ChemComm
Communication
In conclusion, selective synthesis of the 4-6-linked catechin
dimers has been made possible through the use of an acyclic
nucleophilic catechin precursor (seco-catechin), allowing regio-
selective union with an electrophilic catechin unit followed by
pyran cyclization. The efficacy of this strategy has been demon-
strated by the syntheses of homo- and hetero-catechin-(4a-6)-
dimers.
This work was supported by the Grant-in-Aid for Specially
Promoted Research (No. 23000006) from JSPS.
Notes and references
1
(a) E. Haslam and Y. Cai, Nat. Prod. Rep., 1994, 11, 41; (b) S. Quideau,
D. Deffieux, C.-D. Casassus and L. Pouys ´e gu, Angew. Chem., Int. Ed.,
2011, 40, 586; (c) J. B. Harborane and H. Baxter, The Handbook of
Natural Flavonoids, Wiley, 1999; (d) F. Daayf and V. Lattanzio, Recent
Advances in Polyphenol Research, Wiley, 2008, vol. 1; (e) C.-S. Buelga,
M. T.-E. Bailon and V. Lattanzio, Recent Advances in Polyphenol
Research, Wiley, 2010, vol. 2; ( f ) V. Cheynier, P.-S. Manchado and
S. Quideau, Recent Advances in Polyphenol Research, Wiley, 2012, vol. 3.
(a) J. Jankun, S. H. Selman and R. Swiercz, Nature, 1997, 387, 561;
2
3
(
b) P. Cos, T. De Bruyne, N. Hermans, S. Apers, D. V. Berghe and
A. J. Vlietinck, Curr. Med. Chem., 2004, 10, 1345; (c) I. Hauber,
H. Hohenberg, B. Holstermann, W. Hunstein and J. Hauber, Proc.
Natl. Acad. Sci. U. S. A., 2009, 106, 9033.
(a) K. Ohmori, N. Ushimaru and K. Suzuki, Proc. Natl. Acad. Sci. U. S. A.,
2
004, 101, 12002; (b) K. Ohmori, T. Shono, Y. Hatakoshi, T. Yano and
K. Suzuki, Angew. Chem., Int. Ed., 2011, 50, 4862; (c) T. Yano,
K. Ohmori, H. Takahashi, T. Kusumi and K. Suzuki, Org. Biomol.
Chem., 2012, 10, 7685.
Scheme 3 Synthesis of hetero-dimer 18. Reagents and conditions: (a) TMAD,
n-Bu
98%); (c) TBSOTf, 2,6-lutidine, CH
CH Cl
, ꢁ78 - ꢁ25 1C, 1.5 h (90%); (e) Ph
then EtMgBr, 60 1C, 6 h; (f) LiAlH , THF, 0 1C, 6 h (58%, 2 steps); (g) n-Bu
3
P, toluene, RT, 22 h (93%, 499% d.r.); (b) Li
Cl , 0 1C, 6 h (96%); (d) BF
MgLi, HMPA, THF, ꢁ78 - 0 1C, 2 h,
NF,
O, RT, 2 h;
O, pyridine, RT, 48 h (41%, 2 steps). TMAD = N,N,N ,N -tetramethyl-
azodicarboxamide, HMPA = hexamethylphosphoric triamide.
2
NiBr
4
, THF, 0 1C - RT, 19 h
4 (a) H. Kawamoto, F. Nakatsubo and K. Murakami, Mokuzai Gakkaishi,
1991, 37, 741; (b) J. Beauhaire, N.-E. Es-Safi, F.-D. Boyer, L. Kerhoas,
C. le Guernev ´e and P.-H. Ducrot, Bioorg. Med. Chem. Lett., 2005,
(
2
2
3
ꢀOEt (1.2 equiv.),
2
2
2
3
15, 559; (c) N.-E. Es-Safi, S. Ghidouche and P.-H. Ducrot, Molecules,
4
s
4
2007, 12, 2228.
THF, RT, 4 h (78%); (h) H
2 2 2
, ASCA-2 [5% Pd(OH) /C], THF, MeOH, H
5
(a) G. Watanabe, K. Ohmori and K. Suzuki, Chem. Commun., 2013,
0
0
(
i) Ac
2
4
4
9, 5210; (b) Recently, Nakajima et al. developed an approach to the
,6-linked catechin dimers by exploiting intramolecular reaction of
tethered catechin units: personal communication from Prof. Noriyuki
Nakajima, Toyama Prefectural University.
(a) L. L. Creasy and T. Swain, Nature, 1965, 208, 151; (b) J. A. Delcour,
D. Ferreira and D. G. Roux, J. Chem. Soc., Perkin Trans. 1, 1983, 1711;
(c) H. Kolodziej, Phytochemistry, 1985, 24, 2460; (d) H. Kolodziej,
Phytochemistry, 1986, 25, 1209.
For an intriguing reactivity difference in the Friedel–Crafts reaction
of catechol residues protected as a dimethyl ether or a methylene
acetal, see C.-K. Sha, J.-J. Young, C.-P. Yeh, S.-C. Chang and S.-L.
Wang, J. Org. Chem., 1991, 56, 2694.
The C8-iodo congener reacted at C8 not at C6 with a migration of the
iodine atom to C6. (Fig. 3 and see ref. 5a).
1
7
(
2 4
93% yield). The oxirane ring in 12 was cleaved with Li NiBr ,
6
7
8
and the resulting alcohol was protected with a TBS group, giving
seco-gallocatechin 13. Union of 13 with electrophilic unit 4 in the
presence of BF ꢀOEt proceeded smoothly, giving 90% yield of
3
2
the desired product 14 in excellent regio- and stereoselectivity.
The structure of 14 was assigned by extensive NMR studies, such as
0
HSQC, HMBC, and ROESY, confirming the 4-6 connectivity. The
stereochemical assignment at the C4 position of the upper unit
relied on the coupling constant between H3 and H4 ( J3,4 = 9.7 Hz).
The pyran cyclization was carried out by treatment of 14 with
9 T. Higuchi, K. Ohmori and K. Suzuki, Chem. Lett., 2006, 35, 1006.
0 Note that [D ]-benzyl (Bn*) group was employed for the protection of
hydroxy groups, facilitating the H-NMR analysis. See ref. 3b.
1
7
1
Ph MgLi and HMPA (THF, ꢁ78 - 0 1C, 2 h), which was treated
3
11 (a) B. Carpon and S. P. McManus, Neighboring Group Participation,
Springer, vol. 1, 1976; (b) X. Zhu and R. R. Schmidt, Angew. Chem.,
Int. Ed., 2009, 48, 1900.
in situ with EtMgBr and heated (60 1C, 6 h). This sequential
operation allowed complete detachment of the benzolyl group
and partial removal of the bromo substituent, affording a mixture
of bromide 15 and the debrominated product 16, which were
1
2 (a) K. Kitagawa, A. Inoue, H. Shinokubo and K. Oshima, Angew. Chem.,
Int. Ed., 2000, 39, 2481; (b) A. Inoue, K. Kitagawa, H. Shinokubo and
K. Oshima, J. Org. Chem., 2001, 66, 4333.
s
1
3 ASCA-2 , the modified Pearlman’s catalyst, was purchased from
inseparable. Treatment of this mixture with LiAlH
8% overall yield from 14 (3 steps). The TBS group in 16 was
removed with n-Bu NF, giving alcohol 17 in 78% yield. Finally, all
benzyl groups were removed by hydrogenolysis over ASCA-2 (5%
Pd(OH) /C) [THF, MeOH, H O (2/2/1), room temp., 2 h] to afford
4
gave 16 in
N.E.CHEMCAT Co.
4 Pure sample of procyanidin B (2) was obtained by preparative HPLC
6
as off-white powders (66% yield). All physical data of 2 were
consistent with the reported data. See the ESI†.
5 H.-J. Li and M. L. Deinzer, J. Agric. Food Chem., 2006, 54, 4048.
5
1
4
s
1
2
2
16 T. Tsunoda, J. Otsuka, Y. Yamamiya and S. Ito, Chem. Lett., 1994,
catechin-(4a-6)-gallocatechin (18). The workup employed pre-
viously (see Scheme 2) gave the pure compound 18 as a white
powder, which was fully acetylated to give the corresponding
539.
1
1
7 R. D. Dawe, T. F. Molinski and J. V. Turner, Tetrahedron Lett., 1984,
5, 2061.
2
8 Free dimer 18 was unstable and obtained only in 22% yield by
preparative HPLC. See the ESI†.
18
peracetate 19 in 41% yield (2 steps) as a white solid.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 14371--14373 | 14373