Methods in synthesis of flavonoids. Part 2: High yield access to both enantiomers of catechin

Article abstract of DOI:10.1016/S0040-4039(00)01649-X

Resolution of racemic synthetic tetra-O-benzylcatechin 2 is described, through the formation of esters S and 6 derived from dibenzoyl-L-tartaric acid. The diastereoisomer of the natural series 6 was separated by crystallization, the other one being an oil. This process allowed us to prepare enantiomerically pure (+)-catechin 8 in high yield. The pure isomer in the ent-series 9 could be obtained, following the same scheme of reactions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01649-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9049–9051
Methods in synthesis of flavonoids.
Part 2:1 High yield access to both enantiomers of catechin
Bastien Nay, Jean-Pierre Monti, Alain Nuhrich, Ge´rard Deffieux, Jean-Michel Me´rillon
and Joseph Vercauteren*
GESNIT, EA 491, Universite´ Victor Se´galen Bordeaux 2, 146 rue Le´o Saignat, F-33076 Bordeaux Cedex, France
Received 24 July 2000; accepted 20 September 2000
Abstract
Resolution of racemic synthetic tetra-O-benzylcatechin 2 is described, through the formation of esters
5 and 6 derived from dibenzoyl- -tartaric acid. The diastereoisomer of the natural series 6 was separated
L
by crystallization, the other one being an oil. This process allowed us to prepare enantiomerically pure
(+)-catechin 8 in high yield. The pure isomer in the ent-series 9 could be obtained, following the same
scheme of reactions. © 2000 Elsevier Science Ltd. All rights reserved.
Asymmetric total synthesis of flavonoids has been challenged over the two last decades, but,
probably because of the special reactivity of these polyphenolic compounds, successful examples
are scarce.2–4 Concerning the catechin series, it would be very convenient to have such
enantiomerically pure synthetic molecules in order to study the biological as well as the
biophysical properties of one or the other enantiomer. Indeed, flavonoids are considered to be
responsible for most of the benefits that a well balanced diet can bring to health (diminution of
cardiovascular risk,5 known as the ‘French paradox’ and cancer,6 protection against Alzheimer
disease,7 and, as a consequence, increase of the ‘Mediterranean’ people’s life expectancy).
Even though natural catechin is one of the most abundant flavonoid in foods, it proved to be
useless in investigating the above mentioned properties at a cellular level. This is the reason why
we decided to introduce 13C labeling within the skeleton of those molecules. Unfortunately, in
our hands, any trial to get directly to optically pure (+)-catechin by enantioselective total
synthesis failed. This report deals with the resolution steps of racemic catechin derivatives 2, as
an improvement of our total synthesis of ( )-catechin.8 Brown and Fuller9 reported a chemical
resolution of ( )-3%,4%,5,7-tetramethoxyflavan-3,4-diol by crystallization of the salt between its
carboxyphenylborate ester and (−)-ephedrine, in quite poor yields (about 4% of each chiral diol).
While these compounds may be reduced into the corresponding catechins, they are still
* Corresponding author. Fax: (internat.) +33-5/56 96 09 75; e-mail: joseph.vercauteren@gnosie.u-bordeaux2.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01649-X

9050
methylated derivatives. It is worthy of note that most of the syntheses in the field were carried
out with permethylated phenols, which revealed to be deprotected with much difficulty. Our
method describes a preparative resolution of synthetic ( )-tetra-O-benzylcatechin 2 (Scheme 1)
that fully overcomes this problem and makes possible the obtention of native pure (+)-catechin.
Scheme 1.
Racemic compound 2 (770 mg) was obtained according to our previously described synthesis
from 3,4,4%,6%-tetrabenzyloxy-2%-hydroxychalcone 1.8 The best results of chemical resolution were
obtained by esterification of 2 by dibenzoyl- -tartaric acid monomethyl ester 4 (2 equiv., 881
L
mg) in refluxing CH2Cl2 (50 mL) in the presence of DCC (2 equiv., 488 mg) and DMAP (0.05
equiv., 7 mg), giving a pair of diastereoisomers in 82% yield (964 mg of mixture 5/6). Compound
610 was able to crystallize selectively in a mixture of hexane/CH2Cl2 8/2 (v/v). This crop of
crystals was submitted to a single recrystallization (hexane/CH2Cl2 8/2) to yield 366 mg of fine
white crystals (31% from 2, de>99%, based on silica gel HPLC, hexane/CHCl3 85/15). The other
isomer 5 did not crystallize, and gave a colorless oil (570 mg, de=70%) upon concentration of
the mother liquids.
Since all attempts to form esters directly from the anhydride of 3 failed, 4 had to be used to
produce 5 and 6. This monoacid methyl ester 4 was synthesized in two steps and 61% overall
yield from commercially available dibenzoyl- -tartaric acid 3. It was first transformed into the
L

9051
corresponding anhydride in refluxing toluene (Dean–Stark apparatus) in the presence of acetic
anhydride, and then was opened by methanol and sodium acetate (33 wt.%) to give 4.
Compound 6 (345 mg) was hydrolysed in CH3OH/H2O/KOH (27 mL/3 mL/80 mg), leading
to 209 mg (94% yield) of (2R,3S)-tetra-O-benzylcatechin 7, [h]D=+1.5 (c 1, CH2Cl2). Then,
hydrogenolysis of 78 gave 80 mg after lyophilisation (92% yield) of (+)-catechin 8, [h]D=+17 (c
1, H2O), with an ee>99% checked by HPLC on a chiral Cyclobond® I column (b-cyclodextrin).
This method provides an efficient way of preparation of (+)-catechin 8 (22% from racemic
compound 2, in three steps), possibly along with its enantiomeric isomer 9 (ent-catechin) from
5. As an extension of it, the decagram-scale preparation of these molecules, incorporating 13C
labeling, is under progress and will be published elsewhere.
Acknowledgements
We thank the MENRT and ONIVins for financial supports. One of us (B.N.) gratefully
acknowledges receipt of a scholarship from the MENRT.
References
1. Nay, B.; Peyrat, J. F.; Vercauteren, J. Eur. J. Org. Chem. 1999, 2231–2234.
2. Bezuidenhoudt, B. C. B.; Ferreira, D. A. In Plant Polyphenols. Synthesis, Properties, Significance; Hemingway,
R. W.; Lacks, P. E., Eds. Enantioselective synthesis of flavonoids. Plenum: New York, 1992; pp. 143–165.
3. Van Rensburg, H.; Van Heerden, P. S.; Bezuidenhoudt, B. C. B.; Ferreira, D. Tetrahedron 1997, 53, 14141–
14152.
4. Van Rensburg, H.; Van Heerden, P. S.; Ferreira, D. J. Chem. Soc., Perkin Trans. 1 1997, 3415–3421.
5. Renaud, S.; De Lorgeril, M. Lancet 1992, 339, 1523–1526.
6. Renaud, S. C.; Gue´guen, R.; Siest, G.; Salamon, R. Arch. Intern. Med. 1999, 159, 1865–1870.
7. Orgogozo, J.-M.; Dartigues, J.-F.; Lafont, S.; Letenneur, L.; Commenges, D.; Salamon, R.; Renaud, S.; Breteler,
M. B. Rev. Neurol. 1997, 153, 185–192.
8. Nay, B.; Arnaudinaud, V.; Peyrat, J. F.; Nuhrich, A.; Deffieux, G.; Me´rillon, J. M.; Vercauteren, J. Eur. J. Org.
Chem. 2000, 1279–1283.
9. Brown, B. R.; Fuller, M. J. J. Chem. Res. 1986, 140–141.
10. Data for 6: [h]D=−35 (c 1, CH2Cl2). UV/vis (CH3OH): 205 nm, 227, 274. IR (KBr): 3062 cm−1, 3032, 2945, 2870,
1768, 1738 (s), 1619, 1594, 1509, 1499, 1452, 1439, 1378, 1315, 1252 (s), 1180, 1124 (s), 1071, 1020, 912, 853, 808,
1
743, 707, 697. H HR-NMR (500 MHz, CDCl3), l ppm: 2.62 (dd, J=5, 17 Hz, 4-Ha), 2.69 (dd, J=5, 17 Hz,
4-Hb), 3.73 (s, COOCH
(2 s, 3% and 4%-OꢀCH2ꢀC6H5), 5.13 (d, J=5 Hz, 2-H), 5.38 (m, 3-H), 5.97 (m, 2%% and 3%%-H), 6.09 (d, J=2.5 Hz,
6-H), 6.21 (d, J=2.5 Hz, 8-H), 6.78 (dd, J=2, 8.5 Hz, 6%-H), 6.85 (d, J=8.5 Hz, 5%-H), 6.90 (d, J=2 Hz, 2%-H),
7.22–7.48 (m, 20 OꢀCH2ꢀC6H5 and 4 meta-OꢀCOꢀC6H5), 7.53 and 7.58 (2 m, 2 para-OꢀCOꢀC6H5), 8.02 and
8.06 (2 m, 4 ortho-OꢀCOꢀC6H5 H3), 69.7
). 13C NMR (125 MHz, CDCl3), l ppm: 22.3 (C-4), 52.8 (COOC
(5-OꢀCH2ꢀC6H5), 70.1 (7-O-CH2ꢀC6H5), 71.1 (C-3), 71.3 (C-2%% and C-3%%), 71.4 (3%-O- and 4%-OꢀCH2ꢀC6H5), 77.2
(C-2), 93.8 (C-6), 94.4 (C-8), 100.4 (C-4a), 113.1 (C-2%), 115.2 (C-5%), 119.4 (C-6%), 126.9, 127.2, 127.4, 127.5, 127.7,
127.9, 128.3, 128.4, 128.5 and 128.6 (4 para-, 8 ortho- and 8 meta-OꢀCH2ꢀC6H5 and 4 meta-OꢀCOꢀC6H5), 128.6
(2 ipso-OꢀCOꢀC6H5), 129.9 and 130.0 (4 ortho-OꢀCOꢀC6H5), 130.7 (C-1%), 133.4 and 133.5 (2 para-
OꢀCOꢀC6H5), 136.8 (ipso-5-OꢀCH2ꢀC6H5), 136.9 (ipso-7-OꢀCH2ꢀC6H5), 137.0 and 137.2 (ipso-3% and 4%-
OꢀCH2ꢀC6H5), 149.1 (C-3%, C-4%), 154.3 (C-8a), 157.4 (C-5), 158.9 (C-7), 164.9 (3%%-OꢀCOꢀC6H5), 165.0
(2%%-OꢀC
OꢀC6H5), 165.2 (C-1%%), 166.3 (C-4%%). MS (FAB+, glycerol) m/z (%): 1004.6 [M+] (5), 632.0 (80), 542.4
(100). Anal. calcd for C62H52O13: C, 74.09; H, 5.21. Found: C, 74.61; H, 5.09.
6 3), 4.73 and 4.83 (2 d, J=12 Hz, 5-O-CH6 2-C6H5), 5.00 (s, 7-OꢀCH6 2ꢀC6H5), 5.05 and 5.12
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
.