Syntheses of 3-, 4-, and 5-O-feruloylquinic acids

Article abstract of DOI:10.1016/j.tetasy.2013.06.002

The efficient synthesis of 3-, 4-, and 5-O-feruloylquinic acids starting from d-(-)-quinic acid is described. Esterification of suitably protected quinic acid derivatives with 3-(4-acetoxy-3-methoxyphenyl)-acryloyl chloride and subsequent hydrolysis of al

Full text of DOI:10.1016/j.tetasy.2013.06.002

Tetrahedron: Asymmetry 24 (2013) 785–790
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Tetrahedron: Asymmetry
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Syntheses of 3-, 4-, and 5-O-feruloylquinic acids
b
a
Irena Dokli a, , Luciano Navarini , Zdenko Hameršak
⇑
a
-
Division of Organic Chemistry and Biochemistry, Ruder Boškovi´c Institute, PO Box 180, 10002 Zagreb, Croatia
b illycaffè s.p.a, via Flavia 110, I 34147 Trieste, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 March 2013
Accepted 13 June 2013
The efficient synthesis of 3-, 4-, and 5-O-feruloylquinic acids starting from
D
-(ꢀ)-quinic acid is described.
Esterification of suitably protected quinic acid derivatives with 3-(4-acetoxy-3-methoxyphenyl)-acryloyl
chloride and subsequent hydrolysis of all the protecting groups afforded the title products in overall
yields of 33%, 15%, and 45%, respectively, (from quinic acid).
Ó 2013 Elsevier Ltd. All rights reserved.
HO COOH
HO COOH
1. Introduction
O
Numerous studies have shown a protective effect of moderate
coffee drinking on several chronic and degenerative diseases such
as diabetes, cardiovascular, and neurodegenerative disorders, how-
ever the mechanism behind this effect has yet to be elucidated.1 Sev-
eral researchers have suggested that the oxidative stress induced by
reactive oxygen species may be neutralized by the antioxidant activ-
ity of some coffee compounds; caffeine,2 melanoidins,3 and poly-
phenols.4 Chlorogenic acids (CGAs) represent the most abundant
class of phenolic compounds in coffee, which may account for up
to 12% of the dry matter of green coffee beans.5 The term ‘chlorogen-
ic acid’ in fact comprises of quinic acid derivatives, including caf-
feoyl, dicaffeoyl, p-coumaroyl, feruloyl, and caffeoylferuloyl among
many others. The most abundant CGAs in coffee are caffeic acid
esters, including 5-O-caffeoylquinic and its isomers 3- and 4-O-caf-
feoylquinic.6 Additionally, the isomers of dicaffeoylquinic acids,
feruloylquinic acids, diferuloylquinic acids, and p-coumaroylquinic
acids, and many others are found in green coffee beans.4,6
OH
OCH3
OH
HO
OH
O
HO
O
OH
OCH3
O
2
1
HO COOH
O
H3CO
HO
O
OH
OH
3
Figure 1. 3-, 4-, and 5-O-feruloylquinic acid isomers.
Feruloylquinic acid isomers are minor CGAs from a quantitative
point of view and are approximately 4% of the total CGA content in
green coffee beans.7 For this reason feruloylquinic acid isomers
have not yet been the subject of detailed investigations. The
absence of commercially available standards has led to the neces-
sity of employing hyphenated techniques, such as LC–MS/MS, in
order to investigate this class of compounds.8 Their quantitative
determination in coffee brews is not routinely performed and their
biological activity and metabolic fate are scarcely investigated.9
There are several synthetic approaches to quinic acid esters.
Sefkow et al., described the synthesis of 1-, 3-, 4-, and 5-caffeoyl-
quinic acids based on the esterification of quinic acid by cinnamic
acid derivatives.10,11 In another approach, the key reaction was a
Knoevenagel condensation of a suitable aldehyde and a malonate
ester of quinic acid to form a cinnamic (E)-double bond.12
Herein we report the preparation of three feruloylquinic acid
isomers: 3-O-feruloylquinic acid 1, 4-O-feruloylquinic acid 2, and
5-O-feruloylquinic acid 3 shown in Figure 1. We used Sefkow’s
synthetic strategy for the synthesis of caffeoylquinic acids with a
few modifications.
2. Results and discussion
3-(4-Acetoxy-3-methoxyphenyl)-acryloyl chloride 6 was pre-
pared, according to a known procedure,13 from ferulic acid 4 in
two steps in a combined yield of 74% (Scheme 1).
The synthesis of 3-O-feruloylquinic acid 1 is shown in Scheme 2.
The quadruple protection of commercially available
acid 7 to give lactone 8 was carried out with 2,2-dimethoxypropane
D
-(ꢀ)-quinic
⇑
Corresponding author. Tel.: +385 14561029; fax: +385 14680108.
E-mail address: Irena.Dokli@irb.hr (I. Dokli).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.06.002

786
I. Dokli et al. / Tetrahedron: Asymmetry 24 (2013) 785–790
(CH3CO)2O
DMAP
products was 13a:13b = 3:1. Pure 13a was isolated after chroma-
tography in 60% yield (Table 1).
H3CO
COOH
H3CO
COOH
pyridine
0°C, 1h
All protecting groups were, as above, removed using 1 M aque-
ous HCl in THF (4:1) at room temperature. However, we observed
that under the given reaction conditions, acyl migration from the
C-4 hydroxy to the C-5 hydroxy occurred to some extent to give
5-O-feruloylquinic acid 3 as a side product. This made the purifica-
tion and isolation of pure 4-O-feruloylquinic acid 2 by recrystalli-
zation difficult because 4-O-feruloylquinic acid 2 was found to be
more soluble than 5-O-feruloylquinic acid 3 in all of the tested
mixtures of solvents. The longer reaction time required for the full
conversion (8 days), resulted in more acyl migration product 3
(20%). This problem was solved by stopping the reaction at 90%
conversion (5 days), followed by column chromatography (EtOAc)
in order to remove 5-O-feruloylquinic acid (up to 5%), and then
recrystallization from a mixture of THF/diisopropyl ether to afford
pure 4-O-feruloylquinic acid 2 in 36% yield.
H3COCO
HO
5
4
99%
H3CO
COCl
oxalyl chloride, DMF
toluene, -5°C to rt
3 h
H3COCO
6
75%
Scheme 1. Synthesis of 3-(4-acetoxy-3-methoxyphenyl)-acryloyl chloride 6.
and p-toluenesulfonic acid in refluxing EtOAc. The crude lactone 8
was subjected to ethanolysis with NaOEt/EtOH at ꢀ20 °C, to obtain
a mixture of lactone 8 and ester 9 in a ratio of 1:5 as indicated by
1H NMR spectroscopy.14 Pure ester 9 was isolated after column chro-
matography in 76% yield from 7. Esterification of quinate 9 with
chloride 6 in the presence of DMAP and pyridine in dichloromethane
gave compound 9 in 64% yield. All of the protecting groups were
removed using 1 M aqueous HCl in THF (4:1) at room temperature
5-O-Feruloylquinic acid 3 was prepared according to Scheme 4.
D-(ꢀ)-Quinic acid 7 was first converted into ester 14 using ( )-10-
camphorsulfonic acid (CSA) in refluxing methanol. Selective
protection of the C-3 and C-4 vicinal diequatorial hydroxyls with
2,2,3,3-tetramethoxybutane 15 in the presence of CSA and tri-
methyl orthoformate resulted in butane 2,3-bisacetal (BBA) pro-
tected methyl quinate 16 in 76% yield from 7.16 Esterification of
16 with feruloyl chloride 6 was carried out in a mixture of pyridine
and dichloromethane in the presence of DMAP at room tempera-
ture to provide ester 17 in 86% yield. All of the protecting groups
were removed using 1 M aqueous HCl in THF (3:1) at room temper-
ature after 5 days. Again, under the given conditions, acyl migra-
tion from the C-5 hydroxy to the C-4 hydroxy was observed (up
to 10%). Pure 5-O-feruloylquinic acid 3 was isolated after two
recrystallizations from a mixture of THF/diisopropyl ether in 69%
yield.
to afford 3-O-feruloylquinic acid
1 in 67% yield after two
recrystallizations.
4-O-Feruloylquinic acid 2 was prepared according to Scheme 3.
-(ꢀ)-Quinic acid 1 was converted into lactone 11 with p-toluene-
D
sulfonic acid in refluxing toluene. The selective protection of the
C-5 hydroxy group was achieved using tert-butyldimethylsilyl
(TBS) chloride to provide a mixture of monosilylated compounds
12a and 12b in the ratio of 96:4 as indicated by 1H NMR spectros-
copy.15 Pure 12a was isolated after column chromatography in 67%
yield (from 7). Esterification of 12a with 1.5 equiv of chloride 6 in a
mixture of dichloromethane and pyridine in the presence of DMAP
after 4 days at room temperature did not proceed with full conver-
sion (90%) and resulted in a mixture of 4-monoesterificated 13a
3. Conclusion
and 1,4-diesterificated 13b product in
a
molar ratio of
In conclusion, we have described an efficient synthesis of 3-,
13a:13b = 1.5:1. Pure 13a was isolated after chromatography in
45% yield. Better results were obtained when the reaction pro-
ceeded in pyridine with 1.8 equiv of chloride 6 at room tempera-
ture. After 24 h, the conversion was 100%, and the molar ratio of
4-, and 5-O-feruloylquinic acid starting from
Esterification of suitably protected quinic acid derivatives with
D
-(ꢀ)-quinic acid.
feruloyl chloride 6 and subsequent hydrolysis of all the protecting
O
HO COOEt
HO
HO COOH
2,2-dimethoxypropane
1. NaOEt/EtOH, -20°C, 24h
p-TsOH
2. HOAc, -20°C to rt
O
EtOAc
reflux, 3h
OH
O
O
HO
OH
76% from 7
O
O
OH
9
7
8
HO COOEt
HO COOEt
H3CO
COCl
DMAP, pyridine
O
+
CH2Cl2, rt, 24h
64%
OCH3
H3COCO
OH
O
O
O
O
O
OCOCH3
6
9
10
HO COOH
O
1M HCl, THF
rt, 6 days
67%
OCH3
OH
O
HO
OH
1
Scheme 2. Synthesis of 3-O-feruloylquinic acid 1.

I. Dokli et al. / Tetrahedron: Asymmetry 24 (2013) 785–790
787
O
O
O
HO
HO
HO COOH
HO
TBSCl, TBAI,
pTsOH, DMF
DMAP, Et3N
+
toluene
O
O
O
DMF
reflux, 18h
HO
TBSO
-10°C to rt, 6h
HO
OH
HO
OTBS
OH
12a
OH
OH
7
67% from
96:4
11
12b
7
H3COCO
H3CO
O
HO
13a 13b
:
= 3:1
O
HO
H3CO
COCl
+
DMAP
O
O
OCOCH3
OCH3
pyridine
O
O
TBSO
O
H3COCO
+
TBSO
rt, 24h
O
O
OH
OCOCH3
OCH3
O
TBSO
13a
, 60%
O
12a
6
O
13b
HO COOH
1M HCl, THF
rt, 5 days
OH
13a
HO
OH
36%
O
OCH3
O
2
Scheme 3. Synthesis of 4-O-feruloylquinic acid 2.
Table 1
Esterification of 12a (1 equiv) with chloride 6 in the presence of DMAP (0.15 equiv)
Entry
6 (equiv)
Solvent
Time (days)
Conversion (%)
13a:13b
Combined yield (%)
Yield 13a (%)
1
2
3
1.5
1.5
1.8
CH2Cl2/pyridine (4:1)
Pyridine
Pyridine
4
1
1
90
90
100
1.5:1
3:1
3:1
75
—
81
45
46
60
H3CO
H3CO
OCH3
OCH3
HO COOCH3
HO COOCH3
HO COOH
15
CSA, CH3OH
reflux, 24 h
CSA, HC(OCH3)3,
HO
O
HO
OH
HO
OH
CH3OH, reflux, 24 h
OCH3
O
OH
14
OH
7
H3CO
76% from
7
16
HO COOCH3
HO COOCH3
O
H3CO
COCl
+
H3CO
DMAP, pyridine
O
O
HO
O
OCH3
CH2Cl2, rt, 24h
86%
O
OCH3
H3COCO
O
H3COCO
H3CO
H3CO
17
6
16
HO COOH
O
O
1M HCl, THF
rt, 4 days
H3CO
HO
OH
OH
69%
3
Scheme 4. Synthesis of 5-O-feruloylquinic acid 3.

788
I. Dokli et al. / Tetrahedron: Asymmetry 24 (2013) 785–790
groups afforded the title products in overall yields of 33%, 15%, and
45%, respectively, (from quinic acid).
(m, 1H), 5.42–5.50 (m, 1H), 6.37 (d, 1H, J = 16.1 Hz), 7.02–7.12 (m,
3H), 7.65 (d, 1H, J = 16.1 Hz). 13C NMR (75 MHz, CDCl3): d = 14.10,
20.61, 25.84, 28.01, 34.45, 36.96, 55.91, 62.17, 71.03, 73.65, 73.73,
76.91, 109.61, 111.31, 118.23, 121.21, 123.25, 133.34, 141.51,
144.42, 151.41, 165.82, 168.71, 174.32.
4. Experimental
4.1. General methods
4.5. 3-O-Feruloylquinic acid 1
All of the reactions were conducted under an argon atmosphere.
Solvents were puriss p.a. quality. All other reagents were purchased
from commercial sources and used without purification. TLC was
performed on aluminum baked silica plates (60 F254, Merck). UV
light (254 nm) or phosphomolibdic acid reagent was used for visu-
alizing. Column chromatography was performed on silica gel (Silica
gel 60, 70–230 mesh, Fluka). 1H and 13C NMR were recorded on Bru-
ker AV 300 and AV 600 spectrometers. Chemical shifts (dH and dC)
are quoted in parts per million (ppm), referenced to TMS. Chemical
purity determination, and progression of the reactions was per-
formed by HPLC on a Eurospher 100-5 C18, 250 mm ꢁ 4.6 mm col-
umn. Optical rotations were measured using Optical Activity AA-10
automatic polarimeter. High resolution mass spectrometry (HRMS)
was performed on a 4800 Plus MALDI TOF/TOF Analyzer. Com-
pounds 5,13 6,13 and 1516 were prepared according to literature
procedures.
To a solution of ester 10 (580 mg, 1.21 mmol) in THF (10 mL)
was added 1 M aq HCl (40 mL). The mixture was then stirred for
6 days at 25 °C. The solution was saturated with solid NaCl and
the aqueous phase extracted with EtOAc (3 ꢁ 30 mL). The com-
bined organic extracts were dried over Na2SO4, filtered, and con-
centrated under vacuum. The residue was recrystallized twice
from a mixture of MTBE/diisopropyl ether to afford 3-O-feruloyl-
quinic acid 1 (300 mg, 67%) as a white powder. NMR data were
in accordance with the literature data.12,13 1H NMR (300 MHz,
methanol-d4): d = 2.06–2.28 (m, 4H), 3.75 (dd, 1H, J1 = 3.1 Hz,
J2 = 8.4 Hz), 3.91 (s, 1H), 4.18–4.20 (m, 1H), 5.36 (ddd, 1H,
J1 = 4.5 Hz, J2 = 8.9 Hz, J3 = 9.1 Hz), 6.37 (d, 1H, J = 15.9 Hz), 6.83
(d, 1H, J = 8.2 Hz), 7.10 (dd, 1H, J1 = 1.8 Hz, J2 = 8.2 Hz), 7.21 (d,
1H, J = 1.8 Hz), 7.64 (d, 1H, J = 15.9 Hz). 13C NMR (75 MHz, metha-
nol-d4): d = 36.83, 37.38, 55.08, 69.87, 70.61, 72.08, 74.73, 110.44,
114.27, 115.08, 122.70, 126.40, 145.54, 147.97, 149.23, 167.20,
175.62. HRMS (MALDI): m/z: calcd for
C
17H20O9Na [M+Na+]
4.2. (1S,3R,4R,5R)-4,5-O-Isopropylidene-1,3-quinic acid lactone8
391.0999; found: 391.0994. ½a D25
ꢂ
¼ ꢀ35:1 (c 1.14, CH3OH). {lit.12
½
a 2D5
ꢂ
¼ ꢀ19:6 (c 1.12 g lꢀ1, CH3OH)).
At first,
D-(ꢀ)-quinic acid 7 (1 g, 5.2 mmol) was suspended in
EtOAc (30 mL). p-Toluenesulfonic acid monohydrate (10 mg,
0.052 mmol) and 2,2-dimethoxypropane (1.96 mL, 15.6 mmol)
were then added. The mixture was heated at reflux for 3 h. After
cooling, the solvent was removed under reduced pressure. The
residual solid, lactone 8 was used in the next step without further
purification. NMR data were in accordance with the literature
data.14
4.6. (1S,3R,4R,5R)-1,3,4-Trihydroxy-6-oxa-bicyclo[3.2.1]octan-7-
one 11
A solution of
D-(ꢀ)-quinic acid (1.96 g, 10.2 mmol) and p-tolu-
enesulfonic acid (100 mg, 0.52 mmol) in anhydrous toluene
(20 mL) and anhydrous DMF (7 mL) was refluxed under a Dean–
Stark trap for 18 h. The reaction mixture was cooled and concen-
trated under reduced pressure. The residue was diluted with CH2Cl2
(20 mL) and hexane (10 mL). The precipitated product was collected
by vacuum filtration to afford the crude lactone 11 (1.77 g) which
was used in the next reaction step without further purification.
4.3. Ethyl (1R,3R,4S,5R)-4,5-O-isopropylidene-1,3-quinate 9
To a solution of crude lactone 8 in absolute EtOH (30 mL) was
added NaOEt in EtOH (0.208 mmol, 0.16 mL, 0.04 equiv with re-
spect to quinic acid). The mixture was stirred at room temperature
for 1 h, and then overnight at ꢀ20 °C. The reaction mixture was
4.7. (1R,3R,4S,5R)-5-tert-Butyldimethylsiloxy-1,4-dihydroxycy-
clohexane-1,3-carbolactone 12a
neutralized at ꢀ20 °C with acetic acid (13
lL) and then warmed
to room temperature. The solvent was removed under reduced
pressure. 1H NMR spectroscopy showed that the crude product
was a mixture of lactone 8 and ester 9 (ratio 1:5). Column chroma-
tography on silica gel (n-hexane/EtOAc = 1/1) yielded pure 9
(1.03 g, 76% from 7) as a white solid. NMR data were in accordance
with the literature data.14
Crude lactone 11 (1.77 g), DMAP (175 mg, 1.43 mmol), tetrabu-
tylammonium iodide (189 mg, 0.51 mmol) and triethylamine
(1.7 mL, 12.2 mmol) were suspended in dry DMF (20 mL) at
ꢀ10 °C, after which tert-butyldimethylsilyl chloride (1.9 g,
12.5 mmol) was added. The solution was stirred at ꢀ10 °C for 1 h
and then 5 h at room temperature. The reaction mixture was di-
luted with ethyl acetate (100 mL) and filtered over Celite. The fil-
trate was washed successively with 1 M aq HCl (100 mL) and
brine (3 ꢁ 100 mL), dried over Na2SO4, filtered, and concentrated
under vacuum. The crude product was purified by column chroma-
tography on silica gel (diethyl ether/n-hexane = 1/1) to afford
monosilyl product 12a (1.98 g, 67.3%). NMR data were in accor-
dance with the literature data.15
4.4. Ethyl (1S,3R,4R,5R)-3-[3-(4-acetoxy-3-methoxyphenyl)-acr-
yloyloxy]-4,5-O-isopropylidene-1-quinate 10
To
a solution of ethyl 4,5-O-isopropylidene-1,3-quinate 9
(500 mg, 1.9 mmol) and DMAP (35 mg, 0.29 mmol) in CH2Cl2
(25 mL) were added pyridine (6 mL) and 3-(4-acetoxy-3-methoxy-
phenyl)-acryloyl chloride 6 (734 mg, 2.9 mmol). The mixture was
stirred overnight at room temperature and then acidified with
1 M aq HCl. The layers were separated and the aqueous phase ex-
tracted with CH2Cl2 (3 ꢁ 50 mL). The combined extracts were dried
over Na2SO4, filtered, and concentrated under vacuum. The residue
was purified by column chromatography on silica gel (diethyl
ether/CH2Cl2 = 1/1) to afford ester 10 (590 mg, 64%) as a white solid.
1H NMR (300 MHz, CDCl3): d = 1.30 (t, 3H, J = 6.9 Hz), 1.38 (s, 3H),
1.59 (s, 3H), 1.91 (dd, 1H, J1 = 11.3 Hz, J2 = 13.1 Hz), 2.21–2.32 (m,
6H), 3.41 (s, 1H), 3.85 (s, 3H), 4.19–4.27 (m, 3H), 4.51–4.56
4.8. (1R,3R,4S,5R)-4-[3-(4-Acetoxy-3-methoxyphenyl)-acryloyl
oxy]-5-tert-butyldimethylsiloxy-1-hydroxycyclohexane-1,3-car
bolactone 13a and (1R,3R,4S,5R)-1,4-di-[3-(4-acetoxy-3-meth-
oxyphenyl)-acryloyloxy]-5-tert-butyldimethylsiloxy-cyclohex-
ane-1,3-carbolactone 13b
To a solution of monosilyl protected compound 12a (310 mg,
1.07 mmol) and DMAP (20 mg, 0.16 mmol) in pyridine (15 mL) at
room temperature, was added 3-(4-acetoxy-3-methoxyphenyl)-

I. Dokli et al. / Tetrahedron: Asymmetry 24 (2013) 785–790
789
acryloyl chloride 6 (490 mg, 1.92 mmol). The mixture was stirred
overnight at room temperature and then poured onto crushed
ice, after which CH2Cl2 (20 mL) was added. The reaction mixture
was acidified with 1 M aq HCl. The layers were separated and the
aqueous phase extracted with CH2Cl2 (3 ꢁ 50 mL). The combined
organic extracts were dried over Na2SO4, filtered, and concentrated
under vacuum. The crude product was a mixture of 13a and 13b
(3:1). The residue was purified by column chromatography on sil-
ica gel (diethyl ether/CH2Cl2 = 1/1) to afford ester 13a (330 mg,
60%) as a colorless solid, and 13b (160 mg) as a white solid. Com-
pound 13a: 1H NMR (300 MHz, CDCl3): d = 0.05 (s, 3H), 0.08 (s, 3H),
0.83 (s, 9H), 2.11–2.12 (m, 2H), 2.33 (s, 3H), 2.41–2.44 (m, 1H), 2.56
(d, 1H, J = 11.8 Hz), 2.72 (s, 1H), 3.89 (s, 3H), 4.04–4.08 (m, 1H),
4.86–4.87 (m, 1H), 5.43–5.45 (m, 1H), 6.43 (d, 1H, J1 = 15.8 Hz),
7.07–7.16 (m, 3H), 7.69 (d, 1H, J1 = 15.8 Hz). 13C NMR (75 MHz,
CDCl3): d = ꢀ5.56, 17.41, 20.08, 25.07, 37.00, 40.54, 55.48, 65.46,
66.10, 71.49, 73.75, 110.98, 116.79, 120.87, 122.85, 132.55,
141.32, 144.91, 151.02, 164.89, 168.18, 176.75.
aqueous NaHCO3 (30 mL). The aqueous layer was extracted once
with EtOAc (30 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated under vacuum. Crude prod-
uct was recrystallized from EtOAc/n-hexane = 1/5 to afford com-
pound 16 (1.28 g, 76% from quinic acid) as a white solid. NMR
data are in accordance with the literature data.16
4.11. (1R,3R,4S,5R)-5-[3-(4-Acetoxy-3-methoxyphenyl)-acryloyl
oxy]-3,4-O-(20,30-dimethoxybutane-20,30-diyl)-1-hydroxycyclo-
hexanecarboxylic acid methyl ester 17
To a solution of 3,4-BBA protected methyl quinate 16 (750 mg,
2.34 mmol) and DMAP (30 mg, 0.23 mmol) in CH2Cl2 (20 mL) were
added pyridine (2 mL) and 3-(4-acetoxy-3-methoxyphenyl)-acry-
loyl chloride 3 (894 mg, 3.51 mmol). The mixture was stirred over-
night at room temperature and then acidified with 1 M aq HCl. The
layers were separated and the aqueous phase extracted with
CH2Cl2 (3 ꢁ 50 mL). The combined organic extracts were dried over
Na2SO4, filtered, and concentrated under vacuum. The residue was
purified by column chromatography on silica gel (diethyl ether/
CH2Cl2 = 1/1) to afford ester 17 (1.09 g, 86%) as a white solid. 1H
NMR (300 MHz, CDCl3): d = 1.31 (s, 3H), 1.32 (s, 3H), 1.99–2.34
(m, 4H), 2.35 (s, 3H), 3.23 (s, 1H), 3.29 (s, 3H), 3.33 (s, 3H), 3.75
(dd, 1H, J1 = 3.2 Hz, J2 = 10.2 Hz), 3.81 (s, 3H), 3.91 (s, 3H), 4.40–
4.99 (m, 1H), 5.38–5.41 (m, 1H), 6.48 (d, 1H, J = 15.9 Hz), 7.06–
7.16 (m, 3H), 7.69 (d, 1H, J = 15.9 Hz). 13C NMR (75 MHz, CDCl3):
d = 17.12, 17.35, 20.08, 36.20, 38.23, 47.44, 47.54, 52.66, 55.50,
62.30, 69.35, 70.74, 74.14, 99.12, 99.65, 110.74, 118.16, 121.06,
122.67, 133.04, 140.98, 143.95, 150.91, 165.91, 168.16, 174.93.
Compound 13b: 1H NMR (300 MHz, CDCl3): d = 0.05 (s, 3H), 0.08
(s, 3H), 0.83 (s, 9H), 2.26–2.32 (m, 1H), 2.32 (s, 3H), 2.33 (s, 3H),
2.33–2.46 (m, 1H), 2.72 (d, 1H, J = 11.5 Hz), 3.07–3.15 (m, 1H),
3.86 (s, 3H), 3.88 (s, 3H), 4.11–4.19 (m, 1H), 4.91–4.96 (m, 1H),
5.45–5.49 (m, 1H), 6.41 (d, 1H, J1 = 15.9 Hz), 6.45 (d, 1H,
J1 = 15.9 Hz), 7.03–7.16 (m, 6H), 7.67 (d, 2H, J1 = 15.9 Hz). 13C
NMR (75 MHz, CDCl3): d = ꢀ5.60, ꢀ5.57 17.41, 20.09, 25.07,
34.01, 37.19, 55.48, 55.49, 65.34, 66.47, 73.80, 76.12, 110.86,
110.92, 116.56, 116.79, 120.99, 121.02, 122.84, 122.86, 132.41,
132.57, 141.32, 141.44, 144.95, 145.50, 151.03, 164.31, 164.86,
168.12, 168.15, 171.55.
4.9. 4-O-Feruloylquinic acid 2
4.12. 5-O-Feruloylquinic acid 3
To a solution of ester 13a (1.0 g, 1.97 mmol) in THF (15 mL) was
added 1 M aq HCl (60 mL), after which the mixture was stirred for
5 days at room temperature. The solution was saturated with solid
NaCl and the aqueous phase extracted with EtOAc (3 ꢁ 40 mL). The
combined organic extracts were dried over Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel (EtOAc) and then recrystallized from
the mixture of THF/diisopropyl ether to afford 2 (260 mg, 36%) as a
white powder. NMR analysis showed that the obtained powder
was an adduct with THF in a molar ratio 4:1 = 2:THF. Next,
100 mg of this adduct was dissolved in CH3OH and the solvent
was again evaporated to provide THF free product 2. NMR data
were in accordance with the literature data.17 1H NMR (300 MHz,
methanol-d4): d = 1.99–2.28 (m, 4H), 3.92 (s, 3H), 4.27–4.35 (m,
2H), 6.47 (d, 1H, J = 15.9 Hz), 6.84 (d, 1H, J = 8.4 Hz), 7.12 (dd, 1H,
J1 = 1.8 Hz, J2 = 8.4 Hz), 7.22 (d, 1H, J = 1.8 Hz), 7.73 (d, 1H,
J = 15.9 Hz). 13C NMR (75 MHz, methanol-d4): d = 37.04, 41.31,
55.06, 64.16, 68.24, 75.17, 77.92, 110.43, 114.38, 115.11, 122.63,
126.47, 145.56, 147.98, 149.20, 167.53, 175.88. HRMS (MALDI):
m/z: calcd for C17H20O9Na [M+Na+] 391.0999; found: 391.0999.
To a solution of ester 17 (1.4 g, 2.60 mmol) in THF (20 mL), 1 M
aq HCl (60 mL) was added. The mixture was stirred for 4 days at
room temperature. The solution was saturated with solid NaCl
and aqueous phase extracted with EtOAc (3 ꢁ 40 mL). The com-
bined organic extracts were dried over Na2SO4, filtered, and con-
centrated under vacuum. The residue was recrystallized twice
from the mixture of THF/diisopropyl ether to afford 3 (660 mg,
69%) as
a
white powder. 1H NMR (300 MHz, methanol-d4):
d = 1.94–2.22 (m, 4H), 3.67 (dd, 1H, J1 = 3.3 Hz, J2 = 8.5 Hz), 3.92
(s, 3H), 4.14–4.22 (m, 1H), 5.37–5.41 (m, 1H), 6.42 (d, 1H,
J = 15.9 Hz), 6.83 (d, 1H, J = 8.1 Hz), 7.09 (dd, 1H, J1 = 1.9 Hz,
J2 = 8.1 Hz), 7.21 (d, 1H, J = 1.9 Hz), 7.67 (d, 1H, J = 15.9 Hz). 13C
NMR (75 MHz, methanol-d4): d = 35.35, 40.18, 55.05, 66.88,
71.65, 73.46, 74.01, 110.33, 114.84, 115.07, 122.59, 126.57,
145.26, 147.96, 149.08, 167.56, 176.89. HRMS (MALDI): m/z: calcd
for C17H20O9Na [M+Na+] 391.0999; found: 391.0995. ½a 2D5
¼ þ10:9
ꢂ
(c 0.64, CH3OH).
Acknowledgments
½
a 2D5
ꢂ
¼ ꢀ55:7 (c 0.79, CH3OH).
We thank the Ministry of Science, Education and Sports of the
Republic of Croatia (Grant no. 098-0982933-2908). This work is
also a part of a joint project with illycaffè s.p.a in the framework
of the project: ‘Nutrigenomica e consumo di caffè: effetti fisiologici,
genetica del gusto e genetica della pianta’ partially supported by
the POR-FESR 2007-2013 Regione Autonoma Friuli Venezia Giulia,
Italy.
4.10. (1S,3R,4R,5R)-3,4-O-(20,30-Dimethoxybutane-20,30-diyl)-1,5-
dihydroxycyclohexanecarboxylic acid methyl ester 16
To a suspension of
D-(ꢀ)-quinic acid (1 g, 5.2 mmol) in MeOH
(30 mL), ( )-10-camphorsulfonic acid (12 mg, 0.052 mmol) was
added. Reaction mixture was then refluxed overnight. After cool-
ing, 2,2,3,3-tetramethoxybutane 15 (927 mg, 5.7 mmol), trimethyl
orthoformate (2.6 mL, 0.024 mol), and ( )-10-camphorsulfonic
acid (12 mg, 0.052 mmol) were added and mixture again refluxed
overnight. Powdered NaHCO3 (0.1 g) was added to the cold reac-
tion mixture. Solution was concentrated under reduced pressure
and the residue partitioned between EtOAc (30 mL) and saturated
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