First efficient syntheses of 1-, 4-, and 5-caffeoylquinic acid

Article abstract of DOI:10.1002/1099-0690(200107)2001:14<2735::AID-EJOC2735>3.0.CO;2-I

Efficient synthesis of 1-, 4-, and 5-caffeoylquinic acid was achieved in three or four steps with suitably protected quinic acid precursors, in overall yields of 41%, 36%, and 60% [from quinic acid (1)]. 1-Caffeoylquinic acid was prepared by esterificatio

Full text of DOI:10.1002/1099-0690(200107)2001:14<2735::AID-EJOC2735>3.0.CO;2-I

FULL PAPER
First Efficient Syntheses of 1-, 4-, and 5-Caffeoylquinic Acid
Michael Sefkow,*[a] Alexandra Kelling,[b] and Uwe Schilde[b]
Keywords: Acylations / Antioxidants / Carboxylic acids / Natural products / Acetals
Efficient synthesis of 1-, 4-, and 5-caffeoylquinic acid was
achieved in three or four steps with suitably protected quinic
acid derivatives with a free hydroxy group only at either C-
4 or C-5, for the synthesis of 4 and 5, were not successful.
acid precursors, in overall yields of 41%, 36%, and 60% [from Kinetic acetalization of pentasilylated quinic acid 15 using
quinic acid (1)]. 1-Caffeoylquinic acid was prepared by ester-
ification of acetone quinide 7 with caffeoyl chloride 6, fol-
bis(dimethoxy acetals) afforded several crystalline reaction
products which were identified by X-ray diffraction. Diacetal
lowed by a two-step hydrolysis of all protecting groups. Caf- 20, derived from a vicinal cis-diol, was unambiguously iden-
feoylquinic acids 4 and 5 were prepared from known quinic
acid derivatives, 13 and 25, by selective esterification of the
tified for the first time. Unexpectedly, it has two trans-diaxi-
ally oriented methoxy groups, forcing the quinide ring into a
twist-boat conformation.
secondary hydroxy groups and hydrolysis with 1
M HCl.
However, initial attempts to prepare fully protected quinic
Introduction
kinetic acetalization.[12] Here we report the first efficient
and regioselective syntheses of the other, commercially un-
available monocaffeoylquinic acids (2, 4, and 5). Obviously,
all caffeoylquinic acids can be prepared by esterification of
suitable caffeic and quinic acid derivatives. Di-O-acetylcaf-
feoyl chloride (6) was used as the acylating agent because it
had already successfully been employed for the preparation
of 3.[12] The preparations of the selectively protected quinic
acids AϪC (Scheme 1) were more difficult. Quinic acid de-
rivatives corresponding to structure A are known[13] but
those outlined in structures B and C have not yet been de-
scribed.
Quinic acid (1) and its four monocaffeoyl esters 2Ϫ5
(Figure 1) are widespread secondary plant metabolites.[1]
The caffeoylquinic acids possess a broad spectrum of biolo-
gical activities.[2,3] Most intensely studied is 3-caffeoylquinic
acid (chlorogenic acid, 3), which is usually the major re-
gioisomer,[4] and the only commercially available caf-
feoylquinic acid. All other isomers must either be isolated
from plant sources[5] or synthesized by random isomeriz-
ation of the commercially available acid 3.[6,7] Regioselective
syntheses of caffeoylquinic acids have been reported in brief
for 1-caffeoylquinic acid[6c,8] and 5-caffeoylquinic acid[9] (2
and 5). It is to be noted that different rules exist for the
numbering and stereochemical descriptors of the ring sys-
tem of quinic acid (1).[10] By 3-caffeoylquinic acid we refer
below to chlorogenic acid (3), as have the majority of au-
thors.[11]
Figure 1. Quinic acid (1) and its monocaffeic acid esters 2؊5
In a preceding paper, we described a short and efficient
synthesis of 3 from a new quinic acid acetal obtained by
Scheme 1. Quinic acid acetals AϪB as key precursors for the syn-
thesis of caffeoyl ester 2, 4, and 5
[a]
Institut für Organische Chemie und Strukturanalytik,
Universität Potsdam,
Results and Discussion
Karl-Liebknecht-Strasse 24Ϫ25, 14476 Golm, Germany
Fax: (internat.) ϩ 49-331/977-5067
E-mail: sefkow@rz.uni-potsdam.de
(a) 1-Caffeoylquinic Acid
[b]
Institut für Anorganische Chemie und Didaktik der Chemie,
The first synthesis of 1-caffeoylquinic acid (2) was pub-
lished in 1964. It was synthesized from acetone quinide 7[14]
Universität Potsdam,
Karl-Liebknecht-Strasse 24Ϫ25, 14476 Golm, Germany
Eur. J. Org. Chem. 2001, 2735Ϫ2742
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0714Ϫ2735 $ 17.50ϩ.50/0
2735

M. Sefkow, A. Kelling, U. Schilde
FULL PAPER
and di-O-ethylcarbonate-protected caffeoyl chloride, but
neither yields nor conditions were described in detail.[6c,8,15]
In our hands, acetone quinide 7 reacted smoothly with
acid chloride 6 under standard esterification conditions,
providing ester 8 in 58% yield (Scheme 2). Hydrolysis of the
protecting groups was accomplished in a two-step sequence;
all labile esters were cleaved using LiOH in a degassed
water/THF solution under an inert gas, and removal of the
acetal group was then achieved after acidification of the
reaction mixture with 2  HCl, whereupon 1-caffeoylquinic
acid (2) was obtained in 79% yield (41% from 1). The yield
of 2 was less than 20% when the hydrolysis was performed
entirely under acidic conditions (1  HCl) or when the solu-
tion of 8 in water/THF was not carefully degassed prior to
the addition of LiOH. In this case, the solution turned deep
brown after addition of the base and the color remained
even after acidification, indicating that oxidation of the lib-
erated catechol group had occurred to some extent.
Scheme 3. Attempted synthesis of acetals 11 or 12 from quinides 9
or 10
As demonstrated by Abell et al., differentiation of the
secondary hydroxy groups at C-4 and C-5 of quinide 9 was
effectively achieved with TBSCl, providing silyl ether 13 in
over 75% yield (from 9).[18] Although 13 possesses two
sterically hindered hydroxy groups, esterification of 13 with
1.2 equiv. of caffeoyl chloride 6 in pyridine exclusively pro-
vided ester 14 in 55% yield. Interestingly, no esterification
was observed when the reaction was performed in CH2Cl2
containing several equivalents of pyridine. Hydrolysis of all
protecting groups was accomplished with 1  HCl at room
temperature, and 4-caffeoylquinic acid (4) was obtained in
83% yield (36% from 1) (Scheme 4). Use of the sequential
basic and acidic hydrolysis procedure as described above,
however, resulted in cleavage of all esters and quantitative
isolation of caffeic acid.
Scheme 2. Synthesis of caffeoyl ester 2
(b) 4-Caffeoylquinic Acid
4-Caffeoylquinic acid (cryptochlorogenic acid, 4) had not
yet been synthesized regioselectively. The only methods for
obtaining small quantities of this compound were extensive
isolation from plant material or base-induced, random iso-
merization of chlorogenic acid (3).
Scheme 4. Synthesis of 4-caffeoylquinic acid (4) from silyl ether 13
(c) 5-Caffeoylquinic Acid
Our first approach was a regioselective esterification of
the hydroxy group at C-4, using a fully protected quinic
One regioselective synthesis of 5-caffeoylquinic acid
acid derivative (structure B) as outlined in Scheme 1. Since (neochlorogenic acid, 5) has been reported in the literat-
acid-catalyzed acetalizations of quinide 9[16] with ketones or ure.[9] Haslam et al. obtained 5 in six steps from 1 and in
aldehydes generally provide the corresponding dioxol- an overall yield of only 3%. The major drawback was an
anones, such as 7, we expected, when using 2,2,3,3-tetrame- unselective esterification of a quinide derivative with both
thoxybutane (TMB), a regioselective functionalization of secondary hydroxy groups at C-4 and C-5 unprotected,
the hydroxy groups at C-1 and C-5 of quinide 9 or of the since no suitably protected quinic acid derivative (corres-
corresponding tris(trimethylsilyl) ether 10. Usually TMB ponding to structure C in Scheme 1) was available.
does not react with vicinal cis-diols,[17] either acetal 11 or
Our first attempt was the preparation of a quinic acid
12 should be formed by reaction of 9 or 10 with TMB under bis(acetal) with an unprotected hydroxy group at C-5,
thermodynamic or kinetic reaction conditions (Scheme 3). which it was hoped could be synthesized from quinic acid
Unfortunately, proton-catalyzed acetalization of 9 in the (1) using TMB[17] or 1,1,2,2-tetramethoxycyclohexane
presence of MeOH and CH(OMe)3 afforded a series of dif- (TMC).[19] These acetals are common reagents for the pro-
ferent acetals derived from quinide 9 or methyl quinate. tection of vicinal trans-diols and so they might also have
Similarly, the Lewis acid catalyzed cyclization of silyl ether been expected to react with α-hydroxy acids to give the cor-
10 produced several 4,5-protected quinides; these were not responding dioxanones.[20] However, protic acetalization of
structurally identified, but it was apparent that neither 11 1 with these reagents could be ruled out, since quinides are
nor 12 was formed under any acetalization conditions ap- formed under thermodynamic reaction conditions. There-
plied.
fore, pentasilylquinic acid 15[12] was treated with TMB or
2736
Eur. J. Org. Chem. 2001, 2735Ϫ2742

First Efficient Syntheses of 1-, 4-, and 5-Caffeoylquinic Acid
FULL PAPER
TMC under Lewis acid catalysis at low temperature,[21] but ‘‘unfavorable’’ cis configuration of the vicinal diol moiety.
neither of the expected acetals, 16 or 17, was formed under As the consequence, the quinide ring was forced into a
these conditions (Scheme 5).
twist-boat conformation (Figure 2).
Scheme 5. Attempted synthesis of bis(cyclodiacetals) 16 or 17 from
pentasilylquinic acid 15 and TMB or TMC, respectively
Treatment of 15 with TMC afforded at least eight quinic
acid derived products: compounds 18Ϫ22 and correspond-
ing silyl ethers (Scheme 6). Characterization of the reaction
products by spectroscopic methods was difficult, due to the
structural similarity of the hitherto unknown reaction prod-
ucts. For example, compounds 18Ϫ20, three isomers of
C15H22O7, show very similar NMR spectra. Fortunately, all
the compounds shown in Scheme 6 are crystalline and their
structures were elucidated by X-ray diffraction.
Figure 2. X-ray structure of cis-cyclodiacetal 20; ORTEP plot with
50% probability displacement ellipsoids; H atoms have been omit-
ted for clarity (except H71);[26] selected bond lengths [A] and angles
˚
[°]: O5ϪC12 1.483(8), C15ϪO5 1.363(7), O7ϪC10 1.378(7),
O6ϪC15 1.198(8); C1ϪO3ϪC13 115.6(4), C2ϪO4ϪC14 115.1(4),
O6ϪC15ϪO5 120.5(6), O6ϪC15ϪC10 129.6(6), O7ϪC10ϪC11
112.7(5), C10ϪC11ϪC12 98.8(5); the molecules are linked by hy-
drogen bonds between O7 and O6 via H71 [O7···O6 2.813(8),
˚
H71···O6 2.09(8) A, O5ϪO51···O4 158(1)°; symmetry operator of
O6: x Ϫ 1/2, 1/2 Ϫ y, Ϫz]
Two appropriate quinic acid derivatives for the regioselec-
tive synthesis of 5, compounds 21 and 22 (Scheme 6), could
be formed from 15 and TMC, but the yields were too low
to proceed with one of these materials. Unlike the diastereo-
isomers 18 and 19, bis(acetal) 21 (Figure 3) was obtained in
a high diastereoisomeric excess. Two structural features of
diacetal 21 were surprising: (i) a dioxolanone moiety[20] and
(ii) an enol ether adjacent to the dioxolanone acetal. Both
observations could be explained if 15 were to react with 2-
methoxycyclohexenone rather than with TMC. 2-Methoxy-
Scheme 6. Structural diversity in the reaction of 15 with TMC un-
der aprotic conditions
It was known that five-membered ring acetals Ϫ 18 and cyclohexenone was formed as a side product from TMC
19, for example[22] Ϫ can be formed as minor side products under the influence of the Lewis acid.
from the reaction between TMC and vicinal cis-diols.[19]
Aprotic acetalization of 15 with TMB gave similar re-
However, a cis-diol-derived cyclodiacetal, such as 20 (Fig- sults, but in this case only compounds 23 and 24 were isol-
ure 2, Table 1), had not been unambiguously identified be- ated as major products (Scheme 7). The two compounds
fore. Recently, Shih and Wu reported that methyl shikimate were structurally related to quinide 19 and bis(acetal) 21,
reacted with TMB to give a mixture of cis- and trans-diacet- respectively. The structures of 23 and 24 were established by
1
als, but no evidence for the structural assignment was pro- comparison of their H and 13C NMR spectra with those
vided. Since it is known that two diastereoisomeric acetals obtained for 19 and 21.
can be formed from diequatorial diols,[19b] the given assign-
As demonstrated, fully protected bis(acetals) of quinic
ment of the shikimate acetals is not certain.[23] Surprisingly, acid possessing a free hydroxy group at C-5, such as 21 and
the crystal structure of acetal 20 revealed two perfectly 24, can be prepared from 15, although not in useful yields.
trans-diaxially oriented (179.6°) methoxy groups despite the For an efficient synthesis of 5, an alternative strategy invol-
Eur. J. Org. Chem. 2001, 2735Ϫ2742
2737

M. Sefkow, A. Kelling, U. Schilde
FULL PAPER
Table 1. Crystal data and measurement conditions for the com-
pounds 20 and 21
20
21
Empirical formula
Molecular mass
Crystal size [mm]
Crystal system
C15H22O7
314.33
C22H32O9
440.48
1.29 ϫ 0.19 ϫ 0.19 1.56 ϫ 0.75 ϫ 0.57
orthorhombic
orthorhombic
Space group
P212121
P212121
Lattice parameters
˚
a [A]
6.301(3)
13.539(6)
17.333(8)
1477.4(8)
4
1.412
672
0.112
Mo-Kα
0.71073
55.0
9.002(3)
12.945(2)
19.412(2)
2262.0(8)
4
1.293
944
0.100
Mo-Kα
0.71073
60.0
Ϫ12/12
Ϫ18/18
Ϫ27/27
7397
˚
b [A]
˚
c [A]
3
˚
V [A ]
Z
Dcalcd. [g·cmϪ3
F (000)
]
µ [mmϪ1
]
Radiation type
˚
λ [A]
2 Θmax [°]
hmin/hmax
kmin/kmax
lmin/lmax
No. of measured reflections 1529
No. of unique reflections 1529
0/7
0/16
0/20
Figure 3. X-ray structure of compound 21; ORTEP plot with 50%
6582
probability displacement ellipsoids; H atoms have been omitted for
clarity (except H51);[26] selected bond lengths [A] and angles [°]:
˚
No. of observed reflections 770
4638
C9ϪC10 1.512(2), C11ϪO5 1.4238(19), C13ϪO6 1.202(2),
C14ϪC15 1.520(4), C14ϪC19 1.500(4), C15ϪC16 1.500(5),
C16ϪC17 1.484(7), C17ϪC18 1.524(7), C18ϪC19 1.337(4),
C19ϪO7 1.350(4), O7ϪC20 1.416(4); C1ϪO3ϪC21 115.84(15),
[I Ͼ 2σ(I)]
No. of parameters
R factor [I Ͼ 2σ(I)]
Goodness of fit
232
0.0469
0.969
341
0.0411
0.991
C22ϪO4ϪC2
C10ϪC11ϪO5
114.87(13),
112.31(12),
C12ϪC11ϪO5
C11ϪC12ϪC7
107.79(13),
114.20(12),
C8ϪC7ϪC12 111.43(13), O9ϪC7ϪC13 103.38(13), O8ϪC13ϪO6
123.59(17), C7ϪC13ϪO6 127.18(8), O9ϪC14ϪO8 105.75(16),
ving trans-acetal 25[17] (85% from 1) was therefore de-
veloped. The suitability of compound 25 was proved by
quantitative conversion of 25 into quinic acid (1) using 1 
HCl. Selective esterification of the hydroxy group at C-5
was achieved using 1.2 equiv. of acid chloride 6 under
standard conditions. Ester 26 was obtained in 88% yield
(Scheme 8). Cleavage of the protecting groups with 1  HCl
afforded 5-caffeoylquinic acid (5) in 81% yield (60%
from 1).
C19ϪC14ϪC15
C17ϪC18ϪC19
113.1(2),
123.1(4),
C18ϪC19ϪC14
C14ϪC19ϪO7
121.7(3),
110.23(19),
C19ϪO7ϪC20 119.8(2); intermolecular hydrogen bonds were
found between O5 and O4 via H51 [O···O4 2.9728(17), H51···O4
˚
2.23(3) A, O5ϪO51···O4 146(2)°; symmetry operator of O4: x Ϫ
1/2, 3/2 Ϫ y, 2 Ϫ z]
Conclusion
We have shown for the first time that syntheses of 1-, 4-,
and 5-caffeoylquinic acid may be efficiently achieved in
three or four steps, using appropriately protected quinic
acid derivatives. Our initial strategy to prepare the caf-
feoylquinic acids from fully protected quinic acid pre-
Scheme 7. Major products derived from the reaction of 15 with
TMB
cursors with only the desired hydroxy group unprotected Caffeoyl esters 4 and 5 were obtained after hydrolysis in
was successful only for caffeoylquinic acid 2. This acid was 36% and 60% overall yields from 1. On the other hand,
prepared in 41% overall yield from 1 by esterification of quinic acid derivatives with a free hydroxy group at either
acetone quinide 7 with caffeoyl chloride 6, followed by a C-4 or C-5, respectively, were not obtained in sufficient
two-step hydrolysis of all protecting groups. Caffeoylquinic quantities. Neither quinide 9, under thermodynamic condi-
acids 4 and 5 were prepared according to alternative routes tions, nor silyl ether 10, under kinetic reaction conditions,
based on the known quinic acid derivatives 13 and 25. Both reacted with TMB to give acetals with an unprotected hy-
intermediates possess two unprotected hydroxy groups, a droxy group at C-4. Treatment of 15 with TMC or TMB
tertiary at C-1 and a secondary at C-4 or C-5, respectively. afforded several crystalline reaction products, which were
Selective esterifications of the secondary hydroxy groups identified by X-ray diffraction. Unexpectedly, diacetal 20,
were achieved in moderate to good yields (55% and 88%). derived from a vicinal cis-diol, has two perfectly trans-diaxi-
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Eur. J. Org. Chem. 2001, 2735Ϫ2742

First Efficient Syntheses of 1-, 4-, and 5-Caffeoylquinic Acid
FULL PAPER
H), 2.41 (dd, J ϭ 14.5, 3.1 Hz, 1 H), 2.31 (s, 3 H), 2.30 (s, 3 H),
1.54 (s, 3 H), 1.34 (s, 3 H). Ϫ 13C NMR: δ ϭ 173.4 (s), 168.0 (s),
167.9 (s), 164.5 (s), 144.7 (d), 143.8 (s), 142.4 (s), 132.8 (s), 126.5
(d), 124.0 (d), 122.9 (d), 117.9 (d), 109.9 (s), 76.3 (s), 75.4 (d), 72.4
(d), 71.1 (d), 35.5 (t), 30.6 (t), 26.9 (q), 24.3 (q), 20.6 (q), 20.6 (q).
Ϫ MS (70 eV): m/z (%) ϭ 461 (4), 445 (6), 418 (14), 376 (100), 247
(9), 205 (29), 163 (95). Ϫ UV (EtOH): λmax (ε) ϭ 285 (14000), 204
(70000) nm. Ϫ C23H24O10 (460.44): calcd. C 60.00, H 5.26; found
C 59.74, H 5.42.
Preparation of 1-Caffeoylquinic Acid (2): A solution of ester 8
(0.46 g, 1.0 mmol) in a mixture of degassed THF (25 mL) and
water (10 mL) was treated with LiOH (1  in H2O, 4.1 mL,
4.1 mmol) at room temperature. The brownish solution was stirred
for 5 h at room temperature and acidified using aqueous 2  HCl
solution (pH ഠ 1). The yellow reaction mixture was stirred for an
additional 17 h at room temperature and diluted by the addition
of CH2Cl2 (50 mL). The aqueous layer was separated, saturated
with solid NaCl, and extracted with EtOAc (3 ϫ 10 mL). The com-
bined organic phases were dried (MgSO4) and filtered, and the
solvents were removed in vacuo. The residue was triturated with
warm Et2O, providing 0.28 g (79%) of 1-caffeoylquinic acid (1) as
amorphous solid. Ϫ 1H NMR ([D4]MeOH): δ ϭ 7.56 (d, J ϭ
15.9 Hz, 1 H), 7.05 (d, J ϭ 1.7 Hz, 1 H), 6.96 (dd, J ϭ 8.1, 1.7 Hz,
1 H), 6.79 (d, J ϭ 8.1 Hz, 1 H), 6.28 (d, J ϭ 15.9 Hz, 1 H), 4.17
(dd, J ϭ 4.2, 3.3 Hz, 1 H), 4.09 (ddd, J ϭ 10, 8, 4.2 Hz, 1 H), 3.52
(dd, J ϭ 8.2, 3.1 Hz, 1 H), 2.57 (br. dd, J ϭ 14.8, 3.1 Hz, 1 H),
2.45 (br. d, J ϭ 13 Hz, 1 H), 2.20 (dd, J ϭ 14.8, 3.0 Hz, 1 H), 1.96
(dd, J ϭ 13.3, 9.9 Hz, 1 H). Ϫ 13C NMR ([D4]MeOH): δ ϭ 175.4
(s), 168.1 (s), 149.6 (d), 147.3 (s), 146.8 (s), 127.8 (s), 123.0 (d),
116.5 (d), 115.3 (d), 115.1 (d), 81.6 (s), 76.2 (d), 69.5 (d), 67.9 (d),
39.6 (t), 35.9 (t). Ϫ MS (70 eV): m/z (%) ϭ 336 (0.4), 180 (32), 163
(29), 60 (100).
Scheme 8. Synthesis of neochlorogenic acid (5)
ally oriented methoxy groups, forcing the quinide ring into
a twist-boat conformation.
Experimental Section
General Procedures: All reactions were performed in dried glass-
ware under N2. Standard reagents and solvents were purified ac-
cording to known procedures.[24] Ϫ Thin layer chromatographic
(TLC) analyses were performed on Merck 60 F254 silica gel plates.
Column-chromatographic purifications (‘‘flash chromatography’’,
FC) were performed as described.[25] Ϫ Melting points were deter-
mined using a Büchi SMP-20 apparatus and are uncorrected. Ϫ
Optical rotations were measured with a JASCO DIP-1000 polari-
Preparation of Ester 14: DMAP (0.05 g, 0.4 mmol) and caffeic acid
chloride 6 (1.51 g, 5.3 mmol) were added at Ϫ10 °C to a solution of
silyl ether 13[18] (1.53 g, 5.3 mmol) in pyridine (15 mL). Additional
chloride 6 was added after 2.5 h (0.37 g, 1.3 mmol) and 5 h (0.20 g,
0.7 mmol), and the reaction mixture was stirred at room temper-
ature for 17 h. The brownish solution was poured onto ice/CH2Cl2.
The mixture was acidified using 2  HCl and the aqueous layer
was extracted with CH2Cl2 (3 ϫ 20 mL). The combined organic
extracts were dried (MgSO4) and filtered, and the solvent was re-
moved under reduced pressure. The residue was purified by FC
(SiO2, 5 ϫ 30 cm, 25Ϫ70% EtOAc/light petroleum ether) and
recrystallization from EtOAc/light petroleum ether to afford 1.55 g
(55%) of ester 14 as colorless crystals. Ϫ M.p. 171Ϫ172 °C. Ϫ
[α]D23 ϭ ϩ12 (c ϭ 0.2, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3447, 2954, 1791,
1742, 1711, 1638, 1229, 1206, 1119, 839 cmϪ1. Ϫ 1H NMR: δ ϭ
7.66 (d, J ϭ 15.9 Hz, 1 H), 7.43 (dd, J ϭ 8.4, 1.8 Hz, 1 H), 7.40
(d, J ϭ 1.8 Hz, 1 H), 7.25 (d, J ϭ 8.4 Hz, 1 H), 6.44 (d, J ϭ
15.9 Hz, 1 H), 5.43 (t, J ϭ 4.7 Hz, 1 H), 4.85 (t, J ϭ 5.3 Hz, 1 H),
4.04 (ddd, J ϭ 9.6, 8.1, 4.7 Hz, 1 H), 2.79 (br. s, 1 H), 2.53 (d, J ϭ
11.7 Hz, 1 H), 2.42 (dd, J ϭ 11.7, 5.6 Hz, 1 H), 2.32 (s, 3 H), 2.31
(s, 3 H), 2.12Ϫ2.08 (m, 2 H), 0.81 (s, 9 H), 0.06 (s, 3 H), 0.03 (s, 3
H). Ϫ 13C NMR: δ ϭ 177.3 (s), 168.0 (s), 165.2 (s), 144.2 (d), 143.8
(s), 142.5 (s), 132.9 (s), 126.6 (d), 124.0 (d), 122.8 (d), 118.3 (d),
74.2 (d), 72.0 (s), 66.6 (d), 65.9 (d), 40.9 (t), 37.5 (t), 26.5 (q), 20.6
(q), 17.9 (s), Ϫ5.1 (q). Ϫ MS (70 eV): m/z (%) ϭ 535 (4), 477 (43),
321 (33), 279 (49), 247 (59), 205 (100), 163 (48). Ϫ UV (EtOH):
λmax (ε)ϭ 282 (24000), 220 (17000) nm. Ϫ C26H34O10Si (534.63):
calcd. C 58.41, H 6.42; found C 58.27, H 6.21.
1
meter. Ϫ H NMR and 13C NMR spectra were obtained using a
Bruker ARX 300 instrument, at 300.1 and 75.4 MHz, respectively.
Unless otherwise stated, CDCl3 was used as solvent. Ϫ Infrared
(IR) spectra were recorded with a PerkinϪElmer FT-IR 16 PC in-
strument either from KBr plates or neat. Ϫ Ultraviolet (UV) spec-
tra were obtained from alcoholic solutions utilizing an ATI UN-
ICAM UV 3 instrument. Ϫ Mass spectra were measured by elec-
tron impact (EI), using a Finnigan MAT SSQ 710 instrument, and
MALDI-MS were recorded with a Bruker Reflex II (positive ion
mode, matrix: THAP). Ϫ Elemental analyses were performed with
a LECO CHNS-932 instrument.
Preparation of Ester 8: DMAP (0.18 g, 1.5 mmol) and acid chloride
6[12] (1.97 g, 7.0 mmol) were added at room temperature to a solu-
tion of acetone quinide 7[14] (1.07 g, 5.0 mmol) and pyridine (1 mL)
in CH2Cl2 (40 mL). The reaction mixture was stirred at room tem-
perature (4 h) and was then quenched by slow addition of 1  aque-
ous HCl solution (pH ഠ 3). The aqueous layer was extracted with
CH2Cl2 (2 ϫ 20 mL). The combined organic phases were dried
with MgSO4 and filtered, and the solvents were removed under
reduced pressure. Chromatography of the residue (SiO2, 4 ϫ 35 cm,
33% EtOAc/light petroleum ether) followed by recrystallization af-
forded 1.33 g (58%) of ester 8 as white crystals. Ϫ M.p. 126Ϫ128
°C. Ϫ [α]2D5 ϭ ϩ1.8 (c ϭ 0.2, CH2Cl2). Ϫ IR (KBr): ν ϭ 2987,
˜
1803, 1774, 1720, 1639, 1212, 1169 cmϪ1. Ϫ 1H NMR: δ ϭ 7.65
(d, J ϭ 15.9 Hz, 1 H), 7.40 (dd, J ϭ 8.3, 1.8 Hz, 1 H), 7.36 (d, J ϭ
1.8 Hz, 1 H), 7.28 (d, J ϭ 8.3 Hz, 1 H), 6.38 (d, J ϭ 15.9 Hz, 1 H),
4.81 (dd, J ϭ 6.3, 2.3 Hz, 1 H), 4.56 (ddd, J ϭ 7.4, 6.7, 3.2 Hz, 1
H), 4.34 (br. d, J ϭ 6.4 Hz, 1 H), 3.11 (br. dd, J ϭ 11.4, 6.4 Hz, 1 Preparation of 4-Caffeoylquinic Acid (4): THF (ca. 4 mL) was ad-
H), 2.63 (d, J ϭ 11.4 Hz, 1 H), 2.53 (ddd, J ϭ 14.5, 7.6, 2.0 Hz, 1
Eur. J. Org. Chem. 2001, 2735Ϫ2742
ded to a suspension of ester 14 (0.29 g, 0.54 mmol) in aq. HCl (1
2739

M. Sefkow, A. Kelling, U. Schilde
FULL PAPER
, 20 mL) until the solid was completely dissolved. The clear solu-
tion was stirred for 6 d at 23 °C and the reaction progress was
1 H), 2.62 (d, J ϭ 11.6 Hz, 1 H), 2.38 (ddd, J ϭ 11.4, 6.0, 2.7 Hz,
1 H), 2.17 (ddd, J ϭ 11.7, 7.3, 2.7 Hz, 1 H), 1.87Ϫ1.65 (m, 4 H),
monitored by TLC. The solution was saturated with solid NaCl 1.62Ϫ1.48 (m, 2 H), 1.47Ϫ1.24 (m, 2 H). Ϫ 13C NMR: δ ϭ 177.8
and the aqueous layer extracted with EtOAc/THF (3:1, 3 ϫ
(s), 98.5 (s), 97.6 (s), 75.8 (d), 72.3 (s), 66.8 (d), 62.4 (d), 47.7 (q),
20 mL). The combined organic extracts were dried with MgSO4
47.0 (q), 39.2 (t), 37.3 (t), 27.9 (t), 26.8 (t), 21.3 (t), 21.0 (t). Ϫ MS
and filtered, and the solvents were removed under reduced pressure. (70 eV): m/z (%) ϭ 315 (30), 299 (32), 283 (68), 175 (70), 111 (89),
The pale yellow residue was recrystallized twice from a mixture of
67 (100). Ϫ Compound 21: M.p. 190Ϫ192 °C. Ϫ [α]2D9 ϭ ϩ74 (c ϭ
THF, Et2O, and light petroleum ether, affording 0.16 g (83%) of 4 0.25, CH2Cl2). Ϫ IR (KBr): ν ϭ 3556, 2944, 1797, 1664, 1271,
˜
1
as a pale yellow powder containing small amounts of 5-caf-
1102, 1058 cmϪ1. Ϫ H NMR: δ ϭ 4.99 (t, J ϭ 4.1 Hz, 1 H), 4.37
1
1
feoylquinic acid (5) as indicated by the H NMR spectrum. Ϫ H (ddd, J ϭ 12.5, 10.5, 4.2 Hz, 1 H), 4.17 (br. s, 1 H), 3.72 (dd, J ϭ
NMR ([D4]MeOH): δ ϭ 7.64 (d, J ϭ 15.9 Hz, 1 H), 7.06 (d, J ϭ 10.5, 2.9 Hz, 1 H), 3.54 (s, 3 H), 3.22 (s, 3 H), 3.20 (s, 3 H), 2.72
1.8 Hz, 1 H), 6.96 (dd, J ϭ 8.1, 1.8 Hz, 1 H), 6.78 (d, J ϭ 8.1 Hz, (br. d, J ϭ 5 Hz, 1 H), 2.46 (ddd, J ϭ 12.9, 4.1, 1.4 Hz, 1 H),
1 H), 6.37 (d, J ϭ 15.9 Hz, 1 H), 4.80 (dd, J ϭ 9.3, 3.0 Hz, 1 H), 2.18Ϫ2.05 (m, 6 H), 1.90 (t, J ϭ 12.8 Hz, 1 H), 1.85Ϫ1.71 (m, 6
4.37Ϫ4.23 (m,
2
H), 2.29Ϫ1.92 (m,
4
H).
Ϫ
13C NMR H), 1.57Ϫ1.34 (m, 4 H). Ϫ 13C NMR: δ ϭ 173.6 (s), 150.0 (s),
106.8 (s), 102.2 (d), 99.1 (s), 98.6 (s), 80.3 (s), 73.3 (d), 68.6 (d),
([D6]DMSO): δ ϭ 175.2 (s), 166.3 (s), 148.3 (s), 145.6 (s), 144.8 (d),
125.6 (s), 121.2 (d), 115.8 (d), 114.7 (d), 114.6 (d), 77.0 (d), 74.1 62.8 (d), 54.6 (q), 46.8 (q), 46.7 (q), 39.4 (t), 37.6 (t), 36.7 (t), 27.0
(s), 66.6 (d), 63.8 (d), 40.9 (t), 37.6 (t). Ϫ MS (70 eV): m/z (%) ϭ (t), 27.0 (t), 23.4 (t), 21.3 (t), 20.1 (t). Ϫ MS (70 eV): m/z (%) ϭ 440
336 (0.4), 180 (32), 163 (29), 60 (100).
(4), 425 (38), 409 (100), 377 (11), 283 (4), 127 (12). Ϫ Compound 22:
M.p. 149Ϫ150 °C. Ϫ [α]2D9 ϭ ϩ105 (c ϭ 0.16, CH2Cl2). Ϫ IR (KBr):
1
ν ϭ 3457, 3288, 2929, 1744, 1181, 1100, 1060 cmϪ1. Ϫ H NMR:
Preparation of Compounds 18؊22: TMSOTf (40 µL, 0.22 mmol)
was added at Ϫ76 °C to a solution of silyl ether 15 (2.73 g,
4.94 mmol) and 1,1,2,2-tetramethoxycyclohexane (TMC, 2.32 g,
10.0 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred
at that temperature for 1 h and then maintained at Ϫ30 °C for
19 h. An additional quantity of TMSOTf (40 µL, 0.22 mmol) was
added at Ϫ30 °C and the solution was maintained for a further
48 h at that temperature. The brownish solution was poured into a
1:1 mixture of sat. NaHCO3 and NH4Cl (40 mL) and the phases
were separated. The aqueous phase was extracted with CH2Cl2 (3
ϫ 20 mL). The combined organic extracts were dried using MgSO4
˜
δ ϭ 4.48 (ddd, J ϭ 12.0, 10.5, 4.1 Hz, 1 H), 4.27 (br. s, 1 H), 4.21
(m, 1 H), 3.79 (s, 3 H), 3.74 (dd, J ϭ 10.4, 2.7 Hz, 1 H), 3.36 (br.
s, 1 H), 3.22 (s, 3 H), 3.22 (s, 3 H), 2.18 (dt, J ϭ 14.8, 2.8 Hz, 1
H), 2.10 (ddd, J ϭ 12.9, 4.6, 2.8 Hz, 1 H), 2.05 (dd, J ϭ 14.8,
2.9 Hz, 1 H), 1.97 (t, J ϭ 12.4 Hz, 1 H), 1.88Ϫ1.67 (m, 4 H),
1.60Ϫ1.30 (m, 4 H). Ϫ 13C NMR: δ ϭ 174.3 (s), 99.1 (s), 98.7 (s),
75.8 (s), 73.6 (d), 69.4 (d), 63.0 (d), 52.9 (q), 46.8 (q), 38.9 (t), 37.6
(t), 27.1 (t), 26.9 (t), 21.3 (t), 21.3 (t). Ϫ MS (70 eV): m/z (%) ϭ
346 (4), 331 (32), 315 (100), 283 (13), 255 (7), 175 (10), 143 (70).
and filtered, and the solvent was removed in vacuo. The residue Preparation of Compounds 23 and 24: TMSOTf (40 µL, 0.22 mmol)
was purified by FC (6 ϫ 30 cm, 20Ϫ100% EtOAc/light petroleum
ether Ǟ 5Ϫ20% MeOH/EtOAc), yielding 0.20 g (13%) of com-
pound 18, 0.20 g (13%) of compound 19, 0.15 g (10%) of com-
pound 20, 0.36 g (17%) of compound 21, and 0.29 g (17%) of com-
pound 22 as pale yellow solids. Recrystallization of these com-
pounds gave colorless crystals, suitable for X-ray crystallography
was added at Ϫ76 °C to a solution of silyl ether 15 (2.75 g,
4.97 mmol) and 2,2,3,3-tetramethoxybutane (TMB, 4.5 g,
25 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred at
that temperature for 1 h and maintained at Ϫ30 °C for 46 h. An
additional quantity of TMSOTf (40 µL, 0.22 mmol) was added at
Ϫ30 °C and the solution was maintained at that temperature for a
(except for compound 22). Ϫ Compound 18: M.p. 105Ϫ106 °C. Ϫ further 6 d. The brownish solution was poured into a 1:1 mixture
[α]3D0 ϭ Ϫ25 (c ϭ 0.16, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3585, 3477,
of sat. NaHCO3 and NH4Cl (40 mL) and the phases were separ-
3195, 2948, 1787, 1640, 1165, 1068 cmϪ1. Ϫ 1H NMR: δ ϭ 4.75 ated. The aqueous phase was extracted with CH2Cl2 (3 ϫ 20 mL).
(dd, J ϭ 5.7, 2.2 Hz, 1 H), 4.74 (td, J ϭ 7.3, 3.0 Hz, 1 H), 4.51 (br. The combined organic extracts were dried using MgSO4 and fil-
d, J ϭ 6.4 Hz, 1 H), 3.28 (s, 6 H), 2.99 (s, 1 H), 2.55 (d, J ϭ
tered, and the solvent was removed in vacuo. The residue was puri-
11.7 Hz, 1 H), 2.35 (ddd, J ϭ 14.7, 8.0, 2.2 Hz, 1 H), 2.30 (br. dd, fied by FC (6 ϫ 30 cm, 20Ϫ100% EtOAc/light petroleum ether Ǟ
J ϭ 11.7, 6.4 Hz, 1 H), 2.15 (dd, J ϭ 14.6, 2.8 Hz, 1 H), 1.80Ϫ1.68 5Ϫ20% MeOH/EtOAc), yielding 0.44 g (13%) of compound 23,
(m, 4 H), 1.64Ϫ1.55 (m, 2 H), 1.54Ϫ1.44 (m, 2 H). Ϫ 13C NMR: and 0.20 g (17%) of compound 24 as pale brown solids. Recrystal-
δ ϭ 179.0 (s), 111.6 (s), 101.8 (s), 75.8 (d), 73.6 (s), 73.2 (d), 71.5
lization of these compounds gave colorless crystals. Ϫ Compound
(d), 49.1 (q), 49.1 (q), 39.1 (t), 35.2 (t), 34.3 (t), 30.6 (t), 22.8 (t), 23: M.p. 140Ϫ141 °C. Ϫ [α]3D0 ϭ Ϫ18 (c ϭ 0.23, CH2Cl2). Ϫ IR
21.4 (t). Ϫ MS (70 eV): m/z (%) ϭ 314 (0.2), 299 (2), 283 (2), 270 (KBr): ν˜ ϭ 3486, 3374, 2954, 1789, 1100, 1068 cmϪ1. Ϫ H NMR:
1
(1), 224 (10), 175 (6), 143 (10), 111 (32), 101 (100). Ϫ Compound δ ϭ 4.81 (dd, J ϭ 6.1, 2.7 Hz, 1 H), 4.49 (ddd, J ϭ 7.6, 6.8, 4.0 Hz,
19: M.p. 146Ϫ147 °C. Ϫ [α]3D0 ϭ Ϫ24 (c ϭ 0.23, CH2Cl2). Ϫ IR
1 H), 4.32 (dd, J ϭ 6.3, 2.2 Hz, 1 H), 3.29 (s, 3 H), 3.01 (d, J ϭ
11.6 Hz, 1 H), 2.81 (s, 1 H), 2.41 (dd, J ϭ 14.4, 4.0 Hz, 1 H),
1
(KBr): ν˜ ϭ 3527, 3461, 2944, 1799, 1764, 1131, 1060 cmϪ1. Ϫ H
NMR: δ ϭ 4.82 (dd, J ϭ 6.1, 2.9 Hz, 1 H), 4.47 (ddd, J ϭ 7.8, 6.5, 2.32Ϫ2.22 (m, 1 H), 1.37 (s, 3 H), 1.33 (s, 3 H). Ϫ 13C NMR: δ ϭ
4.0 Hz, 1 H), 4.29 (ddd, J ϭ 6.5, 2.8, 0.9 Hz, 1 H), 3.31 (s, 3 H),
179.0 (s), 113.2 (s), 100.9 (s), 76.1 (d), 71.9 (d), 71.8 (d), 71.7 (s),
3.31 (s, 3 H), 3.27 (s, 1 H), 3.06 (d, J ϭ 11.6 Hz, 1 H), 2.46 (dd, 49.9 (q), 38.2 (t), 34.4 (t), 20.1 (q), 18.7 (q). Ϫ MS (70 eV): m/z
J ϭ 14.2, 4.0 Hz, 1 H), 2.34Ϫ2.24 (m, 2 H), 1.86Ϫ1.72 (m, 2 H), (%) ϭ 257 (2), 199 (13), 185 (2), 139 (4), 111 (12), 89 (100). Ϫ
1.68Ϫ1.63 (m, 2 H), 1.56Ϫ1.47 (m, 4 H). Ϫ 13C NMR: δ ϭ 179.2 Compound 24: M.p. 148Ϫ149 °C. Ϫ [α]2D6 ϭ ϩ106 (c ϭ 0.3,
(s), 112.5 (s), 98.9 (s), 76.1 (d), 71.7 (d), 71.6 (d), 71.6 (s), 49.7 (q), CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3478, 2948, 1797, 1130, 1033 cmϪ1. Ϫ
49.4 (q), 38.0 (t), 34.3 (t), 31.9 (t), 31.2 (t), 22.4 (t), 21.5 (t). Ϫ MS 1H NMR: δ ϭ 4.19 (ddd, J ϭ 12.5, 10.2, 4.3 Hz, 1 H), 4.15 (br. q,
(70 eV): m/z (%) ϭ 314 (0.2), 299 (2), 283 (1), 270 (1), 224 (10), 175 J ϭ 3 Hz, 1 H), 3.56 (dd, J ϭ 10.2, 3.1 Hz, 1 H), 3.29 (s, 3 H), 3.27
(7), 143 (8), 111(29), 101 (100). Ϫ Compound 20: M.p. 248Ϫ249 °C. (s, 6 H), 3.23 (s, 3 H), 2.50 (br. s, 1 H), 2.44 (ddd, J ϭ 13.0, 4.1,
Ϫ [α]3D0 ϭ Ϫ120 (c ϭ 0.06, CH2Cl2). Ϫ IR (KBr): ν ϭ 3471, 2955,
1773, 1081, 1049 cmϪ1. Ϫ 1H NMR: δ ϭ 4.74 (dd, J ϭ 6.0, 4.4 Hz, 3.2 Hz, 1 H), 1.81 (dd, J ϭ 13.0, 12.5 Hz, 1 H), 1.62 (s, 3 H), 1.35
1 H), 4.40 (t, J ϭ 4.7 Hz, 1 H), 3.88 (ddd, J ϭ 11.6, 7.3, 5.2 Hz, 1
(s, 3 H), 1.34 (s, 3 H), 1.30 (s, 3 H). Ϫ 13C NMR: δ ϭ 173.3 (s),
H), 3.24 (s, 3 H), 3.24 (s, 3 H), 2.86 (s, 1 H), 2.79 (t, J ϭ 11.6 Hz, 111.8 (s), 100.7 (s), 100.1 (s), 99.7 (s), 80.1 (s), 72.4 (d), 68.2 (d),
2.6 Hz, 1 H), 2.09 (dt, J ϭ 15.0, 2.7 Hz, 1 H), 2.01 (dd, J ϭ 15.0,
˜
2740
Eur. J. Org. Chem. 2001, 2735Ϫ2742

First Efficient Syntheses of 1-, 4-, and 5-Caffeoylquinic Acid
FULL PAPER
62.3 (d), 49.8 (q), 49.7 (q), 47.9 (q), 47.4 (q), 39.5 (t), 36.0 (t), 23.0
(q), 18.6 (q), 17.7 (q), 17.6 (q). Ϫ MS (70 eV): m/z (%) ϭ 389 (11),
357 (6), 331 (3), 240 (9), 115 (52), 101 (93), 89 (100).
Acknowledgments
This work was generously supported by Prof. M. G. Peter and by
the Fonds der Chemischen Industrie. The Deutsche Forschungsge-
meinschaft is acknowledged for a ‘‘habilitation’’ grant (Se 875/1-1).
Thanks go to Mrs. C.-M. Matern for skillful experimentation.
Preparation of Ester 26: DMAP (0.06 g, 0.5 mmol) and acid chlor-
ide 6 (1.65 g, 5.8 mmol) were added at room temperature to a solu-
tion of alcohol 25[17] (1.54 g, 4.8 mmol) in CH2Cl2 (20 mL) and
pyridine (4.0 mL). The reaction mixture was stirred for 24 h and
quenched by the addition of 1  HCl (pH ഠ 3). The aqueous layer
was extracted with CH2Cl2 (3 ϫ 15 mL). The combined organic
phases were dried with MgSO4 and filtered, and the solvents were
evaporated in vacuo. The residue was purified by FC (SiO2, 4 ϫ
30 cm, 33Ϫ100% EtOAc/light petroleum ether), providing 2.40 g
(88%) of ester 26 as a colorless, amorphous powder. Ϫ M.p. 72Ϫ74
[1]
M. N. Clifford, J. Sci. Food Agric. 1999, 79, 362Ϫ372.
P. A. Kroon, G. Williamson, J. Sci. Food Agric. 1999, 79,
355Ϫ361.
[2]
[3]
Phytochemical Dictionary (Eds.: J. B. Harborne, H. Baxter),
Taylor & Francis, London, 1993, p. 1745.
For a distribution analysis of caffeoylquinic acids in coffee, see:
°C. Ϫ [α]2D3 ϭ ϩ56 (c ϭ 0.2, CH2Cl2). Ϫ IR (KBr): ν ϭ 3504, 2953,
˜
[4]
1777, 1735, 1713, 1639, 1207, 1132 cmϪ1. Ϫ 1H NMR: δ ϭ 7.65
(d, J ϭ 15.9 Hz, 1 H), 7.42 (dd, J ϭ 8.4, 1.8 Hz, 1 H), 7.38 (d, J ϭ
1.8 Hz, 1 H), 7.23 (d, J ϭ 8.4 Hz, 1 H), 6.45 (d, J ϭ 15.9 Hz, 1 H),
5.36 (t, J ϭ 3 Hz, 1 H), 4.42 (td, J ϭ 9.9, 6.7 Hz, 1 H), 3.79 (s, 3
H), 3.72 (dd, J ϭ 10.1, 3.2 Hz, 1 H), 3.31 (s, 3 H), 3.27 (s, 3 H),
3.19 (s, 1 H), 2.31 (s, 3 H), 2.30 (s, 3 H), 2.26 (br. d, J ϭ 15.7 Hz,
1 H), 2.12 (dd, J ϭ 15.5, 3.2 Hz, 1 H), 2.06Ϫ1.96 (m, 2 H), 1.30
(s, 3 H), 1.28 (s, 3 H). Ϫ 13C NMR: δ ϭ 175.5 (s), 168.1 (s), 168.0
(s), 166.2 (s), 143.4 (s), 143.1 (d), 142.4 (s), 133.3 (s), 126.5 (d),
123.8 (d), 122.7 (d), 119.6 (d), 74.5 (s), 71.2 (d), 69.9 (d), 62.7 (d),
53.2 (q), 48.04 (q), 47.95 (q), 38.7 (t), 36.6 (t), 20.63 (q), 20.58 (q),
17.8 (q), 17.6 (q). Ϫ MS (70 eV): m/z (%) ϭ 535 (100), 503 (12),
477 (34), 334 (23), 247 (23), 205 (76), 197 (43), 180 (55), 163 (82). Ϫ
UV (EtOH): λmax (ε)ϭ 280 (20000), 219 (15000) nm. Ϫ C27H34O13
(566.56): calcd. C 57.24, H 6.05; found C 57.08, H 6.17.
K. Schrader, A. Kiehne, U. H. Engelhardt, H. G. Maier, J. Sci.
Food Agric. 1996, 71, 392Ϫ398.
[5] [5a]
G. F. Pauli, U. Kuczkowiak, A. Nahrstedt, Magn. Reson.
[5b]
Chem. 1999, 37, 827Ϫ836. Ϫ
G. F. Pauli, F. Poetsch, A.
[5c]
Nahrstedt, Phytochem. Anal. 1998, 9, 177Ϫ185. Ϫ
T. Tate-
fuji, N. Izumi, T. Ohta, S. Arai, M. Ikeda, M. Kurimoto, Biol.
Pharm. Bull. 1996, 19, 966Ϫ970.
[6] [6a]
NaHCO3-mediated isomerization: C. Fuchs, G. Spiteller, J.
[6b]
Mass Spectrom. 1996, 31, 602Ϫ608. Ϫ
Nurmi, J. Loponen, E. Haukioja, K. Pihlaja, J. Chromatogr. A
1996, 721, 59Ϫ68. Ϫ
V. Ossipov, K.
[6c]
L. Nagels, W. van Dongen, J. de
Bruker, H. de Pooter, J. Chromatogr. 1980, 187, 181Ϫ187.
Alternative isomerization procedure using tetrabutylammo-
nium hydroxide: M. N. Clifford, B. Kellard, Food Chem. 1989,
33, 115Ϫ123.
A. C. Weiss, Jr., R. E. Lundin, J. Corse, Chem. Ind. (London )
1964, 1984Ϫ1985.
E. Haslam, G. K. Makinson, M. O. Naumann, J. Cunningham,
J. Chem. Soc. 1964, 2137Ϫ2146.
E. L. Eliel, M. B. Ramirez, Tetrahedron: Asymmetry 1997, 8,
3551Ϫ3554.
[7]
[8]
[9]
Preparation of 5-Caffeoylquinic Acid (5): Ester 26 (2.40 g,
4.24 mmol) was dissolved in a mixture of 1  aq. HCl (120 mL)
and THF (40 mL) at 23 °C. The mixture was stirred at that temper-
ature for 7 d, during which it turned yellow (formation of diacetyl).
The progress of hydrolysis was monitored by TLC. After comple-
tion of the reaction, the aqueous phase was saturated with solid
NaCl and extracted with EtOAc/THF (3:1, 4 ϫ 60 mL). The com-
bined organic extracts were dried with MgSO4 and filtered, and the
solvents were removed under reduced pressure. The yellow residue
was recrystallized twice from a mixture of THF, Et2O, and light
petroleum ether, providing compound 5 (1.22 g, 81%) as a pale yel-
low powder containing small amounts of 4-caffeoylquinic acid (4)
[10]
[11]
There are over 3300 references from 1967 to date for 3-caf-
feoylquinic acid (chlorogenic acid) [327-97-9] and 319 refer-
ences from 1967 to date for 5-caffeoylquinic acid, neochlorog-
enic acid [906-33-2]. Over 50% of these references report on
chlorogenic acid, which is described as 5-caffeoylquinic acid.
M. Sefkow, Eur. J. Org. Chem. 2001, 1137Ϫ1141.
Recent review about selective functionalization of 1: A. Barco,
S. Benetti, C. De Risi, P. Marchetti, G. P. Pollini, V. Zanirato,
Tetrahedron: Asymmetry 1997, 8, 3515Ϫ3545.
[12]
[13]
[14] [14a] J. C. Rohloff, K. M. Kent, M. J. Postich, M. W. Becker, H.
H. Chapman, D. E. Kelly, W. Lew, M. S. Louie, L. R. McGee,
1
1
as indicated by H NMR. Ϫ H NMR ([D4]MeOH): δ ϭ 7.58 (d,
J ϭ 15.9 Hz, 1 H), 7.04 (d, J ϭ 1.8 Hz, 1 H), 6.94 (dd, J ϭ 8.1,
1.8 Hz, 1 H), 6.77 (d, J ϭ 8.1 Hz, 1 H), 6.31 (d, J ϭ 15.9 Hz, 1 H),
5.35 (m, 1 H), 4.16 (ddd, J ϭ 9.5, 8.5, 3.8 Hz, 1 H), 3.64 (dd, J ϭ
8.5, 3.2, 1 H), 2.25Ϫ1.91 (m, 4 H). Ϫ 13C NMR ([D6]DMSO): δ ϭ
176.0 (s), 166.1 (s), 148.2 (s), 145.6 (s), 144.4 (d), 125.7 (s), 121.1
(d), 115.8 (d), 115.1 (d), 114.6 (d), 72.9 (s), 71.3 (d), 71.0 (d), 67.2
(d), 39.2 (t), 35.1 (t). Ϫ MS (70 eV): m/z (%) ϭ 336 (0.4), 180 (32),
163 (29), 60 (100).
E. J. Prisbe, L. M. Schultze, R. H. Yu, L. Zhang, J. Org. Chem.
[14b]
1998, 63, 4545Ϫ4550. Ϫ
H. O. L. Fischer, Ber. Dtsch.
Chem. Ges. 1921, 54, 775Ϫ784.
[15] [15a]
L. E. Rodriguez-Saona, R. E. Wrolstad, Am. Potato J.
[15b]
1997, 74, 87Ϫ106. Ϫ
Venere, V. Linsalata, S. Calmieri, Food Chem. 1994, 50, 1Ϫ7.
[15c] V. I. Litvinenko, T. P. Popola, A. V. Simonjan, I. G. Zoz,
V. Lattanzio, A. Cardinali, D. Di
Ϫ
V. S. Sokolov, Planta Med. 1975, 27, 372Ϫ380.
P. Huang, K. Sabbe, M. Pottie, M. Vandewalle, Tetrahedron
Lett. 1995, 36, 8299Ϫ8302.
J.-L. Montchamp, F. Tian, M. E. Hart, J. W. Frost, J. Org.
Chem. 1996, 61, 3897Ϫ3899.
[16]
[17]
[18]
Crystal Structure Determinations: The crystals were measured with
a STADI-4, four-circle, computer-controlled, single-crystal dif-
fractometer. Crystal data and details of structure determinations
and refinements are summarized in Table 1. Ϫ Crystallographic
data (excluding structure factors) for the structures included in this
paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publications no. CCDC-154963 (20)
and -154964 (21). Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
´
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