Short total synthesis of 8,10-Di-O-methylbergenin

Article abstract of DOI:10.1021/ol026378e

(figure presented) A short, high-yielding synthesis of the C-glucoside 8,10-di-O-methylbergenin is reported. Key elements of the synthesis are a stereoselective installation of a β-C-aryl linkage, a palladium(0)-catalyzed aryl carbonylation, and a regiose

Full text of DOI:10.1021/ol026378e

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2965-2967
Short Total Synthesis of
8,10-Di-O-methylbergenin
Holger Herzner, Emma R. Palmacci, and Peter H. Seeberger*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
seeberg@mit.edu
Received June 17, 2002
ABSTRACT
A short, high-yielding synthesis of the C-glucoside 8,10-di-O-methylbergenin is reported. Key elements of the synthesis are a stereoselective
installation of a â-C-aryl linkage, a palladium(0)-catalyzed aryl carbonylation, and a regioselective lactonization reaction. This pathway should
allow access to a host of bergenin analogues.
C-Glycoside natural products exhibit medicinally interesting
properties and have potential as antifungal and antitumori-
genic treatments.1 In addition, C-glycoside analogues of
biologically active carbohydrates are attractive pharmaceuti-
cal targets since they are not enzymatically degraded in vivo.2
Examination of carbohydrate-protein interactions and cell-
surface carbohydrate signaling is possible by conjugation of
oligosaccharides to molecular probes through a C-alkyl
glycoside tether.3
disclosed. Bergenin-containing extracts from Macaranga
peltata are used in Indian folk medicine for the treatment of
veneral deseases,5 and acetylated bergenin has shown an
antihepatotic effect in animal experiments.6 Bergenin itself
is antidermatic and shows activity against HIV.7 It is the
active pharmaceutical ingredient of a Chinese drug described
to be effective against cough and bronchitis.
Despite the interesting biological properties of this class
of natural products, current methods for the chemical
synthesis of bergenin and its derivatives are unsatisfying.
Schmidt and co-workers reported a 10-step synthesis of 8,10-
di-O-methylbergenin 3 in 8.8% overall yield from perben-
Bergenin 1, norbergenin 2, and 8,10-di-O-methylbergenin
3 (Figure 1) are gallic acid-derived C-glycosides that have
been isolated from a variety of plants.4
(1) For reviews, see: Levy, D. E.; Tang, C. The Chemistry of C-
Glycosides; Pergamon: Elmsford, NY, 1995; Vol. 13. Postema, M. H. D.
C-Glycoside Synthesis; CRC Press: London, 1995.
(2) Weatherman, R. V.; Mortell, K. H.; Chervenak, M.; Kiessling, L.
L.; Toone, E. J. Biochemistry 1996, 35, 3619-3624.
(3) Bertozzi, C. R.; Bednarski, M. D. J. Org. Chem. 1991, 56, 4326-
4329.
(4) (a) Saijo, R.; Nonaka, G.; Chen, I.-S.; Hwang, T.-H. Chem. Pharm.
Bull. 1989, 37, 2940. (b) Ramaiah, P. A.; Row, L. R.; Reddy, D. S.;
Anjaneyulu, A. S. R.; Ward, R. S.; Pelter, A. J. Chem. Soc., Perkin Trans.
1 1979, 2313. (c) Dean, B. M.; Walker, J. Chem. Ind. 1958, 1696.
(5) Chopra, R. N.; Maya, S. L.; Chopra, I. C. Glossary of Indian
Medicinal Plants; Council of Scientific and Industrial Research: New Delhi,
1956; p 156.
Figure 1.
(6) Lim, H.-K.; Kim, H.-S.; Kim, S.-H.; Chang, M.-J.; Rhee, G. S. Choi,
J. Arch. Pharm. Res. 2001, 24, 114.
(7) Piacente, S.; Pizza, C.; deTommasi, N.; Mahmood, N. J. Nat. Prod.
1996, 59, 565.
Numerous reports about the biological and pharmacologi-
cal properties of bergenin-type C-glycosides have been
10.1021/ol026378e CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/23/2002

zylated trifluoroacetyl glucose.8 Martin et al. developed a
synthesis of 3 based on an intramolecular C-glycosylation
of a 2-(3′,4′,5′-trimethoxy)benzyl n-pentenyl glucoside fol-
lowed by oxidation of the benzylic methylene group. 8,10-
Di-O-methylbergenin 3 was prepared in 12.1% yield over
eight steps from peracetylated glucosyl bromide.9 Apart from
the modest overall yield, these syntheses require numerous
protecting group manipulations, thus rendering them unsuit-
able for the synthesis of an extended set of bergenin
derivatives.
Scheme 2. Installation of the C-Aryl Linkage
Here we describe a short and high-yielding total synthesis
of 3 based on an O-to-C rearrangement with 3,4,5-trimethox-
yphenol. A common route to fashion C-aryl glycosidic
linkages involves the initial installation of an O-glycosidic
linkage with an electron-rich phenol, followed by a Fries-
like O-to-C rearrangement (Scheme 1). A glycosyl donor is
of this hydroxyl group, the addition of DMAP as an acylation
catalyst proved to be essential.
Scheme 1 O-to-C Rearrangement
Scheme 3. Completion of the Bergenin Structure
activated to generate an electrophilic anomeric species that
couples to an aromatic phenol to afford an O-glycoside. The
initial O-glycoside then rearranges to the C-aryl bond under
Lewis acidic conditions. The O-to-C conversion exclusively
affords the sterically favored â-C-aryl phenolic glucoside
product.10 We envisioned that the O-to-C rearrangement
product of 3,4,5-trimethoxyphenol could be further func-
tionalized via a carbonylation and subsequent lactone forma-
tion to give the desired bergenin scaffold.
Palladium(0)-catalyzed carbonylation13 at ambient pressure
under careful exclusion of water and oxygen yielded 68%
of C-glucosyl benzoic acid derivative 7. Attempts to convert
6 directly into the C-glycosyl methyl benzoate failed,14 as
did attempts to obtain the methyl ester of 7 by direct
C-glycosylation with methyl 3,4,5-trimethoxybenzoate.
Debenzylation of 7 by hydrogenation with Pearlman’s
catalyst in methanol provided the tetrahydroxyl C-glucoside
in quantitative yield. Regioselective lactonization of the C2
hydroxyl group of the glucose scaffold was achieved by
treatment with DCC/DMAP in DMF to furnish 3 in 71%
yield. A more efficient procedure was the treatment of
deprotected 7 with SOCl2 in methanol to provide cleanly
8,10-di-O-methylbergenin in 90% yield.
Upon activation with trimethylsilyl trifluoromethane-
sulfonate (TMSOTf), 2,3,4,6-tetra-O-benzyl glucopyranosyl
trichloroacetimidate 4a11 and perbenzylated glucosyl diphenyl
phosphate 4b12 reacted with 3,4,5-trimethoxyphenol to give
the â-configured C-glycoside 5 in 67 and 57% yields,
respectively (Scheme 2). Treatment of the phenolic hydroxyl
group of 5 with triflic anhydride/lutidine resulted in the
formation of triflate 6 (Scheme 3). Due to steric hindrance
In conclusion, we have developed a short synthesis of the
bergenin scaffold that provides the target structure 3 in 33%
(8) Frick, W.; Schmidt, R. R. Carbohydr. Res. 1991, 209, 101.
(9) Rousseau, C.; Martin, O. R. Tetrahedron: Asymmetry 2000, 11, 409.
(10) Mahling, J.-A.; Schmidt, R. R. Synthesis 1993, 325.
(11) Nakanishi, N.; Nagafuchi, Y.; Koizumi, K. J. Carbohydr. Chem.
1994, 13, 981.
(13) Cacchi, S.; Lupi, A. Tetrahedron Lett. 1992, 33, 3939.
(14) Dolle, R. E.; Schmidt, S. J.; Kruse, L. I. J. Chem. Soc., Chem.
Commun. 1987, 904.
(12) Sebasan, S.; Neira, S. Carbohydr. Res. 1992, 223, 169.
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Org. Lett., Vol. 4, No. 17, 2002

overall yield in only four steps from common glycosyl
donors. The application of this synthetic route to the
preparation of a series of bergenin derivatives is currently
under examination.
heim (graduate fellowship for E.R.P.) is gratefully acknowl-
edged. Funding for the MIT-DCIF Avance (DPX) 400 was
provided by the NIH (Grant 1S10RR13886-01). We thank
Dr. M. Eckhardt for helpful discussions.
Supporting Information Available: Experimental pro-
cedures for the preparation of compounds 3 and 5-7,
including spectroscopic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from Boehringer
Ingelheim, GlaxoSmithKline (Research Scholar Award to
P.H.S.), the Alfred P. Sloan Foundation (Scholar Award to
P.H.S.), the German Academic Exchange Service DAAD
(postdoctoral scholarship for H.H.), and Boehringer Ingel-
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