Stereoselective substitution of flavan skeletons: Synthesis of dryopteric acid

Article abstract of DOI:10.1016/S0040-4039(02)01826-9

The C(4) acetoxylated catechin and epicatechin derivatives, 4 and 5, smoothly react with various nucleophiles under Lewis acidic conditions, giving C(4)-elaborated flavan-3-ols. Facile synthesis of dryopteric acid (3) was achieved.

Full text of DOI:10.1016/S0040-4039(02)01826-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7753–7756
Stereoselective substitution of flavan skeletons: synthesis of
dryopteric acid
Ken Ohmori, Naoko Ushimaru and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and CREST, Japan Science and Technology Corporation (JST),
O-okayama, Meguro-ku, Tokyo 152-8551, Japan
Received 5 August 2002; revised 22 August 2002; accepted 23 August 2002
Abstract—The C(4) acetoxylated catechin and epicatechin derivatives, 4 and 5, smoothly react with various nucleophiles under
Lewis acidic conditions, giving C(4)-elaborated flavan-3-ols. Facile synthesis of dryopteric acid (3) was achieved. © 2002 Elsevier
Science Ltd. All rights reserved.
Flavonoids or polyphenols designate a wide class of
plant-derived natural products with extreme diversity.
They share, explicitly or implicitly, the flavan-3-ol
1
skeleton, and the diversity arises from change in the
oxidation state, skeletal modification, and oligomer for-
mation. Although these compounds are known to pos-
sess various biological and pharmaceutical effects, the
bioactivities for a single pure compound are often
unclarified, as they are obtained as inseparable
mixtures.
2
During our recent synthetic study of astilbin, a glyco-
sylated flavone natural product, we became interested
more generally in flavone synthesis. We reasoned that
one of the key issues in this context would be the
stereoselective elaboration of the C(4) position of
flavanol skeletons. This would have an important rele-
vance to the structure diversification both in the bio-
genetic origin of complex polyphenols, such as
introducing various groups to two prototypical flavan-
-ol skeletons, catechin (1) and epicatechin (2).
3
Eq. (1) summarizes three significant features: (1) the
utility of C(4)-acetates 4 and 5 as building blocks of
catechin and epicatechin series; (2) their efficient activa-
tion by Lewis acids, such as BF ·OEt , allowing deliv-
3
2
1c
oligomeric catechins and arachnitannin 1, as well as
ery of various nucleophiles at this position, and (3) the
stereochemistry of this substitution reaction.
1d,3
the chemical synthesis of this class of compounds.
This communication describes an efficient method for
Keywords: polyphenol; flavone; flavan; catechin; epicatechin; dry-
opteric acid.
(1)
*
Corresponding author. Tel.: +81-3-5734-2228; fax: +81-3-5734-2228;
e-mail: ksuzuki@chem.titech.ac.jp
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01826-9

7
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K. Ohmori et al. / Tetrahedron Letters 43 (2002) 7753–7756
Scheme 1 shows the preparation of C(4)-acetoxy deriva-
The stereochemical outcomes were determined by
NMR studies (Fig. 1). Although a- and b-isomers of 9
were inseparable, the spectrum was resolved enough to
assess the selectivity, and both compounds showed
diagnostic NOE for the structure assignment.
tives, 4 and 5, from the penta-benzylated catechin 6 and
4
epicatechin 7, respectively. Introduction of an acetoxy
group at C(4) in 6 was achieved by oxidation with
DDQ in wet CH Cl followed by acetylation of the
2
2
resulting alcohol, giving the b-isomer 4 as the sole
product in 41% yield. Direct acetoxylation of 6 was also
attempted with DDQ and acetic acid, which gave a 7/3
Under the same Lewis acidic conditions, we attempted
the reactions of 4 with various carbon- as well as
hetero-nucleophiles (10–15; Table 1). It was found the
chemical yields of these reactions depended on the
5
mixture of 4 and its C(4)-epimer (54% combined yield).
On the other hand, the corresponding epicatechin
derivative 5 was obtained as the single isomer in 51%
yield by applying the direct acetoxylation protocol to
epicatechin derivative 7.
7
nucleophilicity of the reagents. Silyl enolates 10 and 11
were reactive enough, giving the substitution products
in high yields, respectively (runs 1 and 2). However,
allyltrimethylsilane (12) gave only poor yield, and the
8
primary side reaction was the self-condensation of 4.
Thus, if the nucleophile is not reactive enough, compet-
itive attack of the aromatic p-system of other molecule
of 4 becomes predominant, leading to the oligomer
formation (run 3). Allyltriphenylstannane (13), 10 times
7
more nucleophilic than 12, also failed to react
efficiently, giving polymeric products (run 4). On the
other hand, hetero nucleophiles, such as PhSH and
Me SiN , cleanly took part in the reaction (runs 5 and
3
3
6
).
Scheme 1. Reagents and conditions: (a) (i) DDQ (1.5 mol
equiv.), 2% aq. CH Cl , (ii) Ac O, pyridine (41%); (b) DDQ
2
2
2
(
1.5 mol equiv.), AcOH (5 mol equiv.), CH Cl (54%, 4/C(4)-
2 2
epimer of 4=7/3); (c) DDQ (1.5 mol equiv.), AcOH (5 mol
equiv.), CH Cl (51%).
2
2
Catechin series: For the initial feasibility study, we
attempted the reactions of acetate 4 with ketene silyl
acetal (KSA) 8 in the presence of a Lewis acid. Upon
exposure of 4 and KSA 8 (3 mol equiv.) with BF ·OEt
Figure 1.
Table 1.
3
2
(
1 mol equiv., CH Cl , −78°C, 1 h), departure of the
2 2
acetate and trapping with 8 smoothly occurred, giving
the corresponding ester 9 in 95% yield in good b-selec-
6
tivity (a/b=17/83, Eq. (2)). The S 1 nature of the
N
reaction was clearly shown by a comparison experiment
with the C(4)-epimer of 4, which gave exactly the same
stereoselectivity (Eq. (3)).
(
(
2)
3)

K. Ohmori et al. / Tetrahedron Letters 43 (2002) 7753–7756
7755
The reactions were generally b-selective, and the respec-
tive b-product was obtained as the sole isomer, except
for runs 2 and 3. These b-selectivities could be rational-
ized by considering the torsional strain associated with
the quinonemethide intermediate A, generated from 4,
as shown in Fig. 2. The a-attack would give the pseudo-
twist-boat product I as the initial product, which under-
goes conformational change afterwards. On the other
hand, the b-attack directly gives the pseudo-chair
product III, and the latter path would be the lower
energy process.
(
5)
Epicatechin series: These reactions were also applied to
epicatechin derivative 5 (Table 2). Characteristic fea-
tures follow: (1) although 5 was activated by BF ·OEt
3
2
at −78°C, chemical yields were generally lower than the
corresponding catechin series (cf. Table 1); polymeric
byproducts were consistently observed. (2) Reactions
uniformly proceeded in rigorous b-selectivity, including
the case with aromatic nucleophile 16 (run 8, cf. Eq.
Interestingly, a remarkable change of the stereoselectiv-
ity was noted with aromatic nucleophiles, such as
tribenzyl phloroglucinol 16 (Eq. (4)). Thus, the reaction
of acetate 4 with 16 (3 mol equiv.) in the presence of
BF ·OEt (1 mol equiv., CH Cl , −78°C, 1 h) gave a-17
as a major product. Although the origin of this stereo-
chemical reversal is not yet clear, we have some results
suggesting the reversibility of the CꢀC bond formation.
More detailed studies on this particular process are
underway and have an important implication for the
stereoselective synthesis of oligomeric catechins.
3
2
2
2
(
4)). This is not surprising, as the a-face in 5 is blocked
by the C(2)- and C(3)-substituents. (3) KSA 8 and silyl
enolate 11 worked well to give the products in high
yields (runs 1 and 3), while dimethylated KSA 10 gave
substantially lower yield (run 2). (4) Allylations were
again not productive, giving a complex mixture of
11
unidentified byproducts (runs 4 and 5). (5) Sulfur and
nitrogen nucleophiles were smoothly delivered (runs 6
and 7).
(
4)
Table 2.
This finding also drew our attention to the ‘directed’
a-selective reaction, which may be applicable in general
to non-aromatic nucleophiles. By simple analogy with
carbohydrate chemistry, we expected that neighboring-
group participation would work for this purpose.
Although acetyl, benzoyl, or methoxycarbonyl groups
were tested as the C(3) protecting group, the resulting
9
a-selectivities were lower than expected. However, an
excellent a-selectivity was attained by using carbonate
10
derivative 18, previously prepared by Yoneda, giving
a 92/8 selectivity in favor of a-19 (Eq. (5)).
Figure 2.

7
756
K. Ohmori et al. / Tetrahedron Letters 43 (2002) 7753–7756
quent benzylation with benzyl chloride (5.5 mol equiv.)
and NaH (12 mol equiv.) in moist DMF (25°C, 72 h)
gave 6 in 78% yield. Epicatechin derivative 7 was pre-
pared by benzylation of 5,7,3%,4%-tetra-O-benzyl-
3a
epicatechin (BnBr, NaH, DMF, 25°C, 4 h, 91% yield).
. The diastereomers of acetate 4 and its C(4)-epimer were
inseparable, while the separation was possible for the
corresponding alcohol. Thus, C(4)-epimer of 4 was
obtained by applying the procedure to 7/3 mixture of 4
5
Scheme 2.
and C(4)-epimer of 4: (1) 1 M NaOH, H O, MeOH, THF
2
(
24% for a-isomer, 58% for b-isomer); (2) diastereomer
separation by silica gel column chromatography (hex-
Finally, these findings were applied to the synthesis of
dryopteric acid (3), a unique natural product possessing
a flavan acetic acid. Upon reaction of epicatechin
acetate 5 with KSA 20 in the presence of BF ·OEt ,
ester 21 was obtained as the sole product in 95% yield.
All six benzyl protecting groups in 21 were removed by
hydrogenolysis over 20% Pd(OH) /C in THF–MeOH
anes/EtOAc=4/1); (3) re-acetylation (78%).
12
6. Activation of the 4-methoxy derivative of 6 under the
same conditions was much less effective than that of 4.
Product 9 was obtained only in 16% yield, and consider-
able amounts of oligomeric byproducts were observed.
3
2
On the other hand, using TiCl for the reaction of 4 gave
4
2
almost the same result (94% yield, a/b=16/84).
(
6:1) at 25°C for 21 h to give dryopteric acid (3) as an
7
. Nucleophilic index (N) of various p-compounds were
defined by Mayr: Mayr, H.; Patz, M. Angew. Chem., Int.
Ed. Engl. 1994, 33, 938 and references cited therein. See
also: Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.;
Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.;
Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001,
amorphous solid in quantitative yield. All the physical
1
13
data of 3 ( H and C NMR, IR, [h] ) coincided with
D
2
8
those of the natural product, [h] −44 (c 0.69, acetone),
D
2
4
12b
[
lit. [h] −46 (c 0.7, acetone)] (Scheme 2).
D
In conclusion, an effective method has been developed
for introducing various substituents to the C(4) position
of flavan skeletons, and was applied to the synthesis of
dryopteric acid. Currently, we are examining the syn-
thesis of more complex natural polyphenols.
123, 9500.
Acknowledgements
This work was partly supported by a Grant-in-Aid for
Scientific Research (No. 13740351) from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
8. When a large excess of 12 (100 mol equiv.) was employed
for this reaction, the chemical yield was improved to
54%.
9. The chemical yields and stereoselectivities of the reactions
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4
. The pentabenzylated catechin 6 was prepared by a
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5
31.]. Thus, (+)-catechin (1) was acetylated, and subse-