Total synthesis of ellagitannins through regioselective sequential functionalization of unprotected glucose

Article abstract of DOI:10.1002/anie.201500700

Short total syntheses of natural glycosides (ellagitannins) were performed through sequential and regioselective functionalization of the hydroxy groups of unprotected glucose. The key reactions are β-selective glycosidation of a gallic acid derivative by using unprotected glucose as a glycosyl donor and catalyst-controlled regioselective introduction of a galloyl group into the inherently less reactive hydroxy group of the glucoside.

Full text of DOI:10.1002/anie.201500700

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201500700
German Edition: DOI: 10.1002/ange.201500700
Regioselective Catalysis
Total Synthesis of Ellagitannins through Regioselective Sequential
Functionalization of Unprotected Glucose**
Hironori Takeuchi, Kenji Mishiro, Yoshihiro Ueda, Yusuke Fujimori, Takumi Furuta, and
Takeo Kawabata*
Dedicated to Professor Emeritus Kaoru Fuji on the occasion of his 77th birthday (Kiju)
Abstract: Short total syntheses of natural glycosides (ellagi-
tannins) were performed through sequential and regioselective
functionalization of the hydroxy groups of unprotected
glucose. The key reactions are b-selective glycosidation of
a gallic acid derivative by using unprotected glucose as
a glycosyl donor and catalyst-controlled regioselective intro-
duction of a galloyl group into the inherently less reactive
hydroxy group of the glucoside.
N
atural glycosides are known to exhibit a wide range of
Figure 1. Target ellagitannins.
biological activities. Owing to their pharmaceutical potential,
considerable efforts have been devoted to their synthesis.[1–4]
However, the synthesis of carbohydrates including glycosides
is always associated with difficulties in the selective manip-
ulation of multiple hydroxy groups, and has so far been
achieved through multistep protection/deprotection proce-
dures. We developed an extremely short total synthesis of
ellagitannins by eliminating the use of protective groups for
glucose.
esterified gallic acid (galloyl) and hexahydroxy diphenoic acid
(HHDP) groups are added.
Retrosynthetic analyses for strictinin (1) are shown in
Scheme 1. A rational retrosynthetic analysis should lead to
suitably protected precursor 3, which possesses free C(4)-OH,
C(6)-OH, and C(1)-X (X = activating group for glycosida-
Ellagitannins are a large class of plant polyphenols with
a wide variety of biological activities, such as antitumor and
antiviral activities, and specific polyphenol–protein interac-
tions.[1,2] While ellagitannins have been known for a long
time,[5] recent disclosure of the attractive biological activities
of this class of natural glycosides has generated increased
interest in their chemical synthesis.[1–4] Among the ellagitan-
nins, we chose strictinin (1)[6] and tellimagrandin II (2,
eugeniin)[7] as synthetic targets (Figure 1). These compounds
show anti-HSV,[8] antitumor,[9] anti-influenza virus,[10] and
antiallergic activities.[11] Their structures basically consist of
a central sugar core, typically glucose (d-glucose), to which
[*] H. Takeuchi, Dr. K. Mishiro, Dr. Y. Ueda, Y. Fujimori, Dr. T. Furuta,
Prof. Dr. T. Kawabata
Scheme 1. Retrosynthetic analysis for strictinin (1). P= protective
group. X=activating group for glycosylation.
Institute for Chemical Research, Kyoto University
Uji, Kyoto 611-0011 (Japan)
E-mail: kawabata@scl.kyoto-u.ac.jp
[**] We thank Prof. Hidetoshi Yamada, Kwansei Gakuin University, for
the valuable suggestions about oxidative phenol coupling. This
work was financially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Transforma-
tions by Organocatalysts” and a Grant-in-Aid for Scientific Research
(S) from MEXT. H.T. acknowledges the financial support through
JSPS Research Fellowships for Young Scientists.
tion), C(2)-OP (P = protective group), and C(3)-OP to enable
the introduction of an HHDP group at C(4)-O and C(6)-O of
the glucopyranose skeleton. Pioneering studies on the total
synthesis of strictinin (1) via precursors depicted as 3 have
been reported by Khanbabaee and co-workers,[12] as well as by
Yamada and co-workers.[13]
In contrast to these approaches, we envisaged that
strictinin (1) could be synthesized in short steps from
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500700.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
unprotected glucose if galloyl(oxy) groups (G1, G2, G3) could
be introduced to unprotected glucose sequentially and in
a
1,4-dioxane with diisopropyl azodicarboxylate (DIAD) and
PPh3 at room temperature for 30 min gave the desired
product 6 with high stereoselectivity (b/a = 99/1) and in
78% yield. The use of finely ground glucose powder and
ultrasonication of the powder suspension in 1,4-dioxane prior
to the addition of the Mitsunobu reagents were found to be
crucial for the smooth progression of the glycosylation.
Although glucose did not dissolve initially in 1,4-dioxane, it
did dissolve gradually and the reaction proceeded within
30 min to give 6 in a stereoselective manner.
regioselective manner. Oxidative phenol coupling[13]
between the 4- and 6-gallate of 4 was expected to construct
the HHDP moiety of 1. In the sequence toward 4, three
galloyl(oxy) groups were planned to be regioselectively and
sequentially introduced to unprotected glucose in the order
C(1) (blue galloyloxy group), C(4)-OH (red galloyl group),
and C(6)-OH (green galloyl group). After the introduction of
the first galloyloxy group at C(1), introduction of the second
and third galloyl groups in the order C(4)-OH and then C(6)-
OH was expected to be critical to obtain 1,4,6-trigallate 4
because once the second galloyl group was introduced at
C(4)-OH, the third one was assumed to be readily introduced
at C(6)-OH based on the inherently higher reactivity of the
C(6)-OH among the remaining three free hydroxy groups at
C(2), C(3), and C(6). On the other hand, if the second galloyl
group was introduced at C(6)-OH, the third one was expected
to be introduced selectively at C(3)-OH[14] or in a nonselective
manner. Total synthesis of tellimagrandin II (2) was also
planned through the regioselective and sequential introduc-
tion of five galloyl(oxy) groups to unprotected glucose. If this
strategy could be realized, we should be able to eliminate
several steps that would otherwise be required for the
introduction and removal of the protective groups for glucose.
Thus, the synthetic strategy proposed herein is expected to
provide a ground-breaking new route to the synthesis of
natural glycosides, considering that the only reliable approach
to date for the synthesis of glycosides has included the use of
suitably protected intermediates such as 3.
With b-glycoside 6 in hand, we next investigated the
regioselective introduction of a galloyl group to C(4)-OH of 6
(Table 1). We previously developed catalyst 11, which ena-
bled the highly regioselective acylation of octyl b-d-glucopyr-
Table 1: Optimization of organocatalytic regioselective acylation of 6.
The first problem is the stereoselective glycosidation of
unprotected glucose (Scheme 2). While protected glucose
derivatives have generally been used as glycosyl donors for
glycosidation,[1–4,15] methods for the glycosidation of an acidic
Entry
Catalyst
T [8C]
Conc. [m]
Product [%][a]
8
9
10
others
1[b]
2[d]
3
4
5
6
7
8
11
11
11
11
ent-11
12
ent-12
13
À45
20
0.03
0.02
0.02
0.04
0.04
0.04
0.04
0.04
3
0
1
0
21
15
11
11
18
54
83
91
3
35
14
42
6
21
4
6
6
10
4
15
ca. 0[c]
6
3
À40
À40
À40
À40
À40
À40
0
Scheme 2. Direct stereoselective glycosidation.
21
16
16
15
nucleophile with unprotected glucose have been
reported.[16,17] Shoda and co-workers reported the glycosida-
tion of phenol derivatives with unprotected glucose under
Mitsunobu conditions.[16] While the reaction took place
regioselectively at the anomeric carbon, it gave an a/b (1:3)
mixture of the glycosides. Aime and co-workers also reported
that an a/b mixture (a/b = 41/59) of glycosides was obtained
through the treatment of carboxylic acid with unprotected
glucose under Mitsunobu conditions.[17] We examined the
glycosidation of gallic acid trimethoxymethyl ether (5) with
unprotected glucose as a glycosyl donor (Scheme 2). After
a thorough screening of the conditions (see the Supporting
Information), we obtained highly stereoselective glycosida-
tion. Treatment of a suspension of glucose (0.03m) and 5 in
[a] Yields were determined by 1H NMR with 1,3-dinitrobenzene as an
internal standard. [b] Run in CHCl3 in the presence of 1.5 equiv of 2,4,6-
collidine. [c] 70% of the starting material was recovered. [d] Run for 24 h.
anose.[18,19] The catalytic regioselective introduction of a gal-
loyl group with electron-withdrawing acetoxy groups to C(4)-
OH of octyl b-d-glucopyranose was also achieved.[20] Treat-
ment of 6 with anhydride 7 in the presence of catalyst 11
under the previously optimized conditions,[20] however, gave
the desired 1,4-digallate 9 in only 18% yield even after 72 h
(entry 1) owing to the low reactivity of anhydride 7 with the
electron-donating OBn and OMOM groups. The use of
2
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
CHCl3/collidine (9:1) instead of CHCl3 as a solvent gave
much better results. 1,4-Digallate 9 was obtained as the major
product in 54% yield when the reaction was performed at
208C (entry 2). The corresponding reaction at À408C gave 9
in 83% yield with much improved regioselectivity (entry 3).
The observed strong temperature dependence of the regio-
selectivity indicates that the DS° term significantly contrib-
utes to the regioselective reaction, thus suggesting that
hydrogen-bonding interaction between the catalyst and the
substrate may be responsible for the high regioselectivity, as
previously proposed for the regioselective acylation of
carbohydrates.[18,20,21] The best result was obtained in the
reaction at a substrate concentration of 0.04m, which gave 9 in
91% yield (entry 4). Use of catalysts ent-11 and ent-12 with
the (2R,5R)-pyrrolidine skeleton resulted in unselective
reactions (entries 5 and 7). On the other hand, catalysts 12
and 13 with the same (2S,5S)-pyrrolidine skeleton as catalyst
11 gave 9 as the major regioisomer in moderate yields
(entries 6 and 8). These results indicate that the stereochem-
istry of the pyrrolidine skeleton of the catalysts has the major
effects on the regiochemistry of acylation, while the structure
and stereochemistry of the amide side chains has only minor
effects. Thus, catalyst 11 was found to enable the convention-
ally difficult molecular transformation with a significant
reversal of the innate reactivity of the substrate through
fine molecular recognition of the substrate structure.
We next examined the introduction of a galloyl group to
the primary C(6)-OH, which seems to be the most reactive
hydroxy group among three free hydroxy groups of glycoside
9 (Scheme 3a). The regioselective introduction of a galloyl
group to the C(6)-OH of 9 was readily accomplished through
treatment with gallic acid derivative 14 and 2-chloro-1,3-
dimethylimidazolinium chloride (DMC) to give 15 in 72%
yield. Since 14 was expected to be generated in situ from
anhydride 7 and catalyst 11, a one-pot procedure for the
sequential introduction of two galloyl groups at C(4)-OH and
C(6)-OH of 6 was examined (Scheme 3b). The catalyst-
controlled regioselective C(4)-O-galloylation of 6 with 7 in
Scheme 3. a) Substrate-controlled regioselective acylation of C(6)-OH
in 9. b) One-pot regioselective diacylation of 6 through catalyst-
controlled regioselective C(4)-O-galloylation followed by substrate-
controlled C(6)-O-galloylation.
the presence of catalyst 11 followed by substrate-controlled
C(6)-O-galloylation with in situ generated 14 took place
successfully to give 15 in 51% yield in a one-pot reaction
(53 mg of 15 from 40 mg of 6). This key transformation could
be scalable to give 1.07 g of 15 in 50% yield from 6 with
sufficient reproducibility.
The conversion of 15 into strictinin (1) is shown in
Scheme 4. Removal of the benzyl groups of 15 through
hydrogenation proceeded smoothly to give 16 in 98% yield.
The oxidative phenol coupling of the resulting phenol
derivative 16 was accomplished according to the method
developed by Yamada and co-workers.[13] When treating 16
with CuCl2/nBuNH2, intramolecular oxidative phenol cou-
pling between the 4- and 6-gallate took place to give the
corresponding HHDP derivative 17 with complete control of
the newly formed chiral axis (S) in the HHDP moiety.
Removal of the MOM groups of 17 completed the total
Scheme 4. Total syntheses of strictinin (1) and tellimagrandin II (2). Reagents and conditions: a) H2, Pd(OH)2/C, THF, RT; b) CuCl2, nBuNH2,
MeOH/CHCl3 (1:1), RT; c) conc. HCl/iPrOH/THF (1:50:50), RT; d) 5, EDCI·HCl, DMAP, CH2Cl2, RT and then H2, Pd(OH)2/C, THF, RT; e) same as
b); f) same as c). THF=tetrahydrofuran, EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[7] C. K. Wilkins, B. A. Bohm, Phytochemistry 1976, 15, 211 – 214.
[8] M. Kurokawa, T. Hozumi, M. Tsurita, S. Kadota, T. Namba, K.
Shiraki, J. Pharmacol. Exp. Ther. 2001, 297, 372 – 379.
[9] Y. Kashiwada, G. Nonaka, I. Nishioka, K. J.-H. Lee, I. Bori, Y.
Fukushima, K. F. Bastow, K.-H. Lee, J. Pharm. Sci. 1993, 82,
487 – 492.
[10] R. K. Saha, T. Takahashi, Y. Kurebayashi, K. Fukushima, A.
Minami, N. Kinbara, M. Ishitani, Y. M. Sagesaka, T. Suzuki,
Antiviral Res. 2010, 88, 10 – 18.
[11] H. Tachibana, T. Kubo, T. Miyase, S. Tanino, M. Yoshimoto, M.
Sano, M. Yamamoto-Maeda, K. Yamada, Biochem. Biophys.
Res. Commun. 2001, 280, 53 – 60.
[12] K. Khanbabaee, C. Schulz, K. Lçtzerich, Tetrahedron Lett. 1997,
38, 1367 – 1368.
[13] N. Michihata, Y. Kaneko, Y. Kasai, K. Tanigawa, T. Hirokane, S.
Higasa, H. Yamada, J. Org. Chem. 2013, 78, 4319 – 4328.
[14] Examples for selective introduction of acyl groups at C(3)-OH
into 6-O-protected glucopyranosides were reported. See: a) N.
Moitessier, P. Englebiennea, Y. Chapleur, Tetrahedron 2005, 61,
6839 – 6853; b) W. Muramatsu, T. Kawabata, Tetrahedron Lett.
2007, 48, 5031 – 5033.
[15] Handbook of Chemical Glycosylation: Advances in Stereochem-
istry and Therapeutic Relevance (Ed.: A. V. Demchenko), Wiley-
VCH, Weinheim, 2008.
[16] “Process for producing glycoside derivative”: A. Kobayashi, S.
Shoda, S. Takahashi, International Patent WO 2006038440A1,
2006.
[17] F. Reineri, D. Santelia, A. Viale, E. Cerutti, L. Poggi, T. Tichy,
S. S. D. Premkumar, R. Gobetto, S. Aime, J. Am. Chem. Soc.
2010, 132, 7186 – 7193. Besset and co-workers also reported the
direct azidation of unprotected carbohydrates under Mitsunobu
conditions to give a/b mixtures of glycosides. See: C. Besset, S.
Chambert, B. Fenet, Y. Queneau, Tetrahedron Lett. 2009, 50,
7043 – 7047.
synthesis of strictinin (1) in five overall steps and 21% overall
yield from naturally abundant glucose. The overall number of
the steps in the present synthesis is much fewer than for the
previously reported syntheses (11 and 13 steps from glucose,
respectively[12,13]).
We next examined the total synthesis of tellimagrandin II
(2) by using the present strategy (Scheme 4d–f). The intro-
duction of two additional galloyl groups at C(2)-OH and
C(3)-OH of diol 15 through the reaction with 5 in the
presence of EDCI·HCl, followed by hydrogenolysis of the
resulting 1,2,3,4,6-pentagallate gave 18. Pentagallate 18 was
transformed into tellimagrandin II through the same proce-
dure used for the transformation of 16 to strictinin. Tell-
imagrandin II (eugeniin) was synthesized from glucose in six
steps overall and in 18% overall yield. The number of
synthetic steps from glucose is much less than that for the
previous total synthesis of tellimagrandin II (14 steps[22]).
Since carbohydrate synthesis has been developed in
parallel with the development of protective groups, the
current strategies for carbohydrate synthesis still rely largely
on the use of protective groups.[23] On the other hand,
approaches to the direct regioselective manipulation of
carbohydrates have recently been reported.[24–26] We devel-
oped a de novo synthetic route to natural glycosides of an
ellagitannin family through the sequential and regioselective
introduction of galloyl(oxy) groups to unprotected glucose.
The present strategy would provide a new retrosynthetic
approach to a limited class of natural glycosides. We expect
that the concept of catalyst-controlled regioselective func-
tionalization[27] will stimulate the further development of
direct methods for the synthesis of complex natural products
with minimal use of protective groups.
[18] T. Kawabata, W. Muramatsu, T. Nishio, T. Shibata, H. Schedel, J.
Am. Chem. Soc. 2007, 129, 12890 – 12895.
[19] For the pioneering studies for regioselecive acylation of carbo-
hydrates, see: a) T. Kurahashi, T. Mizutani, J. Yoshida, J. Chem.
Soc. Perkin Trans. 1 1999, 465 – 473; b) K. S. Griswold, S. J.
Miller, Tetrahedron 2003, 59, 8869 – 8875.
Keywords: ellagitannin · glycosidation · organocatalysis ·
regioselectivity · total synthesis
[20] Y. Ueda, W. Muramatsu, K. Mishiro, T. Furuta, T. Kawabata, J.
Org. Chem. 2009, 74, 8802 – 8805.
[21] Y. Ueda, K. Mishiro, K. Yoshida, T. Furuta, T. Kawabata, J. Org.
Chem. 2012, 77, 7850 – 7857.
[22] K. S. Feldman, K. Sahasrabudhe, J. Org. Chem. 1999, 64, 209 –
216.
[1] S. Quideau, K. S. Feldman, Chem. Rev. 1996, 96, 475 – 503.
[2] S. Quideau, D. Deffieux, C. Douat-Casassus, L. Pouysꢀgu,
Angew. Chem. Int. Ed. 2011, 50, 586 – 621; Angew. Chem. 2011,
123, 610 – 646.
[3] L. Pouysꢀgu, D. Deffieux, G. Malik, A. Natangelo, S. Quideau,
Nat. Prod. Rep. 2011, 28, 853 – 874.
[4] For the recent studies for total synthesis of ellagitannins, see:
a) Y. Kasai, N. Michihata, H. Nishimura, T. Hirokane, H.
Yamada, Angew. Chem. Int. Ed. 2012, 51, 8026 – 8029; Angew.
Chem. 2012, 124, 8150 – 8153; b) H. Yamada, K. Ohara, T.
Ogura, Eur. J. Org. Chem. 2013, 7872 – 7875; c) T. Hirokane, Y.
Hirata, Y. Ishimoto, K. Nishii, H. Yamada, Nat. Commun. 2014,
5, 3478 – 3487.
[23] C.-C. Wang, J.-C. Lee, S.-Y. Luo, S. S. Kulkarni, Y.-W. Huang, C.-
C. Lee, K.-L. Chang, S.-C. Hung, Nature 2007, 446, 896 – 899.
[24] D. L. Lee, M. S. Taylor, Synthesis 2012, 3421 – 3431.
[25] S. Han, S. J. Miller, J. Am. Chem. Soc. 2013, 135, 12414 – 12421.
[26] X. Sun, H. Lee, S. Lee, K. L. Tan, Nat. Chem. 2013, 5, 790 – 794.
[27] For the selected studies for the catalyst-controlled regioselective
transformations, see: a) P. A. Lichtor, S. J. Miller, Nat. Chem.
2012, 4, 990 – 995; b) T. Hçke, E. Herdtweck, T. Bach, Chem.
Commun. 2013, 49, 8009 – 8011; c) P. E. Gormisky, M. C. White,
J. Am. Chem. Soc. 2013, 135, 14052 – 14055.
[5] K. Freudenberg, Chem. Ber. 1919, 52, 1238 – 1246.
[6] T. Okuda, T. Yoshida, M. Ashida, H. Yazaki, J. Chem. Soc.
Perkin Trans. 1 1983, 1765 – 1772.
Received: January 25, 2015
Published online: && &&, &&&&
4
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Regioselective Catalysis
H. Takeuchi, K. Mishiro, Y. Ueda,
Y. Fujimori, T. Furuta,
T. Kawabata*
&&&& — &&&&
Total Synthesis of Ellagitannins through
Regioselective Sequential
Functionalization of Unprotected
Glucose
Short and sweet: Very short total synthe-
ses of ellagitannins were achieved
through sequential and regioselective
functionalization of the hydroxy groups of
unprotected glucose.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!