Chemoselective Esterification of Phenolic Acids and Alcohols

Article abstract of DOI:10.1021/ol0266471

(Matrix Presented) The Mitsunobu reaction can distinguish between alcohol and phenol hydroxyls in esterification reactions, providing an expeditious and broadly applicable entry into various phenolics and polyphenolics of biomedical and nutritional relevance.

Full text of DOI:10.1021/ol0266471

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3839-3841
Chemoselective Esterification of
Phenolic Acids and Alcohols
Giovanni Appendino,* Alberto Minassi, Nives Daddario, Federica Bianchi, and
Gian Cesare Tron
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche,
Viale Ferrucci 33, 28100 NoVara, Italy
appendino@pharm.unipmn.it
Received July 31, 2002
ABSTRACT
The Mitsunobu reaction can distinguish between alcohol and phenol hydroxyls in esterification reactions, providing an expeditious and broadly
applicable entry into various phenolics and polyphenolics of biomedical and nutritional relevance.
Phenolic alcohol and phenolic acid ester motifs are wide-
spread within bioactive natural products, with examples
being, within primary esters, the NF-κB inhibitors CAPE
(1a)1,2 and capsiate (2),3 the honeybee propolis contact
allergen prenyl caffeate (1b),4 and the EGCG mimic and
HIV-1 reverse transcriptase inhibitor hydroxytyrosol gallate
(3).5 These compounds are structurally unsophisticated, but
their reported syntheses are not easily amenable to the
generation of analogues, due to either a heavy burden of
protecting groups or the use of harsh conditions and/or a
large excess of one of the reactants.2-5
general applicability for the synthesis of primary alkyl (poly)-
phenolic esters. The esterification of phenolic alcohols and
Faced with the problem of building a library of analogues
of CAPE and capsiate to unravel their structure-activity
relationships, we have investigated in detail the esterification
of phenolic acids and phenolic alcohols and report here a
practical and rational solution to the problem, endowed with
phenolic acids via acyl nucleophilic substitution under
nucleophilic catalysis requires protection of phenolic hy-
droxyls, since acids activated in situ (isoureas and mixed
phosphoric anhydrides) or ex situ (chlorides, anhydrides, and
mixed anhydrides) show poor discrimination between hy-
droxyls bound to aliphatic and aromatic carbons. Table 1
vividly demonstrates this, using the synthesis of vanillyl
nonanoate (4), a capsiate mimic,2 as an example.
(1) Abbreviations: CAPE, caffeic acid phenylethyl ester; EGCG, epi-
gallocatechin-3-O-gallate; PPAA, 1-propylphosphonic acid cyclic anhydride;
DEPC, diethyl phosphorocyanidate; DIAD, diisopropyl azodicarboxylate;
TPP, triphenylphosphine.
(2) Natarajan, K.; Singh, S.; Burke, T. R., Jr.; Grunberger, D.; Aggarwal,
B. B. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 9090-9095.
(3) Sancho, R.; Lucena, C.; Macho, A.; Calzado, M. A.; Blanco Molina,
M.; Minassi, A.; Appendino, G.; Mun˜oz, E. Eur. J. Immunol. 2002, 32,
1753-1763.
(4) Stu¨we, H.-T.; Bruhn, G.; Ko¨nig, W. A.; Hausen, B. M. Naturwis-
senshaften 1989, 76, 1989-1990.
(5) Tillekeratne, L. M. V.; Sherette, A.; Grossman, P.; Hupe, L.; Hupe,
D.; Hudson, R. A. Bioorg. Med. Chem. Lett. 2001, 11, 2763-2767.
Phenolic acids have been esterified with excellent chemo-
selectivity in the presence of strong protic acids (Fischer
esterification), but the harsh reaction conditions and the
excess of alcohol required to drive the reaction to a
10.1021/ol0266471 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/08/2002

alcohols, a type of compounds more easily available than
halides, could be directly used in the reaction. In this way,
the reaction could be extended to multifunctional substrates
such as phenolic alcohols, providing an expeditious entry
into several classes of polyphenolics of biomedical and
nutritional interest.
Table 1. Synthesis of Vanillyl Nonanoate (4) under Various
Reaction Conditionsa
We reasoned that in the esterification of acids and alcohols
promoted by the Mitsunobu redox couple, phenolic hydroxyls
present on either substrate should essentially behave as “inert
spectators”, even though the reaction has been largely
employed for the synthesis of phenolic ethers.12 Thus, the
SN2-type mechanism of the reaction rules out aromatic
carbons as electrophilic substrates, while the generation of
the nucleophilic species by deprotonation with a stabilized
azaenolate, a relatively weak base,13 secures that carboxylates
rather than phenates are formed, provided that stoichiometric
amounts of reagents are employed.14 This turned out to be
the case, and the excellent results observed in the Mitsnunobu
esterification of vanillic alcohol with nonanoic acid (Table
1) could be extended to the preparation of esters of phenolic
acids related to CAPE (Table 2) and of esters of phenolic
alcohols related to capsiates (Table 3).
R1)COR
R2)COR
R1)COR
R2)H, (4)
R1)H
R2)COR
X
conditions
pyridine
Cl
22%
17%
36%
4%
9%
13%
29%
25%
10%
11%
42%
14%
19%
67%
7%
9%
OCOR
OPiv
OH
OH
OH
pyridine
TEA, DMAP
DCC, DMAP
DEPC,TEA
PPAA, TEA
Yb(OTf)3, THF
DIAD,TPP,THF
20%
18%
19%
Cl
OH
a Reactions were carried out at room temperature on a 2 mmol scale,
with equimolecular amounts of reagents and condensing agents (DCC,
DEPC, PPAA, DIAD-TPP) and catalytic (10%) amounts of promoters
(DMAP, Yb(OTf)3), when indicated. Reactions were worked up after 24 h,
except for the Yb(OTf)3-promoted esterification, which was worked up after
96 h due to a slower conversion. b Isolated yield after column chromatog-
raphy (silica gel, petroleum ether-EtOAc gradient).
satisfactory degree of conversion make this strategy of
limited applicability.6 A certain degree of chemoselectivity
in the esterification of phenolic alcohols was also reported
for Lewis acid-catalyzed acylations,7 a type of reaction that
takes place under more benign conditions than Fischer
esterification. Indeed, at least with the test reaction of Table
1, excellent chemoselectivity was observed in the ytterbium
triflate-promoted esterification.8 However, the yield was
modest, and the long reaction time requested for the reaction
(96 h) made it unsuitable for more hydroxylated and sensitive
substrates. Apart from protection, no other general strategy
seems possible for the esterification of phenolic acids using
acyl activation.9
Switching from carbonyl- to hydroxyl activation would
be a mechanistically rational alternative to the “protection
racket”,10 since phenolic carbons are not substrates for SN2-
type reactions. Thus, the cesium salts of phenolic acids11 have
been reported to react with alkyl halides in a highly
chemoselective way,4 but the modest yield, also with an
excess of halides, leaves margin for further research and
improvement. In particular, the scope and versatility of the
alkyl activation strategy would be substantially improved if
Table 2. Mitsunobu Esterification of Phenolic Acids
R1
R2
R3
X
yield
H
OMe
H
H
H
H
H
H
OH
OMe
OH
PhCH2-
PhCH2-
(Me)2CdCH-
CH3-(CH2)6-
PhCH2-
PhCH2-
PhCH2-
PhCH2-
(E) -CHdCH-
(E) -CHdCH-
(E) -CHdCH-
(E) -CHdCH-
-CH2-CH2-
-CH2-
54%
59%
42%
59%
81%
78%
58%
64%
OH
OMe
OMe
OMe
H
The application to the synthesis of caffeates is worthy of
mention, since the esterification of caffeic acid is notoriously
troublesome15 and has led to alternative protocols based on
(12) (a) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127-164. (b)
Hughes, D. L. Org. React. 1992, 42, 335-656. (c) Castro, B. R. Org. React.
1983, 29, 1-162. (d) Mitsunobu, O. Synthesis 1981, 1-28.
(13) Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. Am.
Chem. Soc. 1988, 110, 6487-6491.
(6) As an example, treatment of caffeic acid with 15 molar equiv of
â-phenethyl alcohol under the conditions of Fischer esterification (p-
toluenesulfonic acid, refluxing overnight in benzene with a Dean-Stark
trap) has been reported to afford CAPE in 35% yield (Burke, T. R., Jr.;
Fesen, M. R.; Mazumder, A.; Wang, J.; Carothers, A. M.; Grunberger, D.;
Driscoll, J.; Kohn, K.; Pommier, Y. J. Med. Chem. 1995, 38, 4171-4178).
(7) Chandra, K. L.; Saravanan, P.; Singh, R. K.; Singh, V. K. Tetrahedron
2002, 58, 1369-1374.
(8) Damen, E. W. P.; Braamer, L.; Scheeren, H. Tetrahedron Lett. 1998,
39, 6081-6082. See also: Holton, R. A.; Zhang, Z.; Clarke, P. A.;
Nadizadeh, H.; Procter, D. J. Tetrahedron Lett. 1998, 39, 2883-2886.
(9) Deprotection of polyphenolic esters is often not a trivial operation.
See, for instance: Kim, D. S. H. L.; Kim, J. Y. Bioorg. Med. Chem. Lett.
2001, 11, 2541-2543.
(10) Gani, D. Nature 2001, 414, 703-705.
(11) Wang, S.-S.; Gisin, B. F.; Winter, D. P.; Makofske, R.; Kulesha,
I. D.; Tzougraki, C.; Meienhofer, J. J. Org. Chem. 1977, 42, 1286-1290.
(14) The mechanism of the Mitsunobu reaction is still controversial.
Over the years, a proposal involving formation of the “consensus”
alkoxyphosphonium intermediate (C) by alcoholate displacement of an
acyloxyphoshponium ion (B) rather than by direct reaction of an alcohol
with the protonated Mitsunobu betaine (A) has gained support (Hughes, D.
L.; Reamer, R. A. J. Org. Chem. 1996, 61, 2967-2971). This mechanism
is capable of rationalizing the retention of configuration observed in the
Mitsunobu lactonization of hindered secondary hydroxy acids, where
alcoholate attack at the carbonyl rather than the phosphor atom of
intermediate B apparently takes place (Ahn, C.; Correia, R.; DeShong, P.
J. Org. Chem. 2002, 67, 1751-1753). However, the chemoselectivity
observed in the Mitsunobu esterification of phenolic alcohols is better
explained by a mechanism that does not involve deprotonated alcohols,
since phenol etherification should compete with alkyl ester formation if
3840
Org. Lett., Vol. 4, No. 22, 2002

Scheme 1. Mitsunobu Esterification of Polyphenolic Acids
with the Polyphenolic Alcohol 5a
Table 3. Mitsunobu Esterification of Phenolic Alcohols
a Conditions: DIAD, TPP, THF, rt.
the Wittig reaction of 3,4-dihydroxybenzaldehyde and alkoxy-
carbonyl phosphoranes under sonochemical activation.16
elution.19 This procedure was ineffective for the purification
of the more lipophilic esters reported in Tables 2 and 3,
which were purified by conventional gravity column chro-
matography on silica gel.
As a final point, we would like to remark that the
Mitsunobu reaction can also be applied to the chemoselective
esterification of polyphenolic acids with polyphenolic alco-
hols, as demonstrated by the condensation of hydroxytyrosol
(5), a major antioxidant of olive oil,17 with gallic acid and
with caffeic acid (Scheme 1). Compound 3 had previously
been prepared in five steps and 5% overall yield.5 Remark-
ably, under Mitsunobu conditions, it could be prepared in
one step only (48% yield) and without resorting to any
protecting group.
The purification of polar and highly air-sensitive com-
pounds such as 3 and 6 was greatly simplified by gel
permeation chromatography.18 Thus, the strong affinity of
Sephadex LH-20 for polyphenolics made possible an easy
removal of the Mitsunobu byproducts (triphenylphosphine
oxide and hydrazodicarboxylates) by simple step gradient
Despite the growing popularity of the Mitsunobu reaction
to carry out nucleophilic substitutions directly on alcohols,12
its potential for the chemoselective esterification of phenolic
alcohols and phenolic acids had surprisingly gone un-
noticed.20 Due to the mild conditions and the possibility of
capitalizing on Sephadex chromatography for a quick
recovery of the products from the reaction mixture, the
Mitsunobu reaction is especially suitable for the synthesis
of multifunctional and air-sensitive polyphenolics, a class
of compounds of great biomedical and nutritional rel-
evance.21,22
Acknowledgment. We thank MURST (Fondi ex-40%,
Progetto Sostanze Naturali e Analoghi Sintetici con Attivita`
Antitumorale) and EU (Contract QLK3-2000-463) for fi-
nancial support.
deprotonation is not limited to the acid. Similar considerations apply to the
chemoselective Mitsunobu esterification of 2,3-dihydroxyesters, where
esterification has been observed to occur chemoselectively to the least acidic,
and therefore more nucleophilic in the nonionized form, â-hydroxyl (Ko,
S. Y. J. Org. Chem. 2002, 67, 2689-2691).
OL0266471
(19) Synthesis of 3 as a representative protocol. To a cooled (0 °C)
solution of freshly prepared (Baraldi, P. G.; Simoni, D.; Manfredini, S.;
Menziani, E. Liebigs Ann. Chem. 1983, 684-686) hydroxytyrosol (260 mg,
1.64 mmol) and gallic acid (286 mg, 1.64 mmol, 1 molar equiv) in dry
THF (3.5 mL) were added TPP (459 mg, 1.64 mmol, 1 molar equiv) and
DIAD (342 µL, 1.64 mmol). After stirring at room temperature for 48 h,
the reaction was worked up by removal of the solvent, and the residue was
partitioned between EtOAc and saturated NaHCO3 (ca. 50 mL each). The
organic phase was washed with brine, dried (Na2SO4), and evaporated. The
residue was purified by chromatography on Sephadex LH-20 (35 mL after
EtOAc swelling), using EtOAc to remove the Mitsunobu byproducts, and
5:5 EtOAc-MeOH to recover 3 (240 mg, 48%), obtained as a yellowish
powder (HPLC purity: 94%).
(20) The Mitsunobu reaction has, however, been employed to differenti-
ate hydroxyls having different acidities. See ref 14.
(21) Haslam, E. Shikimic Acid. Metabolism and Metabolites; Wiley &
Sons: Chichester, UK, 1993.
(22) For leading studies in polyphenolics synthesis, see: Kozikowski,
A. P.; Tu¨ckmantel, W.; Hu, Y. J. Org. Chem. 2001, 66, 1287-1296 and
previous articles in this series.
(15) For instance, octyl caffeate, a powerful cytotoxic analogue of CAPE,
was recently reported in 7% yield from the reaction of the sodium caffeate
and n-octyl bromide (Etzenhouser, B.; Hansch, C.; Kapur, S.; Selassie, C.
D. Bioorg. Med. Chem. 2001, 9, 199-209). This yield is over 1 order of
magnitude lower than that obtained with the Mitsunobu protocol (Table
2).
(16) Bankova, V. S. J. Nat. Prod. 1990, 53, 821-824.
(17) Visioli, F.; Galli, C. Crit. ReV. Food Sci. Technol. 2002, 43, 209-
221.
(18) Cardellina, J. H., II. J. Nat. Prod. 1983, 46, 196-199.
Org. Lett., Vol. 4, No. 22, 2002
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