Efficient and versatile synthesis of 5-O-acylquinic acids with a direct esterification using a p-methoxybenzyl quinate as a key intermediate

Article abstract of DOI:10.1016/j.tet.2014.08.064

An efficient and versatile synthesis of 5-O-acylquinic acids from commercially available (-)-quinic acid was accomplished. We designed p-methoxybenzyl quinate as a key intermediate, and two problems, the esterification of the sterically hindered 5-OH group for the concise divergent synthesis and the low yield of the final deprotection step, were solved. For the first problem, we improved Tanabe's method, TsCl/NMI-mediated esterification using free carboxylic acids, by the addition of i-Pr₂NEt. For the second problem, we established a TFA- or BCl₃/C₆HMe₅-catalyzed deprotection reaction for the final deprotection step. 5-O-Acylquinic acids were synthesized in seven steps with 45-60% overall yield.

Full text of DOI:10.1016/j.tet.2014.08.064

Tetrahedron xxx (2014) 1e11
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Efficient and versatile synthesis of 5-O-acylquinic acids with a direct
esterification using a p-methoxybenzyl quinate as a key
intermediate
,
b
b
b
Kin-ichi Oyama a , Noriyuki Watanabe , Tomomi Yamada , Masako Suzuki ,
*
Yukiko Sekiguchi b, Tadao Kondo b, Kumi Yoshida b
,
*
a Chemical Instrumentation Facility, Research Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
b Graduate School of Information Science, Nagoya University, Chikusa, Nagoya 464-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and versatile synthesis of 5-O-acylquinic acids from commercially available (ꢀ)-quinic acid
was accomplished. We designed p-methoxybenzyl quinate as a key intermediate, and two problems, the
esterification of the sterically hindered 5-OH group for the concise divergent synthesis and the low yield
of the final deprotection step, were solved. For the first problem, we improved Tanabe’s method, TsCl/
NMI-mediated esterification using free carboxylic acids, by the addition of i-Pr2NEt. For the second
problem, we established a TFA- or BCl3/C6HMe5-catalyzed deprotection reaction for the final de-
protection step. 5-O-Acylquinic acids were synthesized in seven steps with 45e60% overall yield.
Ó 2014 Published by Elsevier Ltd.
Received 19 April 2014
Received in revised form 5 August 2014
Accepted 26 August 2014
Available online xxx
Keywords:
5-O-Acylquinic acid
(ꢀ)-Quinic acid
PMB quinate
Esterification
1. Introduction
particular, possess remarkable and interesting biological activity.
For example, 3,4,5-tri-O-caffeoylquinic acid3a and 3,5-tri-O-caf-
Acylquinic acids are widely distributed in nature as plant-
derived (poly)phenols.1 They have attracted considerable atten-
tion because they exhibit a wide range of biological activities,
including antioxidation,2 anti-HIV-1 activity,3 antitumor activ-
ity,4 hepatoprotective activity,5 antifungal activity,6 collagenase
inhibition,7 flower color development,8 and plant disease pre-
vention.9 Interestingly, chlorogenic acid (3-O-caffeoylquinic acid)
has been detected as a fermentation product of wine by Sac-
charomyces cerevisiae although grapes lack acylquinic acids.10
Thus, 5-O-acylquinic acids and the related compounds will
probably be discovered in a wine during fermentation. Further-
more, acylquinic acid (i.e., chlorogenic acid) has been used to
comprehend the formation mechanism of glutathion-substituted
dihydroxyphenyl compounds formed during the oxidation of
white wine because the caffeic acid plays an important role in
wine oxidation.11 Di- and triacylquinic acid derivatives, in
feoylquinic acid3c are recognized to exhibit high potential as
anti-HIV-1 inhibitors. Of the monoacylquinic acid derivatives,
Cisneros-Zevallos et al. reported that chlorogenic acid and
5-O-caffeoylquinic acid (1) exhibited anti-breast cancer activi-
ty.4b It is well known that 1 and/or 5-O-p-coumaroylquinic acid
(2) work as essential co-pigments to produce the blue color of
hydrangeas.8 Recently, chlorogenic acid and 1 were reportedly
linked to the increased resistance of peaches to brown rot
infection.9
To investigate these unique biological properties of acylquinic
acid derivatives, especially those of 5-O-acylquinic acids, an
efficient and reliable synthetic methodology can be applied
not only for natural ones but also for molecular designed
analogs. Until now,
a number of synthetic routes toward
3-O-acylquinic acids have been reported.12 However, only
two examples for 5-O-acylquinic acids exist (Scheme 1).8b,c,13,14
In these syntheses, there are two problems. One is the esterifi-
cation of the sterically hindered axial 5-OH group. To achieve this
reaction, unstable acyl chloride is required.8b,c,13 The other
problem is the low yield of the final deprotection step. Under
acidic conditions, the competitive deacylation8b,c between the 5-
acyl group and the 1-methyl group and the acyl transfer occurs
* Corresponding authors. Tel./fax: þ81 (0)52 789 5638 (K.Y.); tel.: þ81 (0)52 789
3069; fax: þ81 (0)52 789 3068 (K.-i.O.); e-mail addresses: oyama@nagoya-u.ac.jp
(K.-i. Oyama), yoshidak@is.nagoya-u.ac.jp (K. Yoshida).
http://dx.doi.org/10.1016/j.tet.2014.08.064
0040-4020/Ó 2014 Published by Elsevier Ltd.
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2
K.-i. Oyama et al. / Tetrahedron xxx (2014) 1e11
(Scheme 1).8b,c,13 Thus, the choice of protecting group is crucial.
We overcame these two problems and achieved an efficient
and versatile synthesis of 5-O-acylquinic acids from (ꢀ)-quinic
acids. The key intermediate 4 could be prepared from (ꢀ)-quinic
acid (6).
acid using p-methoxybenzyl (PMB) quinate
4 as a key
intermediate.
Scheme 2. Retrosynthetic analysis of 5-O-acylquinic acids using PMB quinate 4.
2.3. Preparation of PMB quinate 4
Scheme 1. Previously reported route for 5-O-acylquinic acids using methyl quinate 3.
Methyl quinate 3 was prepared based on a previous report14 in
90% yield (Scheme 3). After the alkaline hydrolysis of 3, the PMB
group was introduced by regioselective esterification according to
Frost’s report (Scheme 3).22 However, the yield of this protection
step was quite low (25e40%). Thus, 4 was instead prepared using
protectionedeprotection techniques, as shown in Scheme 3. The
protection of 3 by TBSCl produced the TBS ether 7 in 98% yield.
Subsequent alkaline hydrolysis followed by protection with
PMBCl generated the PMB ester 8 in 93% yield. However, desily-
lation of 8 by TBAF produced PMB quinate 4 in modest yield (55%)
(Table 1, entry 1). A Sc(OTf)3-catalyzed desilylation23 increased
the yield (73%) (Table 1, entry 2). Finally, TBAF/AcOH gave 4 in 96%
yield24 (79% overall yield from 6) (Table 1, entry 3); its structure
was unambiguously proven by X-ray crystallographic analysis
(Fig. 1).
2. Results and discussion
2.1. Re-examination of the deprotection reaction of methyl 5-
O-caffeoylquinate (5) under hydrochloric acid
Initially, we re-examined the deprotection reaction of methyl 5-
O-caffeoylquinate (5) under hydrochloric acid. Sefkow et al. re-
ported that the treatment of 5 in 1 M HCl/THF at 23 ꢁC for 7 days
gave 5-O-caffeoylquinic acid (1) in 81% yield (Scheme 1).13 How-
ever, our re-examination only gave a yield of less than 30%. To in-
vestigate the cause of such a low yield, the stability of 1 was studied
under Sefkow’s deprotection condition.13 More than 40% of 1 was
decomposed after 7 days. Because hydrochloric acid obviously de-
composes 1 gradually, we reasoned that a mild acidic condition and
short reaction time should be required to solve the low yield of the
final deprotection step.
2.2. Synthetic strategy for 5-O-acylquinic acids
Our retrosynthetic analysis of 5-O-acylquinic acids is shown in
Scheme 2. Because the demethylation of 1-carboxylic acid might
require a hard acidic condition and/or a long reaction time, we
decided to replace the methyl group of the 1-carboxylic acid with
a PMB group, which can be easily deprotected by using mild
acidic conditions.15e20 Furthermore, we selected the MOM
(methoxymethyl) group as the protecting group of the hydrox-
ycinnamic moiety for the synthesis of 5-O-caffeoylquinic acid (1)
and 5-O-p-coumaroylquinic acid (2) due to the rapid and mild
deprotection under acidic conditions.21 5-O-Acylquinic acids
would be obtained by one-pot global deprotection from the cor-
responding 5-O-acyl PMB quinates. 5-O-Acyl PMB quinates could
be synthesized by direct esterification using free carboxylic
Scheme 3. Synthesis of PMB quinate 4.
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K.-i. Oyama et al. / Tetrahedron xxx (2014) 1e11
3
examined (Table 2).25,26 Tanabe’s esterification25 was carried out
using 2 equiv of cinnamic acid (9). The yield of the desired ester
10a was low (31%) (Table 2, entry 1). To enhance the nucleo-
philicity of alcohol 4, i-Pr2NEt was added to give a yield of
60%.27,28 As a further optimization, we found that the use of
Table 1
Conditions for optimizing the desilylation of 8
4 equiv of TsCl at 40 ꢁC in C2H4Cl2 in the presence of MS 4 A gave
ꢀ
10a in 81% yield (Table 2, entry 3, method A). Other esterification
methods were examined,26 but the yields were lower than our
improved TsCl/NMI/i-Pr2NEt-mediated esterification (Table 2,
entries 4e8).
Entry
Reagents
Yielda (%)
1
2
3
TBAF, THF
5 mol % Sc(OTf)3, CH3CN, H2O
TBAF, AcOH, THF
55
73
96
Next, 2-naphthoic acid (11) was tested (Table 3, entry 1, method
A). As expected, the desired ester 14a was obtained in high yield
(86%). However, 2-acylimidazole 15, unexpectedly was obtained as
a byproduct of the reaction in 35% yield (based on 11) due to
FriedeleCrafts-type C-acylation.29 In the absence of i-Pr2NEt, 15
was not observed. To prevent the generation of an acceptor of C-
acylation, NMI was added at the final step. As a result, the reaction
using 1.5 equiv of 11 at room temperature was carried out to give
the combined yield of 91% without 15 (Table 3, entry 2, method B).
The esterification of cinnamic acid (9) was re-examined using
method B (Table 3, entry 3), and it was found that method B was
superior to method A (Table 2, entry 3 vs Table 3, entry 3).
a
Isolated yield.
Table 3
TsCl/NMI-mediated esterification between PMB quinate 4 and carboxylic acids (9
and 11e13)
Entry
RCO2H (equiv)
Method Temp (ꢁC) yielda (%)
Fig. 1. X-ray crystal structure of PMB quinate 4.
1
2
3
A
B
B
40
rt
14a (86), 15 (35)b
14a (84), 14b (7)
10a (87), 10b (5)
2.4. Esterification of 5-OH of PMB quinate 4
With the key building block 4 in hand, various direct esteri-
fications to the sterically hindered axial 5-OH group were
rt
Table 2
Direct esterification of PMB quinate 4 with cinnamic acid (9)
4
B
40
16a (94), 16b (3)
5
6
B
C
40
40
17 (65)
17 (72)
Entry Reagents (equiv)
Temp (ꢁC) Solvent Yielda (%)
Method A: (1) RCO2H/TsCl/NMI/i-Pr2NEt¼1:2:3:3; (2) 4.
125
2
TsCl (2), NMI (6)
TsCl (2), NMI (6), i-Pr2NEt (6)
rt
rt
CH2Cl2 31
CH2Cl2 60
C2H4Cl2 81b,c
CH2Cl2 55
CH2Cl2 29
Method B: (1) RCO2H/TsCl/i-Pr2NEt¼1:2:3; (2) 4; (3) NMI (6 equiv).
Method C: (1) RCO2H/TsCl/NMI¼1:2:3; (2) 4.
a
ꢀ
Isolated yield.
3
TsCl (4), NMI (6), i-Pr2NEt (6), MS 4 A 40
b
426a
526b
626c
726d
826e
EDCI (2), DMAP (0.5)
rt
rt
rt
rt
rt
Compound 15 is 1-methyl-2-naphthoylimidazole. Yield is based on 11.
DCC (2), DMAP (2), HOBt (2)
EDCI (2), i-Pr2NEt (4), HOBt (1)
EDCI (2), i-Pe2NEt (4), HOAt (1)
TBTU (2), DBU (4)
DMF
DMF
DMF
4
5
19
With the reaction condition of method B in hand, the esterifi-
cation of 12 and 13 was examined (Table 3, entries 4e6). In the case
of 12 (1.1 equiv), the yield was 94%. However, the esterification of
the aliphatic carboxylic acid 13 gave a moderate yield of 17 (65%)
(Table 3, entry 5), whereas the corresponding esterification in the
absence of i-Pr2NEt afforded a higher yield (72%) (Table 3, entry 6).
Based on these observations, i-Pr2NEt was effective only for the
esterification of aromatic carboxylic acids.
NMI¼N-methylimidazole; EDCI¼1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;
DCC¼N,N0-dicyclohexylcarbodiimide; HOBt¼1-hydroxybenzotriazole; HOAt¼1-
hydroxy-7-azabenzotriazole;
TBTU¼2-(1H-benzotriazol-1-yl)-1,1,3,3-
tetramethyluronium tetrafluoroborate.
a
Isolated yield.
b
Method A: (1) RCO2H/TsCl/NMI/i-Pr2NEt¼1:2:3:;, (2) 4.
c
The corresponding 1,5-O-diacylquinate 10b was obtained in 4% yield.
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4
K.-i. Oyama et al. / Tetrahedron xxx (2014) 1e11
2.5. Deprotection of 5-O-acylquinic acids (10a, 14a, 16a, and
17)
The esterifications of PMB quinate 4 with carboxylic acids
28 and 29 were performed (Table 5) by using our method B.
Although the esterification of 29 needed 6 h, both reactions at
room temperature gave 30a and 31a in 86% and 83% yields,
respectively.
With PMB-protected 5-acylquinates (10a, 14a, 16a, and 17) in
hand, we examined mild deprotection reactions (TFA/PhOH,16
TfOH/p-TolSO2NH2/dioxane,17
CBr4/MeOH,18
CeCl3$7H2O/NaI/
CH3CN,19 and CAN/H2O/CH3CN20). However, the desired depro-
tection products were not obtained cleanly in any case. Then, TFA-
catalyzed deprotection was examined. According to the literature,15
the treatment of 10a with 10% TFA in CH2Cl2 at 25 ꢁC for 2 h was
conducted. This deprotection afforded mainly 18 as observed by
HPLC analysis. Furthermore, this reaction proceeded cleanly even
using 5% TFA in CH2Cl2 at 25 ꢁC for 2 h. As a further optimization,
the treatment of 10a with 5% TFA in CH2Cl2 at 0 ꢁC for 13 h afforded
18 in 87% yield (Table 4, entry 1). The deprotection of 14a, 16a, and
17 under the same TFA-catalyzed conditions gave the correspond-
ing 5-O-acylquinates (19, 20, and 21) in high yields (Table 4, entries
2e4). These deprotection yields were quite improved compared to
our previous results.8b,c
Table 5
TsCl/NMI/i-PrNEt2-mediated esterification between PMB quinate 4 and carboxylic
acids (28 and 29)
Entry
RCO2H (equiv)
Time (h)
Yielda (%)
Table 4
1
2
2
6
30a (86), 30b (<9)
31a (83), 31b (<4)
Global deprotection of 5-O-acyl PMB quinate (10a, 14a, 16a, and 17) using TFA
a
Isolated yield.
Entry
5-Acyl PMB quinate
Product
Yielda (%)
1
2
3
4
10a
14a
16a
17
18
19
20
21
87
80
80
79
The deprotection of 30a and 31a using the above optimized
conditions (5% TFA in CH2Cl2 for 13 h at 0 ꢁC) was conducted. Un-
expectedly, these deprotections gave only trace amounts of the
desired products. Even increasing the concentration of TFA to 10%
afforded 1 and 2 in 39% and 34% yields, respectively (Table 6, entries
1 and 2). To clarify the low yield of the deprotection, the reactions
of 30a and 31a were analyzed by NMR, HPLC, and ESI-Q-TOF-MS.
The NMR and HPLC profiles of the crude reaction mixtures of 30a
and 31a were sluggish due to having many unidentified byproducts
compared to that of 10a. ESI-Q-TOF-MS analysis revealed that the
MOM groups remained at the last stage accompanied with un-
desired decomposition. This might have arisen from the formal-
dehyde derived from the MOM group.30 To overcome these
problems, several protecting groups for the phenolic hydroxyl
moiety, such as PMB31 and 3,4-DMB (3,4-dimethoxybenzyl), were
examined using TFA-catalyzed deprotection conditions (10% TFA in
CH2Cl2 at 0 ꢁC). However, the yield of these reactions could not be
improved.
a
Isolated yield.
2.6. Synthesis of 5-O-caffeoylquinic acid (1) and 5-O-p-cou-
maroylquinic acid (2)
Having established both the esterification for the sterically
hindered 5-OH group and the condition for the final deprotection
step, the synthesis of 5-O-caffeoylquinic acid (1) and 5-O-p-cou-
maroylquinic acid (2) was carried out. The MOM group is well
known to be removed easily by TFA.21a,c,f Therefore, the MOM group
was used for the protection of the phenolic hydroxyl group. MOM-
protected carboxylic acids 28 and 29 were prepared from com-
mercially available 22 and 23, respectively (Scheme 4). Formation
of the methyl ester of 24 in the presence of Dowex Hþ in MeOH
followed by MOM etherification yielded 26. Subsequent hydrolysis
by KOH furnished the desired 28 in high yield. Additionally, car-
boxylic acid 29 was prepared in a similar manner (Scheme 4).
Table 6
Global deprotection of 5-O-acyl PMB quinates (30a and 31a)
Entry 5-Acyl PMB quinate Reaction conditions
Product Yielda (%)
1
30a
31a
30a
31a
10% TFA, 0 ꢁC, 13 h
2
1
2
1
34
39
73
69
2
10% TFA, 0 ꢁC, 13 h
3b
4b
BCl3/C6HMe5, ꢀ40 to 0ꢁC, 5 h
BCl3/C6HMe5, ꢀ40 to 0ꢁC, 3 h
a
Isolated yield.
BCl3 of 10 equiv was used. C6HMe5 (12.5 equiv).
Scheme 4. Synthesis of carboxylic acids 28 and 29.
b
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K.-i. Oyama et al. / Tetrahedron xxx (2014) 1e11
5
Our attention turned to Lewis acid deprotection conditions. BCl3
is a promising deprotection reagent for MOM32 and benzyl33,34
groups. Thus, the deprotection reaction of 31a using BCl3 in
CH2Cl2 was monitored by HPLC. This gave a simple chromatogram
in which 1 was a major peak with some unidentified peaks. To
prevent the side reactions by scavenging electrophiles derived from
the protecting groups, pentamethylbenzene (C6HMe5) as a cation
scavenger was added.34
[MꢀH]ꢀ 453.14, found 453.15). When the reaction temperature was
increased from ꢀ40 to 0 ꢁC for 1 h, 33 and the desired 1 were
detected (Fig. 2C). Eventually, this reaction was completed after 3 h
(Fig. 2D). To our delight, the deprotection of 31a with BCl3/C6HMe5
in CH2Cl2 gave pure 5-O-caffeoylquinic acid (1) in 69% yield by ODS
HPLC (Table 6, entry 4). The deprotection of 30a under the same
BCl3/C6HMe5-catalyzed conditions gave 5-O-p-coumaroylquinic
acid (2) in 73% yield (Table 6, entry 3).
In this reaction at ꢀ78 ꢁC, the MOM and PMB groups were re-
moved immediately, and the bisacetal group was cleaved gradually
(Fig. 2B). During the deprotection, the intermediates 32 and 33
were detected by the negative ESI-Q-TOF-MS (for 32: calcd for
3. Conclusion
In summary, an efficient and versatile synthesis of 5-O-acyl-
quinic acids was developed using PMB quinate 4 as a key in-
termediate. The overall yields were 45e60% in seven steps from
(ꢀ)-quinic acid (6). The key to the success of these syntheses was
the introduction of PMB and MOM groups, and their deprotection
by TFA and BCl3/C6HMe5. In addition, the use of i-Pr2NEt was found
to accelerate the TsCl/NMI-mediated esterification between the
sterically hindered axial alcohol 4 and the aromatic carboxylic
acids. Further applications of our novel synthetic route using PMB
quinate 4 for the synthesis of quinic acid derivatives are being
developed in our group.
C
22H27O11 [MꢀH]ꢀ 467.16, found 467.15, for 33: calcd for C21H25O11
4. Experimental section
4.1. General
Melting points (mp) were determined on a Yanaco MP-3 in-
strument and are uncorrected. Optical rotations were recorded on
a JASCO P-1010-GT polarimeter. Infrared (IR) spectra were recorded
on a JASCO FT/IR 6100 spectrometer. UV/VIS spectra were recorded
on a JASCO V560 spectrometer. 1H and 13C NMR spectra were
recorded on a JEOL JNM A400, a JNM ECA-600, and a JNM A600
spectrometer. Chemical shifts for 1H NMR are reported in parts per
million (ppm) downfield from tetramethylsilane (TMS) and are
referenced to residual solvent signals (CDCl3:
3.31 ppm, DMSO-d6: 2.49 ppm) or TMS (
ternal reference. Chemical shifts for 13C NMR were reported in the
scale relative to the NMR solvent (CDCl3: 77.0 ppm, CD3OD:
49.0 ppm, DMSO-d6: 39.5 ppm) as an internal reference. High-
d
7.26 ppm, CD3OD:
d
d
d 0.00 ppm) as an in-
d
d
d
resolution mass spectra (HRMS) were recorded on a JEOL JMS-700
(FAB) and Bruker micrOTOF-QII (ESI) spectrometer. Analytical HPLC
was conducted by our method8b,35 with an ODS column (Develosil
ODS-HG-5, 4.6 mm
f
ꢂ250 mm, Nomura Chemical) with some
modifications. The chromatography was performed by eluting at
1.0 mL/min with a linear gradient from 10% to 90% CH3CN in H2O
containing 0.5% TFA for 30 min at 40 ꢁC. Preparative ODS-HPLC was
performed by using a column (Develosil ODS-HG-5 20 mm
f
ꢂ250 mm, Nomura Chemical) with isocratic elution with 5%
CH3CN in H2O containing 0.5% TFA at 40 ꢁC.8b,35 Flash column
chromatography was performed on Fuji Silysia silica gel (PSQ 60B).
Analytical thin layer chromatography (TLC) was performed on
Merck precoated analytical plates, 0.25 mm thick, silica gel 60 F254
.
Preparative TLC separations were performed on Merck analytical
plates (0.50 mm thick) precoated with silica gel 60 F254. All com-
mercially available reagents and solvents were used directly
without further purification. All nonaqueous reactions were carried
out under an argon atmosphere.
4.2. Methyl (20S,30S)-3-O,4-O-(20,30-dimethoxybutane-20,30-
diyl)quinate (3)
To a solution of (ꢀ)-quinic acid (6) (1.0 g, 5.2 mmol), methyl
orthoformate (2.8 mL, 26.0 mmol), and 2,3-butandione (0.9 mL,
10.4 mmol) in MeOH (15 mL) was added CSA (12 mg, 5.2 mmol) at
room temperature and the resulting mixture was stirred for 45 h at
Fig. 2. HPLC chromatogram of the global deprotection reaction of 31a using a combi-
nation of BCl3 and C6HMe5 in CH2Cl2.
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6
K.-i. Oyama et al. / Tetrahedron xxx (2014) 1e11
85 ꢁC. The solvent was removed under reduced pressure and the
residue was purified by flash column chromatography (hexane/
AcOEt¼1:4) to give 3 as a white solid (1.495 g, 90%). Mp:
4.5. 4-Methoxybenzyl (20S,30S)-3-O,4-O-(20,30-dimethox-
ybutane-20,30-diyl)quinate (4)
137e138 ꢁC; [
a]
24 þ136.0 (c 1.0, CHCl3); IR (KBr) 3442, 2952, 1727,
To a solution of 8 (8.057 g, 14.9 mmol) in a mixture of THF
(35 mL) and AcOH (3.4 mL) was added TBAF (14.9 mL, 1.0 M in THF)
at room temperature. After stirring for 13 h at this temperature, the
reaction mixture was quenched with saturated aqueous NaHCO3.
The crude products were extracted with AcOEt. The combined ex-
tracts were dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography (50% AcOEt in hexane) to give 4 as a white solid
(6.108 g, 96%). Using EtOAc/hexane as solvent, alcohol 4 could be
crystallized to afford crystal suitable for X-ray analysis. Mp:
D
1451, 1279, 1243, 1133, 1042, 911 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d
1.29 (s, 3H), 1.33 (s, 3H), 1.91 (t, J¼12.5 Hz, 1H), 2.03 (dd, J¼15.0,
3.0 Hz, 1H), 2.09 (ddd, J¼12.5, 4.8, 3.0 Hz, 1H), 2.18 (td, J¼14.8,
3.0 Hz, 1H), 3.25 (s, 3H), 3.26 (s, 3H), 3.59 (dd, J¼10.5, 3.0, Hz, 1H),
3.78 (s, 3H), 4.18 (q, J¼3.0 Hz, 1H), 4.30 (ddd, J¼12.5, 10.5 4.8 Hz,
1H); 13C NMR (150 MHz, CDCl3)
d 17.7, 17.8, 37.4, 38.7, 47.9, 52.9,
62.4, 69.2, 72.8, 75.8, 99.8, 100.4, 174.3; HRMS (FAB) calcd for
C
14H24O8Na [MþNa]þ 343.1369, found 343.1364.
91e92 ꢁC; [
a
]
D
23 þ96.6 (c 1.0, CHCl3); IR (KBr) 3492, 2956, 1740, 1613,
4.3. Methyl (20S,30S)-5-O-tert-butyldimethylsilyl-3-O,4-O-
1515, 1383, 1249, 1130, 1032 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d
1.29
(20,30-dimethoxybutane-20,30-diyl)quinate (7)
(s, 3H), 1.33 (s, 3H), 1.91 (t, J¼12.5 Hz, 1H), 2.02 (dd, J¼14.5, 3.0 Hz,
1H), 2.06 (ddd, J¼12.5, 4.8, 3.0 Hz, 1H), 2.15 (dt, J¼14.5, 3.0 Hz, 1H),
3.24 (s, 3H), 3.25 (s, 3H), 3.56 (dd, J¼10.2, 3.0 Hz, 1H), 3.81 (s, 3H),
4.15 (q, J¼3.0 Hz, 1H), 4.30 (ddd, J¼12.5, 10.2, 4.8 Hz, 1H), 5.11 (d,
J¼12.0 Hz,1H), 5.16 (d, J¼12.0 Hz,1H), 6.88 (d, J¼8.5 Hz, 2H), 7.27 (d,
To a solution of methyl ester 3 (5.125 g, 16.0 mmol) and imid-
azole (2.178 g, 32.0 mmol) in DMF (40 mL) was added TBSCl
(4.823 g, 32.0 mmol) at room temperature. After stirring for 25 h at
this temperature, the reaction mixture was quenched with satu-
rated aqueous NH4Cl. The crude products were extracted with
AcOEt. The combined extracts were dried over anhydrous Na2SO4
and concentrated under reduced pressure. The residue was purified
J¼8.5 Hz, 2H); 13C NMR (150 MHz, CDCl3)
d 17.7, 17.8, 37.5, 38.5, 47.9,
55.3, 62.5, 67.5, 69.1, 72.8, 75.7, 99.7, 100.3, 114.0, 127.2, 130.1, 159.9,
173.9; HRMS (FAB) calcd for C21H30O9Na [MþNa]þ 449.1788, found
449.1778.
by flash column chromatography (15% AcOEt in hexane) to give 7 as
22
a white solid (6.842 g, 98%). Mp: 110e111 ꢁC; [
a
]
þ102.0 (c 0.5,
D
4.6. 4-Methoxybenzyl (20S,30S)-5-O-cinnamoyl-3-O,4-O-(20,30-
dimethoxybutane-20,30-diyl)quinate (10a) and 4-methox-
ybenzyl (20S,30S)-1,5-O-dicinnamoyl-3-O,4-O-(20,30-dimethox-
ybutane-20,30-diyl)quinate (10b) (method A, Table 2, entry 3)
CHCl3); IR (KBr) 3458, 2956, 1736, 1450, 1378, 1248, 1132, 1040, 978,
890, 781 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
0.12 (s, 3H), 0.18 (s, 3H),
0.91 (s, 9H), 1.27 (s, 3H), 1.29 (s, 3H), 1.87 (t, J¼12.5 Hz, 1H),
2.04e2.11 (m, 2H), 2.19 (ddd, J¼12.5, 4.8, 2.5 Hz, 1H), 3.22 (s, 3H),
3.24 (s, 3H), 3.49 (dd, J¼10.5, 2.5 Hz, 1H), 3.76 (s, 3H), 4.24e4.29 (m,
To a solution of carboxylic acid 9 (207 mg, 1.4 mmol), TsCl
(534 mg, 2.8 mmol), i-Pr2NEt (0.73 mL, 4.2 mmol), and MS 4 A (ca.
2.1 g) in dichloroethane (5 mL) was added NMI (0.33 mL,
4.2 mmol) at room temperature and the resulting mixture was
stirred for 30 min at this temperature. To the reaction mixture was
2H), 4.95 (s, H, OH); 13C NMR (125 MHz, CDCl3)
d 17.6,17.8,18.1, 25.7,
ꢀ
38.4, 39.4, 47.6, 47.8, 52.6, 62.4, 70.9, 72.8, 76.2, 99.4, 99.9, 173.7;
HRMS (FAB) calcd for C20H38O8SiNa [MþNa]þ 457.2234, found
457.2223.
added
a solution of alcohol 4 (300 mg, 0.7 mmol) in di-
4.4. 4-Methoxybenzyl (20S,30S)-5-O-tert-butyldimethylsilyl-3-
O,4-O-(20,30-dimethoxybutane-20,30-diyl)quinate (8)
chloroethane (5 mL) at room temperature. After stirring for 2 h at
40 ꢁC, the reaction mixture was quenched with saturated aqueous
NH4Cl. The crude products were extracted with AcOEt. The com-
bined extracts were washed with saturated aqueous NaHCO3, and
dried over anhydrous Na2SO4. The solvent was concentrated under
reduced pressure and the residue was purified by flash column
chromatography (30% AcOEt in hexane) to give 10a (318 mg, 81%)
and 10b (19 mg, 4%).
To a solution of 7 (3.872 g, 8.9 mmol) in THF (12 mL) was added
aqueous KOH (12 mL, 1.0 M) at room temperature. After stirring for
75 min at this temperature, the reaction mixture was neutralized
with 0.5 M NaHSO4 and then the crude products were extracted
with AcOEt. The combined extracts were dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure to give
a crude carboxylic acid. The crude product was used in the next step
without further purification. To a solution of the crude carboxylic
acid and Cs2CO3 (4.354 g, 13.4 mmol) in DMF (20 mL) was added
PMBCl (1.8 mL, 13.4 mmol) at room temperature. After stirring for
2 h at 80 ꢁC, the reaction mixture was quenched with saturated
aqueous NH4Cl. The crude products were extracted with AcOEt. The
combined extracts were dried over anhydrous Na2SO4 and con-
centrated under reduced pressure. The residue was purified by
27
4.6.1. Compound 10a. White solid; mp: 69e70 ꢁC; [
0.5, CHCl3); IR (KBr) 3359, 3260, 2951, 2835, 1714, 1515, 1308, 1249,
1131, 1036 cmꢀ1; UV (CHCl3) lmax/nm ( ), 281 (17,000); 1H NMR
(600 MHz, CDCl3) 1.28 (s, 3H), 1.29 (s, 3H), 1.97e2.03 (m, 2H), 2.09
a
]
þ59.6 (c
D
3
d
(dd, J¼15.0, 3.0 Hz, 1H), 2.24 (td, J¼15.0, 3.0 Hz, 1H), 3.25 (s, 3H),
3.30 (s, 3H), 3.69 (dd, J¼10.0, 3.0 Hz, 1H), 3.82 (s, 3H), 4.43 (td,
J¼10.0, 5.8 Hz, 1H), 5.10 (d, J¼12.0 Hz, 1H), 5.15 (d, J¼12.0 Hz, 1H),
5.33 (q, J¼3.0 Hz, 1H), 6.50 (d, J¼16.2 Hz, 1H), 6.89 (d, J¼8.4 Hz, 2H),
7.26 (d, J¼8.4 Hz, 2H), 7.37e7.40 (m, 3H), 7.53e7.54 (m, 2H), 7.71 (d,
flash column chromatography (15% AcOEt in hexane) to give 8 as
22
a white solid (4.473 mg, 93%). Mp: 71e72 ꢁC; [
a]
þ95.6 (c 0.2,
J¼16.2 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 17.6, 17.9, 36.5, 38.7,
D
CHCl3); IR (KBr) 3437, 2955, 1748, 1610, 1515, 1376, 1262, 1131, 984,
47.9, 48.0, 55.3, 62.9, 67.9, 69.8, 71.2, 74.5, 99.6, 100.1, 114.1, 118.5,
127.0, 128.2, 128.8, 130.2, 130.3, 134.6, 145.1, 160.0, 166.6, 175.0;
HRMS (FAB) calcd for C30H36O10Na [MþNa]þ 579.2206, found
576.2216.
846 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
0.11 (s, 3H), 0.16 (s, 3H), 0.90
(s, 9H), 1.26 (s, 3H), 1.28 (s, 3H), 1.83 (t, J¼12.5 Hz, 1H), 2.02e2.09
(m, 2H), 2.17 (ddd, J¼12.5, 4.5, 3.0 Hz, 1H), 3.20 (s, 3H), 3.22 (s, 3H),
3.46 (dd, J¼10.0, 3.0 Hz, 1H), 3.81 (s, 3H), 4.23 (q, J¼3.0 Hz, 1H), 4.26
(ddd, J¼12.5, 10.0, 4.5 Hz, 1H), 4.91 (s, 1H, OH), 5.08 (d, J¼12.0 Hz,
1H), 5.15 (d, J¼12.0 Hz, 1H), 6.87 (d, J¼8.5 Hz, 2H), 7.28 (d, J¼8.5 Hz,
24
4.6.2. Compound 10b. Colorless amorphous; [
a]
þ45.9 (c 0.27,
D
CHCl3); IR (KBr) 2948, 2836, 1716, 1637, 1517, 1450, 1246, 1170,
1108, 1036, 768 cmꢀ1; UV (CHCl3) lmax/nm ( ), 276 (32,000); 1H
NMR (500 MHz, CDCl3)
12.0 Hz, 1H), 2.24 (dd, J¼16.0, 3.0 Hz, 1H), 2.50 (ddd, J¼13.0, 4.0,
3.0 Hz, 1H), 2.97 (td, J¼16.0, 3.0 Hz, 1H), 3.26 (s, 3H), 3.34 (s, 3H),
2H); 13C NMR (125 MHz, CDCl3)
d
17.6, 17.8, 18.1, 25.7, 38.3, 39.3,
3
47.6, 47.7, 55.3, 62.5, 66.8, 70.9, 72.8, 76.1, 99.4, 99.9, 113.9, 127.8,
130.1, 159.7, 172.9; HRMS (FAB) calcd for C27H44O9SiNa [MþNa]þ
563.2652, found 563.2648.
d
1.27 (s, 3H), 1.30 (s, 3H), 1.92 (dd, J¼13.0,
Please cite this article in press as: Oyama, K.-i.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.08.064

K.-i. Oyama et al. / Tetrahedron xxx (2014) 1e11
7
3.72 (dd, J¼10.0, 3.0 Hz, 1H), 3.79 (s, 3H), 4.43 (ddd, J¼12.0, 10.0,
4.9. Compound 14a and 4-methoxybenzyl (20S,30S)-3-O,4-O-
(20,30-dimethoxybutane-20,30-diyl)-1-O-naphthoylquinate
(14b)
4.0 Hz, 1H), 5.09 (d, J¼12.0 Hz, 1H), 5.14 (d, J¼12.0 Hz, 1H), 5.44 (q,
J¼3.0 Hz, 1H), 6.32 (d, J¼16.5 Hz, 1H), 6.36 (d, J¼16.5 Hz, 1H), 6.85
(d, J¼8.5 Hz, 2H), 7.12 (t, J¼7.5 Hz, 2H), 7.20e7.26 (m, 5H), 7.25 (d,
J¼8.5 Hz, 2H), 7.31e7.36 (m, 3H), 7.63 (d, J¼16.0 Hz, 1H), 7.64 (d,
According to the procedure described for 10a (method B, Table
3, entry 3), 11 (65 mg, 0.376 mmol) was esterified with 4
(107 mg, 0.25 mmol) to afford 14a (122 mg, 84%) and 14b (13 mg,
7%), respectively (solvent used for flash column chromatography:
20e30% AcOEt in hexane).
J¼16.0 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 17.6, 17.8, 32.6, 36.7,
47.9, 48.0, 55.2, 62.8, 67.4, 68.8, 70.9, 79.7, 99.8, 100.1, 114.0, 117.6,
118.3, 127.4, 127.9, 128.1, 128.7, 128.9, 130.0, 130.2, 130.4, 133.9,
134.2, 145.0, 145.8, 159.7, 165.1, 166.2, 170.5; HRMS (FAB) calcd for
C
39H42O11Na [MþNa]þ 709.2625, found 709.2623.
4.9.1. Compound 14b. White solid; mp: 152e154 ꢁC; [
a
]
22 þ97.0 (c
D
0.2, CHCl3); IR (KBr) 2961, 2834, 1715, 1614, 1516, 1466, 1305, 1198,
4.7. Compounds 10a and 10b (method B, Table 3, entry 3)
1112, 930, 825 cmꢀ1; UV (CHCl3) lmax/nm (
3
), 247 (26,000); 1H NMR
(500 MHz, CDCl3)
d
1.25 (s, 3H), 1.34 (s, 3H), 2.13 (dd, J¼13.5, 12.0
To a solution of cinnamic acid 9 (74 mg, 0.5 mmol), TsCl
(191 mg, 1.0 mmol), and MS 4 A (ca. 0.8 g) in dichloroethane
(1.5 mL) was added i-Pr2NEt (262 mL, 1.5 mmol) at room temper-
ature and the resulting mixture was stirred for 30 min at this
temperature. To the reaction mixture was added a solution of al-
cohol 4 (107 mg, 0.25 mmol) in dichloroethane (1.8 mL) and
Hz, 1H), 2.37 (dd, J¼16.5, 3.5 Hz, 1H), 2.71 (td, J¼13.5, 3.5 Hz, 1H),
3.21 (td, J¼16.5, 3.5 Hz, 1H), 3.28 (s, 3H), 3.40 (s, 3H), 3.76 (s, 3H),
3.82 (dd, J¼10.5, 3.5 Hz,1H), 4.72 (ddd, J¼12.0, 10.5, 3.5 Hz,1H), 5.11
(d, J¼12.0 Hz,1H), 5.16 (d, J¼12.0 Hz,1H), 5.56 (q, J¼3.5 Hz,1H), 6.80
(d, J¼8.5 Hz, 2H), 7.11e7.15 (m, 2H), 7.22 (d, J¼8.5 Hz, 1H), 7.26e7.29
(m, 3H), 7.27 (d, J¼8.5 Hz, 2H), 7.34 (d, J¼8.5 Hz, 1H), 7.37 (ddd,
J¼8.0, 6.3, 1.5 Hz, 1H), 7.26e7.29 (m, 3H), 7.42 (td, J¼8.0, 1.0 Hz, 1H),
7.47 (t, J¼8.5 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H), 7.70 (dd, J¼8.5, 1.5 Hz,
1H), 7.75 (dd, J¼8.5, 1.5 Hz, 1H), 8.24 (s, 1H), 8.35 (s, 1H); 13C NMR
ꢀ
subsequently NMI (120
mL, 1.5 mmol) was added at room tem-
perature. After stirring for 2 h at 40 ꢁC, the reaction mixture was
quenched with saturated aqueous NH4Cl. The crude products were
extracted with AcOEt. The combined extracts were washed with
saturated aqueous NaHCO3, and dried over anhydrous Na2SO4. The
solvent was concentrated under reduced pressure and the residue
was purified by flash column chromatography (30% AcOEt in
hexane) to give 10a (122 mg, 87%) and 10b (9 mg, 5%),
respectively.
(125 MHz, CDCl3)
d 17.6, 17.8, 33.3, 36.5, 47.9, 48.1, 55.2, 62.7, 67.4,
70.0, 71.3, 80.3, 99.8, 100.0, 113.9, 124.7, 125.0, 126.1, 126.5, 127.3,
127.4, 127.6, 127.7, 127.8, 128.0, 128.9, 130.1, 131.0, 131.1, 131.9, 132.1,
135.1, 135.2, 159.7, 165.2, 166.4, 170.5; HRMS (FAB) calcd for
C
43H42O11Na [MþNa]þ 757.2625, found 757.2601.
4.10. 4-Methoxybenzyl (20S,30S)-5-O-benzoyl-3-O,4-O-(20,30-di-
methoxybutane-20,30-diyl)quinate (16a) and 4-methoxybenzyl
(20S,30S)-1,5-O-dibenzoyl-3-O,4-O-(20,30-dimethoxybutane-
20,30-diyl)quinate (16b)
4.8. 4-Methoxybenzyl (20S,30S)-3-O,4-O-(20,30-dimethox-
ybutane-20,30-diyl)-5-O-naphthoylquinate (14a) and 1-methyl-
2-naphthoylimidazole (15)
According to the procedure described for 10a (method B, Table
3, entry 3), 12 (60 mg, 0.495 mmol) was esterified with 4
(192 mg, 0.45 mmol) to afford 16a (225 mg, 94%) and 16b (9 mg,
3%), respectively (solvent used for flash column chromatography:
20e30% AcOEt in hexane).
According to the procedure described for 10a (method A, Table
2, entry 3), 11 (241 mg, 1.41 mmol) was esterified with 4 (300 mg,
0.7 mmol) to afford 14a (352 mg, 86%) and 15 (115 mg, 35% based on
11), respectively (solvent used for flash column chromatography:
20e30% AcOEt in hexane).
25
4.10.1. Compound 16a. Colorless amorphous; [
a]
þ31.2 (c 0.5,
D
23
4.8.1. Compound 14a. Colorless amorphous; [
a
]
þ62.1 (c 1.0,
CHCl3); IR (KBr) 3507, 2951, 2834, 1717, 1612, 1516, 1452, 1374, 1282,
1127, 714 cmꢀ1; UV (CHCl3) lmax/nm ( ), 241 (9400); 1H NMR
(400 MHz, CDCl3)
1.22 (s, 3H), 1.28 (s, 3H), 2.02 (d, J¼8.5 Hz, 2H),
D
CHCl3); IR (KBr) 3487, 2952, 2837, 1715, 1515, 1284, 1233,
1131 cmꢀ1; UV (CHCl3) lmax/nm ( ), 246 (27,000); 1H NMR
(600 MHz, CDCl3)
1.23 (s, 3H), 1.30 (s, 3H), 2.06 (d, J¼8.5 Hz,
3
3
d
d
2.14 (dd, J¼15.4, 3.2 Hz, 1H), 2.25 (td, J¼15.4, 1.2 Hz, 1H), 3.20 (br s,
1H, OH), 3.25 (s, 3H), 3.30 (s, 3H), 3.72 (dd, J¼10.2, 3.2 Hz, 1H), 3.82
(s, 3H), 4.54 (td, J¼10.2, 8.5 Hz, 1H), 5.09 (d, J¼12.0 Hz, 1H), 5.15 (d,
J¼12.0 Hz, 1H), 5.46 (q, J¼3.2 Hz, 1H), 6.89 (d, J¼8.5 Hz, 2H), 7.26 (d,
J¼8.5 Hz, 2H), 7.41e7.46 (m, 2H), 7.52e7.57 (m, 1H), 8.08 (dd, J¼8.6,
2H), 2.19 (dd, J¼15.4, 3.0 Hz, 1H), 2.32 (brd, J¼15.4 Hz, 1H), 3.27
(s, 3H), 3.35 (s, 3H), 3.76 (dd, J¼10.0, 3.0 Hz, 1H), 3.82 (s, 3H), 4.63
(td, J¼10.0, 8.5 Hz, 1H), 5.11 (d, J¼12.0 Hz, 1H), 5.16 (d, J¼12.0 Hz,
1H), 5.51 (q, J¼3.0 Hz, 1H), 6.89 (d, J¼7.0 Hz, 2H), 7.27 (d,
J¼7.0 Hz, 2H), 7.53 (t, J¼8.0 Hz, 1H), 7.58 (t, J¼8.0 Hz, 1H), 7.88 (d,
J¼8.0 Hz, 1H), 7.95 (d, J¼8.0 Hz, 1H), 8.10 (d, J¼8.0 Hz, 1H), 8.66 (s,
1.5 Hz, 2H); 13C NMR (150 MHz, CDCl3)
d 17.6, 17.8, 36.7, 38.7, 47.9,
48.0, 55.3, 62.8, 67.9, 70.1, 71.4, 74.5, 99.5, 100.0, 114.1, 127.0, 128.3,
129.9, 130.2, 130.8, 132.8, 160.0, 166.2, 175.1; HRMS (FAB) calcd for
1H); 13C NMR (150 MHz, CDCl3)
d 17.6, 17.8, 36.7, 38.8, 48.0, 55.3,
62.9, 68.0, 70.3, 71.5, 74.5, 99.6, 100.0, 114.1, 125.5, 126.4, 127.0,
127.7, 128.0, 128.1, 129.4, 130.2, 131.5, 132.6, 135.5, 160.0, 166.4,
175.1; HRMS (FAB) calcd for C32H36O10Na [MþNa]þ 603.2206,
found 603.2198.
C
28H34O10Na [MþNa]þ 553.2050, found 553.2039.
25
4.10.2. Compound 16b. Colorless amorphous; [
CHCl3); IR (KBr) 2949, 2835, 1719, 1517, 1282, 1126, 710 cmꢀ1; UV
(CHCl3) lmax/nm ( 1.21 (s,
), 241 (7400); 1H NMR (600 MHz, CDCl3)
a
]
þ56.3 (c 0.5,
D
3
d
4.8.2. Compound 15. Pale yellow oil; IR (neat) 3058, 2957, 1638,
3H), 1.30 (s, 3H), 2.07 (dd, J¼13.0, 12.5 Hz, 1H), 2.31 (dd, J¼16.0,
3.5 Hz, 1H), 2.63 (td, J¼13.0, 3.5 Hz,1H), 3.04 (td, J¼16.0, 3.5 Hz,1H),
3.26 (s, 3H), 3.28 (s, 3H), 3.79 (s, 3H), 3.76 (dd, J¼10.0, 3.5 Hz, 1H),
4.54 (ddd, J¼13.0, 10.0, 3.5 Hz, 1H), 5.09 (d, J¼12.0 Hz, 1H), 5.13 (d,
J¼12.0 Hz, 1H), 5.54 (q, J¼3.5 Hz, 1H), 6.82 (d, J¼8.8 Hz, 2H), 7.11 (t,
J¼8.0 Hz, 2H), 7.18 (t, J¼8.0 Hz, 2H), 7.21 (d, J¼8.8 Hz, 2H), 7.39e7.43
1466, 1401, 1274, 1236, 1162, 1118, 903, 781 cmꢀ1
;
1H NMR
(500 MHz, CDCl3)
d 4.12 (s, 3H), 7.14 (s, 1H), 7.28 (s, 1H), 7.53 (ddd,
J¼8.3, 7.0, 1.0 Hz, 1H), 7.59 (ddd, J¼8.3, 7.0, 1.0 Hz, 1H), 7.88 (d,
J¼8.5 Hz, 1H), 7.92 (d, J¼8.5 Hz, 1H), 8.01 (d, J¼8.5 Hz, 1H), 8.27 (dd,
J¼8.5, 1.5 Hz, 1H), 8.99 (br s, 1H); 13C NMR (125 MHz, CDCl3)
d 36.4,
125.9, 126.4, 126.7, 127.6, 127.8, 128.3, 129.3, 129.9, 132.4, 133.3,
134.5, 135.4, 143.3, 183.9; HRMS (ESI) calcd for C15H13N2O [MþH]þ
237.1022, found 237.1034.
(m, 2H), 7.78 (dd, J¼8.0, 1.0 Hz, 2H), 7.84 (dd, J¼8.0, 1.0 Hz, 2H); 13
C
NMR (150 MHz, CDCl3)
d 17.5, 17.7, 33.6, 36.3, 47.8, 48.0, 55.2, 62.6,
67.4, 69.6, 71.2, 80.3, 99.7, 100.0, 100.6, 113.9, 127.3, 128.0, 128.1,
Please cite this article in press as: Oyama, K.-i.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.08.064

8
K.-i. Oyama et al. / Tetrahedron xxx (2014) 1e11
129.4, 129.7, 130.1, 130.4, 132.5, 133.0, 159.7, 165.0, 166.1, 170.4;
HRMS (FAB) calcd for C35H38O11Na [MþNa]þ 657.2312, found
657.2312.
145.5, 148.4, 166.9; HRMS (FAB) calcd for C10H10O4 [MþH]þ
194.0579, found 194.0578.
4.14. Methyl (E)-4-O-methoxymethyl-p-coumarate (26)
4.11. 4-Methoxybenzyl (20S,30S)-3-O,4-O-(20,30-dimethox-
ybutane-20,30-diyl)-5-O-phenylethylcarbonylquinate (17)
(method C, Table 3, entry 6)
To a solution of methyl ester 24 (2.91 g, 16.3 mmol) and i-Pr2NEt
(5.7 mL, 49.0 mmol) in CH2Cl2 (60 mL) was added MOMCl (3.7 mL,
49.0 mmol) at room temperature and the mixture was stirred for
21 h at this temperature. The reaction mixture was quenched with
saturated aqueous NH4Cl. The crude products were extracted with
AcOEt. The combined extracts were dried over anhydrous Na2SO4
and concentrated under reduced pressure. The residue was purified
by flash column chromatography (10% AcOEt in hexane) to give 26
as a colorless oil (3.52 g, 97%). IR (neat) 2952, 2828,1791,1636,1604,
To a solution of carboxylic acid 13 (75 mg, 0.5 mmol), TsCl
ꢀ
(191 mg, 1.0 mmol), and MS 4 A (ca. 0.8 g) in dichloroethane
(1.5 mL) was added NMI (0.12 mL, 1.5 mmol) at room temperature
and the resulting mixture was stirred for 30 min at this tempera-
ture. To the reaction mixture was added a solution of alcohol 4
(107 mg, 0.25 mmol) in dichloroethane (1.5 mL) at room temper-
ature. After stirring for 2 h at 40 ꢁC, the reaction mixture was
quenched with saturated aqueous NH4Cl. The crude products were
extracted with AcOEt. The combined extracts were washed with
saturated aqueous NaHCO3, and dried over anhydrous Na2SO4. The
solvent was concentrated under reduced pressure and the residue
1510, 1436, 1315, 1242, 1170, 1081, 992, 831 cmꢀ1
;
1H NMR
(600 MHz, CDCl3) 3.45 (s, 3H), 3.79 (s, 3H), 5.20 (s, 2H), 6.32 (d,
d
J¼16.0 Hz, 1H), 7.04 (d, J¼8.5 Hz, 2H), 7.47 (d, J¼8.5 Hz, 2H), 7.65 (d,
J¼16.0 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 51.6, 56.1, 94.2, 115.8,
116.5, 128.2, 129.6, 144.4, 159.0, 167.7; HRMS (FAB) calcd for
C
12H15O4 [MþH]þ 223.0970, found 223.0978.
was purified by flash column chromatography (25% AcOEt in hex-
ane) to give 17 (100 mg, 72%) as a colorless amorphous. [a]
26
D
4.15. Methyl (E)-3,4-di-O-methoxymethylcaffeate (27)
þ66.5 (c 0.5, CHCl3); IR (KBr) 3523, 2952, 2835, 1732, 1615, 1518,
1452, 1376, 1245, 1131, 1032 cmꢀ1; UV (CHCl3) lmax/nm (
), 240
(6000); 1H NMR (600 MHz, CDCl3)
1.27 (s, 3H), 1.28 (s, 3H),
3
To a solution of methyl ester 25 (3.09 g, 15.9 mmol) and i-Pr2NEt
(13.9 mL, 79.6 mmol) in CH2Cl2 (60 mL) was added MOMCl (6.1 mL,
79.6 mmol) at room temperature and the mixture was stirred for
79 h at this temperature. The reaction mixture was quenched with
saturated aqueous NH4Cl. The crude products were extracted with
AcOEt. The combined extracts were dried over anhydrous Na2SO4
and concentrated under reduced pressure. The residue was purified
by flash column chromatography (30% AcOEt in hexane) to give 27
as a white solid (4.3 g, 96%). Mp: 40e41 ꢁC; IR (KBr) 2952, 2837,
1715, 1635, 1599, 1509, 1435, 1315, 1257, 1173, 1130, 1080, 1011,
d
1.92e1.99 (m, 2H), 2.03 (dd, J¼15.4, 3.0 Hz, 1H), 2.09 (td, J¼15.4,
3.0 Hz, 1H), 2.64 (ddd, J¼15.5, 8.5, 7.5 Hz, 1H), 2.72 (ddd, J¼15.5, 8.5,
6.5 Hz, 1H), 2.97e3.00 (m, 2H), 3.24 (s, 3H), 3.25 (s, 3H), 3.63 (dd,
J¼10.3, 3.0 Hz, 1H), 3.81 (s, 3H), 4.34 (td, J¼10.3, 5.5 Hz, 1H), 5.09 (d,
J¼12.0 Hz, 1H), 5.14 (d, J¼12.0, 1H), 5.25 (q, J¼3.0 Hz, 1H), 6.89 (d,
J¼8.4 Hz, 2H), 7.16e7.29 (m, 7H); 13C NMR (150 MHz, CDCl3)
d 17.6,
17.8, 30.9, 36.3, 36.4, 38.5, 47.9, 55.3, 62.6, 67.8, 69.5, 71.1, 74.4, 99.5,
100.0, 114.1, 126.1, 127.0, 128.3, 128.4, 130.2, 140.8, 159.9, 172.5,
174.9; HRMS (FAB) calcd for C30H38O10Na [MþNa]þ 581.2363, found
581.2351.
981 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d 3.51 (s, 3H), 3.53 (s, 3H), 3.79
(s, 3H), 5.25 (s, 2H), 5.26 (s, 2H), 6.32 (d, J¼16.0, 1H), 7.13e7.16 (m,
2H), 7.36 (d, J¼1.2 Hz, 1H), 7.61 (d, J¼16.0, 1H); 13C NMR (150 MHz,
4.12. Methyl (E)-p-coumarate (24)
CDCl3)
d 51.6, 56.2, 56.3, 95.1, 95.6, 115.7, 116.2, 116.4, 123.4, 128.9,
144.4, 147.4, 149.2, 167.5; HRMS (FAB) calcd for C14H18O6 [MþH]þ
To a solution of p-coumaric acid 22 (3.0 g, 18.3 mmol) in MeOH
(40 mL) was added Dowex 50W-X8 (2.4 g) at room temperature
and the resulting mixture was refluxed for 90 h. After the Dowex
50W-X8 was filtered, the solvent was removed under reduced
pressure and the residue was purified by flash column chroma-
tography (30% AcOEt in hexane) to give a methyl ester with trace
impurities. Recrystallization from CHCl3 gave 24 (2.91 g, 89%) as
a white solid in a pure form. Mp: 130e132 ꢁC; IR (KBr) 3384, 2952,
282.1103, found 282.1100.
4.16. (E)-4-O-Methoxymethyl-p-coumaric acid (28)
To a solution of methyl ester 26 (3.49 g, 15.7 mmol) in THF
(20 mL) was added aqueous KOH (37.5 mL, 1.0 M) at room tem-
perature. After stirring for 21 h at room temperature, the reaction
mixture was neutralized with aqueous NaHSO4 (0.5 M) and then
the product was extracted with AcOEt. The combined extracts were
dried over anhydrous MgSO4. After removal of the solvent in vacuo,
the residue was a pure form of 28 (3.21 g, 98%) as a white solid. Mp:
149e150 ꢁC; IR (KBr) 2955, 2825, 2590, 1687, 1623, 1603, 1511, 1430,
1689, 1634, 1602, 1517, 1435, 1284, 1200, 986, 834 cmꢀ1
(600 MHz, CDCl3)
3.80 (s, 3H), 5.33 (s, 1H; OH), 6.30 (d, J¼16.0 Hz,
1H), 6.85 (d, J¼8.5 Hz, 2H), 7.43 (d, J¼8.5 Hz, 2H), 7.64 (d, J¼16.0 Hz,
;
1H NMR
d
1H); 13C NMR (150 MHz, CDCl3)
144.8, 157.8, 168.1; HRMS (FAB) calcd for
179.0708, found 179.0700.
d 51.7, 115.1, 115.9, 127.1, 130.0,
10H11O3 [MþH]þ
1315, 1238, 1176, 1156, 1077, 1004, 829 cmꢀ1 1H NMR (600 MHz,
;
C
CDCl3)
d
3.49 (s, 3H), 5.21 (s, 2H), 6.34 (d, J¼16.0 Hz, 1H), 7.06 (d,
J¼8.5 Hz, 2H), 7.50 (d, J¼8.5 Hz, 2H), 7.75 (d, J¼16.0 Hz, 1H); 13C
4.13. Methyl (E)-caffeate (25)
NMR (150 MHz, CDCl3) d 56.2, 94.2, 115.0, 116.5, 127.8, 130.0, 146.6,
159.3, 171.7; HRMS (FAB) calcd for C11H13O4 [MþH]þ 209.0814,
To a solution of caffeic acid 23 (3.00 g, 16.7 mmol) in MeOH
(40 mL) was added Dowex 50W-X8 (2.4 g) at room temperature
and the resulting mixture was refluxed for 52 h. After filtration, the
solvent was removed under reduced pressure and the residue was
purified by flash column chromatography (50% AcOEt in hexane) to
give 25 as a white solid (3.09 g, 96%). Mp: 148e150 ꢁC; IR (KBr)
3477, 3091, 2952, 1677, 1606, 1445, 1308, 1281, 1243, 1191, 1113,
found 209.0807.
4.17. (E)-3,4-Di-O-methoxymethylcaffeic acid (29)
To a solution of methyl ester methyl ester 27 (4.30 g, 15.2 mmol)
in THF (20 mL) was added aqueous KOH (40 mL, 1.0 M) at room
temperature. After stirring for 21 h at room temperature, the re-
action mixture was neutralized with aqueous NaHSO4 (0.5 M) and
then the product was extracted with AcOEt. The combined extracts
were dried over anhydrous MgSO4. After removal of the solvent in
vacuo, the residue was a pure form of 29 (4.09 g, 99%) as a white
1045, 971, 864 cmꢀ1 1H NMR (600 MHz, DMSO-d6)
; d 3.68 (s, 3H),
6.26 (d, J¼16.0 Hz,1H), 6.75 (d, J¼8.4 Hz,1H), 6.99 (dd, J¼8.4, 2.1 Hz,
1H), 7.04 (d, J¼2.1 Hz, 1H), 7.47 (d, J¼16.0 Hz, 1H); 13C NMR
(150 MHz, DMSO-d6)
d 51.2, 113.7, 114.8, 115.7, 121.4, 125.4, 145.1,
Please cite this article in press as: Oyama, K.-i.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.08.064

K.-i. Oyama et al. / Tetrahedron xxx (2014) 1e11
9
solid. Mp: 120e121.5 ꢁC; IR (KBr) 2961, 2825, 2600, 1669, 1623,
1598, 1510, 1434, 1313, 1253, 1158, 1134, 1081, 1024, 992, 915 cmꢀ1
1H NMR (600 MHz, CDCl3)
3.52 (s, 3H), 3.54 (s, 3H), 5.27 (s, 2H),
2H), 7.37 (s, 1H), 7.63 (d, J¼16.0 Hz, 1H); 13C NMR (150 MHz, CDCl3)
;
d 17.7, 17.8, 36.6, 38.6, 47.9, 48.0, 55.3, 56.2, 56.3, 62.9, 67.9, 69.7,
d
71.2, 74.5, 95.1, 95.5, 99.5, 100.1, 114.1, 115.8, 116.1, 117.0, 123.6, 127.0,
129.1, 130.2, 144.8, 147.3, 149.1, 159.9, 166.7, 174.9; HRMS (FAB) calcd
for C34H44O14Na [MþNa]þ 699.2629, found 699.2604.
5.28 (s, 2H), 6.34 (d, J¼15.6, 1H), 7.17 (s, 2H), 7.39 (s, 1H), 7.71 (d,
J¼15.6 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 56.3, 56.4, 95.1, 95.5,
115.6, 115.9, 116.2, 123.8, 128.5, 146.6, 147.4, 149.6, 171.5; HRMS
(FAB) calcd for C13H16O6 [MþH]þ 268.0947, found 268.0948.
4.19.2. Compound 31b. 1H NMR (400 MHz, CDCl3)
d 1.30 (s, 3H),
1.33 (s, 3H), 1.86 (t, J¼13.0 Hz, 1H), 2.11 (dd, J¼16.0, 3.0 Hz, 1H), 2.44
(td, J¼13.0, 3.0 Hz, 1H), 2.84 (td, J¼16.0, 3.0 Hz, 1H), 3.25 (s, 3H),
3.27 (s, 3H), 3.52 (s, 3H), 3.53 (s, 3H), 3.79 (s, 3H), 4.15 (q, J¼3.0 Hz,
1H), 4.33 (ddd, J¼13.0, 10.0, 3.0 Hz, 1H), 5.09 (s, 1H), 5.10 (s, 1H),
5.25 (s, 2H), 5.27 (s, 2H), 6.31 (d, J¼16.0 Hz, 1H), 6.85 (d, J¼8.5 Hz,
2H), 7.12e7.14 (m, 2H), 7.25 (d, J¼8.5 Hz, 2H), 7.34 (d, J¼2.0 Hz, 1H),
7.60 (d, J¼16.0 Hz,1H); HRMS (FAB) calcd for C34H44O14Na [MþNa]þ
699.2629, found 699.2625.
4.18. 4-Methoxybenzyl (20S,30S)-3-O,4-O-(20,30-dimethox-
ybutane-20,30-diyl)-5-O-(400-O-methoxymethyl-p-coumaroyl)
quinate (30a) and 4-methoxybenzyl (20S,30S) -3-O,4-O-(20,30-
dimethoxybutane-20,30-diyl)-1-O-(400-O-methoxymethyl-p-
coumaroyl)quinate (30b)
According to the procedure described for 10a (method B, Table
3, entry 3), 28 (187 mg, 0.9 mmol) was esterified with 4 (192 mg,
0.45 mmol) to afford 30a (240 mg, 86%) and 30b (24 mg, 9%) with
inseparable impurities, respectively (solvent used for flash column
chromatography: 35% AcOEt in hexane).
4.20. 5-O-(E)-Cinnamoylquinic acid (18)
To a solution of 10a (111 mg, 0.2 mmol) in CH2Cl2 (24 mL) was
added TFA (1.2 mL) at 0 ꢁC and the resulting mixture was stirred for
13 h at this temperature. H2O (40 mL) was added to the reaction
mixture and then CH2Cl2 was removed under reduced pressure at
30 ꢁC. The residual aqueous solution was purified by ODS open
column chromatography (COSMOSIL 75C18-OPN: 5e10% CH3CN in
H2O) to give an aqueous CH3CN solution of 18 containing TFA. A few
times of azeotropic removal of TFA by using 50% aqueous CH3CN
under reduced pressure at 55 ꢁC gave 18 (56 mg, 87%) as a white
27
4.18.1. Compound 30a. Colorless amorphous; [
a
]
þ64.6 (c 0.5,
D
CHCl3); IR (KBr) 3504, 2952, 2833, 1711, 1602, 1511, 1377, 1243, 1131,
992, 831 cmꢀ1; UV (CHCl3) lmax/nm ( ), 299 (23,000); 1H NMR
(600 MHz, CDCl3) 1.27 (s, 3H), 1.29 (s, 3H), 1.96e2.04 (m, 2H), 2.09
3
d
(dd, J¼15.4, 3.0 Hz, 1H), 2.23 (td, J¼15.4, 3.0 Hz, 1H), 3.25 (s, 3H),
3.30 (s, 3H), 3.48 (s, 3H), 3.68 (dd, J¼10.5, 3.0 Hz, 1H), 3.82 (s, 3H),
4.42 (td, J¼10.5, 5.5 Hz, 1H), 5.10 (d, J¼11.7 Hz, 1H), 5.15 (d,
J¼11.7 Hz,1H), 5.20 (s, 2H), 5.33 (q, J¼3.0 Hz,1H), 6.38 (d, J¼15.8 Hz,
1H), 6.89 (d, J¼8.5 Hz, 2H), 7.03 (d, J¼8.5 Hz, 2H), 7.26 (d, J¼8.5 Hz,
2H), 7.48 (d, J¼8.5 Hz, 2H), 7.66 (d, J¼15.8 Hz, 1H); 13C NMR
22
solid. Mp: 190e191 ꢁC; [
3344, 2955, 1706, 1677, 1290, 1126, 978 cmꢀ1
CD3OD)
a
]
D
ꢀ6.6 (c 0.5, CH3OH); IR (KBr) 3465,
;
1H NMR (500 MHz,
d
1.96 (dd, J¼13.5, 3.5 Hz, 1H), 2.12e2.24 (m, 3H), 3.65 (dd,
(150 MHz, CDCl3)
d 17.6, 17.9, 36.6, 38.6, 48.0, 55.3, 56.1, 62.9, 67.9,
J¼9.0, 3.5 Hz, 1H), 4.16 (td, J¼9.0, 3.5 Hz, 1H), 5.38 (q, J¼3.5 Hz, 1H),
6.57 (d, J¼16.0 Hz, 1H), 7.39e7.41 (m, 3H), 7.59e7.61 (m, 2H), 7.73
69.6, 71.2, 74.5, 94.2, 99.5, 100.1, 114.1, 116.4, 116.5, 127.0, 128.4,
129.8, 130.3, 144.7, 158.9, 159.9, 166.8, 174.9; HRMS (FAB) calcd for
(d, J¼16.0 Hz, 1H); 13C NMR (150 MHz, CD3OD)
d 36.7, 41.6, 68.2,
C
32H40O12Na [MþNa]þ 639.2417, found 639.2394.
73.3, 74.8, 75.4, 119.6, 129.2, 130.0, 131.4, 136.0, 146.1, 168.4, 178.3;
HRMS (FAB) calcd for C16H17O7Na2 [MꢀHþ2Na]þ 367.0770, found
367.0769.
4.18.2. Compound 30b. 1H NMR (400 MHz, CDCl3)
d 1.29 (s, 3H),
1.32 (s, 3H), 1.86 (dd, J¼13.3, 12.5 Hz, 1H), 2.11 (dd, J¼16.0, 3.0 Hz,
1H), 2.45 (td, J¼13.3, 3.0 Hz, 1H), 2.84 (td, J¼16.0, 3.0 Hz, 1H), 3.25
(s, 3H), 3.27 (s, 3H), 3.48 (s, 3H), 3.56 (dd, J¼10.0, 3.0 Hz,1H), 3.78 (s,
3H), 4.15 (q, J¼3.0 Hz, 1H), 4.33 (ddd, J¼12.5, 10.0, 3.0 Hz, 1H), 5.10
(s, 1H), 5.11 (s, 1H), 5.20 (s, 2H), 6.31 (d, J¼15.8 Hz, 1H), 6.84 (d,
J¼8.8 Hz, 2H), 7.03 (d, J¼8.8 Hz, 2H), 7.25 (d, J¼8.8 Hz, 2H), 7.45 (d,
J¼8.8 Hz, 2H), 7.63 (d, J¼15.8 Hz, 1H); HRMS (FAB) calcd for
4.21. 5-O-Naphthoylquinic acid (19)
According to the procedure described for 18, 14a (116 mg,
0.2 mmol) was deprotected by TFA (1.6 mL) in CH2Cl2 (32 mL) to
afford 19 (55.3 mg, 80%) as a white solid (solvent used for ODS open
column chromatography: 5e20% CH3CN in H2O). Mp: 171e172 ꢁC;
C
32H40O12Na [MþNa]þ 639.2417, found 639.2421.
[a
]
22 ꢀ9.5 (c 0.2, CH3OH); IR (KBr) 3422, 1691, 1291, 1231, 1199, 1131,
D
1066 cmꢀ1; 1H NMR (500 MHz, CD3OD)
d
2.00 (dd, J¼13.0, 9.5, 1H),
4.19. 4-Methoxybenzyl (20S,30S)-3-O,4-O-(20,30-dimethox-
ybutane-20,30-diyl)-5-O-(300,400-di-O-methoxymethylcaffeoyl)
quinate (31a) and 4-methoxybenzyl (20S,30S)-3-O,4-O-(20,30-di-
methoxybutane-20,30-diyl)-1-O-(300,400-di-O-methox-
ymethylcaffeoyl)quinate (31b)
2.20e2.33 (m, 3H), 3.73 (dd, J¼9.5, 3.5 Hz, 1H), 4.32 (td, J¼9.5,
3.5 Hz, 1H), 5.58 (q, J¼3.5 Hz, 1H), 7.56 (t, J¼8.0 Hz, 1H), 7.61 (t,
J¼8.0 Hz, 1H), 7.92 (d, J¼8.0 Hz, 2H), 8.00 (d, J¼8.0, 1H), 8.10 (d,
J¼8.0 Hz, 1H), 8.69 (s, 1H); 13C NMR (150 MHz, CD3OD)
d 36.8, 41.9,
68.2, 73.9, 75.2, 75.5, 126.5, 127.7, 128.8, 129.0, 129.3, 130.3, 132.3,
133.9, 137.0, 168.0, 178.4; HRMS (FAB) calcd for C18H17O7Na2
[MꢀHþ2Na]þ 391.0770, found 391.0765.
According to the procedure described for 10a (method B, Table
3, entry 3), 29 (135 mg, 0.5 mmol) was esterified with 4 (107 mg,
0.25 mmol) to afford 31a (141 mg, 83%) and 31b (7 mg, 4%) with
inseparable impurities, respectively (solvent used for flash column
chromatography: 40% AcOEt in hexane).
4.22. 5-O-Benzoylquinic acid (20)
According to the procedure described for 18, 16a (106 mg,
0.2 mmol) was deprotected by TFA (1.6 mL) in CH2Cl2 (32 mL) to
afford 20 (47.3 mg, 80%) as a white solid (Solvent used for ODS open
27
4.19.1. Compound 31a. Colorless amorphous; [
a
]
þ60.9 (c 0.5,
D
CHCl3); IR (KBr) 3507, 2955, 2833, 1710, 1513, 1252, 1132, 989,
819 cmꢀ1; UV (CHCl3) lmax/nm ( ), 315 (16,000); 1H NMR (500 MHz,
CDCl3) 1.28 (s, 3H), 1.29 (s, 3H), 1.97e2.05 (m, 2H), 2.09 (dd,
J¼15.3, 3.0 Hz, 1H), 2.23 (td, J¼15.3, 3.0 Hz, 1H), 3.25 (s, 3H), 3.31 (s,
3H), 3.52 (s, 3H), 3.53 (s, 3H), 3.69 (dd, J¼10.5, 3.0 Hz, 1H), 3.82 (s,
3H), 4.43 (td, J¼10.5, 5.5 Hz, 1H), 5.10 (d, J¼12.0 Hz, 1H), 5.15 (d,
J¼12.0, 1H), 5.26 (s, 2H), 5.27 (s, 2H), 5.34 (q, J¼3.0 Hz, 1H), 6.38 (d,
J¼16.0 Hz, 1H), 6.89 (d, J¼8.5 Hz, 2H), 7.15 (s, 2H), 7.26 (d, J¼8.5 Hz,
3
column chromatography: 0e5% CH3CN in H2O). Mp: 200e201 ꢁC;
24
d
[a
]
ꢀ36.2 (c 0.2, CH3OH); IR (KBr) 3484, 3277, 2972, 1731, 1696,
D
1363, 1289, 1123, 1066, 711 cmꢀ1; 1H NMR (500 MHz, CD3OD)
d 1.97
(dd, J¼13.5, 9.0, 1H), 2.16e2.28 (m, 3H), 3.69 (dd, J¼9.0, 3.5 Hz, 1H),
4.24 (td, J¼9.0, 3.5 Hz, 1H), 5.51 (q, J¼3.5 Hz, 1H), 7.45 (t, J¼8.0 Hz,
2H), 7.58 (t, J¼8.0 Hz, 1H), 8.08 (d, J¼8.0 Hz, 1H), 8.09 (d, J¼8.0,
1H);13C NMR (150 MHz, CD3OD)
d 36.8, 41.9, 68.2, 73.8, 75.2, 75.5,
Please cite this article in press as: Oyama, K.-i.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.08.064

10
K.-i. Oyama et al. / Tetrahedron xxx (2014) 1e11
129.3, 130.9, 132.1, 134.0, 167.9, 178.4; HRMS (FAB) calcd for
C
gratitude to SUNBOR (Suntory Institute for Bioorganic Research) for
the GRANT to K.-i.O.
14H15O7Na2 [MꢀHþ2Na]þ 341.0613, found 341.0619.
Supplementary data
4.23. 5-O-Phenylethylcarbonylquinic acid (21)
Copies of 1H NMR and 13C NMR data of products. Crystallo-
graphic data for 4 have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication no. CCDC
996730. Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2014.08.064.
According to the procedure described for 18, 17 (112 mg,
0.2 mmol) was deprotected by TFA (1.6 mL) in CH2Cl2 (32 mL) to
afford 21 (51.2 mg, 79%) as a white solid (solvent used for ODS open
column chromatography: 5e10% CH3CN in H2O). Mp: 154e155 ꢁC;
24
[
a]
ꢀ38.2 (c 0.2, CH3OH); IR (KBr) 3420, 3198, 1729, 1687, 1354,
D
1298, 1198, 1128, 1086 cmꢀ1; UV (CH3OH) lmax/nm (
3 ), 209 (7300);
1H NMR (500 MHz, CD3OD)
d
1.92 (dd, J¼13.0, 9.0 Hz,1H), 2.07e2.15
References and notes
(m, 3H), 2.66 (t, J¼8.0, 1H), 2.67 (t, J¼8.0 Hz, 1H), 2.94 (t, J¼8.0 Hz,
2H), 3.58 (dd, J¼9.0, 3.5 Hz, 1H), 4.08 (td, J¼9.0, 3.5 Hz, 1H), 5.24 (q,
J¼3.5 Hz, 1H), 7.15e7.28 (m, 5H); 13C NMR (150 MHz, CD3OD)
d 31.8,
1. (a) Jaiswal, R.; Patras, A. M.; Eravuchira, P. J.; Kuhnert, N. J. Agric. Food Chem.
2010, 58, 8722e8737; (b) Crozier, A.; Jaganath, I. B.; Clifford, M. N. Nat. Prod. Rep.
2009, 26, 1001e1043; (c) Fang, N.; Yu, S.; Prior, R. L. J. Agric. Food Chem. 2002, 50,
3579e3585.
36.5, 37.1, 41.5, 68.2, 73.3, 74.7, 75.3, 127.1, 129.4, 129.5, 142.3, 174.5,
178.3; HRMS (FAB) calcd for C16H19O7Na2 [MꢀHþ2Na]þ 369.0926,
found 369.0926.
2. (a) Xu, J.-G.; Hu, Q.-P.; Lin, Y. J. Agric. Food Chem. 2012, 60, 11625e11630; (b) Ma,
C.; Dastmalchi, K.; Whitaker, B. D.; Kennelly, E. J. J. Agric. Food Chem. 2011, 59,
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To a solution of 31a (40 mg, 0.06 mmol) and pentam-
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dition of CH3CN under reduced pressure at 30 ꢁC gave 1 (14.7 mg,
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69%) as a white solid. Mp: 187e188 ꢁC; [
a
]
24 þ6.6 (c 0.2, CH3OH); IR
D
(KBr) 3448, 1712, 1686, 1631, 1601, 1291, 1205, 1126, 1077, 813 cmꢀ1
;
1H NMR (500 MHz, CD3OD)
d
1.96 (dd, J¼13.5, 9.0 Hz,1H), 2.11e2.23
(m, 3H), 3.64 (dd, J¼9.0, 3.5 Hz, 1H), 4.15 (td, J¼9.0, 3.5 Hz, 1H), 5.35
(q, J¼3.5 Hz, 1H), 6.31 (d, J¼16.0 Hz, 1H), 6.77 (d, J¼8.5 Hz, 1H), 6.94
(d, J¼8.5 Hz, 1H), 7.04 (s, 1H), 7.59 (d, J¼16.0 Hz, 1H); 13C NMR
(150 MHz, CD3OD)
d 36.7, 41.5, 68.3, 73.0, 74.8, 75.4, 115.1, 115.8,
116.5, 122.9, 128.0, 146.8, 146.8, 149.4, 169.0, 178.3; HRMS (FAB)
calcd for C16H19O9 [MþH]þ 355.1029, found 355.1040.
~
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4.25. 5-O-(E)-p-Coumaroylquinic acid (2)
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According to the procedure described for 1, 30a (123.3 mg,
0.2 mmol) was deprotected by BCl3 (2.0 mL, 2.0 mmol, 1 M in
CH2Cl2) and pentamethylbenzene (C6HMe5) (370.6 mg, 2.5 mmol)
in CH2Cl2 (7 mL) to afford 2 (49.4 mg, 73%) as a white solid (-
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24
tion containing 0.5% TFA). Mp: 169.5e170.5 ꢁC; [
a]
þ10.3 (c 0.2,
D
CH3OH); IR (KBr) 3409, 1692, 1606, 1515, 1278, 1176, 980, 828 cmꢀ1
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1H NMR (500 MHz, CD3OD)
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1.96 (dd, J¼13.5, 9.5 Hz,1H), 2.11e2.23
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CD3OD)
d 36.8, 41.2, 68.5, 72.9, 74.6, 75.5, 115.9, 116.8, 127.4, 131.1,
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This work was supported financially in part by Grant in aid for
scientific research in Priority Areas No. 18032037 (K.Y.), Creative
Scientific Research in (B) No. 24380062 (K.Y.) and Young Scientists
(B) No. 18780086 (K.-i.O.) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. We also express our
Please cite this article in press as: Oyama, K.-i.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.08.064

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