Novel enzymatic synthesis of 4-O-cinnamoyl quinic and shikimic acid derivatives

Article abstract of DOI:10.1021/jo034387a

The first direct synthesis of 4-O-cinnamoyl derivatives of quinic and shikimic acids were accomplished by regioselective esterification with Candida antarctica lipase A. For hydrocinnamic esters, enzymatic transesterification with vinyl esters gave excell

Full text of DOI:10.1021/jo034387a

Novel En zym a tic Syn th esis of
4-O-Cin n a m oyl Qu in ic a n d Sh ik im ic Acid
Der iva tives
Nuria Armesto, Miguel Ferrero, Susana Ferna´ndez, and
Vicente Gotor*
Departamento de Quı´mica Orga´nica e Inorga´nica,
Facultad de Quı´mica, Universidad de Oviedo,
33071-Oviedo, Spain
F IGURE 1. Caffeoyl derivatives of quinic acid.
has antibacterial, antimutagenic, antitumor, and anti-
viral properties.5 It has been shown that a number of
these phenolics act as antioxidants, with plural mecha-
nisms involving free-radical scavenging and metal ion
chelation.4b,c Their antioxidative action could prevent
oxidative damage in vivo relating to various diseases such
as cancer4d,e or cardiovascular diseases,2a,6 as well as
offering other curative properties (anti-inflammatory,
astringent, antispasmodic, antibacterial, etc.).4a,7 Re-
cently, some of these phenolics8 have been shown to
present inhibitory effects on HIV-integrase (2, Figure 1).
vgs@sauron.quimica.uniovi.es
Received March 25, 2003
Abstr a ct: The first direct synthesis of 4-O-cinnamoyl
derivatives of quinic and shikimic acids were accomplished
by regioselective esterification with Candida antarctica
lipase A. For hydrocinnamic esters, enzymatic transesteri-
fication with vinyl esters gave excellent yields. However,
more reactive acylating agents such as anhydrides were used
to synthesize cinnamic derivatives of both acids. An inhibi-
tory effect was observed with this lipase for p-methoxy,
p-hydroxy, and p-acetoxy vinyl ester and anhydride deriva-
tives (coumarate and ferulate derivatives).
Most of the cinnamoyl derivatives described in the
literature are related to quinic acid,4-8 and only a few
publications report on cinnamoyl shikimic acid deriva-
tives.2c,9 Most of these compounds are isolated from plant
sources1-9 or synthesized by random isomerization of the
available acid.8a,10 The occurrence in nature of phenolic
esters with quinic and shikimic acids is extensive, since
the presence of various hydroxyl groups in the molecule
increases the number of possible esters. In fact, several
new derivatives have been isolated over the past few
years.7b,11 Recently, Sefkow12 described the first efficient
synthesis of 1-, 3-, 4-, and 5-caffeoylquinic acids starting
from suitably protected quinic acid precursors. Chemical
synthesis of these esters is difficult due to phenolic acids
Few studies have explored the role of secondary
metabolic pathways in plant response to oxidative stress.
Among them, emphasis is given to the phenylpropanoid
biosynthetic pathway, which is responsible for the syn-
thesis of a diverse array of flavonoids and other phenolic
metabolites, such as tannins, hydroxycinnamate, and
hydroxybenzoate esters.1 Hydroxycinnamic acids, such as
p-coumaric acid (4-hydroxycinnamic acid), caffeic acid
(3,4-dihydroxycinnamic acid), and ferulic acid (4-hydroxy-
3-methoxycinnamic acid), are largely derived from fruits,
vegetables, grains, and coffee and are normally associated
with quinic acid or sugars as esters.1c,2 Lipid-soluble
esters of phenolic compounds consist of hydroxycinna-
mates linked to sterols, terpene alcohols, or triterpenes.3
In recent years, the phenolic functionality has attracted
much attention and has been studied by many research-
ers.4 Cinnamic derivatives of quinic and shikimic acid
present special relevance. Most intensely studied is
5-caffeoylquinic acid (chlorogenic acid, 1, Figure 1), which
(5) (a) Phytochemical Dictionary, Harborne; J . B., Baxter, H., Eds.;
Taylor & Francis: London, 1993; p 1745. (b) Kroon, P. A.; Wiliamson,
G. J . Sci. Food Agric. 1999, 79, 355-361.
(6) Chang, W.-C.; Hsu, F.-L. Prostaglandins, Leukotrienes Essent.
Fatty Acids 1992, 45, 307-312.
(7) (a) Nogata, Y.; Sekiya, K.; Hideaki, O.; Kusumoto, K.-I.; Ishizu,
T. Phytochemistry 2001, 56, 729-732. (b) Peng, L.-Y.; Mei, S.-X.; J iang,
B.; Zhou, H.; Sun, H.-D. Fitoterapia 2000, 71, 713-715. (c) Naish, M.;
Clifford, M. N.; Birch, G. G. Ann. N. Y. Acad. Sci. 1998, 855, 823-
827.
(8) (a) Slanina, J .; Ta´borska´, E.; Bochora´kova´, H.; Slaninova´, I.;
Humpa, O.; Robinson, W. E., J r.; Schram, K. H. Tetrahedron Lett. 2001,
42, 3383-3385. (b) Robinson, W. E., J r.; Cordeiro, M.; Abdel-Malek,
S.; J ia, Q.; Chow, S. A.; Reinecke, M. G.; Mitchell, W. M. Mol.
Pharmacol. 1996, 50, 846-855. (c) Robinson, W. E., J r.; Reinecke, M.
G.; Abdel-Malek, S.; J ia, Q.; Chow, S. A. Proc. Natl. Acad. Sci. U.S.A.
1996, 93, 6326-6331.
(9) (a) Ting, C.; J ianxin, L.; J ingsong, C.; Qiang, X.; Katsuko, K.;
Tsuneo, N. Planta Med. 1999, 65, 56-59. (b) Saito, T.; Yamane, H.;
Murofushi, N.; Takahashi, N.; Phinney, B. O. Biosci. Biotechnol.
Biochem. 1997, 61, 1397-1398. (c) Fukuoka, M. Chem. Pharm. Bull.
1982, 30, 3219-3224. (f) Maier, V. P.; Metzler, D. M.; Huber, A. F.
Biochem. Biophys. Res. Commun. 1964, 14, 124-128.
(10) (a) Fuchs, C.; Spiteller, G. J . Mass Spectrom. 1996, 31, 602-
608. (b) Ossipov, V.; Loponen, N. J .; Haukioja, E.; Pihlaja, K. J .
Chromatogr. A 1996, 721, 59-68. (c) Clifford, M. N.; Kellard, B. Food
Chem. 1989, 33, 115-123. (d) Nagels, L.; Van Dongen, W.; De Bruker,
J .; De Pooter, H. J . Chromatogr. 1980, 187, 181-187.
(11) Um, B. H.; Polat, M.; Lobstein, A.; Weniger, B.; Arago´n, R.;
DeClercq, L.; Anton, R. Fitoterapia 2002, 73, 550-552.
(12) (a) Sefkow, M.; Kelling, A.; Schilde, U. Eur. J . Org. Chem. 2001,
2735-2742. (b) Sefkow, M. Eur. J . Org. Chem. 2001, 1137-1141.
(1) (a) Bate-Smithe, E. C. In The Pharmacology of Plant Phenolic;
Fairbairn, J . W., Ed.; Academic Press: London, 1959; pp 133-149. (b)
Haslam, E. The Biochemistry of Plants; Academic Press: New York,
1981; p 527. (c) Pratt, D. E.; Hudson, B. J . F. In Food Antioxidants;
Hudson, B. J . F., Ed.; Elsevier: London, 1990; p 171.
(2) (a) De Paulis, T.; Schmidt, D. E.; Bruckey, A. K.; Kirby, M. T.;
McDonald, M. P.; Commers, P.; Lovinger, D. M.; Martin, P. R. Eur. J .
Pharmacol. 2002, 442, 215-223. (b) De Mar´ıa, C. A. B.; Trugo, L. C.;
De Mariz e Miranda, L. S. J . Food Compos. Anal. 1999, 12, 289-292.
(c) Adam, K.-P. Phytochemistry 1999, 52, 929-934. (d) Suzuki, M.;
Nagata, T.; Terahara, N. Biosci. Biotech. Biochem. 1997, 61, 1929-
1930.
(3) Seitz, L. M. J . Agric. Food Chem. 1989, 37, 662-667.
(4) (a) Go´ngora, L.; Giner, R. M.; Ma´n˜ez, S.; Recio, M. C.; Schinella,
G.; R´ıos, J . L. Life Sci. 2002, 71, 2995-3004. (b) Cartron, E.;
Carbonneau, M.-A.; Fouret, G.; Descomps, B.; Le´ger, C. L. J . Nat. Prod.
2001, 64, 480-486. (c) Grace, S. C.; Logan, B. A. Philos. Trans. R.
Soc. London B 2000, 355, 1499-1510. (d) Kono, Y.; Shibata, H.;
Kodama, Y.; Sawa, Y. Biochem. J . 1995, 312, 947-953. (e) Tanaka,
T.; Kojima, T.; Kawamori, T.; Wang, A.; Suzui, M.; Okamoto, K.; Mori,
H. Carcinogenesis 1993, 14, 1321-1325.
10.1021/jo034387a CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/17/2003
5784
J . Org. Chem. 2003, 68, 5784-5787

SCHEME 1
F IGURE 2. Cinnamic and hydrocinnamic vinyl ester deriva-
tives.
TABLE 1. Acyla tion of Meth yl Sh ik im a te w ith Vin yl
Cin n a m a te Ester Der iva tives Ca ta lyzed by CAL-A
vinyl
conv
(%)b
C-4 acylb,c
(%)
yield
(%)
being heat-sensitive and susceptible to oxidation under
certain pH conditions.13 In addition, selective function-
alization of polyhydroxylated molecules requires several
protection and deprotection steps. In this respect, using
lipases for esterification may be a worthwhile synthetic
pathway.14 Enzymatic esterification of flavonoid gluco-
sides15 and glucosides16 with cinnamate ester derivatives
is described in the literature.
We previously reported17 the regioselective enzymatic
acylation of methyl shikimate with Candida antarctica
lipase A (CAL-A). This lipase selectively catalyzes the
acylation of methyl shikimate with alkyl and unsaturated
vinyl esters at the secondary C-4 hydroxyl group. Taking
into account the wide range of biological activities of
phenolic derivatives of quinic and shikimic acids, and the
difficulties in their syntheses, we described for the first
time the one-step synthesis of C-4 cinnamate ester
derivatives of both acids by lipase-catalyzed regioselective
transesterification.
For the enzymatic acylation, vinyl cinnamate ester
derivatives were used as acylating agents (Figure 2).
Although the preparation of vinyl coumarate (3b) and
vinyl ferulate (3c) is described in the literature15 by the
vinyl exchange reaction of vinyl acetate and the corre-
sponding aromatic acid with mercury(II) acetate, in our
experience better yields were obtained through esterifi-
cation of the corresponding hydroxycarboxylic acid under
basic conditions in the presence of palladium(II) acetate
as catalyst.18 Thus, vinyl coumarate (3b), vinyl ferulate
(3c), vinyl hydrocinnamate (4a ), and vinyl p-hydroxy-
phenylpropionate (4b) were synthesized in 79%, 77%,
entry
estera
t (h)
1
2
3
4
5
3a
3b
3c
4a
4b
25
72
72
4.5
8.5
30
30 (6a )
NRd
NRd
100
50
100 (7a )
85
mixturee
Ratio 5/vinyl ester (1:10). Based on 1H NMR signal integra-
a
b
tion. c Isolated acyl derivative is indicated in parentheses. NR,
d
no reaction. e Mixture of mono- and diacylated compounds by 1H
NMR.
57%, and 50% yield, respectively (Figure 2). Vinyl cin-
namate (3a ) is the only ester commercially available.
The enzymatic transesterification of methyl shikimate
(5) was carried out with CAL-A at 40 °C with tert-
butylmethyl ether (TBME) as solvent and in the presence
of molecular sieves 4 Å (Scheme 1). CAL-A selectively
catalyzes the acylation at the C-4 hydroxyl group with
vinyl cinnamate (3a ) (entry 1, Table 1), giving rise to
methyl 4-O-cinnamoylshikimate (6a ). However, the reac-
tion did not evolve further, and a maximum 30% conver-
sion was achieved after 25 h. The reactivity of vinyl
coumarate (3b) and vinyl ferulate (3c) was lower, and
no reaction occurred with these acylating agents (entries
2 and 3, Table 1). On the other hand, when vinyl
hydrocinnamate (4a ) was used, 100% conversion and
total selectivity in the acylation of the C-4 hydroxyl were
observed, methyl 4-O-hydrocinnamoylshikimate (7a , Fig-
ure 3) being isolated in 85% yield after flash chromatog-
raphy (entry 4, Table 1).
The influence of the unsaturation in the vinyl esters
is shown in entries 1 and 4 in Table 1, since CAL-A
catalyzes the esterification of 5 with vinyl hydrocin-
namate (4a ) with a higher reaction rate than with vinyl
cinnamate (3a ). Finally, we investigated the acylation of
methyl shikimate with a p-hydroxy-substituted deriva-
tive of 4a . Under the same reaction conditions, the
acylation of 5 with 4b proceeded without regioselectivity,
and a mixture of mono- and diacyl derivatives was
obtained (entry 5, Table 1).
(13) Lloyd, L. I.; Corse, J . J . Am. Chem. Soc. 1951, 73, 5550-5553.
(14) (a) Klibanov, A. M. Nature 2001, 409, 241-246. (b) Koeller, K.
M.; Wong, C.-H. Nature 2001, 409, 232-240. (c) Roberts, S. M.; Turner,
N. J .; Willetts, A. J .; Turner, M. K. Introduction to Biocatalysis Using
Enzymes and Microorganisms; Cambridge University Press: New
York, 2000. (d) Faber, K. Biotransformations in Organic Chemistry,
4th ed.; Springer-Verlag: Berlin, 2000. (e) Carrea, G.; Riva, S. Angew.
Chem., Int. Ed. 2000, 39, 2226-2254. (f) Bornscheuer, U. T.; Kazlaus-
kas, R. J . Hydrolases in Organic Synthesis: Regio- and Stereoselective
Biotransformations; Wiley-VCH: Weinheim, 1999.
(15) Gao, C.; Mayon, P.; MacManus, D. A.; Vulfson, E. N. Biotechnol.
Bioeng. 2001, 71, 235-243.
In view of the poor reactivity of vinyl esters, the
corresponding anhydrides were used as acylating agents.
Only the cinnamic anhydride (8a ) had been prepared
previously.19 Following a similar procedure, we synthe-
(16) (a) Stamatis, H.; Sereti, V.; Kolisis, F. N. J . Mol. Catal. B:
Enzym. 2001, 11, 323-328. (b) Otto, R. T.; Bornscheuer, U. T.; Syldatk,
C.; Schmid, R. D. Biotechnol. Lett. 1998, 20, 437-440. (c) Nakajima,
N.; Ishihara, K.; Matsumura, S.; Hamada, H.; Nakamura, K.; Furuya,
T. Biosci., Biotechnol., Biochem. 1997, 61, 1926-1928.
(17) Armesto, N.; Ferrero, M.; Ferna´ndez, S.; Gotor, V. J . Org. Chem.
2002, 67, 4978-4981.
(18) Lobell, M.; Schneider, M. P. Synthesis 1994, 375-377.
(19) Kocz, R.; Roestamadji, J .; Mobashery, S. J . Org. Chem. 1994,
59, 2913-2914.
J . Org. Chem, Vol. 68, No. 14, 2003 5785

the 3- and 5-position. Because of this, an insoluble
inorganic base such as potassium carbonate, which does
not interfere with the enzyme and does not favor this
migration, was added. For the synthesis of methyl 4-O-
acetylcoumaroylshikimate (10b, Figure 3), the enzymatic
transesterification reaction of 5 with a suitably protected
coumaric anhydride derivative 8b was carried out (entry
2, Table 2). In these conditions, CAL-A was unable to
catalyze the acylation reaction. The same behavior was
observed with 4-O-acetylferulic anhydride (8c) and 4-meth-
oxycinnamic anhydride (8d ) (entries 3 and 4, Table 2).
At first, the low reactivity was ascribed to the poor
solubility of the anhydrides in TBME, and as a result
other solvents such as THF, 1,4-dioxane and acetone were
used. However, no improvements were observed, and so
these results could be attributed to an electronic and/or
steric effect. The inhibitory effect of electron-donating
p-substituents in cinnamic or benzoic acid derivatives has
been previously reported.21 This effect explains the
absence of reactivity for 8d , but not for 8b and 8c. In
these cases the absence of reactivity can be ascribed to
steric effects of the acetoxy group in the 4-position. This
fact was confirmed by acylation of 5 with p-fluorocin-
namic anhydride (8e), which has a smaller deactivated
group in the 4-position. CAL-A gives rise to the corre-
sponding ester 10e (Figure 3) with high regioselectivity
and in good isolated yield (entry 5, Table 2). As expected
the enzymatic acylation of 5 with 2-acetoxycinnamic
anhydride (9a ) takes place in a short reaction time and
with total selectivity, but two 4-O-acyl derivatives, 11a
(Figure 3) and methyl 4-O-acetylshikimate, in a ratio 2:1,
respectively, were obtained (entry 6, Table 2). The latter
arises from an acylation reaction on the ester function
of 9a . As with anhydride 8d , the transesterification with
2-methoxycinnamic anhydride (9b) did not take place
(entry 7, Table 2).
We extended the aforementioned methodology to syn-
thesize cinnamate derivatives of quinic acid. First, we
studied the acylation reaction of methyl quinate (12) with
alkyl and unsaturated vinyl esters in the same conditions
as previously described17 for methyl shikimate. Thus, the
reaction was carried out at 40 °C in the presence of
molecular sieves 4 Å, 10 equiv of acylating agent, TBME
as solvent, and catalyzed by CAL-A (Scheme 2). The
transesterification takes place with total selectivity
toward the C-4 hydroxyl group, C-4-acyl derivatives
14a -d being isolated exclusively in 85-92% yield after
flash chromatography. Lower conversions and no selec-
tivity were observed if more polar solvents such as
acetone, 1,4-dioxane, or acetonitrile were used.
Similarly, various cinnamate ester derivatives of quinic
acid (15 and 16, Figure 5) were effectively synthesized
from 12 and acyl donors such as vinyl hydrocinnamate
(4a ), vinyl p-hydroxyphenylpropionate (4b), cinnamic
anhydride (8a ), and p-fluorocinnamic anhydride (8e) by
direct transesterification using CAL-A. The results are
shown in Table 3.
F IGURE 3. Cinnamic and hydrocinnamic shikimic acid
derivatives.
F IGURE 4. Cinnamic anhydride derivatives.
TABLE 2. Acyla tion of Meth yl Sh ik im a te w ith
Cin n a m ic An h yd r id e Der iva tives Ca ta lyzed by CAL-A
acid
entry anhydridea t (h) (%)
convb C-4 acylb,c C-3 acylb diacylb
(%)
(%)
(%)
1
2
3
4
5
6
7
8a
8b
8c
8d
8e
9a
9b
18
24
32
32
18
6
100
NRd
NRd
NRd
100
65
90 (6a )
5
5
95 (10e)
5
65e
24
NRd
a
b
Ratio 5/acid anhydride (1:5). Based on 1H NMR signal
integration. c Isolated acyl derivative is indicated in parentheses.
NR, no reaction. e Mixture of 11a and methyl 4-O-acetylshiki-
d
mate (ratio 2:1, respectively). The last one arises from reaction
on the acetate ester function of 9a .
sized a series of cinnamic anhydride derivatives 8 and 9
(Figure 4) by reaction of carboxylic acids with bis-
(trichloromethyl)carbonate20 (triphosgene). For effective
synthesis, protection of the hydroxyl group (as acetyl) in
the aromatic ring was necessary.
Methyl 4-O-cinnamoylshikimate (6a ) was prepared in
one step by esterification of 5 with cinnamic anhydride
(8a ) and CAL-A in the presence of molecular sieves 4 Å.
The reaction takes place in 18 h at 40 °C with excellent
regioselectivity toward the acylation of the C-4 hydroxyl
group (entry 1, Table 2). To remove the acid generated,
which inhibited the enzyme, a base should be added to
the reaction mixture. However, we have observed that
in basic media the acyl group migrates from the 4- to
It should be noted that in contrast with methyl
shikimate, the reaction with a p-hydroxy-substituted
(21) (a) Stamatis, H.; Sereti, V.; Kolisis, F. N. J . Am. Oil Chem. Soc.
1999, 76, 1505-1510. (b) Buisman, G. J . H.; Van Helteren, C. T. W.;
Kramer, G. F. H.; Veldsink, J . W.; Derksen, J . T. P.; Cuperus, F. P.
Biotechnol. Lett. 1998, 20, 131-136. (c) Guyot, B.; Bosquette, B.; Pina,
M.; Graille, J . Biotechnol. Lett. 1997, 19, 529-532.
(20) For a review on the use of triphosgene in organic synthesis,
see: Cotarca, L.; Delogu, P.; Nardelli, A.; Sunjic, V. Synthesis 1996,
553-576.
5786 J . Org. Chem., Vol. 68, No. 14, 2003

in methyl shikimate and methyl quinate, giving rise to
a variety of cinnamate ester derivatives of both acids in
excellent yields. In addition, this lipase is immobilized
on a support and was recycled without loss of significant
activity. This method allows easy access to a variety of
aromatic quinic and shikimic esters, important secondary
plant metabolites, and enables further investigation of
their therapeutic and antimicrobial properties.
Exp er im en ta l Section
Gen er a l Meth od s. C. antarctica lipase A (CAL-A, chirazyme
L-5, c-f, lyophilized, 25 U/g using 1-phenylacetate) was obtained
from Roche. C. antarctica lipase B (CAL-B, Novozym 435, 7300
PLU/g) was a gift from Novo-Nordisk. TLC chromatograms were
visualized by heating after spraying with a 5% aqueous sulfuric
acid solution containing cerium sulfate (1%) and molybdophos-
phoric acid (2.5%). Column chromatography was performed over
silica 60 Å (230-400 mesh) except for 6a , 7a , and 10e in which
silica 60 Å (32-63 µm) pH 7 was used. Molecular sieves 4 Å
were dried at 180 °C in a vacuum over 2 h. Methyl shikimate
(5) and methyl quinate (12) were dried in under high vacuum
(10-5 mbar) before use.
F IGURE 5. Cinnamic and hydrocinnamic quinic acid deriva-
tives.
SCHEME 2
En zym a tic Acyla tion of Meth yl Sh ik im a te (5) a n d Meth -
yl Qu in a te (12). Gen er a l P r oced u r e. In a standard procedure,
the acylating agent (ratios are indicated in Tables 1-3), dis-
solved in tert-butyl methyl ether (0.75 mL for vinyl esters and
1.5 mL for anhydrides), was added to an Erlenmeyer flask that
contained triol 5 (13 mg, 0.069 mmol) or 12 (13 mg, 0.062 mmol),
CAL-A (13 mg), potassium carbonate (2.5 equiv, only if anhy-
drides are used as acylating agents), and 4 Å molecular sieves
(13 mg) under nitrogen. The suspension was shaken at 250 rpm
and 40 °C (times are indicated in Tables 1-3). The mixture was
filtered, and the organic solvent was evaporated. Then, the
reaction crude was subjected to flash chromatography (10% CH2-
Cl2/Et2O for 6a ; 30% CH2Cl2/Et2O for 7a ; 15% CH2Cl2/Et2O
for10e; 3% MeOH/EtOAc for 14a ; 10% CH2Cl2/EtOAc for 14b
and 14c; 15% CH2Cl2/EtOAc for 14d ; gradient eluent 30-60%
EtOAc/CH2Cl2 for 15a and 16b; 50% EtOAc/CH2Cl2-EtOAc-
5% MeOH/EtOAc for 15b; and gradient eluent 40-70% EtOAc/
CH2Cl2 for 16a ) to give 6a (white solid, 86% yield), 7a (colorless
oil, 85% yield), 10e (white crystalline solid, 88% yield), 14a
(white crystalline solid, 85% yield), 14b (white solid, 87% yield),
14c (colorless oil, 87% yield), 14d (white solid, 92% yield), 15a
(white solid, 90% yield), 15b (yellow oil, 73% yield), 16a (white
solid, 91% yield), and 16b (white solid, 90% yield). For 6a , 7a ,
and 10e silica 60 Å (32-63 µm) pH 7 was used to avoid
migrations from C-4 to C-3. (This operation should be done
almost immediately to minimize the contact with both the silica
gel and the eluent). Then, the solvents were evaporated at 20
°C under reduced pressure. A practical synthesis was carried
out in a 2 mmol scale of methyl shikimate (5) with cinnamic
anhydride. Longer reaction time (24 h) was observed to retain
the regioselectivity.
TABLE 3. Acyla tion of Meth yl Qu in a te w ith Cin n a m ic
Der iva tives Ca ta lyzed by CAL-Aa
acylating
agent
ratio 12/
acyl agent
convb
(%)
yieldc
(%)
entry
t (h)
1
2
3
4
4a
4b
8a
8e
7
24
21
21
1:10
1:10
1:5
100
86
100
100
90 (15a )
73 (15b)
91 (16a )
90 (16b)
1:5
a
b
C-4 acyl is formed exclusively. Based on 1H NMR signal
integration. c Isolated compound is indicated in parentheses.
hydrocinnamate derivative 4b has proceeded satisfacto-
rily, and after 24 h at 40 °C (the reaction did not evolve
further), the desired product 15b was isolated by flash
chromatography (entry 2, Table 3). The rate of esterifi-
cation was lower than the rate of esterification with vinyl
hydrocinnamate, indicating the inhibitory effect of the
p-hydroxy substituent in the activity of the lipase (entry
1 vs entry 2, Table 3). We also tried the esterification
reaction of quinic and shikimic acids with C. antarctica
lipase B (CAL-B), since this lipase acylated the primary
hydroxyl group of the sugar moiety in flavonoid glycosides
with vinyl esters of phenolic acids.15 However, the process
did not yield the desired product, but hydrolysis of the
vinyl esters and anhydrides took place.
Ack n ow led gm en t. This work has been supported
by grants from MCYT (Spain; Project PPQ-2001-2683)
and the Principado de Asturias (Spain; Project GE-
EXP01-03). S.F. thanks MCYT for a personal grant
(Ramo´n y Cajal Program). We thank Robin Walker for
the English language revision of the manuscript.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for vinyl esters and anhydrides, complete H and 13C
NMR spectral data, mp, IR, microanalysis, optical rotation,
MS, and HRMS data for the new compounds. The level of
purity is indicated by the inclusion of copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, 4-O-cinnamoyl derivatives of quinic and
shikimic acids can be efficiently synthesized in a one-
step enzymatic transesterification reaction with vinyl
esters and anhydrides as acyl donors. C. antarctica lipase
A allows the selective acylation of the C-4 hydroxyl group
J O034387A
J . Org. Chem, Vol. 68, No. 14, 2003 5787