Practical synthesis of mumefural, a component of Japanese apricot juice concentrate

Article abstract of DOI:10.1016/j.tet.2016.10.026

A practical four-step method for the synthesis of mumefural from malic acid is described. The key step of this method involves the alkylation of acetal-protected malic acid with bromoacetate, followed by condensation with 5-(hydroxymethyl)furfural. Some of the¹³C NMR data for our products differed from those previously reported, and further analysis indicated that the previously reported assignments were partly erroneous.

Full text of DOI:10.1016/j.tet.2016.10.026

Tetrahedron xxx (2016) 1e4
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Practical synthesis of mumefural, a component of Japanese apricot
juice concentrate
*
Hideyuki Sugimura , Mao Kikuchi, Saori Kato, Wataru Sekita, Ikuo Sasaki
Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, 5-10-1, Fuchinobe, Chuo-ku,
Sagamihara-shi, 252-5258, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical four-step method for the synthesis of mumefural from malic acid is described. The key step of
this method involves the alkylation of acetal-protected malic acid with bromoacetate, followed by
condensation with 5-(hydroxymethyl)furfural. Some of the 13C NMR data for our products differed from
those previously reported, and further analysis indicated that the previously reported assignments were
partly erroneous.
Received 10 September 2016
Received in revised form 7 October 2016
Accepted 11 October 2016
Available online xxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Citric acid
5-(hydroxymethyl)furfural
Gram-scale synthesis
Correction of 13C NMR data
1. Introduction
Retrosynthetic analysis of mumefural suggested a route that
proceeds via condensation of the appropriately protected citric
Mumefural (1, see Fig. 1), a simple monoester of 5-(hydrox-
ymethyl)furfural (HMF, 3) and citric acid, is known to improve
human blood fluidity.1 It also exhibits potent multiple inhibitory
effects on the pandemic influenza A (H1N1) virus.2 It may be iso-
lated from Japanese apricot juice concentrate as a racemate but is
not detected in the fresh fruit, suggesting that it is produced arti-
ficially during the processing of the fruit. Suzuki et al. have been
reported a thermal condensation process for the production of
mumefural directly from fructose and citric acid;2 however an ap-
propriate synthetic route that could be employed to supply suffi-
cient material for thorough biological screening has not yet been
reported. Therefore, we herein report the development of a practi-
cal synthetic method for mumefural in consideration of the ability
to perform on a gram-scale.
acid derivative 2 and HMF (3), as shown in Scheme 1. The ester
Fig. 1. Structure of mumefural (1).
Scheme 1. Retrosynthetic analysis of mumefural (1).
* Corresponding author. E-mail address: sugimura@chem.aoyama.ac.jp (H. Sugimura).
http://dx.doi.org/10.1016/j.tet.2016.10.026
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2
H. Sugimura et al. / Tetrahedron xxx (2016) 1e4
linkage and acid-sensitive furan ring in mumefural require that
the protecting groups in the citric acid moiety are removable
under mild reaction conditions. As shown in the structure of 2,
cyclic acetal protection was used for the internal carboxylic acid
and hydroxy groups, and tert-butyl ester protection was used for
one of the terminal carboxylic acids because both these pro-
tecting groups can be removed under mildly acidic conditions
without cleavage of the internal ester bond. The protected citric
indicates that cleavage of the ester linkage between the citric moiety
and HMF occurs preferentially over deprotection. Next, we attemp-
ted to remove the trichloroethylidene acetal of 6b by treatment with
zinc dust in an aqueous phosphate buffer, yielding b-elimination
product 8 (Scheme 4). Removal of the dichlorovinyl ether moiety in
compound 8 was attempted under several different acidic condi-
tions, resulting in hydrolysis of the t-butyl ester alone. After several
attempts at hydrolysis of 6b under acidic or basic conditions, we
found that treatment of 6b with 50% CF3CO2H/CH2Cl2 at rt for 3 h
followed by hydrolysis of the resultant cyclic acetal 7b with aqueous
70% CH3CO2H at 100 ꢁC for 16 h afforded mumefural in 68% yield
(Scheme 5).
acid 2 is prepared through the
a-alkylation of acetal-protected
malic acid 4 with t-butyl bromoacetate (5) according to pre-
cedent studies by Tietze et al.3 and Barrett et al.4 Because
mumefural is a racemic compound, inexpensive DL-malic acid
was used as the starting material in this study. However, based
on Seebach’s concept of the self-regeneration of stereogenic
centers,5 optically active 4 may be prepared starting from
D- or L-
malic acid, facilitating an enantioselective synthesis of mume-
fural for future studies.
2. Results and discussion
Our investigation began with the preparation of two cyclic
acetal-protected malic acids, 4a,b based on previously reported
procedures6,7 (see Scheme 2). The conversion of 4a,b into citrate
derivatives 2a,b was achieved by deprotonation with lithium hex-
amethyldisilazide in THF at ꢀ78 ꢁC for 1 h. After addition of t-butyl
bromoacetate, the temperature was raised to ꢀ10 ꢁC over 3 h. These
conditions, reported by Tietze et al.3 as an improvement of the
original procedure developed by Seebach,8 afforded 2a,b in mod-
erate yields, and with high diastereoselectivity for 2b.9 Ester for-
mation between citrate 2a,b and HMF mediated by DCC afforded
the protected mumefural 6a,b in good yields.
Scheme 3. Reagents and conditions: (a) 50% CF3CO2H/CH2Cl2, rt, 4 h, 92%.
Scheme 4. Reagents and conditions: (a) Zn, THF/1 M KH2PO4 aq, rt, 3 h, 74%.
Scheme 5. Reagents and conditions: (a) 50% CF3CO2H/CH2Cl2, rt, 1 h (b) 70% CH3CO2H
aq, 100 ꢁC, 16 h, 68% from 6b in two steps.
The 1H NMR chemical shifts and coupling constants of our
product perfectly matched the values reported for this compound
by Chuda et al.; however, the 13C NMR chemical shifts do not match
their reported values partly (see Table 1).1 In our 13C NMR spec-
trum, there is no peak around 110.0 ppm; instead, there is a peak at
123.2 ppm. The well-established 13C NMR chemical shifts of HMF10
are also shown in Table 1. In addition, the 13C NMR peaks of acet-
ylated HMF (Ac-HMF, 5-acetoxymethyl-furfural) appear at 20.8
(Ac), 57.9, 112.7, 121.8, 153.0, 155.6, 170.5 (Ac), and 178.0 ppm,11
revealing a high degree of similarity in the values for the HMF
moieties in mumefural and Ac-HMF. These data indicate that
123.2 ppm is the correct chemical shift for C-3 and that 113.4 ppm is
correct for C-4, not C-3. Thus, the C-3 and C-4 chemical shifts re-
ported by Chuda et al. appear to be erroneous.
Scheme 2. Reagents and conditions: (a) Ref.
6 for 4a, 84%; Ref. 7c for 4b, 99%
(trans:cis¼6:1) (b) LiHMDS (2 equiv), THF, e78 ꢁC, 1 h, then BrCH2CO2t-Bu to ꢀ10 ꢁC,
3 h, 66% for 2a, 58% for 2b (as a single diastereomer) (c) 3 (1.2 equiv), DCC (1.1 equiv),
DMAP (0.1 equiv), CH2Cl2, rt, 3 h, 69% for 6a, 91% for 6b.
3. Conclusion
Deprotection of compounds 6a,b was then performed. Treatment
of 6a with 50% CF3CO2H in CH2Cl2 gave the terminal carboxylic acid
7a in 90% yield. However, hydrolysis of the acetal protection from 7a
under a variety of both acidic and basic conditions resulted in the
formation of HMF alone as an isolable product (Scheme 3). This
In conclusion, we achieved the total synthesis of mumefural in
four steps and 35% overall yield from DL-malic acid via acetal 4b.
This synthetic route provides practical access to mumefural in the
gram-scale quantities needed for thorough biological screening. In
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H. Sugimura et al. / Tetrahedron xxx (2016) 1e4
3
Table 1
4.3. 2-(4-(2-(tert-Butoxy)-2-oxoethyl)-5-oxo-2-(tri-
chloromethyl)-1,3-dioxolan-4-yl)acetic acid (2b)
Comparison of the 13C NMR data for mumefural obtained in this work with those
reported by Chuda et al.
To a solution of 4b7c (2.64 g, 10.0 mmol) in THF (100 mL) was
added LiHMDS (21 mL, 21 mmol, 1.0 M in THF) dropwise over
a period of 20 min at ꢀ78 ꢁC and stirred for 1 h. After addition of
t-butyl bromoacetate (2.2 mL, 15 mmol) over a period of 5 min,
the temperature was raised to 0 ꢁC over a period 3 h. The
resulting solution was partitioned between EtOAc and 1 M HCl
and extracted with EtOAc. The combined organic layer was dried
over MgSO4, the solvent was removed under reduced pressure,
and the residue was purified by column chromatography
(hexane:EtOAc¼1:1) to give 2b (2.19 g, 58%) as a yellow solid. IR
(KBr) 3426, 2984, 2938, 1827, 1716, 1379, 1334, 1252, 1194, 1068,
Position
Mumefurala
Mumefural (Ref. 1)b
HMF (Ref. 10)c
2
3
4
5
6
7
10
11
12
13
14
153.9
123.2
113.4
156.3
178.6
58.6
43.2
73.7
43.5
171.7
174.8
154.0
113.4
110.0
156.4
178.5
58.6
43.2
73.5
43.5
171.5
174.7
152.1
122.7
109.9
160.4
177.4
57.6
d
856, 648, 632 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼1.48 (s, 9H),
d
2.89 (d, J¼16.0 Hz, 1H), 3.04 (d, J¼17.8 Hz, 1H), 3.09 (d, J¼16.0 Hz,
d
1H), 3.51 (d, J¼17.8 Hz, 1H), 5.95 (s, 1H); 13C NMR (125 MHz,
d
d
CDCl3):
d
¼28.1, 41.2, 41.6, 78.8, 83.1, 96.3, 105.2, 168.8, 171.0,
a
Recorded in acetone-d6 at 125 MHz.
Recorded in acetone-d6 at 75 MHz.
Recorded in CDCl3 at 100 MHz.
172.9; HRMS (ESI) m/z calcd for C12H15O7Cl3Na 398.9776, found
[MþNa]þ 398.9777.
b
c
4.4. tert-Butyl 2-(4-(2-((5-formylfuran-2-yl)methoxy)-2-
oxoethyl)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (6a)
addition, because of high diastereoselectivity observed in the al-
kylation of 2b, enantiomerically pure mumefural will be obtained
when D- or L-malic acid is used as the starting material. Moreover,
To a solution of 2a (1.35 g, 4.7 mmol), 5-hydroxymethylfurfural
(0.66 g, 5.2 mmol), and 4-dimethylaminopyridine (0.20 g,
1.64 mmol) in dichloromethane (20 mL) was added dicyclohex-
ylcarbodiimide (1.06 g, 5.2 mmol) at rt and stirred for 3 h. The re-
action mixture was filtered through a pad of Celite, and the filtrate
was extracted with saturated aqueous NaHCO3. The organic layer
was dried over MgSO4, the solvent was removed under reduced
pressure, and the residue was purified by column chromatography
(hexane:EtOAc¼3:1) to give 6a (1.28 g, 69%) as a dark yellow syrup.
because the mumefural exhibits significant pharmacological ac-
tivity, the specific biological activities of optically active mumefural
are of particular interest, and their synthesis is currently under
investigation in our laboratory.
4. Experimental section
4.1. Materials and methods
IR (neat) 2983, 2941, 1795, 1739, 1684, 1526, 1377, 1226, 936 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼1.46 (s, 9H), 1.58 (s, 3H), 1.62 (s, 3H),
All experiments were performed in well-dried glassware fitted
with rubber septa under argon atmosphere. Solvents and com-
mercially available chemicals were purified by standard methods or
used as purchased. Analytical TLC was performed on silica gel
plates 60 F254 (Merck Co.). Flash column chromatography was
performed on silica gel 60A (Kanto Co.). IR spectra were recorded
on a JASCO FTIR-4100A spectrometer as thin film. NMR spectra
were recorded on a JEOL JMN-500II spectrometer in CDCl3 or ace-
tone-d6 with TMS as the internal standard. HRMS was obtained
using a Thermo Scientific Exactive spectrometer (ESI).
2.79 (d, J¼16.0 Hz, 1H), 2.91 (d, J¼16.0 Hz, 1H), 2.92 (d, J¼16.0 Hz,
1H), 3.13 (d, J¼16.0 Hz, 1H), 5.17 (s, 2H), 6.61 (d, J¼4.0 Hz, 1H), 7.21
(d, J¼4.0 Hz, 1H), 9.65 (s, 1H); 13C NMR (125 MHz, CDCl3):
¼27.6,
d
27.7, 28.0, 41.1, 42.4, 58.3, 77.8, 82.1, 111.0, 112.9, 121.7, 152.9, 154.7,
167.7, 168.2, 172.4, 177.8; HRMS (ESI) m/z calcd for C19H24O9Na
419.1313, found [MþNa]þ 419.1311.
4.5. tert-Butyl 2-(4-(2-((5-formylfuran-2-yl)methoxy)-2-
oxoethyl)-5-oxo-2-(trichloromethyl)-1,3-dioxolan-4-yl)ace-
tate (6b)
4.2. 2-(4-(2-(tert-Butoxy)-2-oxoethyl)-2,2-dimethyl-5-oxo-
1,3-dioxolan-4-yl)acetic acid (2a)
To a solution of 2b (2.10 g, 5.6 mmol), 5-hydroxymethylfurfural
(0.85 g, 6.7 mmol), and 4-dimethylaminopyridine (54 mg,
0.44 mmol) in dichloromethane (30 mL) was added dicyclohex-
ylcarbodiimide (1.26 g, 6.1 mmol) at rt and stirred for 3 h. The re-
action mixture was filtered through a pad of Celite, and the filtrate
was extracted with saturated aqueous NaHCO3. The organic layer
was dried over MgSO4, the solvent was removed under reduced
pressure, and the residue was purified by column chromatography
(hexane:EtOAc¼2:1) to give 6b (2.46 g, 91%) as a white solid. IR
(neat) 2981, 2938, 1820, 1723, 1685, 1525, 1370, 1189, 1154, 1008,
To a solution of 4a6 (2.68 g, 15.4 mmol) in THF (150 mL) was
added LiHMDS (32.2 mL, 32.2 mmol, 1.0 M in THF) dropwise over
a period of 20 min at ꢀ78 ꢁC and stirred for 1 h. After addition of t-
butyl bromoacetate (4.5 mL, 31 mmol) over a period of 5 min, the
temperature was raised to ꢀ10 ꢁC over a period 3 h. The resulting
solution was partitioned between EtOAc and 1 M HCl and extracted
with EtOAc. The combined organic layer was dried over MgSO4, the
solvent was removed under reduced pressure, and the residue was
purified by column chromatography (hexane:EtOAc¼1:1) to give 2a
(2.92 g, 66%) as a yellow syrup. IR (neat) 3545, 3211, 2985, 1793,
1736, 1378, 1298, 1218, 1162, 936 cmꢀ1; 1H NMR (500 MHz, CDCl3):
822, 636 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d¼1.47 (s, 9H), 2.86 (d,
J¼15.5 Hz, 1H), 3.01 (d, J¼17.8 Hz, 1H), 3.05 (d, J¼15.5 Hz, 1H), 3.48
(d, J¼17.8 Hz, 1H), 5.16 (d, J¼13.5 Hz, 1H), 5.22 (d, J¼13.5 Hz, 1H),
5.91 (s, 1H), 6.61 (d, J¼3.4 Hz, 1H), 7.20 (d, J¼3.4 Hz, 1H), 9.64 (s,
d
¼1.47 (s, 9H), 1.62 (s, 3H), 1.64 (s, 3H), 2.80 (d, J¼10.0 Hz, 1H), 2.91
(d, J¼16.0 Hz, 1H), 2.98 (d, J¼16.0 Hz, 1H), 3.12 (d, J¼16.9 Hz, 1H);
13C NMR (125 MHz, CDCl3):
1H); 13C NMR (125 MHz, CDCl3):
96.3, 105.1, 113.0, 121.6, 153.0, 154.6, 167.2, 168.8, 170.9, 177.9; HRMS
(ESI) m/z calcd for C18H19O9Cl3Na 506.9987, found [MþNa]þ
506.9985.
d
¼28.1, 41.2, 41.6, 58.5, 78.8, 83.1,
d
¼27.5, 27.7, 28.0, 41.2, 42.4, 77.7, 82.1,
111.1, 167.8, 172.6, 174.2; HRMS (ESI) m/z calcd for C13H20O7Na
311.1101, found [MþNa]þ 311.1100.
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4
H. Sugimura et al. / Tetrahedron xxx (2016) 1e4
4.6. 2-(4-(2-((5-Formylfuran-2-yl)methoxy)-2-oxoethyl)-2,2-
dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (7a)
J¼3.4 Hz, 1H), 9.64 (s, 1H); 13C NMR (125 MHz, acetone-d6):
d
¼43.2, 43.5, 58.6, 73.6, 113.4, 123.2, 153.9, 156.3, 169.8, 171.7,
174.8, 178.5; HRMS (ESI) m/z calcd for C12H12O9Na 323.0374,
found [MþNa]þ 323.0372.
To a solution of 6a (0.30 g, 0.67 mmol) in dichloromethane
(1.8 mL) was added trifluoroacetic acid (1.8 mL) at 0 ꢁC and stirred
at rt for 4 h. After addition of toluene (20 mL), the solvents was
removed under reduced pressure, and the residue was purified by
column chromatography (CHCl3: MeOH¼19:1) to give 7a (0.21 g,
92%) as a yellow syrup. IR (neat) 3523, 3004, 2941, 1793, 1740, 1682,
4.8.1. Gram-scale reaction. To a solution of 6b (2.58 g, 5.32 mmol)
in CH2Cl2 (16 mL) was added CF3CO2H (16 mL) at 0 ꢁC. The reaction
mixture was stirred at rt for 3 h. After the solvent was removed
under reduced pressure, the residue was dissolved in aqueous 70%
CH3CO2H solution (50 mL). The resulting mixture was stirred at
100 ꢁC for 16 h and concentrated under reduced pressure. The
residue was purified by dry silica gel chromatography
(CHCl3:MeOH¼19:1, CHCl3:MeOH:HCO2H¼19:1:0.05 to 9:1:0.05)
to give 1 (0.77 g, 49%) along with 7b (1.02 g, 45%), which was again
treated with aqueous 70% CH3CO2H in the same manner above to
give 1 (0.33 g). Thus, 1 was obtained in total 1.10 g (69% yield).
1389, 1291, 1224, 1127, 935 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼1.59 (s, 3H), 1.61 (s, 3H), 2.93 (d, J¼16.0 Hz, 1H), 2.95 (d,
J¼16.0 Hz, 1H), 3.10 (d, J¼16.0 Hz, 1H), 3.15 (d, J¼16.0 Hz, 1H), 5.18
(s, 2H), 6.62 (d, J¼4.0 Hz, 1H), 7.22 (d, J¼4.0 Hz, 1H), 9.64 (s, 1H); 13
C
NMR (125 MHz, CDCl3):
d
¼27.6, 27.7, 41.0, 41.2, 58.4, 77.5, 111.5,
113.1, 121.9, 152.9, 154.7, 168.1, 172.2, 173.4, 178.0; HRMS (ESI) m/z
calcd for C15H16O9Na 363.0687, found [MþNa]þ 363.0687.
4.7. 4-(tert-Butoxy)-2-((2,2-dichlorovinyl)oxy)-2-(2-((5-
formylfuran-2-yl)methoxy)-2-oxoethyl)-4-oxobutanoic acid (8)
Acknowledgements
We would like to thank Ms. Nozomi Ogasawara of Instrumental
Analysis Division, Global Facility Center, Creative Research In-
stitution, Hokkaido University for the HRMS measurement.
To a solution of 6b (0.23 g, 0.47 mmol) in THF (1.6 mL) was added
aqueous 1M KH2PO4 (0.32 mL) and zinc dust (0.31 g) at rt and stirred
for 3 h. The reaction mixture was filtered through a pad of Celite, and
the filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography (CHCl3:MeOH¼9:1) to give
8 (0.16 g, 74%) as a dark yellow syrup. IR (neat) 3491, 2981, 2938,
Supplementary data
Supplementary data (copies of 1H and 13C NMR spectra of com-
pounds 2a, 2b, 6a, 6b, and 1) associated with this article can be found
in the online version, at http://dx.doi.org/10.1016/j.tet.2016.10.026.
1737, 1680, 1525, 1370, 1157, 966, 734 cmꢀ1
;
1H NMR (500 MHz,
CDCl3):
d
¼1.45 (s, 9H), 2.94 (d, J¼16.0 Hz, 1H), 3.09 (d, J¼16.0 Hz,
1H), 3.11 (d, J¼16.0 Hz, 1H), 3.20 (d, J¼16.0 Hz, 1H), 5.16 (d, J¼13.2,
1H), 5.20 (d, J¼13.2 Hz, 1H), 6.62 (d, J¼4.0 Hz, 1H), 6.96 (s, 1H), 7.24
(d, J¼4.0 Hz, 1H), 9.61 (s, 1H); 13C NMR (125 MHz, CDCl3):
¼28.0,
d
References and notes
41.0, 42.1, 58.5, 80.9, 82.7, 108.2, 112.9, 122.4, 138.4, 152.8, 155.1,
168.6(ꢂ2), 168.8, 178.1; HRMS (ESI) m/z calcd for C18H20O9Cl2Na
473.0377, found [MþNa]þ 473.0377.
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To a solution of 6b (88 mg, 0.18 mmol) in CH2Cl2 (0.5 mL) was
added CF3CO2H (0.5 mL) at 0 ꢁC. The reaction mixture was stirred
at rt for 3 h. After the solvent was removed under reduced
pressure, the residue was dissolved in aqueous 70% CH3CO2H
solution (1.8 mL). The resulting mixture was stirred at 100 ꢁC for
16 h and concentrated under reduced pressure. The residue was
purified by dry silica gel chromatography (CHCl3:MeOH¼19:1,
CHCl3:MeOH:HCO2H¼19:1:0.05 to 9:1:0.05) to give 1 (37 mg,
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to the enantioselective synthesis will be the subject of a future publication.
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1199 cmꢀ1; 1H NMR (500 MHz, acetone-d6):
d
¼2.87 (d, J¼16.0 Hz,
1H), 2.93 (d, J¼15.5 Hz, 1H), 2.96 (d, J¼16.0 Hz, 1H), 3.01 (d,
J¼15.5 Hz, 1H), 5.19 (s, 2H), 6.76 (d, J¼3.4 Hz, 1H), 7.40 (d,
ꢀ
11. Coelho, J. A. S.; Trindade, A. F.; Andre, V.; Duarte, M. T.; Veiros, L. F.; Afonso, C. A.
M. Org. Biomol. Chem. 2014, 12, 9324e9328.
Please cite this article in press as: Sugimura, H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.10.026