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K. S. Raheem et al. / Tetrahedron Letters 52 (2011) 7175–7177
O
O
O
O
O
BnO
BnO
OBn
OH
HO
HO
HO
OH
OH
d,e
c
b
a
O
O
TBSO
O
TBSO
TBSO
HO
HO
OBn
OBn
OH
OH
OH
10
(-)-quinic acid 4
7
9
8
f
O
HO
OH
O
O
O
O
BnO
BnO
O
HO
O
OBn
OBn
OH
OH
O
OR1
OR2
R1O
O
O
O
O
O
h
i
g
O
O
OH
O
HO
R2O
OBn
OBn
OH
HO
O
HO
O
O
OH
O
OH
11
12
4
R1, R2 = H
3,5-di-O-caffeoylquinic acid
1
2
3
R1 = CH3, R2 = H 3,5-di-O-feruloylquinic acid
R1, R2 =CH3
3,5-(3,4-dimethoxycinnamyl)quinic acid
Scheme 2. Reagents and conditions: (a) p-TsOH, toluene, DMF, reflux, 12 h, 99%; (b) imidazole, DMF, TBSCl, 0 °C for 30 min and 1 h at rt 83%; (c) NaH, DMF, 0 °C, 30 min, then
BnBr, DMF, 60 °C, 12 h, 60%; (d) NaOH, THF–H2O (4:1), rt, 40 min, 93%; (e) Cs2CO3, MeOH–H2O, rt, 20 min, then BnBr, DMF, rt, 12 h, 95%; (f) HF-pyridine, THF, 0 °C to rt, 12 h,
93%; (g) Meldrum’s acid, toluene, 60 °C, 4 h, 79%; (h) Pd(OH)2, H2, MeOH, rt, 36 h, 94%; (i) 5a–c, DMAP, piperidine (cat.), DMF, rt, 8 d, 1 (68%), 2 (72%), 3 (81%).
metabolism studies. This method involved the double condensa-
Supplementary data
tion of a bis-malonic acid ester (4) with two equivalents of
the appropriate benzaldehyde
dehydration.
5 followed by decarboxylative
Supplementary data associated with this article can be found, in
The synthesis of 1 and its derivatives commenced with the
preparation of bicyclic trihydroxy lactone 7 from commercially
available (ꢀ)-quinic acid (6) (Scheme 2). The selective protec-
tion (C-3) of 7 as the TBS ether 8 was achieved in good yield.10
The remaining free hydroxy groups (C-1 and C-4), were then
subjected to benzyl ether protection to provide 9 in 60% yield.11
Hydrolysis of 9 with NaOH in THF–H2O at room temperature,
followed by esterification of the resulting carboxylate by treat-
ment with Cs2CO3 and benzyl bromide afforded the benzyl ester
10 in 55% yield over the two steps.12 Removal of the TBS pro-
tecting group was achieved using HF-pyridine in THF at 0 °C
and furnished diol 11 in a good (93%) yield.13 Diol 11 was then
subjected to a double acylation by treatment with 2.2 equiv of
2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) in toluene
at 60 °C. This gave diester 12 in 79% yield.14 Cleavage of the
benzyl protecting groups was achieved in 94% yield by hydrog-
enolysis [Pd(OH)2, MeOH] to give the deprotected diester 4 as
the immediate precursor to three dicaffeoylquinic acids. The
final step of the syntheses involved a double Knoevenagel con-
densation without any protecting groups. Accordingly, treatment
of 4 with aldehydes 5a–c, DMAP and piperidine in anhydrous
DMF afforded the target compounds in moderate to good yields
[3,5-DCQA (1)15 (68%), 3,5-diferuloylquinic acid (2)16 (72%) and
3,5-(3,4-dimethoxycinnamyl)quinic acid (3)17 yield (81%)].
In conclusion, the development of a protocol for the synthesis of
3,5-DCQA (1), 3,5-diferuloylquinic acid (2) and 3,5-(3,4-dimeth-
oxycinnamyl)quinic acid (3) is described, exploiting a Knoevenagel
strategy. This protocol should be amenable to a wide range of sym-
metrical difunctionalised derivatives.
References and Notes
1. Clifford, M. N.; Marks, S.; Knight, S.; Kuhnert, N. J. Agric. Food Chem. 2006, 54,
4095.
2. Robinson, W. E., Jr.; Reinecke, M. G.; Abdel-Malek, S.; Chow, S. A. Proc. Natl.
Acad. Sci. U.S.A. 1996, 93, 6326.
3. Tamura, H.; Akioka, T.; Ueno, K.; Chujyo, T.; Okazaki, K.-i.; King, P. J.; Robinsion,
W. E. Mol. Nutr. Food Res. 2006, 50, 396.
4. Ojwang, J. O.; Wang, Y.-H.; Wyde, P. R.; Fischer, N. H.; Schuehly, W.; Appleman,
J. R.; Hinds, S.; Shimasaki, C. D. Antiviral Res. 2005, 68, 163.
5. Antonio, A. G.; Moraes, R. S.; Perrone, D.; Maia, L. C.; Santos, K. N.; Lurio, N. L. P.;
Farah, A. Food Chem. 2010, 118, 782.
6. Rechner, A. R.; Pannala, A. S.; Rice-Evans, C. A. Free Radical Res. 2001, 35, 195.
7. Yang, B.; Meng, Z.; Dong, J.; Yan, L.; Zou, L.; Tang, Z.; Dou, G. Drug Metab. Dispos.
2005, 33, 930.
8. Sefkow, M.; Kelling, A.; Schilde, U. Eur. J. Org. Chem. 2001, 2735.
9. Smarrito-Menozzi, C.; Munari, C.; Robert, F.; Barron, D. J. Org. Biomol. Chem.
2008, 6, 986.
10. Glebocka, A.; Sicinski, R. R.; Plum, L. A.; Clagett-Dame, M.; DeLuca, H. F. J. Med.
Chem. 2006, 49, 2909.
11. Kaila, N.; Somers, W. S.; Thomas, B. E.; Thakker, P.; Janz, K.; DeBernardo, S.;
Tam, S.; Moore, W. J.; Yang, R.; Wrona, W.; Bedard, P. W.; Crommie, D.; Keith, J.
C.; Tsao, D. H. H.; Alvarez, J. C.; Ni, H.; Marchese, E.; Patton, J. T.; Magnani, J. L.;
Camphausen, R. T. J. Med. Chem. 2005, 48, 4346.
12. Montchamp, J.-L.; Peng, J.; Frost, J. W. J. Org. Chem. 1994, 59, 6999.
13. Evans, D. A.; Gage, R. J.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434.
14. Ryu, Y.; Scott, A. I. Tetrahedron Lett. 2003, 44, 7499.
15. Selected analytical data for (1Sn,3R,4Sn,5R)-3,5-O-dicaffeoylquinic acid (1):18
½ ꢁ +76 (c 0.1, MeOH) dH (500 MHz, DMSO-d6) 9.59 (2H, s),9.16 (2H, s, 1-H),
a 2D5
7.47 (1H, d, J = 16.0 Hz), 7.46 (1H, d, J = 16.0 Hz), 7.04 (1H, d, J = 1.8 Hz), 7.05
(1H, d, J = 1.8 Hz), 7.00 (1H, dd, J = 8.1, 1.8 Hz), 6.99 (1H, dd, J = 8.1, 1.8 Hz), 6.77
(2H, d, J = 8.1 Hz,), 6.20 (1H, d, J = 16.0 Hz,), 6.19 (1H, d, J = 16.0 Hz), 5.25 (1H,
td, J = 8.4, 3.9 Hz), 4.95 (1H, s), 4.59 (1H, d, J = 4.3 Hz), 4.1–10 (1H, m), 3.6–58
(1H, m), 2.3–26 (3H, m), 1.9–88 (1H, m); dc (75.46 MHz, DMSO-d6) 172.9,
166.4, 165.7, 148.9, 148.8, 146.0, 145.9, 145.6, 126.0, 125.9, 121.8. 121.7, 116.2,
115.2, 114.6, 79.5, 71.2, 70.3, 67.8, 36.1, 34.5; m/z (ESꢀ) 515 [(MꢀH)ꢀ, 100%];
HRMS: Calcd. for C25H23O12 515.1190, found 515.1190.
16. Selected analytical data for (1Sn,3R,4Sn,5R)-3,5-di-O-feruloylquinic acid (2).18
½ ꢁ +39 (c 0.5, MeOH); v
a D25 max(film)/cmꢀ1 3460, 1592, 1513, 1270, 1158; dH
Acknowledgment
(500 MHz, DMSO-d6) 9.63 (1H, s), 9.62 (1H, s), 7.54 (1H, d, J = 16.0 Hz), 7.53
(1H, d, J = 16.0 Hz), 7.32 (1H, d, J = 1.8 Hz), 7.30 (1H, d, J = 1.8 Hz), 7.11 (1H, dd,
J = 8.1, 1.8 Hz), 7.08 (1H, dd, J = 8.1, 1.8 Hz), 6.80 (2H, d, J = 8.1 Hz), 6.45 (1H, d,
J = 16.0 Hz), 6.39 (1H, d, J = 16.0 Hz), 5.24 (1H, ddd, J = 3.5, 3.5, 4.1 Hz), 4.95
Financial support from the BBSRC and Nestle, is gratefully
acknowledged.