Synthesis of modified proanthocyanidins: Easy and general introduction of a hydroxy group at C-6 of catechin; efficient synthesis of elephantorrhizol

Article abstract of DOI:10.1016/j.bmcl.2004.11.061

A general procedure for the oxidation of catechin derivatives is described, leading to the introduction of a new hydroxy group at C-6. This procedure has been applied for the synthesis of elephantorrhizol, a natural flavan-3-ol exhibiting a fully substitu

Full text of DOI:10.1016/j.bmcl.2004.11.061

Bioorganic & Medicinal Chemistry Letters 15 (2005) 563–566
Synthesis of modified proanthocyanidins: easy and
general introduction of a hydroxy group at C-6 of
catechin; efficient synthesis of elephantorrhizol
Franc¸ois-Didier Boyer,a Nour-Eddine Es-Safi,a,c Josiane Beauhaire,a
b
Christine Le Guerneve and Paul-Henri Ducrot
a,
*
´
a
´ ´
Unite de Phytopharmacie et Mediateurs Chimiques, Inra, Route de Saint-Cyr, 78026 Versailles Cedex, France
bUMR Sciences pour l’Œnologie, Inra, 2, place Viala, 34060 Montpellier Cedex, France
c
´
´
´
Laboratoire de Chimie Organique et d’Etudes Physico-chimiques, Ecole Normale Superieure,
B.P. 5118, Takaddoum Rabat, Morocco
Received 6 October 2004; revised 15 November 2004; accepted 18 November 2004
Available online 16 December 2004
Abstract—A general procedure for the oxidation of catechin derivatives is described, leading to the introduction of a new hydroxy
group at C-6. This procedure has been applied for the synthesis of elephantorrhizol, a natural flavan-3-ol exhibiting a fully substi-
tuted cycle A.
Ó 2004 Elsevier Ltd. All rights reserved.
Proanthocyanidins are known as condensed or non-
hydrolyzable tannins.1–3 Many biological activities, par-
ticularly a powerful free-radical scavenging4–9 activity,
have been reported for flavonoids, and their investiga-
tion is now increasingly important. Most of the descri-
bed procyanidins 1 involve oligomerization of catechin
derivatives 2a–d (Fig. 1). However, other flavan-3-ols
have also been described with additional hydroxy
groups on their aromatic rings. Gallocatechins 2c,d,
exhibiting three hydroxy groups on the B ring, are the
most encountered. However, 11 hydroxylation patterns
have been reported in the literature involving in some
cases the presence of up to four free phenolic groups
on the A ring. Recently indeed, two new flavan-3-ols
with new hydroxylation patterns on ring A have been
described. (+)-30, 40, 5, 6, 7, 8-hexahydroxyflavan-3-ol
3 (elephantorrhizol) was identified in Elephantorrhiza
goetzei10,11 and 3-acetyl-5-methoxy-7,30,40-trihydroxy-
8-O-glucoside-flavan-3-ol, barbatoflavan 4, from Cam-
panula barbata (Fig. 1).12 Due to the increasing interest
Figure 1.
devoted to this type of compounds, according to their
potential pharmacological properties, it is of interest
to investigate structure–activity relationships and, there-
fore, to have access to synthetically modified flavanols.
Several reports have been already published about the
oxidation of flavanoids using various oxidizing re-
agents13–15 but, surprisingly, none of them was devoted
Keywords: Catechin; Procyanidin; Elephantorrhizol; Flavanol.
*
Corresponding author. Tel.: +33 1 30 83 36 41; fax: +33 1 30 83 31
19; e-mail: ducrot@versailles.inra.fr
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.11.061

564
F.-D. Boyer et al. / Bioorg. Med. Chem. Lett. 15 (2005) 563–566
Figure 2.
Scheme 1.
to the hydroxylation of the aromatic ring A of catechin
derivatives. Indeed, most of these studies were devoted
to the oxidation of flavanoids exhibiting an oxygenated
function at C-4, which are known to be very important
for the chemical reactivity of flavanoids.
ble sites of oxidation, namely compounds 5, 6 and 12.
Indeed, albeit allowing only moderate yielding transform-
ations (10–20%), both sets of experimental procedures
yielded only C-6 hydroxylated compounds. The oxida-
tion of 6 in both conditions allowed the characterization
of the yellow quinone 14 (traces) as the only C-8 oxi-
dized compound.
In an ongoing program aimed at the synthesis of modi-
fied proanthocyanidins, we were interested in the prepa-
ration of modified catechin derivatives involving
introduction of substituents either at C-6 and/or C-8
in order to modify their ability to form oligomers. Sev-
eral procedures are available for the introduction of var-
ious substituents at C-8, including an hydroxy group,
allowing in particular the synthesis of compounds 5-
11,16 which will be used, beside already reported perace-
tyl catechin 12 and bromide 13,17 (Fig. 2) as starting
materials in the present study devoted to the introduc-
tion of an hydroxy group at C-6 of catechin derivatives.
The regiochemistry of the reaction was unambiguously
established on compound 23, obtained through acetyl-
ation of 16 (Scheme 2). Indeed, the HSQC/HMBC spec-
tra of 23 allowed a complete attribution of the 13C
resonances and the observation, beside other character-
istic long range correlations (Fig. 3), of a correlation be-
tween the remaining aromatic proton on ring A with
C-8a, which is only possible if the proton is located on
carbon C-8, thus confirming the structure.
Beside numerous unsuccessful attempts, two very promis-
ing sets of conditions were found, resulting in a general
introduction of a new hydroxy group at C-6. The main
results are gathered in Scheme 1 and Table 1 and
involve either use of m-CPBA or dimethyldioxirane
(DMDO).
It seems that the experimental conditions involving the
use of DMDO as oxidizing agent at low temperature
is in most of the cases the more efficient one, as reported
for several other flavanoids, and results in good trans-
formation yields, up to 50% in the case of the trifluoro-
acetylcatechin 10. Moreover, the presence of an
electron-withdrawing group at C-8 seemed to induce a
slightly better transformation with DMDO, when yields
The most important fact is the regioselectivity of the
reaction when performed on compounds with two possi-
Table 1.
Substrate
Conditionsa
Temp (°C)
Time (h)
Product
Yield (%)
1
5
DMDO
m-CPBA, NaHCO3
DMDO
ꢀ15
ꢀ10
ꢀ15
ꢀ10
ꢀ40
rt
0.6
3
15
15
16
16
17
18
18
19
20
20
21
21
n.r.
22
10–15
20
13
2
5
3
6
0.6
3
4
6
m-CPBA, NaHCO3
DMDO
10–15
38
—
5
7
7.5
48
0.6
7.5
48
20
48
36
—
7.5
6
8
m-CPBA, NaHCO3
DMDO
DMDO
7
8
ꢀ15
ꢀ40
rt
30–45
34
8
9
9
10
10
11
11
12
13
m-CPBA, NaHCO3
DMDO
9
49
10
11
12
13
14
ꢀ30
rt
m-CPBA, NaHCO3
DMDO
20
37
ꢀ30
—
m-CPBA or DMDO
DMDO
—
33–36
ꢀ40
a All reactions were carried out in CH2Cl2.18

F.-D. Boyer et al. / Bioorg. Med. Chem. Lett. 15 (2005) 563–566
565
Scheme 2.
Scheme 4.
Figure 3. Main 1H–13C long range correlations observed for com-
pound 23.
tives in the course of such oxidation reactions, since we
were not able to isolate any compounds with an oxidized
B ring when other studies15–17 have demonstrated the
sensitivity of this ring to similar oxidative procedures
in the presence of free phenolic groups; moreover, the
protecting groups used for the protection of the phenolic
groups have to be carefully chosen, since the penta-
O-acetyl catechin 12 did not react in these conditions.
Secondly, we have demonstrated the importance of the
substituent at C-8 in the yield of the transformation.
obtained with m-CPBA were not significantly affected
by the substitution pattern at C-8.
Another important feature of this transformation lies in
its versatility. Indeed, the oxidation of bromide 13 re-
sults in the formation in ca. 35% yield (Table 1, entry
14) of the desired 6-hydroxy-8-bromocatechin derivative
22. Hydroxy group at C-6 can be thereafter protected as
its benzyl ether and the bromide hydrolyzed (t-BuLi,
H2O), finally affording pentahydroxy flavan-3-ol 2419
in 87% yield (two steps, Scheme 3). The overall yield
of this synthetic sequence is furthermore better than
the yield obtained directly from 5. This result shows
that, even if C-6 has been proven to be the more reactive
site of catechin derivatives in these conditions, introduc-
tion of a bromine atom on carbon C-8 allows the protec-
tion of C-8, which is easily removed later through
hydrolysis.
References and notes
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The synthesis of elephantorrhizol was thereafter obvi-
ously achieved through protection of the hydroxy group
at C-6 of aldehyde 17 followed by a Dakin reaction20
performed on aldehyde 25 (Scheme 4) to furnish hexa-
O-benzyl elephantorrhizol 26. Total hydrogenolysis of
benzyl groups led to (+)-elephantorrhizol, spectroscopic
data of which were in agreement with those reported for
the natural product.11
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Scheme 3.

566
F.-D. Boyer et al. / Bioorg. Med. Chem. Lett. 15 (2005) 563–566
16. (a) Beauhaire, J.; Es-Safi, N.-E.; Boyer, F.-D.; Kerhoas,
´
132.33 (C-10), 128.62–127.29 (Bn + C-6), 120.78 (C-60),
115.29 (C-50), 114.11 (C-20), 107.36 (C-4a), 97.99 (C-8),
80.47 (C-2), 75.36 (t, Bn), 74.47 (C-3), 71.79 (t, Bn), 71.61
(t, Bn), 71.35 (t, Bn), 70.93 (t, Bn), 26.75 (C-4), 20.51
(CH3CO). 24: 13C NMR (75 MHz, CDCl3): d 152.06 (s),
150.87 (s), 150.44 (s), 149.04 (s), 138.07 (s), 137.87 (s),
137.80, 137.42 (s), 137.38 (s), 136.99 (s), 136.10 (s), 132.50
(s), 128.73 (d), 128.59 (d), 128.38 (d), 128.16 (d), 128.02 (d),
127.90 (d), 127.72 (d), 127.56 (d), 127.48 (d), 127.41 (d),
120.65 (d), 115.21 (d), 114.04 (d), 107.28 (s), 98.02 (d), 80.25
(d), 75.90 (t), 75.24 (t), 74.55 (d), 71.61 (t), 71.55 (t), 71.32
(t), 70.96 (t), 26.61 (t). 26: 13C NMR (75 MHz, CDCl3): d
149.16 (s), 149.07 (s), 142.40 (s), 139.96 (s), 138.84 (s),
137.97 (s), 137.87, 137.80 (s), 137.76 (s), 137.72 (s), 137.51
(s), 137.31 (s), 134.76 (s), 132.14 (s), 128.61 (d), 128.54 (d),
128.21 (d), 128.11 (d), 127.92 (d), 127.56 (d), 127.46 (d),
120.64 (d), 115.21 (d), 114.15 (d), 110.55 (s), 80.33 (d), 76.22
(t), 75.73 (t), 75.47 (t), 74.67 (d), 71.74 (t), 71.61 (t), 71.43
(t), 26.58 (t).
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18. Typical procedure for DMDO mediated oxidation of
catechin derivatives: to
a solution of 7 (300 mg,
0.39 mmol) in CH2Cl2 (6 mL) at ꢀ40 °C was added
dropwise under argon a solution of DMDO (Adam, W.;
Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124, 2377–
2377) (12 mL). The resultant mixture was stirred at
ꢀ40 °C for 7 h 30 min and evaporated under reduced
pressure without warming. The residue was purified by
chromatography on silica gel (EtOAc/cyclohexane, 2:8) to
give 113 mg (38%) of 17 as a colourless oil.
19. Compound 23: 13C NMR (75 MHz, CDCl3) d = 169.22
(CH3CO), 152.43 (C-8a), 150.52 (C-7), 150.00 (C-5), 149.17
(C-30, C-40), 138.00, 137.56, 137.46, 137.37, 136.76 (s, Bn),
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1984, 49, 4741–4743.