Sustainability from agricultural waste: Chiral ligands from oligomeric proanthocyanidins via acid-mediated depolymerization

Article abstract of DOI:10.1016/j.tetlet.2010.09.123

Oligomeric proanthocyanidins (OPCs, Ar′ = 3,4-(HO)₂(C ₆H₃) are abundant natural products found in agricultural and forestry waste such as pine bark, grape seeds, and the peels of mangosteen. We have demonstrated that the O

Full text of DOI:10.1016/j.tetlet.2010.09.123

Tetrahedron Letters 51 (2010) 6322–6324
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sustainability from agricultural waste: chiral ligands from oligomeric
proanthocyanidins via acid-mediated depolymerization
Caili Fu, Wei Chen, Yi Ling Quek, Runyan Ni, Amylia Bte Abdul Ghani, Wendy Wen Yi Leong, Huaqiang Zeng,
⇑
Dejian Huang
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Oligomeric proanthocyanidins (OPCs, Ar0 = 3,4-(HO)2(C6H3) are abundant natural products found in agri-
cultural and forestry waste such as pine bark, grape seeds, and the peels of mangosteen. We have dem-
onstrated that the OPCs can be converted into small molecule chiral ligands by using proper nucleophiles
for acid depolymerization of the OPCs. The chiral ligands may have potential for sustainable asymmetric
catalysis.
Article history:
Received 3 July 2010
Revised 14 September 2010
Accepted 24 September 2010
Available online 1 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Environmentally benign and sustainable catalytic processes are
a major theme of current chemical research in response to the de-
mand for greener chemical processes with minimal energy con-
sumption.1 Full utilization of natural products in fine chemicals
production is increasingly important because natural products
are not only renewable and sustainable but also structurally di-
verse and complex. They would typically take many steps to be ‘to-
tally synthesized’ from fossil fuel derived basic chemicals. Some
shining examples are the privileged asymmetric catalysts such as
cinchona alkaloids and tartaric acid derivatives, which are derived
from natural products.2 There are many more under-utilized natu-
ral products, particularly those from agricultural and forestry
waste; oligomeric proanthocyanidins (OPCs) are oligomers of cate-
chins/epicatechins. OPCs are abundant secondary metabolites in
nature and are found in mangosteen peels (5% in dry matter), grape
seeds (17%),3 pine bark (5%),4 cinnamon bark (8%),5 sorghum bran
(6%),6 and in many other plants.5 OPCs have diverse bioactivity and
are potent radical scavengers, inhibitors of digestive enzymes,7 and
have antimicrobial activity.8 With the large number of phenolic
groups, OPCs are good metal chelators, yet their potential as
ligands for transition metal catalysts has not been explored, pre-
sumably due to the various chelating sites and modes. In the hope
of taking advantage of the rich source of OPCs as raw materials for
fine chemical synthesis, presented herein are our results on con-
verting OPCs into a wide range of chiral multidentate ligands
through acid-mediated depolymerization and transformations.
It has been known for a long time that acid-mediated depoly-
merization of OPCs in the presence of carbon (phloroglucinol9) or
thiol (benzylmercaptan10) nucleophiles leads to b-C-4 substituted
epicatechin derivatives,11 yet the utility of the resulting products
was rarely investigated.
By selecting appropriate carbon nucleophiles, we were able to
obtain a number of novel epicatechin derivatives by acid-mediated
depolymerization of mangosteen OPCs (Scheme 1). These reagents
are grouped into two main types: carbon and sulfur based nucleo-
philes. Depolymerization of OPCs in the presence of an unsubstitut-
ed pyrrole, a potent carbon nucleophile, yielded only a black mixture
probably due to polymerization or unselective nucleophilic substi-
tution on the a- or b-carbon substituted analogs, while 2,3-dimeth-
ylpyrazole and 3-ethyl-2,4-dimethylpyrrole successfully yielded 1
and 2. The products were isolated conveniently by normal phase sil-
ica gel column chromatography. The HPLC chromatograms of the
compounds all gave rise to one sharp peak indicating a single diaste-
reomer for 1 and 2, consistent with epicatechin derivatives. The ste-
reochemistry of C4 was determined by comparing the 1H NMR
spectral pattern of C ring protons with known compounds.12 Com-
pounds 1 and 2 are rare examples of alkaloid-like flavonoid deriva-
tives. Naturally, there are only three reported examples, that is,
lotthanongine (a flavonoidal indole derivative),13 ficine/isoficine,14
and phyllospadine.15 The bioactivity of these compounds has re-
mained largely unexplored. Our method for preparing 1 and 2 is very
mild and straightforward for large scale synthesis for further inves-
tigation. Regarding metal chelation, compounds 1 and 2 have two
bidentate sites, one chiral (N, O) and the other achiral (catecholic
unit on the B ring) and thus have potential as ligands to prepare
bimetallic complexes. Alternatively, the catecholic unit on the B ring
can be blocked selectively by reaction with methyl propiolate in the
presence of dimethylaminopyridine (DMAP) as base in moderate
yield. The resulting product 3 exists as two diastereomers as demon-
*
strated by the two equally populated configurations of CH–(CH2)
unit as revealed by two equal intensity doublet of doublets around
6.52–6.48 ppm.
Weaker carbon nucleophiles such as 3,5-dimethoxyphenol and
3,5-dimethoxyaniline led to depolymerization products 4 and 5
but in lower yields. Both 4 and 5 could be modified further by
⇑
Corresponding author. Tel.: +65 6516 8821; fax: +65 6775 7895.
E-mail address: chmhdj@nus.edu.sg (D. Huang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.123

C. Fu et al. / Tetrahedron Letters 51 (2010) 6322–6324
6323
O
O
Ar'
HO
O
HO
O
Ar'
OH
Ar'
HO
O
O
HO
HO
Ar'
O
OCH3
O
OH
OH
OH
HN
OH
S
S
d
20%
OH
OH
OH
OH
HN
OH
HN
OH
S
+
N
HS
OH
Ar'
2
1
13
14
3
g
O
O
a, 56%
b
HO
HO
50%
70%
O
Ar'
Ar'
O
HO
Ar'
OH
O
Ar'
HO
O
S
HO
HO
c
O
O
OCH3
O
OH
O
OH
HO
OH
OH
OCH3
OH
OH
OH
S
N
Ar'
OH
X
d
h
49%
f
OH
OCH3
OH
X
55%
6, X = OH, 32%
7, X = NH2, 28%
OH
OH
HO
tBu
HO
H2N
n
Ar'
OH
OCH3
O
H
OCH3
h
11
4
, X = OH, 42%
(X = NH2)
100%
12
5, X = NH2 47%
OH
O
Ar'
O
Ar'
e
HO
O
HO
O
OCH3
63%
O
O
OH
h
OH
OCH3
OH
OH
OH
S
N
OH
H2N
100%
OH
S
tBu
OH
N
tBu
OCH3
H
H
8
9
10
Scheme 1. From oligomeric proanthocyanidins (n = 2–50) in mangosteen peels (inset) to multidentate ligands, (Ar0 = 3,4-dihydroxyphenyl). Acid mediated depolymerization
conditions are 0.22% HCl in CH3OH, 45 °C, 2–8 h. (a) 2,3-Dimethylpyrazole; (b) 3-ethyl-2,4-dimethylpyrrole; (c) 3,5-dimethoxyphenol (for 4), or 3,5-dimethoxyaniline (for 5);
(d) 4-(N,N-dimethylamino)pyridine, HCCCOOCH3 CH3CN, rt, 12 h; (e) o-thioaniline; (f) cysteamine; (g) 1,2-dithioethane; (h) 3-tert-butylsalicylaldehyde, CH3OH, AcOH, 1
drop, rt. Percentage conversion was determined by HPLC.
protection of the catecholic units to give 6 and 7. In addition, 7 was
readily converted into tridentate Schiff base, 8, in quantitative
yield. The presence of a chiral tridentate pocket makes it a candi-
date for use in asymmetric catalysis in combination with transition
metals.
of OPCs, we were able to isolate mono and di-substituted products,
13 and 14. The latter is particularly interesting as a tetradentate
(O2S2) ligand with a C2 axis which is believed to be desirable in
certain asymmetric reactions.17
In summary, we have demonstrated that mangosteen OPCs can
be sustainable and renewable starting materials for a wide range of
epicatechin derivatives. It is remarkable that their synthesis can be
achieved in one or two steps without the need of protecting
groups. Given the fact that there are plentiful resources for OPCs,
large scale industrial applications would be feasible.
Thiols are strong nucleophiles, and in fact, even highly odorous
benzylmercaptan has been widely used for determination of the
degree of polymerization of OPCs as the yield is almost quantita-
tive. Herein, we prepared a number of new multidentate ligands
using various thiols. The odorless o-thioaniline was found to be
an excellent nucleophile in the depolymerization of OPCs as it gave
9 with high yield after a simple isolation. The multidentate Schiff
base 10 was obtained after condensation with 3-tert-butylsalicylal-
dehyde. Although 9 and 10 are stable under acidic conditions, they
readily eliminate thiol under weak basic solution (pH >8.5). The
unobserved quinone methide intermediate can be trapped by other
carbon nucleophiles such as 3-ethyl-2,4-dimethylpyrrole to give 2,
which is stable under the same conditions (Eq. 1). Hence, 9 is an
alternative intermediate for the preparation of epicatechin
derivatives.16
Acknowledgment
The authors are grateful for financial support from the Ministry
of Education of Singapore (grant number R-143-000-299-112).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.123.
References and notes
Ar
O
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ð1Þ
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9
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