Synthesis of proanthocyanidins. Part 1. The first oxidative formation of the interflavanyl bond in procyanidins

Article abstract of DOI:10.1021/ol801353u

(Chemical Equation Presented) A novel and efficient method for the oxidative condensation of tetra-O-methyl-3-oxocatechin 4 with tetra-O-methylcatechin is described. Treatment of a solution of 3 (2 equiv) and 4 (1 equiv) with silver tetrafluoroborate read

Full text of DOI:10.1021/ol801353u

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3865-3868
Synthesis of Proanthocyanidins. Part 1.
The First Oxidative Formation of the
Interflavanyl Bond in Procyanidins
Matthew C. Achilonu, Susan L. Bonnet, and Jan H. van der Westhuizen*
Department of Chemistry, UniVersity of the Free State, Nelson Mandela AVenue,
Bloemfontein, 9301, South Africa
Vdwestjh.sci@ufs.ac.za
Received June 16, 2008
ABSTRACT
A novel and efficient method for the oxidative condensation of tetra-O-methyl-3-oxocatechin 4 with tetra-O-methylcatechin is described. Treatment
of a solution of 3 (2 equiv) and 4 (1 equiv) with silver tetrafluoroborate readily affords the phenolic per-O-methyl ethers of 3-oxocatechin-
(4–8)-catechin 18 and 19. Subsequent metal hydride reduction provides access to procyanidin B-3 analogues with the 3,4-cis diastereomers
predominating.
Condensed tannins or proanthocyanidins are ubiquitous in
plants and are important constituents of the human diet. A
wide range of potentially significant biological activities
including antioxidant,1 antiatherosclerotic,2 anti-inflamma-
tory,3 antitumor,4 antiosteoporotic,5 and antiviral6 effects
have been attributed to this class of compounds. The
procyanidins consist of oligo- and polymers having (+)-
catechin 1 or (-)-epicatechin 2 (Figure 1) as constituent units
and linked via the 4- and 8- or 4- and 6-positions. Progress
in the chemistry and biology of these compounds has been
(1) Korkina, L. G.; Afanas’ev, I. B. ADV Pharmacol. 1997, 38, 151–
163.
(2) (a) Hertog, M. G.; Kromhout, D.; Aravanis, C.; Blackburn, H.;
Buzina, R.; Fidanza, F.; Giampaoli, S.; Jansen, A.; Menotti, A.; Nedeljkovic,
S. Arch. Intern. Med. 1995, 155, 381386; (b) Knekt, P.; Jarvinen, R.;
Reunanen, A.; Matela, J. BMJ 1996, 312, 478–481.
(3) (a) Laughton, M. J.; Evans, P. J.; Morony, M.A.; Hoult, J. R.;
Halliwell, B. Biochem. Pharmacol. 1991, 42, 1673–1681. (b) Yoshimoto,
T.; Furukawa, M.; Yamamoto, S.; Horie, T.; Watanabi-Kohno, S. Biochem.
Biophys. Res. Commun. 1983, 116, 612–618.
Figure 1. Structures of catechin 1 and epi-catechin 2.
slow due to the difficulty of isolating and synthesizing pure
free phenolic compounds.
The introduction of phenolic and flavanyl moieties at
C-4 of flavan-3,4-diols was affected by acid-catalyzed
condensation of the appropriate nucleophilic and electro-
philic flavanoid units.7 These initial stereoselective syn-
(4) Stefani, E. D.; Boffetta, P.; Deneo-Pellegrini, H. Nutr. Cancer 1999,
34, 100–110.
(5) Hegarty, V. M.; May, H. M.; Khaw, K. T. Am. J. Clin. Nutr. 2000,
71, 1003–1007.
(6) Wang, H. K.; Xia, Y.; Yang, Z. Y.; Natschke, S. L.; Lee, K. H.
AdV. Exp. Med. Biol. 1998, 439, 191–225.
10.1021/ol801353u CCC: $40.75
Published on Web 08/05/2008
2008 American Chemical Society

thetic methods played an important role in the structure
elucidation of the economically important profisetinidins
and prorobinetinidins from Acacia mearnsii (Black Wattle)
and Schinopsis spp up to the tetrameric level.7e,f,8,9
However, such methods were hampered by the laborious
extraction procedures required to obtain optically active
starting materials that occur in low concentrations in plant
material.
The generation of electrophilicity at the C-4 benzylic position
of commercially available (+)-catechin 1 and (-)-epicatechin
2 by introducing a C-4 oxygen leaving group greatly enhanced
the synthetic access to procyanidin dimers and oligomers.10
Selective bromination at C-4 of compounds 1 and 2 is only
possible with peracetates where the reactivity of the aromatic
rings toward competing bromination is supressed by electron-
withdrawing acetate groups.11 To control the degree of polym-
erization, protection at C-8 of the electrophilic species prior to
condensation was required.10c,e
Herein, we report a novel and facile method for the
introduction of a phenolic unit at unfunctionalized C-4 of per-
O-methylcatechin and hence to synthesize procyanidin B-3 type
dimer derivatives. Treatment of tetra-O-methyl-3-oxo-catechin
4, available almost quantitatively from tetra-O-methylcatechin
3 via Dess-Martin periodinane (DMP) oxidation,10b with 1,3,5-
tri-O-methylphloroglucinol in the presence of AgBF4 in THF
afforded the C-4 phloroglucinol adducts 5 (45%) and 6 (13%)
(Scheme 1).12
Figure 2. Observed NOE correlations between C-2 and C-4
of 6.
The requirement of an excess of AgBF4 and the observa-
tion of a silver mirror (reduction of AgI to Ag0) indicate a
two-electron oxidative mechanism (Scheme 2).
No self-condensation or further condensation products were
evident, probably due to the deactivation of the nucleophilic
properties of the A-ring of 4 via the enolic tautomer of the
C-ring.
Subsequent reduction of 5 and 6 with NaBH4 in aqueous
NaOH/MeOH afforded the 4-arylflavan-3-ol derivatives 14
(98%) and 16 (95%), respectively (Scheme 3).
1H NMR coupling constants13 and CD data14 permitted
assignment of (2R,3S,4S) and (2R,3S,4R) absolute configu-
ration for 14 and 16, respectively.7c
The AgBF4-catalyzed condensation reaction between 4
and 3 afforded the anticipated dimers 18 (38%) and 19
(6%) (Scheme 4) with [2R,4S (C-ring):2R,3S (F-ring)] and
[2R,4R (C-ring):2R,3S (F-ring)] configurations, respec-
tively, based on NMR coupling constants and NOESY data
(Figure 3). The relatively low yields are explicable in terms
of poor recovery for silica chromatography substrates, possible
Scheme 1. Condensation Reaction between 4 and
1,3,5-Tri-O-methylphloroglucinol
(8) Botha, J. J.; Viviers, P. M.; Young, D. A.; Du Preez, I. C.; Ferreira,
D.; Roux, D. G.; Hull, W. E. J. Chem. Soc., Perkin Trans. 1 1982, 527–
533.
(9) Young, D. A.; Kolodziej, H.; Ferreira, D.; Roux, D. G. J. Chem.
Soc., Perkin Trans. 1 1985, 25372544..
(10) (a) Steynberg, P. J.; Nel, R. J. J.; Van Rensburg, H.; Bezuidenhoudt,
B. C. B.; Ferreira, D. Tetrahedron 1998, 8153–8158. (b) Tu¨ckmantel, W.;
Kozikowski, A. P.; Romanczyk, L. J. J. Am. Chem. Soc. 1999, 121, 12073–
12081. (c) Kozikowski, A. P.; Tu¨ckmantel, W.; George, C. J. Org. Chem.
2000, 65, 5371–5381. (d) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata,
M. Biosci. Biotechnol. Biochem. 2002, 66 (8), 1764–1767. (e) Ohmori, K.;
Nakajima, N.; Suzuki, K. PNAS 2004, 101 (33), 12002–12007. (f) Mohri,
Y.; Sagehashi, M.; Yamada, T.; Hattori, Y.; Morimura, K.; Kamo, T.; Hirota,
M.; Makabe, H. Tetrahedron Lett. 2007, 48, 5891–5894.
(11) Steenkamp, J. A.; Malan, J. C. S.; Ferreira, D. J. Chem. Soc., Perkin
Trans. 1 1988, 217, 9–2183.
(12) Standard coupling method. A solution of tetra-O-methyl-catechin
(0.435 mmol) in THF (3 mL) was added dropwise to a mixture of AgBF4
(1.1 mmol) and tetra-O-methyl-3-oxocatechin (0.145 mmol) in THF (3 mL)
and refluxed under nitrogen for 4 h. Filtration on SiO2 and silica gel TLC
yielded the desired products.
Their respective (2R,4S)- and (2R,4R)- configurations
were assessed via NMR NOESY spectral data (Figure 2).
(7) (a) Geissman, T. A.; Yoshimura, N. N. Tetrahedron Lett. 1966, 7
(24), 2669–2773. (b) Barrett, M. W.; Klyne, W.; Scopes, P. M.; Fletcher,
A. C.; Porter, L. J.; Haslam, E. J. Chem. Soc., Perkin Trans. I 1979, 2376.
(c) Botha, J. J.; Ferreira, D.; Roux, D. G. J. Chem. Soc., Chem. Commun.
1978, 698–513. (d) Botha, J. J.; Young, D. A.; Ferreira, D.; Roux, D. G.
J. Chem. Soc., Perkin Trans. 1 1981, 1213–1219. (e) Botha, J. J.; Ferreira,
D.; Roux, D. G. J. Chem. Soc., Perkin Trans. 1 1981, 1235–1244. (f)
Delcour, J. A.; Ferreira, D.; Roux, D. G. J. Chem. Soc., Perkin Trans. 1
(13) 1H NMR coupling constants of the C-ring resonances are used to
distinguish between the four diastereoisomers of 4-arylflavan-3-ols. The
characteristic coupling constants for 2,3-trans-3,4-trans isomers are J2,3
)
10 Hz and J3,4 ) 8.5-9.8 Hz, respectively. For 2,3-trans-3,4-cis isomers,
it is 8-10 and 5.0-6.5; for the 2,3-cis-3,4-cis-isomers, it is 1.2 and
4.75-4.9; and for 2,3-cis-3,4-trans, it is <1 and 1.9-3.8.16
(14) Empirically established CD rules for 4-arylflavan-3-ols predicts a
positive Cotton effect at 240 nm with ꢀ-configuration at C-4 and a negative
Cotton effect at the same wavelength with R-configuration.15,16
1983, 1711–1717
.
3866
Org. Lett., Vol. 10, No. 17, 2008

Scheme 2. Proposed Mechanism for the Oxidative Formation of the Interflavanyl Bond
oxidation of the enol form of the 3-keto flavan to the corre-
sponding anthocyanidin, and the small scale of the reaction.
We are currently investigating protocols to increase yields.
Self-condensation of the C-4-functionalized precursors in
existing methods to synthesize procyanidin B-3 derivatives
cannot be avoided, and a complex mixture of dimers, trimers,
tetramers, and higher oligomers can be formed. Our 3-oxo-
Scheme 4. Condensation Reaction between 3 and 4
Scheme 3. Reduction of 5 and 6 Using NaBH4
Figure 3. Observed NOESY interactions between H-4(C) and
H-2(C) and H-2(F), respectively, for 19.
Org. Lett., Vol. 10, No. 17, 2008
3867

catechin precursor does not undergo self-condensation and
allows isolation of the dimer as the sole product. Oxidation
of the 3′′-hydroxyl group in the catechin moiety of the dimer
20 to a 3′′-oxo group would allow introduction of a second
catechin molecule and isolation of a trimer. We envisage a
stepwise controlled synthesis of oligomers of catechin based
on repeated cycles of oxidation and condensation.
Reduction of 18 afforded the 2,3-trans-3,4-cis octa-O-
methyl ether of catechin-(4ꢀf8)-catechin 20, quantitatively
(Scheme 5).15,16
cis isomer. Stereochemistry is controlled by the 3-hydroxy
substituent that directs attack from the anti position to give
3,4-trans configuration. In our reaction, the tetrahedral sp3
3-hydroxy substituent has been replaced by a planar sp2
carbonyl group, and stereochemistry is now controlled by
the 2-aryl substituent. We observed the opposite distribution
of diastereoisomers with a ꢀ:R ratio ranging from 3.5:1
(Scheme 2) to 6:1 (Scheme 4). Such a preference for ꢀ-face
diastereoselectivity and hence the favoring of procyanidins
with 3,4-cis interflavanyl bonds is, no doubt, caused by the
R-orientated B-ring in intermediate 9 (Scheme 2).
We have thus developed a unique and facile synthesis of
(+)-catechin dimer derivatives which circumvents the need
for C-4 functionalization and avoids competing polymeri-
zation. This method, based upon oxidative C-4-C-8 inter-
flavanyl bond formation will contribute significantly to ready
synthetic access to proanthocyanidin analogues, especially
procyanidins with 3,4-cis configured (+)-catechin chain
extension units. Work is in progress to synthesize the free
phenolic analogues of these dimers.
Scheme 5. Reduction of 18 Using NaBH4
Supporting Information Available: Experimental details
for the syntheses and 1H and 13C NMR spectra of compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Surprisingly and in contrast to the 3-hydroxy dimers 14
and 16 and 20, respectively, the 3-oxo dimers 5 and 6 and
18 and 19, respectively, did not demonstrate rotational
isomerism in their NMR spectra.
OL801353U
(15) Van der Westhuizen, J. H.; Ferreira, D.; Roux, D. G. J. Chem.
Soc., Perkin Trans. I 1981, 122, 0–1226.
Previously, formation of procyanidin B-3 derivatives from
4-functionalized flavan-3-ol precursors yielded predominantly
the 3,4-trans isomer and only minute quantities of the 3,4-
(16) Van der Westhuizen, J. H. ‘n Nuwe Reeks Fotochemiese Reaksies
in Flavono¨ıedsintese, Ph. D Thesis, 1979, 99.
3868
Org. Lett., Vol. 10, No. 17, 2008