A novel efficient and versatile route to the synthesis of 5-O-feruloylquinic acids

Article abstract of DOI:10.1039/b719132d

A novel synthesis of 5-O-feruloylquinic acid, a polyphenolic compound found in coffee beans, and its methyl ester derivative has been optimized. The sequence involves 6 steps and is compatible with the preparation of potential human metabolites of these c

Full text of DOI:10.1039/b719132d

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A novel efficient and versatile route to the synthesis of 5-O-feruloylquinic acids
Candice Menozzi Smarrito, Caroline Munari, Fabien Robert and Denis Barron*
Received 11th December 2007, Accepted 29th January 2008
First published as an Advance Article on the web 12th February 2008
DOI: 10.1039/b719132d
A novel synthesis of 5-O-feruloylquinic acid, a polyphenolic
compound found in coffee beans, and its methyl ester deriva-
tive has been optimized. The sequence involves 6 steps and is
compatible with the preparation of potential human metabo-
lites of these compounds. The key reaction is a Knoevenagel
condensation of 4-hydroxy-3-methoxy-benzaldehyde and a
malonate ester of quinic acid.
Herein we describe a new flexible approach towards chlorogenic
acids and its first application to the synthesis of 5-O-feruloylquinic
acid 1 and its methyl ester derivative 2.
In our convergent approach to 5-O-feruloyquinic acid 1 and
5-O-feruloyquinic acid methyl ester 2, the (E)-double bond will
be formed in the last step by the condensation of the aldehyde
4 and malonates 3a–b derived from quinic acid (Scheme 2).
Advantageously, this Knoevenagel reaction did not require the
protection of the phenol 4 and the malonyl quinic fragments 3a–b.
Using this approach, the desired hydroxycinnamoyl quinic acid
was directly obtained with no deprotection step, thus eliminating
any additional reaction on the sensitive FQA skeleton.
Chlorogenic acids are natural polyphenolic compounds contain-
ing quinic acid and trans-cinnamic acid units. The main subgroup
is formed by the 5-mono-esters of caffeic (5-CQA), p-coumaric
(5-pCoQA) and ferulic acid (5-FQA) (Scheme 1), present in coffee
beans, potatoes and many fruits and vegetables.1 Chlorogenic
acids possess many biological properties such as antibacterial,
antioxidant, antimutagenic, antitumor and antiviral activities.2,3
Consequently there is a lot of interest in the chemistry of chloro-
genic acids and their potential human metabolites. The previously
reported syntheses of chlorogenic acids and their derivatives were
based on the esterification of quinic acid by a cinnamic acid
derivative (Scheme 1).4 However, the regioselective esterification
requires suitable protection of both precursors, and the final
deprotection step could be delicate. In fact, the chlorogenic
acid skeleton may be sensitive to hydrogenative, basic or strong
acidic conditions under which some double bond reduction,
isomerisation (transesterification) and/or ester cleavage reactions
can take place.
Scheme 2
The synthesis of malonates 3a–b was readily achieved starting
from commercially available quinic acid 5 (Scheme 3). The
latter was first dehydrated and protected to the benzylidene
quinide derivative 6 (92%) by heating it to reflux in toluene
with benzaldehyde and a catalytic amount of p-toluenesulfonic
acid.5 Protection of the free 1-hydroxyl group in 6 under standard
benzylation conditions (NaH, BnBr, DMF)6 provided the lactone
7 in 87% yield. Saponification using NaOH in THF–H2O at room
temperature, followed by esterification of the resulting carboxylate
by treatment with Cs2CO3 (0.5 eq.) and benzyl bromide,7 afforded
benzyl ester 8a in 94% yield over the two steps. The methyl
ester 8b was directly prepared by treatment of the lactone 7
with MeONa in MeOH (94%).5 The 5-alcohol functions of 8a–
b were then esterified by refluxing in toluene with commercially
available 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid),8
to lead to the corresponding malonates 9a–b in 92% and 79%
yields, respectively. Removal of all protective groups was then
performed in one step using hydrogenative conditions (Pd/C 5%,
MeOH/H2O), to give the quinic acid fragments 3a–b (70% and
Scheme 1
Nestle´ Research Center, Vers Chez Les Blanc, 1000, Lausanne 26, Switzer-
land. E-mail: denis.barron@rdls.nestle.com; Fax: (+41) 021 785 8554;
Tel: (+41) 021 785 9497
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Scheme 3 Reagents and conditions: a) PhCHO, p-TsOH, toluene, reflux, 16 h, 92%; b) NaH, DMF, 0 ◦C, 30 min then BnBr, DMF, rt, 12 h, 87%; c)
NaOH, THF–H2O, rt, 40 min, quant.; d) Cs2CO3, MeOH–H2O, rt, 20 min then BnBr, DMF, rt, 8 h, 8a 94%; e) NaOMe, MeOH, rt, 1 h, 8b 94%; f)
Meldrum’s acid, toluene, reflux, 3 h 30 min, 9a 92%, 9b 79%; g) H2, Pd/C 5%, MeOH–H2O, rt, 40 h, 3a 70%, 3b quant.; h) vanillin 4, DMAP, piperidine,
DMF, rt, 7 days, 1 40%, 2 75%
quantitative, respectively). Finally, DMAP-catalysed Knoevenagel
condensation was achieved on vanillin 4 and malonates 3a–b, using
the mild conditions developed by List et al. (rt, 7 days).9 This
afforded 5-O-feruloyquinic acid10 1 (40%) and 5-O-feruloylquinic
acid methyl ester11 2 (75%). The analytical data (1H and 13C NMR)
of synthetic 5-O-feruloyquinic acid 1 were in good agreement with
the reported data for the natural product.12
In conclusion, starting from quinic acid and vanillin, the
syntheses of 5-O-feruloylquinic acid and 5-O-feruloyquinic acid
methyl ester were achieved in 19% and 44% overall yields,
respectively. This new efficient route to chlorogenic acids could
be applied in the future to the synthesis of potential human
metabolites of these compounds (sulfo-and glucuro-conjugates),
which are not compatible with the deprotection step conditions
used in the previous reported syntheses. Work on the synthesis of
these conjugates is in progress in our laboratory and the details
will be published in a forthcoming paper.
4 (a) K. Ishikawa, Y. Sakurai, T. Ariyiama, S. Yoshioka, T. Shiraki,
H. Horikoshi, H. Kuwano, T. Kinoshita and M. Boriboon, Sankyo
Kenkyusho Nempo, 1991, 43, 99–110; (b) H. Hemmerle, H.-J. Burger,
P. Below, G. Schubert, R. Rippel, P. W. Schindler, E. Paulus and A. W.
Herling, J. Med. Chem., 1997, 40, 137–145; (c) M. Sefkow, Eur. J. Org.
Chem., 2001, 1137–1141.
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J. Chem. Soc., Perkin Trans. 1, 1996, 2371–2377.
6 N. Kaila, W. S. Somers, B. E. Thomas, P. Thakker, K. Janz, S.
DeBernardo, S. Tam, W. J. Moore, R. Yang, W. Wrona, P. W. Bedard, D.
Crommie, J. C. Keith, D. H. H. Tsao, J. C. Alvarez, H. Ni, E. Marchese,
J. T. Patton, J. L. Magnani and R. T. Camphausen, J. Med. Chem.,
2005, 48, 4346–4357.
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6999–7007.
8 Y. Ryu and I. Scott, Tetrahedron Lett., 2003, 44, 7499–7502.
9 B. List, A. Doehring, M. T. Hechavarria Fonseca, A. Job and R. Rios
Torres, Tetrahedron, 2006, 62, 476–482.
10 Data for compound 1: white solid, [a]25 = −19.64 (c = 1.12 g l−1
,
D
MeOH); 1H NMR (360 MHz, MeOD-d4, TMS as reference) d 7.63 (d,
J = 15.9 Hz, 1H), 7.15 (d, J = 1.9 Hz, 1H), 7.04 (dd, J = 8.3, 1.8 Hz,
1H), 6.77 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 15.9 Hz, 1H), 5.38 (ddd, J
= 11.3, 10.1, 5.0 Hz, 1H), 4.15 (q, J = 2.8 Hz, 1H), 3.87 (s, 3H, MeO),
3.69 (dd, J = 9.9, 3.1 Hz, 1H), 2.19–1.92 (m, 4H); 13C NMR (90 MHz,
MeOD-d4, TMS as reference) d 182.4, 170.8, 153.8, 151.2, 148.4, 128.1,
125.8, 118.3, 116.4, 112.8, 79.1, 76.4, 74.4, 73.9, 57.7, 42.2, 40.4; EIMS
(70 eV) m/z [M − 1]−: 367.09 (M − H), 191.05; EIMS (70 eV) m/z [M
+ 1]+: 177.05.
Notes and references
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& Francis, London, 1993, p. 1745; (b) A. A. P. Almeida, A. Farah,
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H. Iwashashi, S. Toda, Y. Shirataki, M. Kimura and R. Kido,
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11 Data for compound 2: white foam, [a]25 = −31.25 (c = 1.12 g l−1
,
D
MeOH); 1H NMR (360 MHz, CDCl3, TMS as reference) d 7.62 (d, J
= 15.9 Hz, 1H), 7.00 (dd, J = 8.2, 1.9 Hz, 1H), 6.99 (d, J = 1.8 Hz,
1H), 6.90 (d, J = 8.2 Hz, 1H), 6.28 (d, J = 15.9 Hz, 1H), 6.07 (s, OH),
5.38 (ddd, J = 11.6, 9.8, 4.8 Hz, 1H), 4.32 (s, OH), 4.24 (m, 1H), 3.90
(s, 3H), 3.80 (s, 3H), 3.70 (m, 1H), 3.24 (d, J = 8.3 Hz, OH), 2.35 (ddd,
J = 13.0, 4.7, 3.0 Hz, 1H), 2.25 (td, J = 14.8, 3.1 Hz, 1H), 2.09 (dd,
J = 14.8, 3.2 Hz, 1H), 1.95 (dd, J = 12.9, 11.7, Hz, 1H); 13C NMR
(90 MHz, CDCl3, TMS as reference) d 174.4, 167.6, 148.1, 146.8, 145.8,
126.7, 123.2, 114.8, 114.7, 109.4, 75.6, 73.9, 70.8, 70.6, 55.9, 53.2, 38.7,
36.8.; EIMS (70 eV) m/z [M − 1]−: 381.10.
12 (a) K. Iwai, N. Kishimoto, Y. Karino, K. Mochida and T. Fujita,
J. Agric. Food Chem., 2004, 52, 4893–4898; (b) E. J. Gentry, H. B.
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Telikepalli and L. A. Mitscher, J. Nat. Prod., 1998, 61, 1187–1193.
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