Stereochemical study of chiral tautomeric flavorous furanones by vibrational circular dichroism

Article abstract of DOI:10.1021/ol801966t

(Equation Presented) 2-Substituted-3(2H)-furanone derivatives are industrially significant aroma compounds possessing a unique keto - enol tautomeric feature causing their racemization. Absolute configurations of two flavorous furanones, which have remained unclear for the past 40 years since their discovery, were clarified by the vibrational circular dichroism technique as well as chemical relay reactions. Odor evaluation of each enantiomer revealed relationships between their configurations and their odor activities.

Full text of DOI:10.1021/ol801966t

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4883-4885
Stereochemical Study of Chiral
Tautomeric Flavorous Furanones by
Vibrational Circular Dichroism
Yoshihiro Yaguchi,† Atsufumi Nakahashi,‡ Nobuaki Miura,‡ Daisuke Sugimoto,†
Kenji Monde,*,‡ and Makoto Emura*,†
Corporate Research and DeVelopment DiVision, Takasago International Corporation,
4-11, 1-Chome, Nishi-yawata, Hiratsuka city, Kanagawa 254-0073, Japan, and
Graduate School of AdVanced Life Science, Frontier Research Center for Post-Genome
Science and Technology, Hokkaido UniVersity, Kita-ku, Sapporo 001-0021, Japan
kmonde@glyco.sci.hokudai.ac.jp
Received August 22, 2008
ABSTRACT
2-Substituted-3(2H)-furanone derivatives are industrially significant aroma compounds possessing a unique keto-enol tautomeric feature
causing their racemization. Absolute configurations of two flavorous furanones, which have remained unclear for the past 40 years since their
discovery, were clarified by the vibrational circular dichroism technique as well as chemical relay reactions. Odor evaluation of each enantiomer
revealed relationships between their configurations and their odor activities.
The naturally occurring furanones represented by 2,5-
dimethyl-4-hydroxy-3(2H)-furanone (DMHF, 1), 2,5-dimeth-
yl-4-methoxy-3(2H)-furanone (DMMF, 2), and 2(or 5)-ethyl-
4-hydroxy-5(or 2)-methyl-3(2H)-furanone (EMHF, 3a or 3b)
are major flavor components in numerous fruits such as
pineapples and strawberries.1 (Compounds 1 and 2 have
frequently been called “Furaneol” as a commodity name and
“mesifuran”, respectively. “Furaneol” is a registered trade-
mark of Firmenich SA, Switzerland.) They have also been
found in a range of highly cooked foodstuffs as pleasant odor
components that are formed mainly via Maillard reactions
between sugars and amino acids during heating.1 These
furanones are known to play an important role in flavor
because of their extremely low threshold values and their
burnt sugar odor characteristics. For instance, odor threshold
values in water for 1, 2, and 3 are 60, 0.4, and 20 ppb,
respectively.2 Therefore, these compounds have been inves-
tigated extensively as significant flavor chemicals. Since the
discovery of these important aroma chemicals, large quanti-
ties have been utilized as raw materials in the flavor and
fragrance industry, with worldwide annual consumption of
up to almost 100 t.3
These flavor-related furanones are believed to be biosyn-
thesized via a glycoside from 6-deoxy-L-mannose in
plants.1a,4 However, most of the naturally occurring ones
were isolated as optically inactive compounds1a,5 due to their
unique keto-enol tautomeric structures causing racemization.
(2) Buttery, R. G.; Huber, U. A. In FlaVor Chemistry: Thirty Years of
Progress; Kluwer Academic/Plenum Publishers: New York, 1999; pp
353-365.
(3) Safety eValuation of certain food additiVes: WHO Food AdditiVes
Series 2006; IPCS - International Programme on Chemical Safety; World
Health Organization: Geneva, 2006; Vol. 54, pp 494-495.
(4) (a) Wein, M.; Lewinsohn, E.; Schwab, W. J. Agric. Food Chem.
2001, 49, 2427–2432. (b) Orruno, E.; Apenten, R. O.; Zabetakis, I. FlaVour
† Takasago International Corporation.
‡ Hokkaido University.
(1) (a) Zabetakis, I.; Gramshaw, J. W.; Robinson, D. S. Food Chem.
1999, 65, 139–151. (b) Slaughter, J. C. Biol. ReV. 1999, 74, 259–276. (c)
Raab, T. Ph.D. Thesis, University of Wurzburg, 2003. (d) Hauck, T. Ph.D.
Thesis, University of Wurzburg, 2004.
Fragr. J. 2001, 16, 81–84
(5) Mosandl, A.; Bruche, G.; Askari, C.; Schmarr, H. G. J. High Resolut.
Chromatogr. 1990, 13, 660–662
.
.
10.1021/ol801966t CCC: $40.75
Published on Web 09/26/2008
2008 American Chemical Society

Detailed examination of the chirality of these compounds
over the past decade has revealed that these inherently chiral
furanones can be separable by recent chiral GC,5,6a-c CE,6d,7
and HPLC6e techniques. Moreover, it has been shown that
enzymatic reaction can produce enantiomerically enriched
1 followed by spontaneous racemization in only a few hours
depending on their pH conditions.7
Table 1. Specific Optical Rotation Value, Enantiomeric Excess,
and Odor Evaluation of Each Enantiomer
eeb
[%]
a
20
[R]D
odor evaluation
(+)-1
(-)-1
(+)-2
(-)-2
+172
-153
+148
-188
80 obviously strong, sugary, jammy, sweet
82 extremely weak
94 burnt, intensive caramel
However, attempts to determine absolute configurations
of the compounds have not been successful due to rapid
racemization through the keto-enol tautomerism and ex-
traordinary chemical reactivity of the enol and carbonyl
groups obstructing their derivatization toward an X-ray
crystallographic study and a standard Mosher method.
Consequently, we applied the vibrational circular dichroism
(VCD) technique to more stable methyl ether 2 (DMMF).
VCD measures differential absorption of left-versus-right
circularly polarized IR radiation by molecular vibrational
transitions, which have both advantages of CD and IR
features.8 VCD is an emerging reliable technique for
stereochemical analyses in the field of life sciences as well
as material sciences in combination with DFT theoretical
calculation. Herein, we report the absolute configurations of
these unique molecules, which have remained unclear for
the past 40 years since their isolation.9
91 lactone, coumarin like, no caramelic odor
a (+)-1: (c 0.472, CCl4), (-)-1: (c 0.526, CCl4), (+)-2: (c 0.324, CCl4),
(-)-2: (c 0.262, CCl4). b Determined by the chiral GC.
phase HPLC.10 After several trials, efficient optical separation
of 1 and 2 was achieved by the use of CHIRALPAK IA
with chiral stationary phase using 2-propanol (1: R ) 1.12,
2: R ) 1.22).11 Semipreparative scale chromatography with
multiple injections gave approximately 30 mg of each
enantiomer. The afforded enantiomers had specific optical
rotation values shown in Table 1. The enantiomeric ratio
was determined by chiral GC with a Chirasildex CB
column.11 No racemization was observed during the workup
such as collection of fractions and evaporation of solvent.
The IR and VCD spectra of each enantiomer were
measured on a commercial Fourier transform VCD spec-
trometer as CCl4 solution through a 100-µm path length cell
with CaF2 windows.11 Unfortunately, 1 was decomposed
during measurement because of its low stability in CDCl3
and CCl4, whereas enantiomers of its methyl ether (2) showed
entirely opposite VCD signals. An enantiomer (+)-2 showed
a strong positive Cotton effect at around 1300 cm-1 attribut-
able to C-H bending at the chiral center.
The IR and VCD spectra of 2 were theoretically calculated
based on the density functional theory at the B3PW91/
6-31G(d,p) level of theory. Conformational analysis offered
a sole stable conformer for 2 in which the methoxy group
was rotated (Figure 1).
Optical resolution of 1 and 2 was efficiently performed
by an environmental friendly CO2 supercritical fluid chro-
matography (SFC) chiral separation technique with normal-
(6) (a) Dietrich, A.; Maas, B.; Messer, W.; Bruche, G.; Karl, V.;
Kaunzinger, A.; Mosandl, A. J. High Resolut. Chromatogr. 1992, 15, 590–
593. (b) Bruche, G.; Dietrich, A.; Mosandl, A. Z Lebensm Unters Forsch
1995, 201, 249–252. (c) Fischer, N.; Hammerschmidt, F.-J. Chem. Mikro-
biol. Technol. Lebensm. 1992, 14, 141–148. (d) Raab, T.; Schmitt, U.;
Hauck, T.; Knecht, A.; Holzgrabe, U.; Schwab, W. Chromatographia 2003,
57, 501–504. (e) Bruche, G.; Mosandl, A.; Kinkel, J. N. J. High Resolut.
Chromatogr. 1993, 16, 254–257
(7) Raab, T.; Hauck, T.; Knecht, A.; Schmitt, U.; Holzgrabe, U.; Schwab,
W. Chirality 2003, 15, 573–578
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(8) (a) Keiderling, T. A. In Circular Dichroism: Principles and
Applications; Berova, N., Nakanishi, K., Woody, R. W. Eds.; Wiley-VCH:
New York, 2000; pp 621-666. (b) Freedman, T. B.; Cao, X.; Dukor, R. K.;
Nafie, L. A. Chirality 2003, 15, 743–758. (c) Polavarapu, P. L.; He, J. Anal.
Chem. 2004, 76, 61A–67A. (d) Taniguchi, T.; Miura, N.; Nishimura, S.-I.;
Monde, K. Mol. Nutr. Food Res. 2004, 48, 246–254. (e) Nafie, L. A.; Dukor,
R. K. In Chiral Analysis; Busch, K. W., Busch, M. A., Eds.; Elsevier:
Amsterdam, 2006; pp 505-544. (f) Taniguchi, T.; Monde, K. Trends
Glycosci. Glycotech. 2007, 19, 149–166. (g) Kellenbach, E. R.; Dukor, R. K.;
Nafie, L. A. Spectrosc. Eur. 2007, 19, 15–17. (h) Polavarapu, P. L. Chem.
Rec. 2007, 7, 125–136. (i) Stephens, P. J.; Devlin, F. J.; Pan, J.-J. Chirality
2008, 20, 643–663.
Figure 1. Most stable conformer of (R)-2.
After harmonic vibrational analysis, simulated absorption
and VCD spectra were obtained by using convolution with
Lorentzian functions with 8 cm-1 full width at half-height.
(9) (a) Willhalm, B.; Stoll, M.; Thomas, A. F. Chem. Ind. London 1965,
38, 1629–1630. (b) Rodin, J. O.; Himel, C. M.; Silverstein, R. M.; Leeper,
R. W.; Gortner, W. A. J. Food Sci. 1965, 30, 280–285.
(10) (a) Terfloth, G. J. Chromatogr., A 2001, 906, 301–307. (b) Phinney,
K. W. Anal. Bioanal. Chem. 2005, 382, 639–645.
(11) See Supporting Information.
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Org. Lett., Vol. 10, No. 21, 2008

The frequency was scaled with 0.97. All of the calculations
were conducted with Gaussian03 program code. The ob-
served VCD spectrum of (+)-2 was essentially identical to
the calculated spectrum of (R)-2 (Figure 2), while IR spectra
of them were almost superimposed. Therefore, (+)-2 was
shown to have an R configuration.
Odor evaluation of each enantiomer of 1 and 2 was carried
out. As expected, these enantiomers exhibited different odor
characteristics, dramatically as shown in Table 1. The R
isomers were found as a burnt caramel note, which represents
an odor characteristic of 2-substituted-3(2H)-furanones.
Thus, we succeeded in efficient chiral separation by the
SFC technique and in determination of the absolute con-
figurations of (R)-(+)-2, (S)-(-)-2, (R)-(+)-1, and (S)-(-)-1
by using the recent VCD technique. We also investigated
the structure-activity relationships between absolute con-
figurations and odor characteristics. We believe that the VCD
method is also useful chiroptical characterization of other
aroma active compounds which absolute chemistry has been
unclear.
Scheme 1
Figure 2. Comparison of IR (lower frame) and VCD (upper frame)
spectra observed (CCl4, c ) 0.17 M, l ) 100 µm) for (+)-2 with
one calculated for (R)-2.
Acknowledgment. We thank Prof. S.-I. Nishimura, Dr.
T. Taniguchi at Hokkaido University, and Mr. Y. Kawakami
at Takasago International Corporation for their valuable
suggestions. This work was supported in part by a grant-in-
aid for scientific research (Grants 20310127) from the
Ministry of Education, Science, Sports, and Culture of Japan.
A.N. gratefully acknowledges a fellowship from the Japan
Society of the Promotion of Science.
To determine the absolute configuration of the tautomeric
compound 1, derivatization from 1 to 2 by mild methylation
reactions was attempted. Careful treatments of (+) and (-)-1
with trimethylsilyl-diazomethane to prevent racemization
successfully afforded the corresponding optically active 2.11
The methyl ether derivative from (+)-1 was identified as
(R)-(+)-2 by chiral GC/MS analysis,11 whereas (-)-1 was
Vice Versa. Therefore, the relationship of absolute configu-
ration and optical rotation of 1 was confirmed as (R)-(+)-1
and (S)-(-)-1, respectively.
Supporting Information Available: Details of VCD
spectroscopy measurements, the optical resolutions of 1 and
2 by the chiral SFC system, derivatization reactions, and
chiral GC analyses of 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
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