New Synthetic Approach to Optically Activate Matsutakeol, the Major Flavor Component of Tricholoma matsutake, from L-Tartaric Acid

Full text of DOI:10.1002/bkcs.11020

Communication
DOI: 10.1002/bkcs.11020
BULLETIN OF THE
W.-H. Lee et al.
KOREAN CHEMICAL SOCIETY
New Synthetic Approach to Optically Activate Matsutakeol, the Major
Flavor Component of Tricholoma matsutake, from L-Tartaric Acid
Won Hyung Lee,†,§ Il Hak Bae,†,‡,§ B. Moon Kim,‡ and Young-Bae Seu†,
*
†School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-701,
Republic of Korea. *E-mail: ybseu@knu.ac.kr
‡Department of Chemistry, Seoul National University, Seoul 08826, South Korea
Received August 8, 2016, Accepted October 31, 2016, Published online December 1, 2016
Keywords: Matsutakeol, L-Tartaric acid, Enzyme reaction, Total synthesis
Many physiologically active molecules contain stereogenic
carbon centers, whose stereochemistry often determines
their biological activities in organisms such as animals,
plants and microorganisms.1 This dependence of character-
istic bioactivities of the chiral molecules on their absolute
configurations of the stereogenic centers results from how a
protein receptor responds differently to the three-
dimensional pharmacophoric groups of each stereoisomer.2
One enantiomer might be characterized as biologically
active, exhibiting desirable efficacy (eutomer), while the
other enantiomer show reduced or no activity, or may even
be toxic to the organism (distomer).3 In particular, the dis-
tinctive recognition capability of sensory receptors relies on
whether (R)- or (S)- stereochemistry of the binding mole-
cules leads to discrepancies in its biological activities such
as smell and taste.4 Tricholoma matsutake (Songi mush-
room) belongs to Tricholomataceae, and grows around pine
trees in Korea, Japan, and China. This mushroom is edible
and well known for its health benefits, including blood cho-
lesterol reduction, anti-cancer activity, blood circulation
improvement, digestion enhancement, and prevention of
several diseases, such as arterial sclerosis, heart disease,
diabetes, and hyperlipidemia.5 Although the demand for
Tricholoma matsutake is increasing significantly due to
these advantages, it is quite expensive, difficult to artifi-
cially cultivate using mycelium, and limited to the amount
that can be acquired in nature.5 Unique aroma compounds
in matsutake mushroom include 1-octen-3-o1 (known as
matsutakeol) (60–70%), methyl cinnamate (13%), 2-
octeno1 (8%), and octyl alcohol (3%), and the smell can be
different during the cooking process because of the differ-
ent volatility of some components.6 Matsutakeol is an ali-
phatic alcohol based on a C-8 skeleton and has a chiral
carbon at the C-3 position, which attributes to its aroma;
optically active (R)-(–)-matsutakeol ((R)-11) has a stronger
mushroom smell than (S)-(+)-matsutakeol ((S)-11).7 In this
paper, we report a simple synthesis of each optically active
matsutakeol isomer via enzyme-mediated regioselective
hydrolysis, regioselective alkylation using an organocuprate
coupling reaction, and Mitsunobu-type stereoinversion
reaction from readily available L-tartaric acid.
We developed a synthetic strategy towards (S)-11 in
10 steps from inexpensive, natural (2R,3R)-L-tartaric acid (1)
(Scheme 1).8 Initially, acid-catalyzed esterification of starting
material 1 in EtOH provided dihydroxydiester 2 in 88% yield.
Next, acetalization with 2,2-dimethoxypropane afforded pro-
tected compound 3 in 89% yield. Through the use of LAH,
diester 3 was reduced to diol 4 in high yield (89%). Then,
4 was treated with butyric anhydride in pyridine to provide
dibutanoate 5 smoothly in a high yield (96% yield). To hydro-
lyze selectively either at the C-1 or C-4 position of the dibuty-
rate 5, we investigated various enzyme-mediated hydrolysis
conditions and found that TOYOBO lipase (LIP-301) pro-
vides the best result (Figure S1, Supporting Information).9
With the optimized reaction conditions using the TOYOBO
lipase in hand, we carried out the selective hydrolysis to obtain
mono-hydroxyl ester 6 in high yield (90% yield). Conversion
of the C-4 alcohol of 6 to O-tosyl protected compound 7 pro-
ceeded in 89% yield. To complete the 8-carbon framework of
matsutakeol, we carried out a mild nucleophilic substitution
reaction.10 From the reaction of a Gilman reagent and tosy-
lated ester 7, 1-octanol-derivate 8 was obtained in 78% yield.
Tosylation of alcohol 8 followed by iodine substitution gave
iodide compound 10 in excellent yield (80% yield, two steps).
Installation of the olefin moiety from compound 10 via zinc-
mediated ketal cleavage and E2 elimination reaction furnished
(S)-11 in excellent yield (96% yield), and the stereochemical
configuration of (S)-11 was identified from the comparison of
the optical rotation value with a reported one.11
In an alternate approach, to shorten the synthetic route to
O-tosylated octane 9, we investigated the following syn-
thetic procedure based on mono-alkylation (Scheme 2).
Treatment of diol 4 with p-TsCl in the presence of TEA and
DMAP gave ditosylate 12 in 82% yield. Using a synthetic
method similar to that described above, mono-alkylation of
12 using 4 equiv of the Gilman reagent proceeded to afford
key intermediate 9 in a moderate yield (44%).
Next, inversion of the stereochemical configuration of
(S)-(+)-matsutakeol ((S)-11) to (R)-(–)-matsutakeol ((R)-11)
was performed as shown in Scheme 3.12 Coupling of (S)-1-
§. These authors contributed equally to this work.
Bull. Korean Chem. Soc. 2016, Vol. 37, 1910–1911
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BULLETIN OF THE
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NO2
HO
HO
OH
OH
HO
OH
OEt
a
c
O
O
b
O
O
EtO
EtO
OEt
O
O
O O
HO
O
OH
O
O
OH
a
OH
b
O
O
1
2
3
4
13
(S)-11
(R)-11
O
O
O
O
O
e
h
d
f
i
O
O
O
O
HO
O
TsO
O
O
Scheme 3. Synthesis of (R)-(–)-matsutakeol by Mitsunobu inver-
sion. (a) p-Nitrobenzoic acid, DIAD, PPh3, THF, 79%;
(b) K2CO3, MeOH, 59%.
Pr
Pr
Pr
Pr
O
5
6
7
O
g
O
O
O
O
O
OH
OTs
I
CF3
10
9
H3CO
8
OH
a
O
O
74%
j
OH
(S)-11
(3S,R)-MTPA ester
(3R,R)-MTPA ester
(S)-11
OH
(R)-11
a
Scheme 1. Synthesis of (S)-(+)-matsutakeol. (a) H2SO4, EtOH,
88%; (b) 2,2-dimethoxypropane, p-TsOH, benzene, 89%;
(c) LAH, Et2O, 89%; (d) Pr(CO)2O, pyridine, 96%; (e) TOYOBO
lipase, pH 6.4 buffer, 90%; (f ) p-TsCl, 4-DMAP, TEA, CH2Cl2,
89%; (g) (C4H9)2CuLi, ether, 78%; (h) p-TsCl, 4-DMAP, TEA,
CH2Cl2, 90%; (i) NaI, acetone, 89%; (j) Zn, EtOH, 97%.
48%
Scheme 4. Synthesis of diastereomers from enantiomers. (a) (R)-
MTPA-Cl, DMAP, TEA, CH2Cl2.
Mosher’s ester. We expect this simple synthetic approach
to matsutakeol enantiomers to be useful in large scale syn-
thesis in perfume and food additive industry.
a
b
O
O
O
O
O
O
Acknowledgments. This research was supported by the
Kyungpook National University Research Grant.
HO
OH
TsO
OTs
OTs
4
12
9
Scheme 2. Mono-alkylation. (a) p-TsCl, TEA, 4-DMAP, CH2Cl2,
82%; (b) (C4H9)2CuLi, ether, THF, 44%.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
octen-3-ol ((S)-11) and p-nitrobenzoic acid with diisopropyl
azodicarboxylate (DIAD) and triphenylphosphine (PPh3) in
THF successfully proceeded to afford stereoinverted ester
13 (79% yield). Base hydrolysis of ester 13 furnished natu-
ral (R)-(–)-matsutakeol ((R)-11) in 59% yield.
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Finally, to identify enantiomeric purity of each enantio-
meric product, we synthesized Mosher’s ester using the chi-
ral derivatization reagent, Mosher’s acid chloride.13
Coupling ((S)-11) or ((R)-11) with (R)-(−)-α-methoxy-
α-(trifluoromethyl)phenylacetyl chloride ((R)-MTPA-Cl)
was accomplished in moderate to good yield (Scheme 4,
74 and 48%, respectively). Then, each diastereomer ((3S,R)-
MTPA ester and (3R,R)-MTPA ester) was successfully
separated by gas chromatography (GC) (Figures S2 and S3).
The result indicated that the enantiomeric excess (ee) of (S)-
11 was over 99%, and that of (R)-11 was 97% ee.
In summary, we achieved a facile synthesis of (S)-
(+)-matsutakeol ((S)-11) in 10 steps including effective
enzyme-mediated regioselective hydrolysis, a mild alkyla-
tion, and a zinc-based elimination reaction in 32% overall
yield from L-tartaric acid (1). In addition, we used mono-
alkylation as a key step to provide (S)-(+)-matsutakeol ((S)-
11) in 7 steps in 21% overall yield, saving four steps from
the previous strategy. Furthermore, we succeeded in synthe-
sizing natural (R)-(–)-matsutakeol ((R)-11) from (S)-
(+)-matsutakeol ((S)-11) via Mitsunobu inversion, and
identified the structure of each stereoisomer via the
12. K. C. Swamy, N. N. Kumar, E. Balaraman, K. V. Kumar,
Chem. Rev. 2009, 109, 2551.
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Bull. Korean Chem. Soc. 2016, Vol. 37, 1910–1911
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1911