Hydroxylation of ring A of flavan-3-ols: Influence of the ring A substitution pattern on the oxidative rearrangement of 6-hydroxyflavan-3-ols

Article abstract of DOI:10.1055/s-2006-950224

A general procedure for the oxidation of catechin derivatives is described, leading to the introduction of a new hydroxyl group at C-6. This procedure has been used for the synthesis of a number of 6-hydroxy flavan-3-ols, including elephantorrhizol, a natural flavan-3-ol exhibiting a fully substituted A ring. The substitution at C-8, albeit of poor influence on the course of this oxidation reaction, has been demonstrated to be preponderant for the further spontaneous oxidation and rearrangement of 6-hydroxy-flavan-3-ols into p-benzoquinones. The whole procedure allows the preparation of 6-alkyl substituted benzoquinones derived from catechin. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950224

3250
PAPER
Hydroxylation of Ring A of Flavan-3-ols: Influence of the Ring A Substitution
Pattern on the Oxidative Rearrangement of 6-Hydroxyflavan-3-ols
H
ydroxylation
r
of Ring
a
A
of Flava
n
n-3-ols çois-Didier Boyer,a Josiane Beauhaire,a Marie Thérèse Martin,b Paul-Henri Ducrot*a
a
INRA, Unité de Phytopharmacie et Médiateurs Chimiques, Route de Saint-Cyr, 78026 Versailles Cedex, France
Fax +33(1)30833119; E-mail: ducrot@versailles.inra.fr
b
CNRS, ICSN, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
Received 31 May 2006; revised 15 June 2006
least-encountered and -investigated site of oxidation of
the flavan skeleton.
Abstract: A general procedure for the oxidation of catechin deriv-
atives is described, leading to the introduction of a new hydroxyl
group at C-6. This procedure has been used for the synthesis of a
number of 6-hydroxy flavan-3-ols, including elephantorrhizol, a
natural flavan-3-ol exhibiting a fully substituted A ring. The substi-
tution at C-8, albeit of poor influence on the course of this oxidation
reaction, has been demonstrated to be preponderant for the further
spontaneous oxidation and rearrangement of 6-hydroxy-flavan-3-
ols into p-benzoquinones. The whole procedure allows the prepara-
tion of 6-alkyl substituted benzoquinones derived from catechin.
Several reports have been published about the oxidation
of flavanoids using various oxidizing reagents.12–15 The
most recent of these15 was devoted to the hydroxylation at
C-8 of the aromatic ring A of catechin derivatives leading
to the corresponding p-benzoquinones, which were as-
sumed by the authors to be valuable leads for new phar-
macological screenings since numerous active substances
are derived from this structural feature.16 Moreover, most
of the earlier reports were devoted to the oxidation of fla-
vanoids exhibiting an oxygenated function at C-4, mostly
a carbonyl group, that considerably changes the reactivity
of the aromatic A ring; this report15 is, to our knowledge,
one of the first to describe the regioselective C-8 oxida-
tion of flavanols exhibiting a chemically sensitive benzyl-
ic methylene at C-4, that could also be susceptible to the
oxidative process.17,18
Key words: phenols, quinones, oxidations, rearrangements, diox-
iranes
Proanthocyanidins 1 are known as condensed or non-hy-
drolysable tannins and are found in large amounts in many
fruits and derived products such as beer, wine and cider.1–3
Many biological activities, mainly powerful free-radical
scavenging3–8 activity, have been reported for this type of
flavonoid, and the investigation of the biological activity
of flavan-3-ol derived compounds is now increasingly im-
portant. Most of the described procyanidins involve oligo-
merization of catechin derivatives 2a–d (Figure 1). Apart
from catechins 2a and 2b, gallocatechins 2c and 2d, ex-
hibiting three hydroxyl groups on their B ring are the most
commonly encountered. However, eleven hydroxylation
patterns have been reported in the literature involving ei-
ther supplementary hydroxylation on ring B or ring A. Re-
cently indeed, two new flavan-3-ols with new
hydroxylation patterns on ring A have been described. El-
ephantorrhizol, (+)-3¢,4¢,5,6,7,8-hexahydroxyflavan-3-ol
(3), was identified in Elephantorrhiza goetzei9,10 and bar-
batoflavan, 3-acetyl-5-methoxy-7,3¢,4¢-trihydroxy-8-O-
glucoside-flavan-3-ol (4), from Campanula barbata
(Figure 1).11 The oxidation pattern of this type of com-
pound is a crucial feature regarding their biological activ-
ity since it may considerably affect their in vivo stability
as well as their chemical stability, which is related to their
ability to undergo oligomerisation under various oxida-
tive conditions, as encountered for example during the
wine aging process. Despite the structural diversity en-
countered in this type of natural compounds, the hydrox-
ylation at C-6 should be regarded, to our knowledge, as the
In our ongoing programme aimed at the synthesis of mod-
ified proanthocyanidins,19,20 and other related flavanol
pseudo dimers21,22 we were interested in the preparation of
modified catechin derivatives involving the introduction
of substituents either at C-6 and/or C-8 in order to modify
their ability to form oligomers.
OH
OH
3'
OH
R1
OH
R1
4'
B
8
1'
3
8a
4a
HO
O
HO
O
C
7
2
A
6
OR2
X
5
4
OH
OH
n
1 : n = 2 to >100
2 a : X =
, R1 = H
catechin
epi-catechin
OH
R1 = H, OH
b : X = OH , R1 = H
R2 = H or R3C(=O)
c : X = OH , R1 = OH gallo-catechin
d : X = OH , R1 = OH epi-gallo catechin
OH
OH
OH
OH
OH
OH
OGlc
OMe
HO
HO
O
HO
O
OH
OAc
3
4
SYNTHESIS 2006, No. 19, pp 3250–3260
Advanced online publication: 04.09.2006
x
x.
x
x
.
2
0
0
6
Figure 1
DOI: 10.1055/s-2006-950224; Art ID: P06206SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Hydroxylation of Ring A of Flavan-3-ols
3251
OR2
OR2
R3
R2O
R
O
OR1
OR2
5a R = H, R1 = H, R2 = Bn, R3 = H
6a R = H, R1 = Bn, R2 = Bn, R3 = H
18 R= OAc, R1= Bn, R2= Bn
5b R = OH, R1 = H, R2 = Bn, R3 = H
6b R = OH, R1 = R2 = Bn, R3 = H
18 R = OAc, R1 = R2 = Bn, R3 = H
7b R = OH, R1 = R2 = Bn, R3 = CHO
8b R = OH, R1 = R2 = Bn, R3 = CO2H
9b R = OH, R1 = R2 = Bn, R3 = CF3CO
5c R = OH, R1 = H, R2 = H, R3 = H
18 R= OAc, R1= Bn, R2= Bn
18 R= OAc, R1= Bn, R2= Bn
7a R = H, R1 = Bn, R2 = Bn, R3 = CHO
8a R = H, R1 = Bn, R2 = Bn, R3 = CO2H
9a R = H, R1 = Bn, R2 = Bn, R3 = CF3CO
10a R = H, R1 = H, R2 = Bn, R3 = CF3CO
11a R = H, R1 = Ac, R2 = Ac, R3 = H
18 R= OAc, R1= Bn, R2= Bn
8c R = OH, R1 = H, R2 = H, R3 = CO2H
9c R = OH, R1 = H, R2 = H, R3 = CF3CO
10b R = OH, R1 = H, R2 = Bn, R3 = CF3CO 10b R= OH, R1= H, R3= CF3CO
11b R = OH, R1 = Ac, R2 = Ac, R3 = H
11b R= OH, R1= Ac, R2= Ac
23 R = OH, R1 = H, R2 = H, R3 = CH3
14b R= OH, R1= H, R2= Me
15b
12a R = H, R1 = Bn, R2 = Bn, R3 = CH2OAc 12b R = OH, R1 = R2 = Bn, R3 = CH2OAc
13a R = H, R1 = H, R2 = Bn, R3 = Br
14a R = H, R1 = H, R2 = Me, R3 = H
15a R = H, R1 = Ac, R2 = Bn, R3 = CHO
13b R = OH, R1 = H, R2 = Bn, R3 = Br
14b R = OH, R1 = H, R2 = Me, R3 = H
15b R = OH, R1 = Ac, R2 = Bn, R3 = CHO
R= OH, R1= Ac, R3= CHO
OH
OBn
OBn
OH
OBn
OBn
O
O
HO
O
BnO
O
BnO
O
O
H3C
OH
OBn
OBn
O
O
O
16
17
24
Figure 2
In this paper, we want to report our results related to the Vilsmeier–Haack reaction effected on perbenzylated cat-
oxidation of the A ring of flavanols. The main feature of echin 6a led to the clean formation of a unique isolated re-
this work is the regioselective introduction of a hydroxyl gioisomer 7a.24 We did not determine the regiochemistry
group at C-6 of all the flavanol derivatives tested with a of this reaction at this stage and 7a was directly oxidized
variety of substituents at C-8. The presence of a hydroxyl to the corresponding benzoic acid 8a. The orientation of
group at C-6 thereafter allows, after deprotection of the the substituent at C-8 was thereafter unambiguously es-
phenolic groups and depending on the substituent at C-8, tablished through NMR spectroscopy [HSQC/HMBC-de-
a subsequent spontaneous oxidative rearrangement to oc- rived long-range 1H–13C correlations (Figure 3)].
cur leading to the formation of p-benzoquinones derived
OBn
from the flavan skeleton and possibly exhibiting a carbon-
OBn
OBn
ated substituent at C-6.
OBn
H8
R
H2
H2
BnO
H6
O
BnO
AcO
O
BnCl, NaH,
DMF
0 °C to r.t.,
77%
1. Ac2O, py
2. POCl3, DMF, 75 °C
OBn
OBn
OBn H4
5a
OBn H4
2a
15a
7a
8a: R = CO2H
9a: R = COCF3
18
BnBr, NaH,
DMF
0 °C to r.t.,
95%
62% (2 steps)
POCl3, DMF
6a
NaClO2, t-BuOH,
H3PO4,
8a
Figure 3 Main H–13C long-range correlations observed for com-
1
85%
r.t., 62%
pounds 8a, 9a and 18.
1. LiAlH4, THF
2. Ac2O, py
(CF3CO)2O,
CH2Cl2, r.t.
9a from 6a, 42%
10a from 5a, 64%
12a
The direct Friedel–Crafts acylation with trifluoroacetic
anhydride in dichloromethane, led to the formation of 10a
(64% after hydrolysis of its trifluoroacetate at C-3 that is
indeed obtained as the primary product of the reaction)
and 9a (42%) starting from 5a and 6a, respectively.
Acetylation of 5a under standard conditions (Ac2O, py)
followed by a Vilsmeier–Haack reaction afforded 8-
formyl 3-O-acetyl 5,7,3¢,4¢-tetra-O-benzyl catechin 15a.
Lithium aluminium hydride reduction of aldehyde 7a, fol-
55% (2 steps)
Scheme 1
The substrates 5a–15a (Figure 2) in our study were pre-
pared as follows (Scheme 1). Tetra-O-benzyl catechin 5a
and penta-O-benzyl catechin 6a were sequentially pre-
pared through classical procedures (NaH, BnCl/BnBr,
DMF)18,23 from commercially available (+)-catechin 2a.
Synthesis 2006, No. 19, 3250–3260 © Thieme Stuttgart · New York

3252
F.-D. Boyer et al.
PAPER
lowed by acetylation cleanly afforded acetoxy methyl The regiochemistry of the reaction was unambiguously
penta-O-acetyl catechin 12a. Compounds 11a, 13a and established for compound 18, obtained through acetyla-
14a were obtained as described in the literature.18,25
tion of 6b (Scheme 2). Indeed, the HSQC/HMBC spectra
of 18, allowed a complete attribution of the 13C resonanc-
es and the observation, besides other characteristic long-
range correlations (Figure 3), of a correlation between the
remaining aromatic proton on ring A with C-8a, which is
only possible if the proton is located on carbon C-8, thus
unambiguously confirming the structure.
The first possible hydroxylation at C-6 was unexpectedly
observed when attempting to perform a Baeyer–Villiger
reaction on trifluoroacetyl catechin 10a. Indeed, under
classical experimental conditions, namely in the presence
of MCPBA, the reaction did not proceed as expected, no
Baeyer–Villiger product was detected and the only ob-
served product resulted from the introduction of a hydrox- It seems that the experimental conditions involving the
yl group at C-6, in low yield. This result prompted us to use of DMDO as an oxidizing agent at low temperature is,
examine other related oxidative conditions on catechin in most cases, the more efficient and results in good
derivatives 5a–15a. Beside numerous unsuccessful at- yields, up to 50% in the case of the trifluoroacetylcatechin
tempts, two very promising sets of conditions arose, re- 9a. Moreover, the presence of an electron-withdrawing
sulting in a general method for the introduction of a new group at C-8 induces a better transformation with DMDO
hydroxyl group at C-6. The main results are gathered in when yields obtained with MCPBA are not affected by the
Table 1 and involve either the use of MCPBA or DMDO. substituent at C-8.
The most important fact is the regioselectivity observed Another important feature of this transformation lies in its
for this reaction when performed on compounds with two versatility. Indeed, the oxidation of bromide 13a results in
possible sites of oxidation, namely compounds 5a, 6a and the formation in ca. 35% yield (Table 1, entry 14) of the
14a. Although the transformations resulted in only a mod- desired 6-hydroxy-8-bromocatechin derivative 13b. The
erate yield (10–20%), both sets of experimental procedure hydroxyl group at C-6 can be thereafter protected as its
yielded only C-6 hydroxylated compounds. The oxidation benzyl ether and the bromide hydrolysed (t-BuLi, H2O),
of 6a under both sets of conditions allowed the character- finally affording pentabenzyloxy flavan-3-ol 19 in 87%
ization of quinones 16 and 17 (traces) as the only C-8 ox- yield (3 steps, Scheme 2).
idized compound.
Table 1 C-6 Oxidation of Catechin Derivatives
Compd
5a
Oxidationa
Temp (°C)
–15
–10
–15
–10
–40
r.t.
Time (h)
0.6
3
Yield (%)
Product
5bb
5b
1
2
DMDO
10–15
20
5a
MCPBA, NaHCO3
DMDO
3
6a
0.6
3
13
6b
4
6a
MCPBA, NaHCO3
DMDO
10–15
38
6b
5
7a
7.5
48
7b
6
8a
MCPBA, NaHCO3
DMDO
–
8bb
8b
7
8a
–15
r.t.
0.6
48
30–45
9
8
9a
MCPBA, NaHCO3
DMDO
9bb
9b
9
9a
–30
r.t.
20
49
10
11
12
13
14
15
16
10a
10a
11a
12a
13a
14a
15a
MCPBA, NaHCO3
DMDO
48
20
10b
10b
n.r.
12bc
13b
14b
15b
–30
–
36
37
MCPBA, NaHCO3
DMDO
–
–
–40
–40
0
7.5
7.5
3
34
DMDO
33–36
20
MCPBA
DMDO
–40
7.5
35
a All reactions were carried out in CH2Cl2.
b Subsequent hydrogenation (H2, Pd/C, MeOH) afforded the corresponding product 5c (from 19), 8c or 9c.
c Hydrogenation (H2, Pd/C, MeOH) gave 23 and 24 after spontaneous rearrangement.
Synthesis 2006, No. 19, 3250–3260 © Thieme Stuttgart · New York

PAPER
Hydroxylation of Ring A of Flavan-3-ols
3253
Ac2O, py
OH
OH
6b
18
OH
OH
70%
O
O
O
O
OBn
HO
HO
O
HO
O
OBn
1. NaH, BnBr, DMF
0 °C to r. t.
BnO
BnO
O
OH
H3C
OH
13b
H4
H4
OBn
2. t-BuLi, THF
22
24
–78 °C to r.t. then H2O
87% (2 steps)
OBn
19
Figure 4 Main H–13C long-range correlations observed for com-
1
OBn
pounds 22 and 24.
OBn
R3
NaH, BnBr,
BnO
O
H2, Pd/C,
MeOH–THF
penta-O-benzyl derivatives 19 [the five-step transforma-
tion of 13a into 5c (via 19) was found to be as efficient as
the two-step sequence affording 5c from 5a], 8b, 9b and
12b, respectively, through hydrogenolysis of the benzyl
groups (Table 1, in the case of 12b, the benzylic acetoxy
group on the methylene attached to the C-8 of the flavanol
was also hydrogenolysed under these conditions, giving
rise to the 8-methyl flavanol 23).
DMF
0 °C to r.t.
3
7b
BnO
OBn
88%
OBn
20: R3 = CHO
77%
H2O2, H2SO4,
MeOH–CH2Cl2, –10 °C, 74%
21: R3 = OH
OH
OH
O
We observed in methanolic solution good stability toward
air oxidation for carboxylated and trifluoroacetylated de-
rivatives 8c and 9c. We also found C-6 hydroxylated com-
pound 5c was stable under the same conditions. On the
other hand, methyl derivative 23 spontaneously gave an
oxidation product, similarly to elephantorrhizol 3, that has
been identified as p-benzoquinone 24. In this particular
case, the formation of the p-benzoquinone has to be ex-
plained by rearrangement of an o-quinonic compound
formed as the first product of the reaction, with the open-
ing of ring C of the flavan skeleton through addition of a
molecule of water. Noteworthy, formation of a methylene
quinone intermediate, involving the benzylic methyl
group, seems to be an irrelevant mechanistic pathway,
since we did not observe hydrogen–deuterium exchange
when this rearrangement was performed with deuterated
solvents. A proposed mechanism is shown in Scheme 3.
The rearrangement observed in this case has, in our opin-
ion, to be advocated in order to explain the formation
(even at very low yield) of p-benzoquinone 16 during the
oxidation of flavan 6a.
acetone–MeOH
air, r.t.
HO
O
HO
OH
O
22
Scheme 2
These results clearly show the importance of the protec-
tion pattern of the phenolic groups of the catechin deriva-
tives on the course of such oxidation reactions, since no
compounds with an oxidized B ring were observed in our
study when other reports12–15 have demonstrated the sen-
sitivity of this ring to similar oxidative procedures in the
presence of free phenolic groups. On the other hand, the
protecting groups used for the protection of the phenolic
groups have to be carefully chosen, since the penta-O-
acetyl catechin 11a did not react under these conditions,
while tetra-O-methyl catechin 14a reacted analogously to
the compounds with benzyl protecting groups.
The synthesis of elephanthorrhizol 3 was thereafter obvi-
ously achieved through protection of the hydroxyl group
at C-6 of aldehyde 7b followed by a Dakin reaction26 per-
formed on aldehyde 20 (Scheme 2) to furnish slowly the
hexa-O-benzyl elephantorrhizol 21. Total hydrogenolysis
of benzyl groups led to (+)-elephantorrhizol 3, spectro-
scopic data of which were in agreement with those report-
ed for the natural product.10
Our efforts aimed at the synthesis of elephantorrhizol 3
have allowed us to design a new and easy oxidation of the
A ring of flavan-3-ol, leading to the formation of the cor-
responding 6-hydroxy flavans. However, the presence of
an electron-donating group at C-8, such as an alkyl group
thereafter allows a spontaneous oxidative rearrangement
to occur, leading to the corresponding p-benzoquinone
where the substituent at C-8 has formally migrated to the
C-6 position. This procedure therefore opens new per-
spectives for the preparation of C-6 substituted fla-
vonoids, which are difficult to obtain through other
methodologies, due to the low reactivity of the C-6 posi-
tion in usual nucleophilic addition reactions.
Surprisingly, thereafter we observed that (+)-elephantor-
rhizol 3 was rather unstable in acetone–MeOH solution
and underwent spontaneous oxidation affording the p-
benzoquinone 22. The structure of 22 was established by
HSQC/HMBC spectroscopy, allowing the 13C resonances
to be assigned completely (Figure 4).
This behaviour prompted us to study the stability of cat-
echin derivatives with extra hydroxyl groups on ring A.
Compounds 5c, 8c, 9c and 23 were prepared from tetra- or
Melting points were recorded on a Buchi 510 and are uncorrected.
NMR data (1H: 300 MHz; 13C: 75.5 MHz) were recorded on a
VARIAN Mercury plus 300 instrument or a Bruker Avance 600 (for
Synthesis 2006, No. 19, 3250–3260 © Thieme Stuttgart · New York

3254
F.-D. Boyer et al.
PAPER
OH
OH
OH
OH
OH
OH
HO
+ H2O
– H2O
– H2O
OH
[O]
HO
O
HO
O
O
23
24
OH
OH
O
O
OH
OH
O
OH
O
OH
Scheme 3 Proposed mechanism for the formation of 24.
HMBC and HSQC experiments of some compounds as mentioned
in the text). All NMR spectra were recorded in CDCl3, except where
indicated otherwise. Chemical shifts are reported relative to CHCl3
added dropwise and the solution was basified by the addition of
NaOH (2 N, pH 8). Et2O (50 mL) was added and the resulting mix-
ture was stirred vigorously for 2 h. The phases were separated, the
aqueous phase was extracted with Et2O (2 × 50 mL). The combined
organic layers were washed with H2O (2 × 50 mL), brine (50 mL),
dried over MgSO4 and concentrated. The residue was chromato-
graphed (EtOAc–cyclohexane, 2:8→3:7) to yield 560 mg (62%) of
7a.
1
(CDCl3) as internal reference: 7.27 ppm for H NMR (77.14 ppm
for 13C NMR). For the other solvents, residual solvent was also used
as the internal standard.27 1H and 13C NMR spectral assignments
were established by 1D NMR DEPT and 2D NMR COSY, NOESY,
HMBC and HSQC spectra. MS were obtained on a Micromass
(Manchester, United Kingdom) Quattro LC spectrometer (ESI). IR
were obtained on a Nicolet Avatar 320 FT-IR. Optical rotations
were measured on a Perkin-Elmer 241 polarimeter in a 1-dm cell.
HPLC was performed on a Varian 9012 equipped with a photodiode
array detector (Varian 9065). All reactions were monitored by TLC
carried out on E. Merck pre-coated silica gel 60F 254 plates (Ref.
5554). Chromatography was performed on silica gel. Visualization
was accomplished with UV light then 7–10% ethanolic phospho-
molybdic acid solution was used as the developing agent followed
by heating. CH2Cl2 and DMF were distilled from CaH2.
Clear yellow oil; Rf 0.17 (EtOAc–cyclohexane, 2:8); [a]D20 –35.3 (c
3.8, CHCl3).
1H NMR: d = 10.46 (s, 1 H, CHO), 7.50–7.10 (m, 25 H), 7.01 (d,
J = 1.8 Hz, 1 H, H-2¢), 6.94–6.90 (m, 2 H, H-5¢, H-6¢), 6.18 (s, 1 H,
H-6), 5.20–5.12 (m, 8 H), 5.02 (d, J = 7.3 Hz, 1 H, H-2), 4.27, 4.15
(AB, J = 12.0 Hz, 2 H), 3.74 (m, 1 H, H-3), 2.85 (dd, J = 16.5, 5.1
Hz, 1 H, H-4), 2.65 (dd, J = 16.5, 7.8 Hz, 1 H, H-4).
13C NMR: d = 187.42 (CHO), 161.83 (C), 160.12 (C), 157.83 (C),
148.82 (2 × C), 137.85 (C), 137.25 (C), 137.12 (C), 136.42 (C),
136.01 (C), 131.69 (C-1¢), 128.68–126.86 (Bn-CH), 119.88 (C-6¢),
114.99 (C-5¢), 113.65 (C-2¢), 108.88 (C), 102.56 (C), 90.96 (C-6),
79.58 (C-2), 73.56 (C-3), 71.36 (2 × CH2), 71.19, 70.82, 70.19
(CH2), 24.95 (C-4).
3,5,7,3¢,4¢-Penta-O-benzylcatechin (6a)
A solution of (+)-tetra-O-benzyl catechin (5a, 8.09g, 12.4 mmol) in
anhyd DMF (20 mL) was added dropwise to a solution of NaH
(60% dispersion in oil; 0.96 g, 24.9 mmol) in anhyd DMF (10 mL)
at 0 °C under argon, followed by BnBr (1.7 mL, 13.7 mmol). The
reaction mixture was stirred in the thawing ice bath for 6 h. After
cooling to 0 °C, H2O (10 mL) was added to the reaction mixture.
The phases were separated and the aqueous phase was extracted
with Et2O (3 × 100 mL). The combined organic layers were washed
with H2O (2 × 50 mL), brine (50 mL), dried over MgSO4 and con-
centrated. The residue was chromatographed (EtOAc–cyclohexane,
2:8→3:7) to yield 8.11 g (88%) of 6a.
MS (ESI): m/z (%) = 769 (M + H+, 100), 679 (10).
HRMS (MALDI): m/z calcd for C51H44O7Na+: 791.2984; found:
791.3002.
3,5,7,3¢,4¢-Penta-O-benzyl-8-carboxycatechin (8a)
To a solution of aldehyde 7a (200 mg, 0.26 mmol) and 2-methyl-
butene (0.45 mL) in t-BuOH (1.4 mL) was added a solution of
NaClO2 (40 mg) dropwise in NaH2PO4 buffer (pH 3.5, 0.4 mL). The
resulting slightly yellow solution was stirred for 4 h at r.t. The mix-
ture was diluted with brine (5 mL), acidified with HCl (6 N) and ex-
tracted with Et2O (4 × 20 mL). The combined organic layers were
dried over MgSO4 and concentrated under reduced pressure. The
residue was purified by chromatography (EtOAc–cyclohexane,
3:7→4:6) to yield 173 mg (84%) of 8a as a white solid.
Yellow oil; Rf 0.35 (EtOAc–cyclohexane, 2:8).
1H NMR: d = 7.53–7.10 (m, 25 H), 7.02 (d, J = 1.9 Hz, 1 H, H-2¢),
6.95 (d, J = 8.5 Hz, 1 H, H-5¢), 6.94 (dd, J = 8.5, 1.9 Hz, 1 H, H-6¢),
5.21–4.87 (m, 8 H), 4.76 (d, J = 7.9 Hz, 1 H, H-2), 4.28, 4.12 (AB,
J = 12.0 Hz, 2 H), 3.72 (m, 1 H, H-3), 3.11 (dd, J = 15.7, 5.5 Hz, 1
H, H-4), 2.68 (dd, J = 15.7, 8.7 Hz, 1 H, H-4).
13C NMR: d = 158.99 (C), 157.91 (C), 155.59 (C), 149.19 (2C),
149.13 (C), 138.26 (C), 137.54 (C), 137.44 (C), 137.26 (C), 137.19
(C), 132.72 (C-1¢), 128.72–127.38 (CH), 120.78 (C-6¢), 115.38 (C-
5¢), 114.26 (C-2¢), 102.62 (C-4a), 94.75, 94.02 (C-6, C-8), 80.31 (C-
2), 74.89 (C-3), 72.32 (CH2), 71.77 (CH2), 71.67 (CH2), 70.42
(CH2), 70.34 (CH2), 26.22 (C-4).
Rf 0.21 (EtOAc–cyclohexane, 3:7); mp 130–132 °C; [a]D20 –2.1 (c
1.26, CHCl3).
IR: 3500–2800 (br), 3063, 3033, 2926, 1724, 1695, 1603 cm–1.
1H NMR: d = 7.45–7.21 (m, 23 H), 7.11–7.08 (m, 2 H), 7.05 (d,
J = 1.8 Hz, 1 H, H-2¢), 6.92–6.88 (m, 2 H, H-5¢, H-6¢), 6.21 (s, 1 H,
H-6), 5.18–5.00 (m, 8 H), 4.96 (d, J = 8.0 Hz, 1 H, H-2), 4.32, 4.22
(AB, J = 12.0 Hz, 2 H), 3.73 (m, 1 H, H-3), 2.88 (dd, J = 16.5, 5.0
Hz, 1 H, H-4), 2.72 (dd, J = 16.5, 8.0 Hz, 1 H, H-4).
MS (ESI): m/z (%) = 741 (M + H+, 100), 651 (5).
13C NMR: d = 166.70 (COOH), 159.31 (C-5), 157.93 (C-7), 153.94
(C-8a), 149.05, 148.94 (C-3¢, C-4¢), 137.93 (Bn-C), 137.41 (Bn-C),
137.34 (Bn-C), 136.53 (Bn-C), 136.40 (Bn-C), 131.61 (C-1¢),
128.74–127.13 (Bn-CH), 119.95 (C-6¢), 115.19 (C-5¢), 113.61 (C-
2¢), 103.88 (C-8), 103.32 (C-4a), 92.31 (C-6), 79.96 (C-2), 73.78
(C-3), 71.63 (2 × CH2), 71.50 (CH2), 71.19 (CH2), 70.29 (CH2),
25.36 (C-4).
3,5,7,3¢,4¢-Penta-O-benzyl-8-formylcatechin (7a)
POCl3 (0.5 mL, 5.3 mmol) was added dropwise to anhyd DMF (1
mL) at 0 °C under argon and the resulting mixture was stirred for 20
min at r.t. A solution of 6a (900 mg, 1.2 mmol) in anhyd DMF (2
mL) was added dropwise at r.t. The mixture was warmed at 75 °C
for 4 h, overnight at r.t. and then cooled to 0 °C. H2O (10 mL) was
Synthesis 2006, No. 19, 3250–3260 © Thieme Stuttgart · New York

PAPER
Hydroxylation of Ring A of Flavan-3-ols
3255
MS (ESI): m/z (%) = 823 (M + K+, 100), 807 (M + Na+, 60), 785 (M
The residue was chromatographed (EtOAc–cyclohexane, 1:9) to
yield 145 mg (55%) of 12a.
+ H+, 40).
HRMS (MALDI): m/z calcd for C51H44O8Na+: 807.2933; found:
Colourless oil; Rf 0.44 (EtOAc–cyclohexane, 3:7).
807.2937.
IR: 2925, 2849, 1731, 1603, 1501, 1228 cm–1.
1H NMR: d = 7.44–7.22 (m, 23 H), 7.08–7.05 (m, 2 H), 6.99 (br s,
1 H, H-2¢), 6.91 (s, 2 H, H-5¢, H-6¢), 6.20 (s, 1 H, H-6), 5.25–5.02
(m, 10 H), 4.86 (d, J = 7.5 Hz, 1 H, H-2), 4.30, 4.16 (AB, J = 12.0
Hz, 2 H), 3.69 (m, 1 H, H-3), 2.96 (dd, J = 16.2, 5.1 Hz, 1 H, H-4),
2.71 (dd, J = 16.2, 8.0 Hz, 1 H, H-4), 1.97 (s, 3 H).
13C NMR: d = 171.33 (CO), 157.87 (C), 157.48 (C), 154.34 (C),
148.88 (C), 138.09 (C), 137.42 (C), 137.29 (C), 137.11 (C), 136.96
(C), 132.53 (C), 128.69–127.08 (Bn-CH), 120.23 (C-6¢), 115.02 (C-
2¢), 113.95 (C-5¢), 104.67 (C), 102.74 (C), 91.20 (C-6), 79.75 (C-2),
74.55 (C-3), 71.84 (CH2), 71.50 (CH2), 71.32 (CH2), 70.74 (CH2),
70.18 (CH2), 56.47 (CH2OAc), 25.76 (C-4), 21.22 (CH3CO).
(2R,3S)-3,5,7,3¢,4¢-Penta-O-benzyl-8-(2,2,2-trifluoroacetyl)fla-
van (9a)
Prepared from 6a by the same procedure as for 10a without stirring
for 2 h with SiO2 in Et2O.
Yield: 230 mg (38%); colourless oil; Rf 0.40 (EtOAc–cyclohexane,
1:9).
1H NMR: d = 7.52–7.28 (m, 23 H), 7.13–7.11 (m, 2 H), 7.03 (br s,
1 H, H-2¢), 6.99–6.91 (m, 2 H, H-5¢, H-6¢), 6.24 (s, 1 H, H-6), 5.23–
5.06 (m, 8 H), 4.92 (d, J = 7.5 Hz, 1 H, H-2), 4.32, 4.21 (AB,
J = 12.0 Hz, 2 H), 3.74 (m, 1 H, H-3), 2.98 (dd, J = 16.5, 5.1 Hz, 1
H, H-4), 2.72 (dd, J = 16.5, 8.1 Hz, 1 H, H-4).
13C NMR: d = 184.40 (q, JC-F = 38 Hz, CO), 160.46 (C), 157.66 (C),
154.27 (C), 148.98 (2 × C), 137.95 (C), 137.40 (C), 137.33 (C),
136.24 (C), 136.16 (C), 131.53 (C), 128.79–127.12 (Bn-CH),
120.15 (C-6¢), 116.34 (q, JC-F = 290 Hz, CF3), 115.00 (C-2¢), 113.61
(C-5¢), 105.60 (C), 103.11 (C), 91.05 (C-6), 80.05 (C-2), 74.08 (C-
3), 71.73 (CH2), 71.48 (CH2), 71.23 (CH2), 71.07 (CH2), 70.40
(CH2), 25.63 (C-4).
3-Acetoxy-5,7,3¢,4¢-tetra-O-benzyl-8-formylcatechin (15a)
Ac2O (6 mL) was added dropwise at r.t. to a solution of (+)-tetra-O-
benzyl catechin 5a (3.0 g, 4.6 mmol) in anhyd py (8 mL) and DMAP
(20 mg). The reaction mixture was stirred overnight and then dilut-
ed with Et2O (50 mL). The resultant mixture was washed with an aq
solution of HCl (1 M; 20 mL), an aq solution of sat. NaHCO3 (20
mL), brine (20 mL), dried over MgSO4 and concentrated. The resi-
due was chromatographed (EtOAc–cyclohexane, 2:8) to yield 2.9 g
(91%) of 3-acetoxy-5,7,3¢,4¢-tetra-O-benzylcatechin.
HRMS (MALDI): m/z calcd for C52H43O7F3Na+: 859.2858; found:
859.2818.
Colourless oil; Rf 0.57 (EtOAc–cyclohexane, 2:8).
(2R,3S)-5,7,3¢,4¢-Tetra-O-benzyl-8-(2,2,2-trifluoroacetyl)fla-
van-3-ol (10a)
1H NMR: d = 7.45–7.27 (m, 20 H), 6.98 (br s, 1 H, H-2¢), 6.90–6.88
(m, 2 H, H-5¢, H-6¢), 6.28 (d, J = 2.1 Hz, 1 H), 6.26 (d, J = 2.1 Hz,
1 H), 5.32 (m, 1 H, H-3), 5.16–4.98 (m, 9 H), 2.86 (dd, J = 15.7, 5.5
Hz, 1 H, H-4), 2.72 (dd, J = 15.7, 8.5 Hz, 1 H, H-4), 1.94 (s, 3 H,
CH3CO).
13C NMR: d = 158.99 (C), 157.91 (C), 155.59 (C), 149.19 (2 × C),
149.13 (C), 138.26 (C), 137.54 (C), 137.44 (C), 137.26 (C), 137.19
(C), 132.72 (C-1¢), 128.72–127.38 (CH), 120.78 (C-6¢), 115.38 (C-
5¢), 114.26 (C-2¢), 102.62 (C-4a), 94.75, 94.02 (C-6, C-8), 80.31 (C-
2), 74.89 (C-3), 72.32 (CH2), 71.77 (CH2), 71.67 (CH2), 70.42
(CH2), 70.34 (CH2), 26.22 (C-4).
A solution of 5a (680 mg, 1.04 mmol) and TFAA (8.4 mL, 60.44
mmol) in CH2Cl2 (8 mL) was stirred overnight at r.t. The reaction
mixture was concentrated under reduced pressure and the residue
diluted with Et2O (50 mL), washed with H2O (30 mL), a sat. solu-
tion of NaHCO3 (30 mL), brine (30 mL), dried over MgSO4 and
concentrated under reduced pressure. The residue was diluted with
Et2O (10 mL) and SiO2 (5 g). The resultant mixture was stirred for
2 h at r.t. and concentrated under reduced pressure. The residue was
chromatographed (EtOAc–cyclohexane, 3:7) to yield 501 mg
(64%) of 10a.
MS (ESI): m/z (%) = 741 (M + H+, 100), 651 (5).
Colourless oil; Rf 0.36 (EtOAc–cyclohexane, 3:7).
1H NMR: d = 7.51–7.30 (m, 20 H), 7.06 (br s, 1 H, H-2¢), 6.98–6.90
(m, 2 H, H-5¢, H-6¢), 6.28 (s, 1 H, H-6), 5.24–5.02 (m, 8 H), 4.71 (d,
J = 8.1 Hz, 1 H, H-2), 3.87 (m, 1 H, H-3), 3.11 (dd, J = 16.5, 5.4 Hz,
1 H, H-4), 2.65 (dd, J = 16.5, 8.7 Hz, 1 H, H-4).
3-Acetoxy-5,7,3¢,4¢-tetra-O-benzylcatechin was transformed into
15a by the same procedure described for the synthesis of 7a but the
reaction mixture was stirred for 2 h at r.t. without warming to 75 °C.
Yield: 1.81 g (62%); colourless oil; Rf 0.35 (EtOAc–cyclohexane,
13C NMR: d = 184.30 (q, JC-F = 38 Hz, CO), 160.63 (C), 157.77 (C),
154.18 (C), 149.49 (C), 149.23 (C), 137.32 (C), 137.21 (C), 136.20
(C), 136.15 (C), 130.40 (C), 128.77–127.16 (Bn-CH), 120.26 (C-
6¢), 116.44 (q, JC-F = 290 Hz, CF3), 115.08 (C-2¢), 113.81 (C-5¢),
105.64 (C), 103.19 (C), 91.26 (C-6), 81.86 (C-2), 71.45 (2 × CH2),
71.14 (CH2), 70.41 (CH2), 67.56 (C-3), 27.36 (C-4).
4:6).
1H NMR: d = 10.49 (s, 1 H, CHO), 7.40–7.30 (m, 20 H), 6.97 (br s,
1 H, H-2¢), 6.88–6.82 (m, 2 H, H-5¢, H-6¢), 6.20 (s, 1 H, H-6), 5.35
(m, 1 H, H-3), 5.29 (d, J = 7.3 Hz, 1 H, H-2), 5.15–4.98 (m, 8 H),
2.77–2.62 (m, 2 H, H-4), 1.98 (s, 3 H, CH3CO).
13C NMR: d = 187.36 (CHO), 170.25 (CO), 161.95 (C), 161.55 (C),
156.88 (C), 148.98 (C), 137.23 (C), 137.10 (C), 136.37 (C), 135.90
(C), 130.73 (C-1¢), 128.75–127.01 (Bn-CH), 119.12 (C-6¢), 115.05
(C-5¢), 113.15 (C-2¢), 108.90 (C), 101.52 (C), 90.83 (C-6), 77.81
(C-2), 71.35 (2 × CH2), 70.91 (CH2), 70.33 (CH2), 67.88 (C-3),
26.97 (C-4), 21.11 (CH3CO).
HRMS (MALDI): m/z calcd for C45H37O7F3Na+: 769.2388; found:
769.2414.
(2R,3S)-3,5,7,3¢,4¢-Penta-O-benzyl-8-acetoxymethylflavan (12a)
LiAlH4 (1 M, THF; 390 mL, 0.39 mmol) was added to a solution of
aldehyde 7a (250 mg, 0.32 mmol) in Et2O (10 mL) at 0 °C. The re-
sultant mixture was stirred for 2 h at 0 °C, then H2O (15 mL), an aq
solution of NaOH (15%; 15 mL) and H2O (45 mL) were added suc-
cessively. The mixture was stirred at r.t. for 30 min, filtered and
concentrated under reduced pressure. The residue (250 mg) was dis-
solved in py (0.4 mL) and Ac2O (0.4 mL) and the resultant mixture
was stirred for 18 h at r.t. The mixture was diluted with Et2O (20
mL) and washed with an aq solution of HCl (2 M; 15 mL), a sat. so-
lution of NaHCO3 (20 mL) and brine (20 mL). The organic extracts
were dried over MgSO4 and concentrated under reduced pressure.
Hydroxylation of the C-6 Position of Catechin Derivatives; Typ-
ical Procedure
To a solution of aldehyde 7a (300 mg, 0.39 mmol) in CH2Cl2 (6 mL)
at –40 °C was added a solution of DMDO27 (12 mL) dropwise under
argon. The resultant mixture was stirred at –40 °C for 7.5 h and then
concentrated under reduced pressure without warming. The residue
was purified by chromatography (EtOAc–cyclohexane, 2:8) to give
7b.
Synthesis 2006, No. 19, 3250–3260 © Thieme Stuttgart · New York

3256
F.-D. Boyer et al.
PAPER
(2R,3S)-3,5,7,3¢,4¢-Penta-O-benzyl-8-formyl-6-hydroxyflavan
(7b)
(m, 8 H), 4.88 (d, J = 7.5 Hz, 1 H, H-2), 4.25, 4.14 (AB, J = 12.0
Hz, 2 H), 3.68 (m, 1 H, H-3), 2.88 (dd, J = 16.8, 5.4 Hz, 1 H, H-4),
2.67 (dd, J = 16.8, 8.1 Hz, 1 H, H-4).
13C NMR: d = 164.00 (CO), 149.49 (C), 149.23 (C), 147.12 (C),
146.56 (C), 146.13 (C), 137.67 (C), 137.41 (C), 137.27 (C), 137.18
(C), 137.08 (C), 136.79 (C), 130.78 (C), 129.00–127.44 (Bn-CH),
120.21 (C-6¢), 115.27 (C-2¢), 113.73 (C-5¢), 111.41 (C), 107.92 (C),
81.07 (C-2), 74.52 (CH2), 73.59 (C-3), 71.75 (CH2), 71.53 (2 ×
CH2), 71.45 (CH2), 26.42 (C-4).
Yield: 113 mg (38%); colourless oil; Rf 0.20 (EtOAc–cyclohexane,
2:8); [a]D20 –28.0 (c 5.1, CHCl3).
IR: 3504, 3061, 3042, 2928, 2870, 1679, 1588, 1445 cm–1.
1H NMR: d = 10.37 (s, 1 H, CHO), 7.50–7.27 (m, 23 H), 7.09–7.05
(m, 2 H), 6.94 (d, J = 8.5 Hz, 1 H, H-5¢), 6.93 (d, J = 1.5 Hz, 1 H,
H-2¢), 6.87 (dd, J = 8.5, 1.5 Hz, 1 H, H-6¢), 5.45 (s, 1 H, OH), 5.21–
5.11 (m, 8 H), 4.85 (d, J = 7.5 Hz, 1 H, H-2), 4.27, 4.15 (AB,
J = 12.0 Hz, 2 H), 3.63 (m, 1 H, H-3), 2.84 (dd, J = 17.0, 5.5 Hz, 1
H, H-4), 2.65 (dd, J = 17.0, 7.5 Hz, 1 H, H-4).
MS (ESI): m/z (%) = 801 (M + H+, 100), 783 (M + H+ – H2O, 60),
783, 693, 675.
13C NMR: d = 188.18 (CHO), 151.37 (C), 149.45 (C), 149.23 (C),
149.07 (C), 145.54 (C), 137.92 (C), 137.40 (C), 137.27 (2 × C),
137.04 (C), 136.31 (C), 131.81 (C), 129.02–127.51 (Bn-CH),
120.27 (C-6¢), 115.20 (C-5¢), 113.99 (C-2¢), 113.37 (C), 111.21 (C),
80.16 (C-2), 77.89 (CH2), 74.46 (CH2), 73.87 (C-3), 71.69 (CH2),
71.61 (CH2), 71.51 (CH2), 26.22 (C-4).
(2R,3S)-6-Hydroxy-3,5,7,3¢,4¢-penta-O-benzyl-8-(2,2,2-trifluo-
roacetyl)flavan (9b)
Prepared from 9a by the typical procedure, but with a reaction tem-
perature of –30 °C.
Yield: 49 mg (49%); colourless oil; Rf 0.17 (EtOAc–cyclohexane,
2:8).
MS (ESI): m/z (%) = 785 (M + H+, 100), 420 (40).
1H NMR: d = 7.42–7.23 (m, 23 H), 7.04–7.01 (m, 2 H), 6.93–6.91
(m, 2 H, H-2¢, H-5¢), 6.84 (dd, J = 8.4, 1.5 Hz, 1 H, H-6¢), 5.19–5.00
(m, 8 H), 4.76 (d, J = 7.8 Hz, 1 H, H-2), 4.17, 4.08 (AB, J = 12.0
Hz, 2 H), 3.60 (m, 1 H, H-3), 2.93 (dd, J = 16.5, 5.4 Hz, 1 H, H-4),
2.68 (dd, J = 16.5, 8.4 Hz, 1 H, H-4).
13C NMR: d = 184.60 (q, JC-F = 38 Hz, CO), 149.17 (C), 149.07 (C),
147.98 (C), 146.49 (C), 144.14 (C), 137.40 (C), 137.33 (C), 136.24
(C), 136.16 (C), 131.53 (C), 128.79–127.12 (Bn-CH), 120.15 (C-
6¢), 116.34 (q, JC-F = 290 Hz, CF3), 115.00 (C-2¢), 113.61 (C-5¢),
105.60 (C), 103.11 (C), 91.05 (C-6), 80.05 (C-2), 74.08 (C-3), 71.73
(CH2), 71.48 (CH2), 71.23 (CH2), 71.07 (CH2), 70.40 (CH2), 25.63
(C-4).
HRMS (MALDI): m/z calcd for C51H44O8Na+: 807.2933; found:
807.2952.
(2R,3S)-5,7,3¢,4¢-Tetra-O-benzyl-6-hydroxyflavan-3-ol (5b)
Prepared from 5a by the typical procedure, but with a reaction tem-
perature of –15 °C.
Yield: 23 mg (15%); Rf 0.20 (EtOAc–cyclohexane, 2:8).
IR: 3523, 2922, 1495, 1260, 1124 cm–1.
1H NMR: d = 7.44–7.27 (m, 20 H), 6.97 (br s, 1 H, H-2¢), 6.94–6.88
(m, 2 H, H-5¢, H-6¢), 6.35 (s, 1 H, H-8), 5.26 (s, 1 H, OH), 5.20–5.04
(m, 8 H), 4.53 (d, J = 8.1 Hz, 1 H, H-2), 3.90 (m, 1 H, H-3), 3.01
(dd, J = 16.5, 5.7 Hz, 1 H, H-4), 2.57 (dd, J = 16.5, 9.0 Hz, 1 H, H-
4).
HRMS (MALDI): m/z calcd for C52H43O8F3Na+: 875.2807; found:
807.2797.
13C NMR: d = 149.58 (C), 149.37 (C), 146.96 (C), 145.98 (C),
143.82 (C), 137.76 (C), 137.34 (C), 137.20 (C), 136.49 (C), 133.42
(C), 131.27 (C), 128.84–127.40 (Bn-CH), 120.70 (C-6¢), 115.37 (C-
5¢), 114.21 (C-2¢), 107.40 (C), 97.10 (C-8), 80.56 (C-2), 74.46 (Bn-
CH), 71.53 (3 × CH2), 68.30 (C-3), 28.24 (C-4).
(2R,3S)-6-Hydroxy-5,7,3¢,4¢-tetra-O-benzyl-8-(2,2,2-trifluoro-
acetyl)flavan-3-ol (10b)
Prepared from 10a by the typical procedure, but with a reaction tem-
perature of –30 °C.
MS (ESI): m/z (%) = 689 (M + Na+, 20), 667 (M + H+, 100), 649,
631, 181.
HRMS (MALDI): m/z calcd for C43H38O7Na+: 689.2515; found:
Yield: 46 mg (37%); colourless oil; Rf 0.42 (EtOAc–cyclohexane,
3:7).
IR: 3504, 2916, 1718, 1607, 1513, 1453 cm–1.
1H NMR: d = 7.45–7.33 (m, 20 H), 6.96 (d, J = 1.8 Hz, 1 H, H-2¢),
6.94 (d, J = 8.5 Hz, 1 H, H-5¢), 6.87 (dd, J = 8.5, 1.8 Hz, 1 H, H-6¢),
5.20–5.02 (m, 8 H), 4.58 (d, J = 8.4 Hz, 1 H, H-2), 3.87 (m, H-3),
3.11 (dd, J = 16.8, 5.7 Hz, 1 H, H-4), 2.65 (dd, J = 16.8, 9.3 Hz, 1
H, H-4).
689.2509.
(2R,3S)-3,5,7,3¢,4¢-Penta-O-benzyl-6-hydroxyflavan (6b)
Prepared from 6a by the typical procedure, but with a reaction tem-
perature of –15 °C.
13C NMR: d = 184.40 (q, JC-F = 38 Hz, CO), 149.69 (C), 149.28 (C),
148.06 (C), 146.35 (C), 144.22 (C), 137.27 (C), 137.14 (C), 136.70
(C), 136.64 (C), 136.31 (C), 129.96 (C), 128.84–127.41 (Bn-CH),
120.47 (C-6¢), 117.44 (q, JC-F = 290 Hz, CF3), 115.05 (C-2¢), 113.86
(C-5¢), 112.39 (C), 102.74 (C), 111.23 (C), 81.93 (C-2), 77.56
(CH2), 75.08 (CH2), 71.53 (CH2), 71.46 (CH2), 67.66 (C-3), 28.50
(C-4).
Yield: 13 mg (13%); Rf 0.40 (EtOAc–cyclohexane, 2:8).
1H NMR: d = 7.44–7.18 (m, 20 H), 7.00–6.98 (m, 5 H), 6.35 (s, H-
8), 5.18–4.90 (m, 8 H), 4.68 (d, J = 8.1 Hz, 1 H, H-2), 4.15, 4.00
(AB, J = 12.0 Hz, 2 H), 3.62–3.55 (m, 1 H, H-3), 2.97 (dd, J = 16.2,
5.4 Hz, 1 H, H-4), 2.58 (dd, J = 16.2, 9.0 Hz, 1 H, H-4).
HRMS (MALDI): m/z calcd for C50H44O7Na+: 779.2984; found:
779.2993.
+
MS (ESI): m/z (%) = 785 (M + Na+, 90), 780 (M + NH4 , 80), 763
(M + H+, 75), 745 (M + H+ – H2O, 100).
(2R,3S)-8-Carboxyl-6-hydroxy-3,5,7,3¢,4¢-penta-O-benzyl-
flavan (8b)
Prepared from 8a by the typical procedure, but with a reaction tem-
HRMS (MALDI): m/z calcd for C45H37O8F3Na+: 785.2338; found:
785.2314.
perature of –15 °C.
(2R,3S)-3,5,6,7,3¢,4¢-Hexa-O-benzyl-8-acetoxymethylflavan
Yield: 18 mg (45%); colourless oil; Rf 0.50 (EtOAc–cyclohexane,
6:4).
IR: 3500–2900 (br), 3030, 1699, 1604, 1513, 1453 cm–1.
1H NMR: d = 7.49–7.25 (m, 23 H), 7.06–7.00 (m, 2 H), 6.94–6.90
(m, 2 H, H-2¢, H-5¢), 6.85 (dd, J = 8.5, 1.8 Hz, 1 H, H-6¢), 5.20–5.02
(12b)
Prepared from 12a by the typical procedure, but with a reaction tem-
perature of –40 °C.
Synthesis 2006, No. 19, 3250–3260 © Thieme Stuttgart · New York

PAPER
Hydroxylation of Ring A of Flavan-3-ols
3257
Yield: 35 mg (34%); colourless oil; Rf 0.53 (EtOAc–cyclohexane,
3:7).
1H NMR: d = 7.02–6.97 (m, 2 H, H-2¢, H-6¢), 6.90 (d, J = 8.0 Hz, 1
H, H-5¢), 6.32 (s, 1 H, H-8), 4.42 (d, J = 8.1 Hz, 1 H, H-2), 4.06 (m,
1 H, H-3), 3.90 (s, 3 H, CH3O), 3.89 (s, 3 H, CH3O), 3.88 (s, 3 H,
CH3O), 3.82 (s, 3 H, CH3O), 3.17 (dd, J = 16.5, 5.7 Hz, 1 H, H-4),
2.72 (dd, J = 16.5, 9.0 Hz, 1 H, H-4).
13C NMR: d = 149.67 (C), 149.64 (C), 147.23 (C), 146.91 (C),
133.00 (C), 130.49 (C), 120.15 (C-6¢), 111.57 (C-5¢), 110.30 (C-2¢),
106.59 (C-4a), 95.73 (C-8), 81.93 (C-2), 68.43 (C-3), 60.37
(CH3O), 56.29 (CH3O), 56.14 (2 × CH3O), 56.10 (CH3O), 28.26 (C-
4).
IR: 3521, 3062, 3031, 2920, 2853, 1735, 1606, 1512, 1453, 1223
cm–1.
1H NMR: d = 7.43–7.21 (m, 23 H), 7.11–7.03 (m, 2 H), 6.94 (d,
J = 1.5 Hz, 1 H, H-2¢), 6.92 (d, J = 8.1, Hz, 1 H, H-5¢), 6.92 (dd,
J = 8.1, 1.5 Hz, 1 H, H-6¢), 5.20–4.89 (m, 10 H), 4.79 (d, J = 7.8 Hz,
1 H, H-2), 4.23, 4.12 (AB, J = 12 Hz, 2 H), 3.62 (m, 1 H, H-3), 2.90
(dd, J = 16.5, 5.1 Hz, 1 H, H-4), 2.70 (dd, J = 16.5, 8.1 Hz, 1 H, H-
4), 1.94 (s, 3 H).
13C NMR: d = 171.00 (CO), 149.03 (2 × C), 146.52 (C), 145.42 (C),
145.12 (C), 138.03 (C), 137.46 (C), 137.35 (C), 137.27 (C), 137.03
(C), 136.26 (C), 132.60 (C), 128.82–127.46 (Bn-CH), 120.23 (C-
6¢), 115.18 (C-2¢), 114.11 (C-5¢), 112.18 (C), 110.71 (C), 79.68 (C-
2), 76.72 (CH2), 74.99 (CH2), 74.51 (C-3), 71.73 (CH2), 71.61
(CH2), 70.48 (CH2), 56.91 (CH2OAc), 26.60 (C-4), 21.14 (CH3CO).
MS (ESI): m/z (%) = 363 (M + H+, 100), 193 (10), 183 (50), 151
(15).
p-Benzoquinone (16)
Traces of 16 were obtained by treating 6b with DMDO followed by
purification by preparative TLC.
Yellow oil; Rf 0.25 (EtOAc–cyclohexane, 3:7).
+
MS (ESI): m/z (%) = 846 (M + NH4 , 100), 829 (M + H+, 80).
IR: 3064, 3031, 2924, 2869, 1690, 1648, 1628, 1513, 1453, 1124
cm–1.
1H NMR: d = 7.45–7.27 (m, 18 H), 7.13–7.11 (m, 2 H), 6.90 (d,
J = 8.0 Hz, 1 H, H-5¢), 6.77–6.73 (m, 2 H, H-2¢, H-6¢), 5.86 (s, 1 H,
H-6), 5.18–5.06 (m, 7 H), 4.38, 4.29 (AB, J = 12.0 Hz, 2 H), 3.72
(m, 1 H, H-3), 2.60–2.40 (m, 2 H, H-4).
(2R,3S)-8-Bromo-3,6-dihydroxy-5,7,3¢,4¢-tetra-O-benzylflavan
(13b)
Prepared from 13a by the typical procedure, but with a reaction tem-
perature of –40 °C.
Yield: 37 mg (36%); colourless oil; Rf 0.21 (EtOAc–cyclohexane,
13C NMR: d = 186.23 (C), 175.77 (C), 156.02 (C), 151.34 (C),
149.40 (C), 149.11 (C), 137.50 (C), 137.23 (C), 137.18 (C), 134.38
(C), 130.52 (C), 128.99–127.43 (Bn-CH), 119.81 (C-6¢), 116.66
(C), 115.29 (C-5¢), 113.74 (C-2¢), 108.49 (C-6), 80.51 (C-2), 72.60
(C-3), 71.55 (3 × CH2), 71.23 (CH2), 23.20 (C-4).
3:7).
IR: 3515, 3087, 3064, 3031, 2921, 1605, 1512, 1453 cm–1.
1H NMR: d = 7.52–7.28 (m, 25 H), 7.00 (br s, 1 H, H-2¢), 6.94–6.87
(m, 2 H, H-5¢, H-6¢), 5.23–4.94 (m, 8 H), 4.72 (d, J = 6.9 Hz, 1 H,
H-2), 4.67 (s, 1 H, OH), 4.00–3.87 (m, 1 H, H-3), 2.91 (dd, J = 16.5,
4.5 Hz, 1 H, H-4), 2.61 (dd, J = 16.5, 7.8 Hz, 1 H, H-4).
MS (CI, NH3): m/z (%) = 682 (M+· +NH4 , 100), 665 (MH+·, 50).
+
13C NMR: d = 149.39 (C), 149.20 (C), 144.11 (C), 143.45 (2 × C),
137.34 (2 × C), 137.16 (2 × C), 136.74 (C), 130.92 (C), 128.86–
127.09 (Bn-CH), 120.03 (C-6¢), 115.19 (C-2¢), 113.76 (C-5¢),
111.81 (C), 100.31 (C), 81.52 (C-2), 75.80 (CH2), 74.67 (CH2),
71.48 (2 × CH2), 67.81 (C-3), 28.08 (C-4).
o-Benzoquinone (17)
Traces of 17 were obtained by treating 6b with DMDO followed by
purification by preparative TLC.
Deep red oil; Rf 0.11 (EtOAc–cyclohexane, 3:7).
IR: 3064, 3030, 2926, 2870, 1648, 1633, 1580, 1453, 1160 cm–1.
MS (ESI): m/z (%) = 764 (100), 762 (90), 747 (50), 745 (M + H+,
1H NMR: d = 7.45–7.25 (m, 18 H), 7.10–7.06 (m, 2 H), 6.79 (d,
J = 2.0 Hz, 1 H, H-5¢), 6.77–6.75 (m, 2 H, H-2¢, H-6¢), 5.80 (s, 1 H,
H-6), 5.21–4.99 (m, 7 H), 4.40, 4.25 (AB, J = 12.0 Hz, 2 H), 3.71–
3.64 (m, 1 H, H-3), 2.62–2.48 (m, 2 H, H-4).
13C NMR: d = 175.69 (C), 165.28 (C), 151.94 (C), 149.62 (C),
149.17 (C), 141.05 (C), 137.46 (C), 137.12 (C), 134.55 (C), 130.13
(C), 128.99–127.11 (Bn-CH), 120.14 (C-6¢), 115.12 (C-5¢), 113.83
(C-2¢), 107.95 (C-8), 105.77 (C-4a), 82.43 (C-2), 72.70 (C-3), 71.64
(CH2), 71.53 (CH2), 71.40 (CH2), 71.02 (CH2), 22.51 (C-4).
45), (729 (20), 727 (25).
(2R,3S)-3-Acetoxy-5,7,3¢,4¢-tetra-O-benzyl-8-formyl-6-
hydroxyflavan (15b)
Prepared from 15a by the typical procedure, but with a reaction tem-
perature of –40 °C.
Yield: 220 mg (35%); colourless oil; Rf 0.26 (EtOAc–cyclohexane,
3:7).
1H NMR: d = 10.43 (s, 1 H, CHO), 7.42–7.31 (m, 20 H), 6.91–6.89
(m, 2 H, H-2¢, H-5¢), 6.80 (dd, J = 8.5, 1.5 Hz, 1 H, H-6¢), 5.58 (s, 1
H, OH), 5.28–5.05 (m, 10 H), 2.70–2.64 (m, 2 H, H-4).
13C NMR: d = 187.94 (CHO), 170.08 (CO), 150.46 (C), 149.31 (C),
149.19 (C), 149.02 (C), 145.93 (C), 137.23 (C), 137.07 (C), 136.95
(C), 136.85 (C), 136.27 (C), 130.59 (C), 128.92–127.38 (Bn-CH),
119.39 (C-6¢), 115.09 (C-5¢), 113.31 (C-2¢), 109.95 (C), 78.09 (C-
2), 77.56 (CH2), 74.31 (CH2), 71.50 (CH2), 71.42 (CH2), 68.16 (C-
3), 23.79 (C-4), 21.09 (CH3CO).
(2R,3S)-6-Acetoxy-3,5,7,3¢,4¢-penta-O-benzyl-6-hydroxy-
flavan (18)
Acetylation of 6b with py and Ac2O at r.t. for 18 h gave 18.
Yield: 17 mg (70%); colourless oil; Rf 0.44 (EtOAc–cyclohexane,
2:8).
1H NMR: d = 7.53–7.10 (m, 28 H), 7.02–6.93 (m, 5 H), 6.39 (s, 1
H, H-6), 5.21 (s, 2 H), 5.17, 5.06 (AB, J = 8.6 Hz, 2 H), 5.03 (s, 2
H), 5.02, 4.97 (AB, J = 11.0 Hz, 2 H), 4.72 (d, J = 8.0 Hz, 1 H, H-
2), 4.18, 4.02 (AB, J = 12.0 Hz, 2 H), 3.62 (m, 1 H, H-3), 3.01 (dd,
J = 16.0, 6.0 Hz, 1 H, H-4), 2.64 (dd, J = 16.0, 8.0 Hz, 1 H, H-4),
2.18 (s, 3 H, CH3CO).
13C NMR: d = 169.22 (CH3CO), 152.43 (C-8a), 150.52 (C-7),
150.00 (C-5), 149.17 (C-3¢, C-4¢), 138.00, 137.56, 137.46, 137.37,
136.76 (Bn-C), 132.33 (C-1¢), 128.62–127.29 (Bn, C-6), 120.78 (C-
6¢), 115.29 (C-5¢), 114.11 (C-2¢), 107.36 (C-4a), 97.99 (C-8), 80.47
(C-2), 75.36 (CH2), 74.47 (C-3), 71.79 (CH2), 71.61 (CH2), 71.35
(CH2), 70.93 (CH2), 26.75 (C-4), 20.51 (CH3CO).
(2R,3S)-6-Hydroxy-5,7,3¢,4¢-tetra-O-methylflavan-3-ol (14b)
MCPBA (70%, H2O; 224 mg, 0.867 mmol) was added to a solution
of (+)-tetra-O-methyl catechin21 (14a, 100 mg, 0.289 mmol) at
–10 °C. The resultant mixture was warmed to 0 °C, stirred for 3 h
and KF (106 mg, 1.82 mmol) was added. After stirring for 30 min
at r.t., the mixture was filtered and the solution was concentrated un-
der reduced pressure. The residue was purified by preparative TLC
(EtOAc–cyclohexane, 6:4) to give 21 mg (20%) of 14b.
Colourless oil; Rf 0.10 (EtOAc–cyclohexane, 6:4).
Synthesis 2006, No. 19, 3250–3260 © Thieme Stuttgart · New York

3258
F.-D. Boyer et al.
PAPER
(2R,3S)-3,5,6,7,3¢,4¢-Hexa-O-benzylflavan (19)
H-5¢), 6.89 (dd, J = 8.5, 1.5 Hz, 1 H, H-6¢), 5.30–5.04 (m, 10 H),
4.95 (d, J = 7.0 Hz, 1 H, H-2), 4.31, 4.22 (AB, J = 12.0 Hz, 2 H),
3.69 (m, 1 H, H-3), 2.83 (dd, J = 16.5, 5.5 Hz, 1 H, H-4), 2.69 (dd,
J = 16.5, 7.0 Hz, 1 H, H-4).
13C NMR: d = 188.37 (CHO), 155.96 (C), 153.57 (C), 153.21 (C),
148.97 (C), 148.90 (C), 139.32 (C), 137.88 (C), 137.37 (C), 137.24
(C), 137.14 (C), 137.05 (C), 136.88 (C), 131.70 (C), 129.03–127.40
(Bn-CH), 120.02 (C-6¢), 115.28 (C), 115.16 (C-5¢), 113.85 (C-2¢),
111.28 (C), 79.83 (C-2), 77.31 (CH2), 76.25 (CH2), 75.23 (CH2),
73.57 (C-3), 71.60 (CH2), 71.54 (CH2), 71.41 (CH2), 25.94 (C-4).
NaH (60% dispersion in oil; 20 mg, 0.3 mmol) and BnBr (20 mL,
0.18 mmol) were added successively to a solution of 13b (60 mg,
0.08 mmol) in anhyd DMF (0.5 mL) at 0 °C under argon. The reac-
tion mixture was stirred at 0 °C for 2 h, then diluted with Et2O (10
mL) and H2O (1 mL). The phases were separated, the aqueous phase
was extracted with Et2O (2 × 10 mL). The combined organic layers
were washed with H2O (2 × 10 mL), brine (10 mL), dried over
MgSO4 and concentrated. The residue was chromatographed
(EtOAc–cyclohexane, 2:8→3:7) to yield 62 mg (83%) of (2R,3S)-
8-bromo-3,5,6,7,3¢,4¢-hexa-O-benzylflavan.
MS (ESI): m/z (%) = 913 (M + K+, 10), 897 (M + Na+, 50), 875 (M
Colourless oil; Rf 0.46 (EtOAc–cyclohexane, 3:7).
IR: 3088, 3063, 3031, 2925, 2869, 1592, 1513, 1453 cm–1.
+ H+, 100).
(2R,3S)-3,5,,6,7,3¢,4¢-Hexa-O-benzyl-8-hydroxyflavan (21)
To a solution of aldehyde 20 (409 mg, 0.467 mmol) in MeOH–
CH2Cl2 (7:11, 10 mL) at –10 °C was added H2O2 (30%, H2O; 43
drops) and concd H2SO4 (34 drops). The reaction was monitored by
HPLC and was complete after stirring for 55 h at –10 °C. The reac-
tion mixture was diluted with CH2Cl2 (50 mL). The organic layer
was separated, washed with brine (50 mL), dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
chromatography (EtOAc–cyclohexane, 1:9→2:8) to give 300 mg
(74%) of phenol 21.
1H NMR: d = 7.55–7.21 (m, 28 H), 7.10–7.07 (m, 2 H), 7.00 (br s,
1 H, H-2¢), 6.97–6.85 (m, 2 H, H-5¢, H-6¢), 5.18–5.02 (m, 10 H),
4.95 (d, J = 6.9 Hz, 1 H, H-2), 4.28, 4.19 (AB, J = 12.0 Hz, 2 H),
3.64 (m, 1 H, H-3), 2.82 (dd, J = 17.1, 5.1 Hz, 1 H, H-4), 2.69 (dd,
J = 17.1, 7.8 Hz, 1 H, H-4).
13C NMR: d = 149.88 (C), 149.59 (C), 149.01 (C), 148.94 (C),
147.57 (C), 140.38 (C), 137.99 (C), 137.43 (C), 137.38 (C), 137.32
(C), 137.29 (C), 137.11 (C), 132.06 (C), 128.81–127.41 (Bn-CH),
120.00 (C-6¢), 115.17 (C-2¢), 113.78 (C-5¢), 111.76 (C), 101.40 (C),
79.91 (C-2), 76.33 (CH2), 75.58 (CH2), 75.23 (CH2), 74.09 (C-3),
71.60 (CH2), 71.50 (CH2), 71.34 (CH2), 26.15 (C-4).
20
Colourless oil; Rf 0.42 (EtOAc–cyclohexane, 2:8); [a]D +35.4 (c
1.9, CHCl3); HPLC (Kromasil C18, 250 × 4.6 mm, 5 mm, flow rate
1 mL/min, UV detection at 280 nm) using the following gradient of
solvent B (0.5% H3PO4 in H2O) in solvent A (0.5% H3PO4 in
MeCN): 0–20 min, 15–0% B; 20–30 min, 0% B; tR 22.75 min.
t-BuLi (1.5 M, pentane; 100 mL, 0.15 mmol) was added to a solution
of (2R,3S)-8-bromo-3,5,6,7,3¢,4¢-hexa-O-benzylflavan (60 mg,
0.064 mmol) in anhyd THF (0.5 mL) at –78 °C under argon. The re-
action mixture was stirred at –78 °C for 15 min, warmed to r.t., di-
luted with Et2O (10 mL) and H2O (1 mL) was added to the reaction
mixture. The phases were separated, the aqueous phase was extract-
ed with Et2O (2 × 10 mL). The combined organic layers were
washed brine (10 mL), dried over MgSO4 and concentrated. The
residue was chromatographed (EtOAc–cyclohexane, 1:9→ 2:8) to
yield 48 mg (87%) of 19.
IR: 3511, 3064, 3029, 2867, 1513, 1453 cm–1.
1H NMR: d = 7.47–7.21 (m, 28 H), 7.02–7.00 (m, 2 H), 6.94 (br s,
1 H, H-2¢), 6.92 (d, J = 8.5 Hz, 1 H, H-5¢), 6.87 (d, J = 8.5 Hz, 1 H,
H-6¢), 5.24–5.99 (m, 10 H), 4.76 (d, J = 8.0 Hz, 1 H, H-2), 4.22,
4.09 (AB, J = 12.0 Hz, 2 H), 3.63 (m, 1 H, H-3), 2.93 (dd, J = 16.5,
5.0 Hz, 1 H, H-4), 2.63 (dd, J = 16.5, 8.0 Hz, 1 H, H-4).
Colourless oil; Rf 0.50 (EtOAc–cyclohexane, 2:8).
13C NMR: d = 149.16 (C), 149.07 (C), 142.40 (C), 139.96 (C),
138.84 (C), 137.97 (C), 137.87 (C), 137.80 (C), 137.76 (C), 137.72
(C), 137.51 (C), 137.31 (C), 134.76 (C), 132.14 (C), 128.61–127.46
(Bn-CH), 120.64 (C-6¢), 115.21 (C-2¢), 114.15 (C-5¢), 110.55 (CH),
80.33 (C-2), 76.22 (CH2), 75.73 (CH2), 75.47 (CH2), 74.67 (C-3),
71.74 (CH2), 71.61 (CH2), 71.43 (CH2), 26.58 (C-4).
1H NMR: d = 7.47–7.28 (m, 30 H), 7.02–6.88 (m, 3 H, H-2¢, H-5¢,
H-6¢), 6.39 (s, H-8), 5.19–5.00 (m, 10 H), 4.71 (d, J = 7.8 Hz, 1 H,
H-2), 4.22, 4.08 (AB, J = 12.0 Hz, 2 H), 3.62 (m, 1 H, H-3), 2.95
(dd, J = 16.2, 5.4 Hz, 1 H, H-4), 2.62 (dd, J = 16.2, 8.7 Hz, 1 H, H-
4).
13C NMR: d = 152.06 (C), 150.87 (C), 150.44 (C), 149.03 (C),
138.07 (C), 137.87 (C), 137.42 (C), 136.99 (C), 136.10 (C), 132.50
(C), 128.73–127.41 (Bn-CH), 120.65 (C-6¢), 115.21 (C-2¢), 114.04
(C-5¢), 107.28 (C), 98.01 (C-8), 80.25 (C-2), 75.90 (CH2), 75.24
(CH2), 74.55 (C-3), 71.61 (CH2), 71.58 (CH2), 71.32 (CH2), 70.96
(CH2), 27.03 (C-4).
MS (ESI): m/z (%) = 880 (100), 863 (M + H+, 50), 420 (40).
(2R,3S)-2,5,6,7,8,3¢,4¢-Heptahydroxyflavan (3)
A solution of compound 21 (120 mg, 0.138 mmol) in THF (9 mL)
and MeOH (9 mL) was hydrogenated at atmospheric pressure (bal-
loon) over Pd/C (10%, 20 mg) for 3 h. The catalyst was filtered
through cotton under an argon atmosphere and washed with MeOH
(10 mL). The solution was concentrated under reduced pressure to
give 39 mg of 3 (88%) as a yellow oil. Spectroscopic data in CD3OD
were in agreement with those reported for the natural product but
led to the fast disappearance of the title compound.
(2R,3S)-3,5,6,7,3¢,4¢-Hexa-O-benzyl-8-formylflavan (20)
To a solution of phenol 7b (113 mg, 0.144 mmol) in DMF (2.2 mL)
at –10 °C, were added NaH (60% in mineral oil; 15 mg, 0.348
mmol) and BnBr (30 mL, 0.252 mmol) dropwise under argon The
resultant mixture was warmed to r.t. and stirred for 1 h. The reaction
mixture was hydrolysed with H2O (3 mL) and the aqueous phase
was extracted with Et2O (2 × 10 mL). The combined organic layers
were washed with H2O (2 × 10 mL), dried over MgSO4 and concen-
trated under reduced pressure. The residue was purified by chroma-
tography on silica gel (EtOAc–cyclohexane, 1:9→2:8) to give 97
mg (77%) of benzyl ether 20.
1H NMR (Acetone-d6): d = 6.86 (d, J = 1.8 Hz, 1 H, H-2¢), 6.78 (d,
J = 8.1 Hz, 1 H, H-5¢), 6.72 (dd, J = 8.1, 1.8 Hz, 1 H, H-6¢), 4.48 (d,
J = 7.5 Hz, 1 H, H-2), 4.01–3.97 (m, 1 H, H-3), 2.98 (dd, J = 16.5,
5.4 Hz, 1 H, H-4), 2.58 (dd, J = 16.5, 8.4 Hz, 1 H, H-4).
13C NMR (Acetone-d6): d = 145.78 (C), 145.66 (C), 136.67 (C),
133.90 (C), 132.11 (C), 128.05 (C), 127.19 (C), 120.28 (CH),
115.73 (CH), 115.41 (C), 100.87 (C), 82.75 (C-2), 68.65 (C-3),
29.21 (C-4).
20
Colourless oil; Rf 0.42 (EtOAc–cyclohexane, 2:8); [a]D –18.6 (c
2.2, CHCl3); tR 23.28 min.
p-Benzoquinone (22)
IR: 3089, 3065, 3032, 2916, 2874, 2849, 1684, 1583, 1454 cm–1.
Product 3 (39 mg) was dissolved in acetone-d6 (0.6 mL). After a re-
action time of 10 d at r.t. (monitored by NMR spectroscopy) com-
pound 22 was isolated as a dark red compound (39 mg).
1H NMR: d = 10.38 (s, 1 H, CHO), 7.50–7.29 (m, 28 H), 7.13–7.10
(m, 2 H), 6.97 (d, J = 1.5 Hz, 1 H, H-2¢), 6.96 (d, J = 8.5 Hz, 1 H,
Synthesis 2006, No. 19, 3250–3260 © Thieme Stuttgart · New York

PAPER
Hydroxylation of Ring A of Flavan-3-ols
3259
1H NMR (Acetone-d6): d = 6.84 (s, 1 H, H-2¢), 6.81 (d, J = 8.0 Hz,
1 H, H-5¢), 6.71 (dd, J = 8.0, 2.0 Hz, 1 H, H-6¢), 4.91 (d, J = 5.0 Hz,
1 H, H-2), 4.13 (q, J = 5.0 Hz, 1 H, H-3), 2.57 (dd, J = 19.0, 5 Hz,
1 H, H-4), 2.41 (dd, J = 19.0, 5.0 Hz, 1 H, H-4).
13C NMR (Acetone-d6): d = 183.8 (C-5), 178.7 (C-8), 152.2 (C-8a),
146.2 (C-4¢), 146.0 (C-3¢), 137.4, 135.31 (C-6, C-7), 130.2 (C-1¢),
119.5 (C-6¢), 116.1 (C-5¢), 114.7 (C-2¢), 113.0 (C-4a), 83.9 (C-2),
66.5 (C-3), 26.0 (C-4).
After 18 h in CD3OD H-4 underwent deuterium exchange with the
solvent, resulting in the disappearance of signals at 5.92 ppm in the
1H NMR and 95.6 ppm in the 13C NMR spectra.
MS (ESI): m/z = 307 (M + H+), 289, 165, 123.
p-Benzoquinone (24)
Compound 23 (13 mg) was dissolved in acetone-d6 (0.6 mL). After
a reaction time of 10 d at r.t. (monitored by NMR) compound 24 (39
mg) was isolated as an orange compound.
IR: 3360, 2922, 2853, 1685, 1669, 1623, 1522 cm–1.
MS (ESI): m/z = 319 (M – H+), 301, 291, 169, 138.
(2R,3S)-8-Carboxylic Acid 5,6,7,3¢,4¢-Pentahydroxyflavan-3-ol
(8c)
Prepared from 8b by the same procedure as that described for 3.
1H NMR (Acetone-d6): d = 6.83 (d, J = 2.0 Hz, 1 H, H-2¢), 6.81 (d,
J = 7.0 Hz, 1 H, H-5¢), 6.70 (dd, J = 7.0, 2.0 Hz, 1 H, H-6¢), 4.82 (d,
J = 6.9 Hz, 1 H, H-2), 4.10 (m, 1 H, H-3), 2.58 (dd, J = 18.0, 5.1 Hz,
1 H, H-4), 2.41 (dd, J = 18.0, 8.0 Hz, 1 H, H-4) 1.85 (s, 3 H, CH3).
Yield: 20 mg (100%); colourless oil.
1H NMR (CD3OD): d = 6.85 (s, 1 H, H-2¢), 6.81–6.71 (m, 2 H, H-
5¢, H-6¢), 4.83 (d, J = 8.0 Hz, 1 H, H-2), 4.10 (q, J = 8.0 Hz, 1 H, H-
3), 2.93 (dd, J = 16.5, 5.4 Hz, 1 H, H-4), 2.58 (dd, J = 16.5, 8.0 Hz,
1 H, H-4).
13C NMR (Acetone-d6): d = 187.2 (C-5), 178.0 (C-8), 151.2 (C-7),
150.6 (C-8a), 145.5 (C-3¢), 145.4 (C-3¢), 129.7 (C-1¢), 117.5 (C-4a),
116.5 (C-6), 119.3 (C-6¢), 115.8 (C-5¢), 114.5 (C-2¢), 83.3 (C-2),
66.5 (C-3), 26.8 (C-4), 8.0 (Me).
13C NMR (CD3OD): d = 173.1 (C), 151.9 (C), 151.7 (C), 148.8 (C),
147.0 (C), 146.6 (C), 130.2 (C), 128.2 (C), 120.0 (CH), 116.5 (CH),
115.0 (CH), 101.6 (C), 94.0 (C), 84.6 (CH), 67.5 (CH), 28.4 (CH2).
MS (ESI): m/z = 317 (M + H+), 299, 167, 155, 139.
Acknowledgment
MS (ESI): m/z = 351 (M + H+).
Authors would like to thank M. Guérineau (ICSN, Gif-sur-Yvette,
France) for HRMS (EI) spectra.
(2R,3S)-5,6,7,3¢,4¢-pentahydroxy-8-(2,2,2-trifluoroacetyl)fla-
van-3-ol (9c)
Prepared from 9b by the same procedure as that described for 3.
References
Yield: 21 mg (100%); yellow oil.
1H NMR (CD3OD): d = 6.79 (d, J = 1.8 Hz, 1 H, H-2¢), 6.74 (d,
J = 8.4 Hz, 2 H, H-5¢), 6.67 (dd, J = 8.4, 1.8 Hz, 1 H, H-6¢), 4.57 (d,
J = 7.8 Hz, 1 H, H-2), 3.98 (dd, J = 7.8, 5.7 Hz, 1 H, H-3), 2.89 (dd,
J = 16.5, 5.7 Hz, 1 H, H-4), 2.53 (dd, J = 16.5, 8.0 Hz, 1 H, H-4).
13C NMR (CD3OD): d = 183.7 (q, JC-F = 37 Hz, C), 155.5 (C),
152.8 (C), 151.8 (C), 146.4 (C), 146.1 (C), 130.8 (C), 127.5 (C),
120.3 (CH), 116.4 (CH), 115.5 (CH), 102.0 (C), 102.7 (C), 83.9
(CH), 67.8 (CH), 28.5 (CH2); CF3 signal was missing.
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MS (ESI): m/z = 403 (M + H+).
(2R,3S)-3,5,6,7,3¢,4¢-Hexahydroxy-8-methylflavan (23)
Prepared from 12b by the same procedure as that described for 3.
Yield: 13 mg (100%); colourless oil.
1H NMR (Acetone-d6): d = 6.90 (s, 1 H, H-2¢), 6.78–6.76 (m, 2 H,
H-5¢, H-6¢), 4.54 (d, J = 6.9 Hz, 1 H, H-2), 3.95 (q, J = 6.9 Hz, 1 H,
H-3), 2.93 (dd, J = 16.0, 6.9 Hz, 1 H, H-4), 2.58 (dd, J = 16.0, 8.0
Hz, 1 H, H-4) 1.98 (s, 3 H, CH3).
13C NMR (Acetone-d6): d = 146.3 (C), 144.9 (2 × C), 143.5 (C),
141.9 (C), 132.1 (C), 126.5 (C), 119.1 (CH), 115.1 (CH), 102.7 (C),
100.3 (C), 81.7 (CH), 67.9 (CH), 28.3 (CH2), 7.8 (CH3).
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ESI MS: m/z = 319 (M – H+).
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(2R,3S)-3,5,6,7,3¢,4¢-Hexahydroxyflavan (5c)
Prepared from 19 by the same procedure as that described for 3.
Yield: 20 mg (100%); colourless oil.
1H NMR (CD3OD): d = 6.86 (d, J = 1.8 Hz, 1 H, H-2¢), 6.78 (d,
J = 8.4 Hz, 2 H, H-5¢), 6.76 (dd, J = 8.4, 1.8 Hz, 1 H, H-6¢), 5.92 (s,
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13C NMR (Acetone-d6): d = 149.0 (C), 146.3 (C), 146.2 (2 × C),
145.5 (C), 132.4 (C), 127.9 (C), 120.1 (C), 116.1 (CH), 115.4 (CH),
101.4 (C), 95.6 (CH), 82.7 (CH), 68.9 (CH), 29.0 (CH2).
Synthesis 2006, No. 19, 3250–3260 © Thieme Stuttgart · New York

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