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Keywords:

  • vibrational circular dichroism;
  • VCD;
  • keto-enol tautomerism;
  • racemization;
  • DFT calculation;
  • aroma;
  • absolute configuration

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. LITERATURE CITED
  9. Supporting Information

A mixture of tautomers with unique keto-enol structures, 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one and 2-ethyl-4-hydroxy-5-methylfuran-3(2H)-one (EHMF, homofuraneol, 1a and 1b), comprises four structural isomers including their enantiomers. The four isomers were successfully separated by chromatographic optical resolution, and their odor evaluation was performed. Determination of the absolute chemistry of 1a and 1b were accomplished for the first time by direct measurement of the VCD spectra of their methyl ether derivatives 4a and 4b compared with the calculated ones as well as chemical relay reaction. The relationship between odor characteristics and stereochemistry was also examined. Chirality 21:E110–E115, 2009. © 2009 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. LITERATURE CITED
  9. Supporting Information

2-Substituted-furan-3(2H)-ones represented as 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one and 2-ethyl-4-hydroxy-5-methylfuran-3(2H)-one (EHMF, homofuraneol, 1a and 1b),1 2,5-dimethyl-4-hydroxyfuran-3(2H)-one (DMHF, furaneol®, trademark of Firmenich S.A., Switzerland, 2),2 2,5-dimethyl-4-methoxyfuran-3(2H)-one (DMMF, mesifuran, 3),2 have been discovered as significant aromas in a wide variety of fruits and foods (Fig. 1). The naturally occurring 2-substituted-furan-3(2H)-one derivatives are industrially important aroma compounds possessing a unique keto-enol tautomeric feature. In 1976, Nunomura isolated homofuraneol (1a) and(1b) as an influential aroma contributor of soy sauce,3 which is the most popular seasoning in Japan. In contrast to simple keto-enol structures in 2, homofuraneol exists in two tautomeric forms through the keto-enol isomerization as 1a and 1b in ratio of 1:3 to 1:2, which are in equilibrium with each other (Fig. 2).

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Figure 1. Homofuraneol (1), DMHF (Furaneol®, 2), and their methyl ethers.

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Figure 2. Keto-enol equilibrium and racemization of homofuraneol (1).

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Homofuraneol has an extremely low odor threshold (20 ppb),4 and possesses an intense caramel like sweet flavor reminiscent of soy sauce. It is also known to be present at high levels in soy sauce (ca. 50–100 ppm),5 and their increased concentration in the fermentation process are one of the indexes of the quality of a soy sauce. In addition to soy sauce, homofuraneol has also been found as a natural ingredient in coffee,6 muskmelon,1 lovage,7 and Emmentaler Swiss cheese.8 Moreover, Japanese people consume 750 mg/year of 1a and 1b per capita based on average consumption of 10 liters of soy sauce per capita.1 On the other hand, 1a and 1b have been industrially developed as a flavored raw material since 1988. Current worldwide annual use of 1a and 1b in the flavor industry arrives at over 2 tons.9

Biogenesis of 1a and 1b is proposed to occur from sugars via ribulose-5-phosphate in the metabolic pentose cycle during fermentation as well as from pentose sugars in the presence of amines or amino acids in Maillard reaction.1, 10 However, naturally occurring 1a and 1b were isolated as optically inactive compounds due to their unique keto-enol tautomeric structures which cause their spontaneous racemization as shown in Figure 2.

The enantiomers of 1a and 1b, which possess an inherent chirality, have been separated by using a gas chromatography technique in 1990.11 Interestingly, Bruche reported that each enantiomer of 1a and 1b possesses a different odor intensity and character according to a chiral gas chromatography-olfactometry study, and one of the enatiomers, 1a has an intense sweet odor.12 However, their stereochemical study has never been reported so far. Due to the keto-enol tautomerism which obstructs asymmetric synthetic approach or chemical derivatization, neither absolute configuration nor optical rotation has yet been clarified for over 40 years since its first discovery.13, 14

Very recently, we have succeeded in the determination of the absolute configurations of the DMHF (furaneol, 2) and its methyl ether, DMMF (mesifuran, 3) by utilizing the vibrational circular dichroism (VCD) technique.15 VCD measures the differential absorption of left versus right circularly polarized infrared radiation by molecular vibrational transition.16–19 The recent commercially available VCD equipment prompted determination studies of small organic chiral molecules' absolute configurations20–23 as well as stereochemical analysis of biologically significant macromolecules, such as proteins24 and carbohydrates.25 In keeping with our chiroptical studies on natural products,15, 26–29 the VCD methods were applied to homofuraneol (1a), (1b) and chemically stable methyl ether derivatives of them. In this report, the first approach to their stereochemistry is described, and the structure activity relationships are discussed.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. LITERATURE CITED
  9. Supporting Information

1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were recorded on a Bruker Biospin AVANCE DRX500 with TMS as an internal standard. EI-MS and ESI-MS were measured on a Shimadzu GCMS-QP2010 and a Shimadzu LCMS-IT-TOF, respectively. Optical rotations were measured on a JASCO polarimeter P-1020 or a Perkin–Elmer 343 spectrometer. The chiral GC analyzes were conducted on a Hewlett Packard 5890 GC system equipped with a FID detector using a Chirasildex CB column (25 m × 0.25 mm i.d., 0.25 μm-film, Varian). The supercritical fluid chromatography (SFC) was performed using a JASCO preparative SFC system equipped with a CHIRALPAK® IA column (250 × 20 mm i.d., Daicel Chemical Industries). HPLC was conducted on an Agilent 1100 series HPLC system. Reverse phase HPLC was performed on a Cosmosil C-18 column (250 × 20 mm i.d., Nacalai Tesque), and chiral HPLC was conducted on a CHIRALPAK® IA column (250 × 20 mm i.d. or 250 × 4.6 mm i.d., Daicel Chemical Industries). Ethyl acetate, 2-propanol, and methanol were purchased from Nacalai Tesque. Carbon tetrachloride and trimethylsilyldiazomethane (ca. 10% in Hexane, ca. 0.60 mol/L) were purchased from Wako Pure Chemical and Tokyo Chemical Industry, respectively. Purity of each enantiomer was checked by the chiral GC system after optical resolution.

Chiral Optical Resolution and Isolation of 5-ethyl-4-hydroxy-2- methylfuran-3(2H)-one (1a) and 2-ethyl-4-hydroxy-5-methylfuran-3(2H)-one (1b)

A solution of 150 mg/mL of racemic furanone 1a and 1b in ethyl acetate was injected by portion of 30 μL into preparative HPLC system equipped with CHIRALPAK® IA. Flow conditions were 8 mL/min with hexane and ethyl acetate (90:10) as a mobile phase. After multiple injections, (+)-1a, (−)-1a, (+)-1b and (−)-1b were isolated in about 5 mg yield, respectively.

Methylation of 1a and 1b with trimethylsilyldiazomethane

To a stirred solution of homofuraneol (1a and 1b, 1.00 g, 7.04 mmol) in methanol (2 mL) and ethyl acetate (2 mL), a 0.6 M trimethylsilyldiazomethane solution (25 mL, 10% in hexane, 15 mmol) was added dropwise at a rate of 1 mL/min. The mixture was stirred at room temperature for 5 hrs, monitoring the completion of the methylation and the purity of methyl ether derivatives 4a and 4b (96%) by GC/MS. The residue was subjected to HPLC on a preparative ODS column (Cosmosil C-18: 250 × 20 mm i.d.) with acetonitrile and water to give the fractions containing either methyl ether 4a or 4b. From each fraction acetonitrile was evaporated, and the resulting water layer was extracted with ethyl acetate three times. The water layer was further treated on an ODS cartridge column with acetonitrile to recover an additional amount of 4a or 4b, respectively. The combined 4a was amounted to 0.11 g in 43% yield (99% purity). 4b (0.38 g) was obtained in 54% yield (89% purity). 4a, HR-ESI-MS calcd. for C8H13O3 (M+H)+ 157.0859, found 157.0859, EI-MS (27 eV) m/z 156 (M+, 100), 141 (33), 71 (40), 57 (60).

1H NMR (500 MHz, CDCl3) δ(ppm) 1.23 (t, J = 7.6 Hz, 3H), 1.45 (d, J = 7.2 Hz, 3H), 2.58 (q, J = 7.6 Hz, 2H), 3.81 (s, 3H), 4.41 (q, J = 7.2 Hz, 1H), 13C NMR (125 MHz, CDCl3), 10.58 (CH3), 16.91 (CH3), 21.36 (CH2), 60.40 (CH3O), 80.75 (CH[BOND]O), 136.09 (C[BOND]O), 182.76 (C[BOND]O), 199.13 (C[DOUBLE BOND]O); 4b, HR-ESI-MS calcd. for C8H13O3 (M+H)+ 157.0859, found 157.0859, EI-MS (27 eV) m/z 156 (M+, 98), 141 (50) 128 (61), 43 (100), 1H NMR (500 MHz, CDCl3) δ(ppm) 0.99 (t, J = 7.4 Hz, 3H), 1.74 (dqd, J = 14.5, 7.3, 7.3 Hz, 1H), 1.97 (dqd, J = 14.5, 7.3, 4.4 Hz, 1H), 2.20 (s, 3H, C-8), 3.80 (s, 3H), 4.30 (dd, J = 7.4, 4.4 Hz, 1H).

13C NMR (125 MHz, CDCl3), 8.88 (CH3), 13.80 (CH3), 24.88 (CH2), 60.29 (CH3O), 85.37 (CH[BOND]O), 137.84 (C[BOND]O), 178.90 (C[BOND]O), 198.02 (C[DOUBLE BOND]O).

Optical Resolution and Isolation of 5-ethyl-4-methoxy-2-methylfuran-3(2H)-one (4a)

0.11 g of racemic furanone 4a in 0.32 mL of ethyl acetate was injected by portion of 50 μL into preparative SFC system equipped with CHIRALPAK® IA. Flow conditions were 20 mL/min CO2 with 0.08 mL/min 2-propanol. The optically active compounds were recovered with ethyl acetate as a line-wash solvent. After all samples were subjected, (+)-4a and (−)-4a were isolated with 99%, 99% ee, respectively.

Optical Resolution and Isolation of 2-ethyl-4-methoxy-5-methylfuran-3(2H)-one (4b)

0.38 g of racemic furanone 4b in 0.76 mL of ethyl acetate was injected by portion of 50 μL into preparative SFC system equipped with CHIRALPAK® IA. Flow conditions were 20 mL/min CO2 with 0.08 mL/min 2-propanol. The optically active compounds were recovered with ethyl acetate as a line-wash solvent. After eleven injections, (+)-4b and (−)-4b were isolated with 92%, 99% ee for (+)-4b, 98%, 99%ee for (−)-4b, respectively.

VCD Spectroscopy

VCD spectra were measured on a Bomem/BioTools ChiralIR spectrometer with a resolution of 8 cm−1 at ambient temperature. All VCD spectra were recorded for 3 hrs. Samples were dissolved in CCl4 and placed in a 100 μm CaF2 cell. The IR and VCD spectra were corrected by a solvent spectrum obtained under the same experimental conditions and presented in molar absorptivity ε (L/mol cm).

The Density Functional Calculation of (R)-4a and (S)-4b

The CONFLEX searches30, 31 based on the molecular mechanics with MMFF94S force fields were carried out for (R)-4a and (S)-4b. Since both molecules have just two rotatable bonds, the number of the conformers with low-energy were 5 for (R)-4a and 6 for (S)-4b, respectively. For these conformers, the geometry optimizations and harmonic frequency analysis were carried out using the density functional calculations at the B3PW91/6-31G(d,p) level. Using the frequency and intensity sets, the IR and VCD spectra were obtained for each conformer by convolution with the Lorentzian function. These spectra were averaged with the Boltzmann-weighted population. The frequencies were scaled with a factor 0.97. The Boltzmann weighted populations were evaluated with the DFT energy corrected with the thermal free energy with respect to the vibration motion. Since the summation of the Boltzmann weight for the low-lying two conformers covered 99.97% for (R)-4a, these two conformers were used to calculate the IR and VCD spectra. On the other hand, all 6 conformers for (S)-4b were required to describe the IR and VCD spectra. All DFT calculations were conducted with the Gaussian03 (revision C02) program code,32 and calculations of the IR and VCD spectra from the frequency and intensity sets were carried out with an in-house program code.

RESULTS AND DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. LITERATURE CITED
  9. Supporting Information

As a mixture of tautomers with unique keto-enol structures, homofuraneol (1a) and (1b) comprises four structural isomers including their enantiomers isomers. Since this is a complex feature, there have been no reports on their absolute configurations, practical optical resolutions, or optical rotations, although it was reported that a chiral GC/MS afforded the separated peaks corresponding to each isomer.12 Therefore, we at first attempted to determine a practical optical resolution method. The all four isomers were successfully isolated by a normal phase HPLC equipped with a chiral column (CHIRALPAK® IA). An on-line polarimeter equipped with the HPLC system also clearly showed each optical rotation sign of plus or minus (Fig. 3).

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Figure 3. Chiral HPLC analysis of homofuraneol (1a) and (1b) on a 250 mm × 20 mm i.d. CHIRALPAK® IA column using hexane/ethyl acetate = 90:10 at a flow rate of 10 mL/min.

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Although all four fractions were separated, each in pure state, direct measurements of their VCD spectra were unsuccessful, owing to their instability after the isolation, similar to that of DMHF (2). Therefore, chemically stable methyl ether derivatives of homofuraneol were prepared. Treatment of homofuraneol with trimethylsilyldiazomethane in methanol afforded a mixture of four methyl ethers quantitatively. The mixture was subjected to HPLC on an ODS column to afford regioisomers, 4a and 4b. Distinction between regioisomers 4a and 4b was based on their NMR data. Each optical resolution of 4a and 4b was performed on the chiral SFC system (Fig. 4). Minor regioisomer 4a and major isomer 4b were efficiently separated on CHIRALPAK® IA into their enantiomers (4a: Fr-1: (+)-4a [α]D20+187.0 (c 0.20, CCl4), Fr-2: (−)-4a [α]D20 −101.3 (c 0.39, CCl4), 4b: Fr-1: (+)-4b [α]D20 +244.0 (c 2.0, CCl4), Fr-2: (−)-4b [α]D20 −240.9 (c 2.0, CCl4)).

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Figure 4. Separation of the four isomers of methylated homofuraneols.

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The resulting four isomers were subjected to a VCD study. Theoretical calculations of 4a and 4b were performed with DFT at the B3PW91/6-31G(d,p) level. The initial geometries were generated with the CONFLEX search. DFT conformational analysis revealed two and six low-lying conformers for 4a and 4b, respectively (see Supporting Information). The observed IR and VCD spectra of the minor component, homofuraneol 4a, and calculated IR and VCD spectrum of (R)-4a were shown in Figure 5. VCD spectrum of a first eluted enantiomer (+)-4a, and second eluted one (−)-4a are mirror images. The calculated IR spectrum of (R)-4a is identical with the observed IR spectrum of (+)-4a and (−)-4a. This suggests that the calculation performed in this study is highly reliable. The calculated VCD signals of (R)-4a and observed VCD signals of (+)-4a are also identical in their carbonyl and fingerprint regions. The characteristic IR and VCD signals around 1700 cm−1 and 1640 cm−1 could be assigned to stretching modes of its carbonyl double-bond and its enol ether double-bond on 4a. Therefore, we could undoubtedly conclude the absolute stereochemistry of the minor component, 4a, to be (R)-(+)-4a and (S)-(−)-4a.

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Figure 5. Comparison of IR (lower frame) and VCD (upper frame) spectra observed (CCl4, c = 0.15 M, l = 100 μm) for (+)-4a (solid line) and (–)-4a (dotted line) with one calculated for (R)-4a.

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Absolute configuration of the major component 4b was also determined. Most of the characteristic signals of 4a and 4b in their VCD spectra were very similar. The calculated VCD spectrum of (S)-4b was superimposed on the observed VCD spectrum of (−)-4b (Fig. 6). Thus, their absolute configurations were concluded as (R)-(+)-4b and (S)-(−)-4b in a similar manner to that of 4a.

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Figure 6. Comparison of IR (lower frame) and VCD (upper frame) spectra observed (CCl4, c = 0.15 M, l = 100 μm) for (–)-4b (solid line) and (+)-4b (dotted line) with one calculated for (S)-4b.

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Chemical transformations were examined to determine the absolute configuration of homofuraneols 1a and 1b on the basis of the stereochemistry of their methyl ethers 4a and 4b (Fig. 4). Under the aforementioned conditions (Fig. 3) for the chiral HPLC resolution on a semipreparative scale, incomplete separation of the isomers including optical ones was carried out. The resulting three fractions including almost pure (−)-1a, a mixture of (+)-1a and (+)-1b, and almost pure (−)-1b, were subsequently subjected to the methylation reaction with trimethylsilyl–diazomethane. Each methyl ether fraction was analyzed by the chiral GC method (Chirasildex CB; 25 m × 0.25 um) (Fig. 7).

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Figure 7. Analysis of the four isomers of methylated homofuraneol by a chiral gas chromatography on a 25 m × 0.25 mm i.d. Chirasildex CB fused capillary column coated with 0.25 μm film: carrier gas, helium, 100 kPa; oven temperature, started at 70°C up to 200°C at an increasing speed of 1.0°C/min. detector, FID. (i) Chiral analysis of racemates (4a and 4b). Each peak assignment was based on a single injection of the corresponding authentic sample, which was used on its VCD study. (ii) Chiral analysis of methyl ether obtained from the first eluted (−)-1a fraction. (iii) Chiral analysis of methyl ether obtained from a mixture of (+)-1a and (+)-1b fraction. (iv) Chiral analysis of methyl ether obtained from the last eluted (−)-1b fraction.

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The first eluted (−)-1a fraction afforded (S)-(−)-4a indicating the absolute configuration of (−)-1a as S [Fig. 7 (ii)], while a peak of the methyl ether (S)-(−)-4b was obtained from the methylation reaction of the (−)-1b fraction showing S configuration of (−)-1b [Fig. 7 (iv)]. Since inversion of the stereochemistry does not occur during their methylation reactions, their stereochemistries of 1a and 1b were unambiguously assigned as (R)-(+)-1a, (S)-(−)-1a, (R)-(+)-1b and (S)-(−)-1b, respectively (Fig. 8).

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Figure 8. Odor evaluation of the four isomers of homofuraneol (1).

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Odor evaluation of four isomers 1a and 1b was carried out. These enantiomers exhibited dramatically different odor characteristics as shown in Figure 8. Only one isomer (R)-(+)-1a was found to have a strong roasted sweet scent. We have already reported that (R)-(+)-isomers of DMHF (2) and DMMF (3) possess a roast sweet aroma. It is of interest that (R)-methyl group for 1, 2 and 3 might play an important role for representing intense sweet note for 2-substituted-furan-3(2H)-ones.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. LITERATURE CITED
  9. Supporting Information

Four structural isomers including their enantiomers with unique keto-enol structures, 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one and 2-ethyl-4-hydroxy-5-methyl furan-3(2H)-one (EHMF, homofuraneol, 1a and 1b) were successfully separated by enantioselective HPLC. The four optically active isomers of homofuraneol methyl ethers 4a and 4b were obtained by a reverse phase HPLC followed by an enantioselective SFC, as well. The result of the direct measurements of the VCD spectra of 4a and 4b with comparison of the calculated ones led to determine their absolute configuration. Finally, the absolute configuration of 1a and 1b were unveiled for the first time as (R)-(+)-1a, (S)-(−)-1a, (R)-(+)-1b, and (S)-(−)-1b, via the chemical relay reaction. The relationship between odor characteristics and stereochemistry was also examined, and (R)-(+)-5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one was found to have a strong roasted sweet note.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. LITERATURE CITED
  9. Supporting Information

The authors are grateful to Prof. S.-I. Nishimura, Dr. T. Taniguchi at Hokkaido University, and Mr. Y. Kawakami at Takasago International Corporation for their valuable suggestions.

LITERATURE CITED

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. LITERATURE CITED
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. LITERATURE CITED
  9. Supporting Information

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