562
J. Beauhaire et al. / Bioorg. Med. Chem. Lett. 15 (2005) 559–562
were assigned to the H-3, H-4, and H-2 of the extension
C ring catechin system. These protons were correlating
with carbon resonances appearing at 74.03, 70.29, and
80.82 ppm, respectively. The furthest upfield carbon
and proton chemical shifts were in agreement with the
presence of an oxygen atom on the corresponding car-
bon atom. This was also confirmed by comparison of
the chemical shifts of the H-4 and H-3 resonances of
both the C and the F rings with those of their precur-
sors. In addition, the HETCOR spectra showed correla-
tions between the B and E ring protons and their
corresponding carbons, which were thus unambiguously
assigned.
References and notes
1. Ferreira, D.; Desmond, S. Nat. Prod. Rep. 2002, 19, 517–
541.
2. The flavonoids—Advances in Research Since 1986; Har-
borne, J. B., Ed.; Chapmann & Hall: London, 1994.
3. Harborne, J. B.; Baxter, H. The Handbook of Natural
Flavanoids; John Wiley & Sons: New York, 1999.
4. Ariga, T.; Koshiyama, I.; Fukushima, D. Agric. Biol.
Chem. 1998, 52, 2717–2722.
5. Jovanovic, S. V.; Steenken, S.; Tosic, M.; Marjanovic, B.;
Simic, M. G. J. Am. Chem. Soc. 1994, 116, 4846–4851.
6. Bors, W.; Michel, C. Free Radical Biol. Chem. 1999, 27,
1413–1426.
7. Jankun, J.; Selman, S. H.; Swiercz, R.; Skrypczak-Jankun,
E. Nature 1997, 387, 561.
A (4-O-3) mode of linkage was concluded to occur be-
tween the two flavan-3-ol units. Moreover, coupling con-
stants for the AMX spin system of the C-ring protons
(J3,4 = 3.2 Hz) indicated a 3,4 cis relative configuration
for this ring, that is a 4b linkage between both flavanol
units. The complete stereoselectivity of the reaction re-
mains, however, to be explained and should presumably
be due to a participation of the hydroxy group at C-3 of
6. However, its involvement in the stereochemical course
of the reaction cannot be, in our case, related to the form-
ation of a protonated epoxide similar to that reported by
Ferreira and co-workers18 in a work dealing with the
dimerization of epioritin-4-ol derivatives.
8. Garbisa, S.; Biggin, S.; Cavallarin, N.; Sartor, L.; Benelli,
R.; Albini, A. Nat. Med. 1999, 5, 1216.
9. de Lorgeril, M.; Salen, P. Lancet 1999, 533, 1067.
10. Stein, J. H.; Keevil, J. G.; Wiebe, D. A.; Aeschlimann, S.;
Folts, J. D. Circulation 1999, 100, 1050–1055.
11. Smith, M. A.; Perry, G.; Richey, P. L.; Sayre, L. M.;
Anderson, V. E.; Beal, M. F.; Kowall, N. Nature 1996,
383, 120–121.
12. Porter, L. J. In The Flavonoids—Advances in Research
since 1980; Harborne, J. B., Ed.; Chapman & Hall:
London, 1988; pp 21–62.
13. Hemingway, R. W. In Natural Products of Woody Plants;
Rowe, J. W., Ed.; Springer: New York, 1990; pp 571–651.
14. Ferreira, D.; Li, X.-C. Nat. Prod. Rep. 2000, 17, 193–212.
15. Foo, L. Y. J. Chem. Soc., Chem. Commun. 1989, 1505–
1506.
16. Coetzee, J.; Malan, E.; Ferreira, D. Tetrahedron 1998, 54,
9153–9160.
17. Coetzee, J.; Malan, E.; Ferreira, D. J. Chem. Res. 1998,
23, 526–527.
18. Bennie, L.; Coetzee, J.; Malan, E.; Woolfrey, J. R.;
Ferreira, D. Tetrahedron 2001, 57, 661–667, and references
cited therein.
19. Elix, J. A.; Jiang, H.; Wardlaw, J. H. Aust. J. Chem. 1990,
43, 1745–1758.
Indeed, the stereochemical outcome of the reaction in
our case should be rather more consistent with a chela-
tion process of the Lewis acid by both hydroxy groups
of 11 and 8, therefore inducing the approach of the
nucleophile from the b face of 11. The possible partici-
pation of the oxygen atoms of the ethylene glycol moiety
of 11, in such a chelation process, thereby inducing a
quasi-concerted process has also to be considered.
In order to verify the presence of other dimeric struc-
tures the mixture was explored by HPLC coupled to
mass spectrometry detection operating in the positive
ion mode. An extracted ion current chromatogram re-
corded at m/z: 1395 and 1412 amu and corresponding
to a dimeric structure molecular weight showed the pres-
ence, in addition to compound 12, of a minor com-
pound, which may well be the carbon–carbon coupled
dimer 13 but which was, however, less predominant
compared to the ether linked one.
20. Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M.
Tetrahedron Lett. 2003, 44, 5449–5452.
21. Tuckmantel, W.; Kozikowski, A. P.; Romanczyk, L. J., Jr.
¨
J. Am. Chem. Soc. 1999, 121, 12073–12081.
22. 1H NMR (500 MHz) and 13C NMR (125.7 MHz) spectral
data (CDCl3, 298 °K) for compound 4 (resonances of the
benzyl groups are not mentioned).
1H d (ppm)
J (Hz)
13C d
(ppm)
1H d (ppm)
J (Hz)
13C d (ppm)
JC-F
The almost exclusive, high yielding formation, in these
conditions, of this novel ether-linked procyanidin as
main compound rather than its carbon–carbon C-4
! C-6 coupled analogue reflects the importance of the
electronic features in the formation of flavan-3-ol di-
mers. Indeed, the poor nucleophilicity of the A ring in
the monomeric precursor 8 has to be related to the pres-
ence of the COCF3 group, hence permitting alternative
nucleophilic sites of the molecule to participate in the
interflavanyl bond formation.
2
4.85 (d, 10)
3.83 (m, J3,4 = 3.2)
5.06 (m)
80.82
74.03 400
3
2.61 (dd, 16.7, 4.4) 27.15
2.78 (dd, 16.7, 6.6)
4
70.29
6
6.27 (d, 2.2)
6.12 (d, 2.2)
97.61 600
98.84 800
106.78 4a00
160.99 8a00
162.72 500
165.59 700
136.70 1000
118.57 2000
153.66 3000
153.59 4000
119.07 5000
125.33 6000
84.57 CO
74.59 CF3
6.20 (s)
95.15
8
109.60
106.62
158.79
165.29
161.88
136.15
116.35
153.4
4a
8a
5
7
10
20 7.08 (d, 1.8)
30
40
6.78 (d, 1.3)
6.80 (d, 8.2)
152.94
118.57
500 7.01 (d, 8.2)
These results form the starting point of a new metho-
dology for the management of the regiochemical fea-
tures related to the dimerization reaction of flavan-3-ol
monomers. Further results will be reported in due course.
6
7.00 (dd, 8.2, 1.8)
6.63 (dd, 8.2, 1.3) 123.51
188.89, 38
115.67, 292
200 4.99 (m)
300 4.49 (m)