016, 64, 8563−8571

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mercapto-2-pentanone, 4-mercapto-2-heptanone, and 2-mercapto-4heptanone and for the (R)- and (S)-MPA thioesters of (R)-2heptanethiol and (R)-2-mercapto-4-heptanone, hexane/ethyl acetate (90/10, v/v) at 2.5 mL/min. NMR Spectroscopy. CDCl3 was used as the solvent. 1H NMR and 13 C NMR spectra were recorded at 500 and 126 MHz, respectively with Avance500 spectrometers. 1H-detected experiments were done with an inverse 1H/13C probehead. Direct 13C measurements were performed with a QNP 13C/31P/29Si/19F/1H cryoprobe. The experiments were done in full automation using standard parameter sets of the TOPSPIN 3.0 software package (Bruker, Bremen, Germany). 13C NMR spectra were recorded in proton-decoupled mode. The spectra were recorded at 27 °C. All signals were assigned by proton−proton and proton−carbon correlation experiments (e.g., COSY, HSQC, and HMBC). Data processing was typically done with the MestreNova software. VCD Spectroscopy. VCD and IR spectra were measured on a BioTools Chiralir-2X spectrometer (BioTools, Jupiter, Florida) for 6752 and 150 scans, respectively. All spectra were recorded in CDCl3 using a 100 μm CaF2 cell at a resolution of 8 cm−1 at ambient temperature. All spectroscopic data were corrected by a solvent spectrum obtained under identical experimental conditions without correction based on the percent ee of each sample and presented as Δε and ε (both in M−1 cm−1). CDCl3 used for VCD measurements was purchased from Cambridge Isotope Laboratories (Tewksbury, MA). Computation. Molecular mechanics force field (MMFF) MonteCarlo search was performed on SPARTAN′10 software,21 and density functional theory (DFT) calculations were carried out using the Gaussian 09 package.22 All calculations were conducted without considering solvent effects. Theoretical calculations of VCD and IR spectra started with a preliminary MMFF search using the (R)-enantiomers, whose configuration was arbitrarily chosen for each compound as the starting geometries. The obtained conformers within 9 kJ/mol from the most stable of each compound (7, 27, and 53 conformers for 1, 2, and 3, respectively) were further optimized using the DFT/B3LYP/6311+G(2df,2p) level of theory. VCD and IR spectra of the resultant stable conformers were calculated at the DFT/B3LYP/6-311+G(2df,2p) level and simulated with Lorentzian lineshapes of 10 cm−1 width. The calculated frequencies ν were scaled with the equation of 0.9894ν − 0.0000104ν2. Final spectra were obtained based on the Boltzmann population average of the spectrum of each conformer. GC Analyses. Capillary Gas Chromatography (GC-FID). The column used was a 30 m × 0.25 mm i.d., 0.5 μm, DB-WAX (J&W Scientific, Waldbronn, Germany) installed into a HP5890 A gas chromatograph (Hewlett-Packard INC, Waldbronn, Germany) equipped with a split/splitless injector (215 °C, split ratio of 1/10) and an FID (350 °C); temperature program: from 40 °C (5 min hold) to 240 °C (30 min hold) at 4 °C/min; carrier gas: hydrogen at a constant pressure of 150 kPa. A 30 m × 0.25 mm i.d., 1.0 μm, DB-1 column (J&W Scientific) was installed into a 6890N instrument (Agilent Technologies, Waldbronn, Germany) equipped with a split/splitless injector (230 °C, split ratio of 1/10) and an FID (300 °C); temperature program: from 60 °C (5 min hold) to 250 °C (5 min hold) at 5 °C/min; carrier gas: hydrogen at a constant pressure of 72 kPa. Linear retention indices (LRI) were determined according to van den Dool and Kratz23 using C8−C40 n-alkane standard solutions (Fluka). Enantioselective Analysis. For the enantioselective analysis of 4mercapto-2-pentanone and 4-mercapto-2-heptanone as well as their respective acetylthioalkanones, a 30 m × 0.25 mm i.d., 0.25 μm, CycloSil-B column with 30% heptakis(2,3-di-O-methyl-6-O-tert-butyl dimethylsilyl)-β-cyclodextrin in DB-1701, (Agilent J&W GC columns) was used in a 6890N chromatograph (Agilent Technologies) equipped with a split/splitless injector (230 °C, split ratio of 1/10) and an FID (300 °C); temperature program: from 75 °C (0 min hold) to 120 °C (0 min hold) at 0.5 °C/min and from 120 to 180 °C (5 min hold) at 2 °C/min; carrier gas: hydrogen at a constant pressure of 72 kPa.

methanol (pH 1−2) under reflux for 24 h. The reaction mixture was cooled to RT, diluted with 30 mL of Et2O, and washed with water (3 × 10 mL). After being dried with sodium sulfate, the solvent was removed under reduced pressure to yield both enantiomers (2-E2-PPL and 2-E2-ANL). In Table 1, the employed enzymes, reaction times, conversion rates, enantiomeric excesses, purities, and yields are presented. Formation of Diastereoisomers with Chiral Auxiliaries. (S)and (R)-MαNP Thioesters and Esters. A solution of DCC (2 equiv) and DMAP (1 equiv) in dichloromethane was added to a solution of (S)- or (R)-MαNP (1 equiv) and the respective mercaptoalkanone, 2heptanethiol, or 2-heptanol (0.0868 mmol) in dichloromethane. The mixture was stirred at RT for 20 h. The reaction was quenched with 0.2 mL of water. After the mixture was stirred for another hour, 1 mL of dichloromethane and sodium sulfate were added; the solution was filtered and dried under a N2 stream. The residue was dissolved in 5 mL of ethyl acetate, dried with sodium sulfate, and evaporated at a maximum temperature of 28 °C. The residue was separated by semipreparative HPLC. (S)-MαNP thioester of 1: peak I, 7: 8.5 mg, yield: 29.6%, peak II, 8: 7.1 mg, yield: 24.7%; (S)-MαNP thioester of 2: peak I, 9: 5.0 mg, yield: 16.0%, peak II, 10: 11.7 mg, yield: 37.7%; (S)-MαNP thioester of 3: peak I, 11: 7.0 mg, yield: 22.5%, peak II, 12: 9.8 mg, yield: 30.3%; (R)-MαNP thioester of (R)-2-mercapto-4heptanone, 13: 11 mg, yield: 36.8%; (R)-MαNP ester of (R)-2heptanol, 14: 17.5 mg, yield: 64.2%; (S)-MαNP ester of 2-heptanol: peak I, 15: 9.6 mg, yield: 35.1%, peak II, 16: 11.8 mg, yield: 43.2%; (S)-MαNP thioester of (R)-2-heptanethiol, 17: 3.4 mg, yield: 11.9%; (R)-MαNP thioester of (R)-2-heptanethiol, 18: 13.4 mg, yield: 46.8%. (R)-Hydratropic Acid (HTA) Thioesters. In a 50 mL round-bottom flask equipped with a drying tube filled with calcium chloride, (R)HTA (1.67 mmol) and 1.1 mL oxalyl chloride were stirred at RT. After 10 min, the excess oxalyl chloride was removed by rotary evaporation; the residue was mixed with toluene (3 × 3 mL), and the solvent was evaporated. The mixture was suspended in 2 mL of chloroform and 0.6 mmol of the respective mercaptoalkanone enantiomer dissolved in 3 mL of chloroform was added dropwise. The glassware was rinsed with 3 mL of chloroform. The reaction mixture was heated at 55 °C under reflux, and the conversion was checked by GC. After 48−72 h, the sample was cooled and diluted with 20 mL of water. The mixture was extracted with Et2O (3 × 15 mL), and the organic phase was washed with water (2 × 10 mL), dried with sodium sulfate, and evaporated. The product was purified by semipreparative HPLC: (R)-HTA thioester of 1-E1, 19: 84.2 mg, yield: 65.5%, 1-E2, 20: 98.2 mg, yield: 70.9%; (R)-HTA thioester of 2-E2-PPL, 21: 74.6 mg, yield: 75.0%, 2-E2-ANL, 22: 50.3 mg, yield: 50.0%; (R)-HTA thioester of 3E1, 23: 40.2 mg, yield: 32.6%, 3-E2, 24: 30.5 mg, yield: 28.9%; 1H NMR data are presented in Table 3. (S)- and (R)-MPA Thioesters. The derivatization was performed according to Porto et al.20 using 0.0868 mmol (1 equiv) of the thiol or mercaptoalkanone, 0.1042 mmol (1.2 equiv) of the respective (R)- and (S)-MPA, 0.1736 mmol (2 equiv) of DCC, and DMAP (catalytic) in 1 mL of dry dichloromethane. The reaction mixtures were stirred for 2 h under RT. After work-up, purification was achieved by semipreparative HPLC. (S)-MPA thioester of (R)-2-heptanethiol, 25: 17.0 mg, yield: 69.8%; (R)-MPA thioester of (R)-2-heptanethiol, 26: 26.7 mg, yield: 109.6%; (S)-MPA thioester of (R)-2-mercapto-4-heptanone, 27: 7.7 mg, yield: 30.1%; (R)-MPA thioester of (R)-2-mercapto-4-heptanone, 28: 14.3 mg, yield: 56.0%. High Performance Liquid Chromatography (HPLC). Semipreparative separations of the diastereoisomers of (S)-MαNP and (R)HTA thioesters of mercaptoalkanones were carried out on a Dionex HPLC system (UltiMate 3000 series, Dionex, Germering, Germany) equipped with a 3100 wavelength detector set at 254 nm using a 250 × 8 mm i.d. Nucleosil 50−5 column (CS Chromatography, Langerwehe, Germany). Isocratic elution was performed at 30 °C with the following eluents and flow rates: for (S)-MαNP thioesters of 4-mercapto-2pentanone (RS: 1.66, α: 1.15) and 4-mercapto-2-heptanone (RS: 1.41, α: 1.18), hexane/isopropanol (96/4, v/v) at 2 mL/min; for (S)-MαNP thioester of 2-mercapto-4-heptanone (RS: 2.94, α: 1.19), hexane/ethyl acetate (20/1, v/v) at 3.5 mL/min; for (R)-HTA thioesters of 48565


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Journal of Agricultural and Food Chemistry 2-Mercapto-4-heptanone and 2-acetylthio-4-heptanone were separated on a 25 m, 0.25 mm i.d., 0.25 μm MEGA-DEX DET-Beta column with diethyl tert-butylsilyl-β-cyclodextrin (Mega s.n.c., Legnano, Italy) installed into a 6890N chromatograph (Agilent Technologies) equipped with a split/splitless injector (230 °C, split ratio of 1/10) and an FID (300 °C); temperature program: from 80 °C (0 min hold) to 115 °C (0 min hold) at 1.5 °C/min and from 115 to 180 °C (10 min hold) at 2 °C/min; carrier gas: hydrogen at a constant pressure of 72 kPa. Gas Chromatography−Mass Spectrometry (GC−MS). A 30 m × 0.25 mm i.d., 0.5 μm, DB-WAXetr fused silica capillary column (J&W Scientific) installed into a GC 8000TOP gas chromatograph directly coupled to a Fisons MD8000TOP mass spectrometer (Thermo Fisher Scientific, Dreieich, Germany) was used for compound identifications. The temperature was programmed from 40 °C (5 min hold) to 240 °C (25 min hold) at 4 °C/min. A split/splitless injector (220 °C, split ratio 1/50) was used, and the carrier gas was helium at a constant inlet pressure of 75 kPa. The mass spectra in the electron impact mode (EI) were measured at 70 eV in a scan range from m/z 30−250. The source temperature was 200 °C, and the interface temperature 240 °C. Data acquisition was done via Xcalibur software version 1.4 (Thermo Fisher Scientific). Determination of Optical Rotations. Optical rotations were measured on a Polartronic-E polarimeter (Schmidt & Haensch, Berlin, Germany) fitted with a measuring cell (path length 1 dm) and a sodium lamp (wavelength 589 nm). Samples were diluted in ethanol, and the measurements were performed at a temperature of 24 °C. 1E1: [α]D −63.6; concentration (c): 1.89 g/100 mL; GC purity (p): 94.1%; ee: 87.7%. 1-E2: [α]D +51.7; c: 1.10; p: 97.9; ee: 98.3. 2-E2ANL: [α]D +22.7; c: 1.48; p: 73.0; ee: 89.3. 3-E1 [α]D −48.1; c: 1.61; p: 90.8; ee: 94.2. 3-E2 [α]D +51.4; c: 2.05; p: 98.6; ee: 94.0.

NMR; the data are presented in Table 2. For determining the absolute configurations, the sector rule was applied as previously described for secondary alcohols.10,11 Following this rule, the (S)-MαNP ester group is fixed in the down/front side, and the methine proton of the secondary alcohol is fixed in the down/rear side (Figure 3A). The protons with a negative Δδ are placed on the left side, and the protons with a positive Δδ are placed on the right side. Consequently, the absolute configuration of the compound eluted as LC-peak I is defined as Δδ = δ (second peak) − δ (first peak). When applying this rule shown in Figure 3A to the (S)-MαNP thioesters of 1, the Δδ values of H-1 and H-3 are positive (0.04 and 0.04, respectively) and are placed on the right side, whereas the Δδ value for H-5 is negative (−0.01) and is placed on the left side (Figure 3A). This result suggested the (S)-configuration at the C-4 position of the first eluting compound (LC-peak I, 7). The same result was found for the (S)-MαNP thioesters of the mercaptoalkanone 2. For 3, the configuration at C-2 was again deduced as (S) for the first eluting fraction (LC-peak I, 11). In the next step, enantiomerically enriched mercaptoalkanones were obtained by lipase-catalyzed kinetic resolutions of the respective racemic acetylthioalkanones. As demonstrated via GC analysis using chiral stationary phases, the opposite enantiomers of 1 and 3 were obtained using CAL-B* as the hydrolysis products (enantiomers E1) and for the remaining substrates (enantiomers E2), respectively. As example, the reaction sequence for the lipase-catalyzed hydrolysis of 4 is presented in Figure 4. No commercially available lipase preparation was found suitable to produce one of the enantiomers of 2 in sufficiently high optical purity as the hydrolysis product of the respective thioacetate 5. Therefore, the two opposite enantiomers were obtained via reflux with MeOH/H2SO4 from the substrate remaining after the kinetic resolution using either lipase from A. niger (2-E2-ANL) or porcine pancreas (2-E2-PPL) as a biocatalyst (Table 1). Each enantiomer of the β-mercaptoalkanones obtained by lipase-catalyzed kinetic resolution was then reacted with (S)MαNP. By a comparison of the order of elution of the (S)MαNP thioesters of racemic (Figure 2A) and enantiomerically enriched 1, 2, and 3, the absolute configurations of the enantiomers were deduced. The enantiomers 1-E1, 2-E2-PPL, and 3-E1 were tentatively assigned as (S), and the enantiomers 1-E2, 2-E2-ANL, and 3-E2 were tentatively assigned as (R). To confirm these assignments of the absolute configurations, the obtained enantiomers were also subjected to VCD experiments. A preliminary MMFF conformational search and subsequent DFT/B3LYP/6-311+G(2df,2p) optimization were conducted for the arbitrarily chosen (R)-enantiomer of 1, resulting in 5 stable conformers within 1.59 kcal/mol of the most stable one (Figure 5A). VCD and IR spectra were calculated for these conformers at the DFT/B3LYP/6-311+G(2df,2p) level of theory. As shown in Figure 5B, the overall features of VCD spectra were very sensitive to the molecular conformations.24−26 In particular, the conformers 1(00)−1(02) exhibited patterns completely different than those of 1(03) and 1(06): the former exhibited a positive CO stretching band at ∼1730 cm−1, while the latter showed a negative band. The comparison of the conformations and the VCD spectra for each conformer indicates that the sign of the CO stretching is highly influenced by the rotation of the C3−C4 bond. On the other hand, the differences in the theoretical IR spectra of each conformer were rather subtle (Figure 5C). The final VCD and

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RESULTS AND DISCUSSION Acetylthioalkanones 4−6 were synthesized by Michael-type addition of thioacetic acid to 3-penten-2-one, 3-hepten-2-one, and 2-hepten-4-one, respectively, and transformed into mercaptoalkanones 1−3 by refluxing with methanol. These racemic mercaptoalkanones were reacted with (S)-MαNP, and the resulting diastereoisomeric thioesters were separated and isolated by semipreparative HPLC using a silica gel column. As an example, the separation of the (S)-MαNP derivatives of 1 is shown in Figure 2A. The diastereoisomeric thioesters (LC-peak I, 7 and II, 8, respectively) were collected and analyzed by

Figure 2. (A) HPLC separation of (S)-MαNP thioesters of racemic 1. (B) HPLC separation of (S)-MαNP thioester of (R)-(−)-4-mercapto2-pentanone, (S,R)-7. (C) HPLC separation of (S)-MαNP thioester of (S)-(+)-4-mercapto-2-pentanone, (S,S)-8. 8566


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Table 2. 1H NMR Data and Δδ Values of (S)-MαNP Thioesters of 4-Mercapto-2-pentanone (1), 4-Mercapto-2-heptanone (2), and 2-Mercapto-4-heptanone 3 4-mercapto-2-pentanone (1) H 1 2 3 3′ 4 5 6 6′ 7 a

LC-peak Ia 7

LC-peak IIa 8

1.99 (s)

2.03 (s)

2.66 2.52 3.79 1.24

2.70 2.52 3.79 1.23

(dd, 16.7, 4.9) (dd, 16.6, 8.5) (m) (d, 6.9)

(dd, 16.6, 5.4) (dd, 16.6, 8.1) (m) (d, 6.9)

4-mercapto-2-heptanone (2) Δδ

LC-peak Ia 9

0.04

1.97 (s)

2.03 (s)

2.61 (d, 2.1) 2.60 (d, 3.1) 3.75 (m) 1.51 (m) 1.33 (m) 1.26 (m) 0.8 (t, 7.3)

2.66 2.59 3.75 1.50 1.35 1.25 0.77

0.04 0 0 −0.01

LC-peak IIa 10

(dd, 16.5, 6.4) (dd, 18.8, 7.0) (m) (m) (m) (m) (t, 7.3)

2-mercapto-4-heptanone (3) Δδ 0.06 0.05 −0.01 0 −0.01 0.02 −0.01 −0.03

LC-peak Ib 11 1.24 3.79 2.64 2.49

LC-peak IIb 12

(d, 7.0) (m) (dd, 16.6, 4.9) (dd, 16.6, 8.6)

1.22 3.83 2.68 2.49

(d, 6.8) (m) (m) (dd, 16.5, 8.2)

Δδ −0.02 0.04 0.04 0

2.22 (td, 7.3, 3.0) 1.46 (q, 7.4)

2.27 (td, 7.2, 1.5) 1.49 (q, 7.4)

0.05 0.03

0.77 (t, 7.4)

0.81 (m)

0.04

Eluent: hexane/isopropanol 96/4 (v/v). bEluent: hexane/ethyl acetate 20/1 (v/v).

The peak positions, relative intensities, and the signs of each signal in the observed VCD spectrum of 1-E1 showed an excellent agreement with those calculated for (R)-1. Thus, these VCD results suggested the absolute configurations of 1E1 and 1-E2 as (R) and (S), respectively, which are opposite to those deduced from the NMR analysis using (S)-MαNP. The stereochemistry of 2 was also studied by VCD spectroscopy in a similar manner. DFT optimization of arbitrarily chosen (R)-2 produced many more conformers compared to 1 because of its flexible longer alkyl chain. Twelve conformers within 1.52 kcal/mol of the most stable one were taken into account for VCD and IR calculations. The resultant final spectra were compared with the observed spectra of 2-E2PPL and 2-E2-ANL (Figure 6B). Unlike the VCD spectra for 1, spectra with high S/N were obtained for both enantiomers of 2 at concentrations of ca. 0.3 M. Despite the expected difficulties in accurate predictions of vibrational properties of flexible molecules, the experimental VCD spectroscopic features of 2E2-PPL agreed quite well with the theoretical features for (R)2. For example, both spectra showed a strong negative CO stretching band at ∼1720 cm−1 and a positive C−H bending band at ∼1320 cm−1. Meanwhile, 2-E2-ANL exhibited an almost mirror-image VCD spectrum compared to the calculated one for (R)-2. These results led to the assignment of 2-E2-PPL and 2-E2-ANL as (R) and (S), respectively, which was again opposite to the assignments based on MαNP. Furthermore, VCD experiments of 3 also yielded results contradictory to those by (S)-MαNP. Conformational studies on (R)-3 using DFT yielded 14 conformers in a 1.43 kcal/mol energy window from the most stable, whose VCD and IR spectra were then calculated and averaged based on their abundance. Comparison of the theoretical spectrum for (R)-3 and the experimental ones for 3-E1 and 3-E2 (Figure 6C) strongly suggested the stereochemistry of 3-E1 and 3-E2 as (R) and (S), respectively. The assignment of the absolute configurations of the enantiomers of 1−3 via VCD spectroscopy resulted in opposite results compared to the assignment via the 1H NMR anisotropy method using (S)-MαNP as the chiral auxiliary. Figures 2B and 2C show the order of elution of the (S)-MαNP diastereoisomers obtained by derivatization of the enantiomers of 1 based on the configurations determined via VCD. According to the data obtained by VCD, the order of elution of the (S)MαNP diastereoisomers is (S,R) before (S,S). This also applies to 4-mercapto-2-heptanone and 2-mercapto-4-heptanone. Considering these conflicting conclusions, a third method based on 1H NMR spectroscopic behavior of diastereoisomeric

Figure 3. (A) Sector rule developed for the determination of the absolute configurations of secondary alcohols with (S)-MαNP as chiral derivatizing agent.10,11 (B) Sector rule used for the determination of the absolute configurations of chiral β-mercaptoalkanones with (S)MαNP as chiral derivatizing agent based on the results elaborated in this study.

Figure 4. Preparation of the enantiomers of 4-mercapto-2-pentanone 1-E1 and 1-E2 via kinetic resolution of 4 catalyzed by CAL-B*.

IR spectra were obtained based on the Boltzmann population average of the spectrum of each conformer (Figure 6A). Experimental spectra of 1-E1 and 1-E2 were obtained as CDCl3 solutions at concentrations of 0.282 and 0.124 M, respectively. The VCD spectrum of 1-E2 showed a poor S/N due to its low sample concentration; nevertheless, a mirror image relationship was recognized between the VCD spectra of 1-E2 and 1-E1. 8567


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Figure 5. (A) Stable conformers of (R)-(−)-1 and their relative energies. The Boltzman populations of each conformer simulated at 298 K are shown in parentheses. (B) VCD spectra of each conformer and the population-weighed final VCD spectrum of (R)-(−)-1. (C) IR spectra of each conformer and the population-weighed final IR spectrum of (R)-1.

Figure 6. Comparison of VCD (upper frame) and IR (lower frame) spectra of (A) 1, (B) 2, and (C) 3.

(R)-HTA thioesters of 1-E1, 19 and 1-E2, 20 are shown in Figures 7A and B, respectively. The comparison of the equivalent protons of the terminal CH3 groups and the CH2 group of both diastereoisomers show characteristic shifts. The protons of the methyl group (C5) of (R)-HTA thioester of 1E2, 20 show a relative upfield shift compared to that of the protons of (R)-HTA thioester of 1-E1, 19. In contrast, the protons of the other terminal methyl group (C1) and of the

hydratropic acid thioesters as described by Helmchen and Schmierer16 was applied to determine the absolute configurations of the mercaptoalkanones. The principle of this method is based on the difference of the chemical shift of constitutionally equivalent protons in diastereoisomeric derivatives. The mercaptoalkanone enantiomers obtained via lipase-catalyzed kinetic resolution were reacted with (R)hydratropic acid chloride. As examples, 1H NMR spectra of 8568


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the C1 terminal methyl group and the methylene bridge at C3 of the (R)-HTA thioester of 2-E2-PPL, 21 show the upfield shift. For 3, the terminal methyl group of C1 of the (R)-HTA thioester of 3-E2, 24 and the protons of C3, C5, C6, and C7 of the (R)-HTA thioester of 3-E1, 23 show the upfield shift. On the basis of these observations, the absolute configurations for the enantiomers of 1, 2, and 3 can be confirmed as (R) for 1E1, 2-E2-PPL, and 3-E1 and (S) for 1-E2, 2-E2-ANL, and 3-E2. These assignments of the configurations of β-mercaptoalkanones via 1H NMR spectroscopy of their (R)-HTA thioesters are in agreement with the results of VCD experiments. For a final confirmation, 2-methoxy-2-phenylacetic acid (MPA), a chiral derivatizing reagent previously shown to be suitable for the assignment of the absolute configurations of chiral thiols, was applied.17 Figure 8 shows the ΔδRS signs

Figure 7. (A) 1H NMR spectrum of the (R)-hydratropic acid thioester of 1-E1, 19 (corresponds to diastereoisomer (R,R)). (B) 1H NMR spectrum of the (R)-hydratropic acid thioester of 1-E2, 20 (corresponds to diastereoisomer (R,S)).

Figure 8. Structures of (R)- and (S)-MPA thioesters of 3-E1 28 and 27 and (R)-2-heptanethiol, 26 and 25 with δ values (ppm) and ΔδRS values (ppm). L1 (front side) and L2 (rear side) correspond to the side chains at the asymmetric centers of the mercaptoalkanone and the thiol moieties, respectively.

CH2 group of the (R)-HTA thioester of 1-E1, 19 undergo an upfield shift compared to that of the equivalent protons of (R)HTA thioester of 1-E2, 20. Because the absolute configuration of the used hydratropic acid is known and the described shifting effects can be attributed to a cisoid arrangement of the acid’s phenyl ring to the depicted constellations of (R)-HTA thioester of 1-E1, 19 and 1-E2, 20, the absolute configuration of 1 can be concluded. Therefore, the (R)-HTA thioester of 1-E1, 19 is assigned as (R,R), whereas the (R)-HTA thioester of 1-E2, 20 is assigned as (R,S). In Table 3, 1H NMR data of (R)-HTA thioesters of the enantiomers of 1, 2, and 3 are shown. From examination of the data of 2, it can also be seen that the terminal methyl group (C7) as well as the protons of the two methylene bridges (C5 and C6) of the (R)-HTA thioester of 2E2-ANL, 22 undergo an upfield shift, whereas the protons of

determined for the (R)- and (S)-MPA thioesters obtained after derivatization of the enantiomer 3-E1, 28 and 27 assigned as (R) based on VCD and 1H NMR spectroscopy of (R)-HTA esters. According to the model developed by Porto et al.,17 the spatial arrangement of the L1/L2 side chains confirmed the (R)configuration of the β-mercaptoalkanone. The analogous ΔδRS signs obtained for the (R)- and (S)-MPA thioesters of (R)-2heptanethiol, 26 and 25 demonstrated that the additional presence of the carbonyl group did not impact the suitability of the model used for the configurational assignment (Figure 8). The same phenomenon was observed for (R)- and (S)MαNP thioesters of 3-E1, 13 and 11 and (R)-2-heptanethiol, 18 and 17. For both the mercaptoalkanone and the thiol,

Table 3. 1H NMR Data of (R)-HTA Thioesters of the Enantiomers of 4-Mercapto-2-pentanone (1), 4-Mercapto-2-heptanone (2), and 2-Mercapto-4-heptanone (3) 4-mercapto-2-pentanone (1)

4-mercapto-2-heptanone (2)

2-mercapto-4-heptanone (3)

(R)-HTA thioester 1-E1 H 1 2 3 3′ 4 5 5′ 6 6′ 7

1-E2

(R,R)-19 2.00 (s)

(R,S)-20 2.05 (s)

2.65 (dd, 16.9, 4.8) 2.49 (dd, 16.9, 8.4) 3.79 (m) 1.22 (d, 7.0)

2.71 (dd, 16.9, 5.3) 2.54 (dd, 16.9, 8.1) 3.78 (m) 1.18 (d, 7.0)

Δδ 0.05 0.06 0.05 −0.01 −0.04

2-E2-PPL

2-E2-ANL

(R,R)-21 1.98 (s)

(R,S)-22 2.05 (s)

2.62 (dd, 16.9, 5.6) 2.55 (dd, 16.9, 7.4) 3.77 (m) 1.50 (m) 1.46 (m) 1.30 (m) 1.23 (m) 0.81 (td, 7.1, 1.9)

2.68 (dd, 16.8, 6.1) 2.62 (dd, 16.8, 7.1) 3.76 (m) 1.45 (m) 1.45 (m) 1.21 (m) 1.17 (m) 0.76 (t, 7.3) 8569

Δδ 0.07 0.06 0.07 −0.01 −0.05 −0.01 −0.09 −0.06 −0.05

3-E1

3-E2

Δδ

(R,R)-23 1.22 (d, 7.0) 3.81 (m) 2.62 (dd, 16.8, 4.9) 2.46 (dd, 16.7, 8.4)

(R,S)-24 1.18 (d, 7.0) 3.81 (m) 2.68 (dd, 16.7, 5.3) 2.51 (dd, 16.8, 8.1)

−0.04 0 0.06 0.05

2.23 (td, 7.2, 3.5)

2.28 (t, 7.3)

0.05

1.47 (m)

1.51 (dt, 14.7, 7.4)

0.04

0.79 (t, 7.4)

0.82 (t, 7.4)

0.03


Article

Journal of Agricultural and Food Chemistry application of the Porto et al. model17 involving the consideration of the signs of the ΔδRS values results in the (R)-configuration (Figure 9). In contrast, the ΔδRS signs determined for the (R)- and (S)-MαNP esters of (R)-2heptanol, 14 and 15 are opposite to those of the thioesters.

means that the side chains in proximity to the plane of the naphthalene moiety and thus their anisotropy effects are different for MαNP esters and MαNP thioesters. Therefore, when applying MαNP as chiral auxiliary for the assignment of the configurations of β-mercaptoalkanones, the sector rule as developed for secondary alcohols (Figure 3A) has to be changed, as shown in Figure 3B. In conclusion, the previously assigned configurations of mercaptoalkanones and the respective acetylthioalkanones deduced via NMR investigation of (S)-MαNP derivatives have to be revised.8,12

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.6b03670. Figures of stable conformers of (R)-(−)-2 and (R)-(−)-3 with their relative energies and Boltzmann populations of each conformer simulated at 298 K, VCD spectra of each conformer and population-weighed final VCD spectrum of (R)-(−)-2 and (R)-(−)-3, Δδ distributions of MαNP thioesters and HTA thioesters of 1, 2, and 3, MαNP derivatives of 3 and 2-heptanol, MPA thioesters of 3 and 2-heptanethiol, tables of 1H NMR data and Δδ values of (R)- and (S)-MPA thioesters of (R)-(−)-2-mercapto-4heptanone 3-E1 and (R)-(−)-2-heptanethiol, 1H NMR data and Δδ values of (R)- and (S)-MαNP thioesters of (R)-(−)-2-heptanethiol and (R)-(−)-2-mercapto-4-heptanone 3-E1, 1H NMR data and Δδ values of (R)- and (S)-MαNP esters of (R)-(−)-2-heptanol, [α]D values of acetylthioalkanone enantiomers, and 13C NMR data of synthesized diastereoisomeric derivatives (PDF)

Figure 9. Structures of (R)- and (S)-MαNP thioesters of (R)-2heptanethiol, 18 and 17 and 3-E1, 13 and 11, and (R)- and (S)-MαNP esters of (R)-2-heptanol, 14 and 15 with δ values (ppm) and ΔδRS values (ppm). L1 (front side) and L2 (rear side) correspond to the side chains at the asymmetric centers of the thiol, mercaptoalkanone and alcohol moieties, respectively.

This may be explained by the different predominant conformers. Application of the MαNP acid method for the determination of the absolute configurations of chiral secondary alcohols is based on the fact that the derivatization results in stable and preferred conformations of the MαNP esters. Conformational analysis demonstrated that in MαNP esters the oxygen atom of the methoxy group is syn-periplanar to the ester carbonyl oxygen atom, which is also syn-periplanar to the methine proton of the alcohol moiety (Figure 10A).27

■

AUTHOR INFORMATION

Corresponding Author

*Tel.: +49-(0)8161-71-4250; Fax: +49-(0)8161-71-4259; Email: [email protected]. Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS We thank Christine Schwarz for recording the NMR spectra. REFERENCES

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Figure 10. Predominant syn-periplanar (sp) and anti-periplanar (ap) conformers of (A and C) (S)-MαNP and (B and D) (S)-MPA esters and thioesters, respectively.

Analogously, the syn-periplanar conformation is also dominating for MPA-esters (Figure 10B), whereas conformers in which the methoxy group is anti-periplanar to the carbonyl oxygen are the most populated for MPA thioesters (Figure 10D).17 The higher stability of the anti-periplanar conformation has also been demonstrated for thioesters of other arylmethoxyacetic acids.20 Therefore, it may be assumed that also for MαNP thioesters the methoxy and carbonyl oxygen prefer antiperiplanar conformers (Figure 10C). In consequence, this 8570


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Reinvestigation of the Absolute Configurations of Chiral Î²

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