Synthesis of anemoclemoside B, the first natural product with an open-chain cyclic acetal glycosidic linkage

Article abstract of DOI:10.1021/ol050324y

(Chemical Equation Presented) Anemoclemoside B (1), the first natural product containing a brand-new glycosidic linkage, the open-chain cyclic acetal linkage, was synthesized.

Full text of DOI:10.1021/ol050324y

ORGANIC
LETTERS
2005
Vol. 7, No. 10
1935-1938
Synthesis of Anemoclemoside B, the
First Natural Product with an
Open-Chain Cyclic Acetal Glycosidic
Linkage
Jiansong Sun,† Xiuwen Han,† and Biao Yu*,‡
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China, and State Key Laboratory of Catalyst,
Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, China
byu@mail.sioc.ac.cn
Received February 15, 2005 (Revised Manuscript Received April 11, 2005)
ABSTRACT
Anemoclemoside B (1), the first natural product containing a brand-new glycosidic linkage, the open-chain cyclic acetal linkage, was synthesized.
In 1999, Vinogradov and Bock discovered a new type of
sugar-sugar linkage in the core region of the lipopolysac-
charides (LPS) from the outer membrane of two Proteus
bacteria.1 The new linkage consisted of an open-chain
N-acetylgalactosamine linked as a cyclic acetal to positions
4 and 6 of a normal galactosamine R-pyranoside unit (Figure
1), which has since been found in several other strains of
Gram-negative bacteria.2 The new glycosidic linkage prob-
ably arises from a new, but as yet unknown, biosynthetic
pathway.3 Prior to the 1999 report, an open-chain cyclic
acetal glycosidic linkage had only been found in two
compounds isolated from plant extracts. Thus, Li et al., in
† Dalian Institute of Chemical Physics.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Vinogradov, E.; Bock, K. Angew. Chem., Int. Ed. 1999, 38, 671.
(b) Vinogradov, E.; Bock, K. Carbohydr. Res. 1999, 319, 92. (c)
Vinogradov, E.; Bock, K. Carbohydr. Res. 1999, 320, 239.
(2) (a) Vinogradov, E.; Sidorczyk, Z. Carbohydr. Res. 2001, 330, 537.
(b) Vinogradov, E.; Korenevsky, A.; Beveridge, T. J. Carbohydr. Res. 2003,
338, 1991. (c) Moule, A. L.; Galbraith, L.; Cox, A. D.; Wilkinson, S. G.
Carbohydr. Res. 2004, 339, 1185. (d) Michael, F. S.; Brisson, J. R.;
Larocque, S.; Monteiro, M.; Li, J. J.; Jacques, M.; Perry, M. B.; Cox, A.
D. Carbohydr. Res. 2004, 339, 1973.
Figure 1. Open-chain linkage in the LPS of bacteria.
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Scheme 1
1995, disclosed the structure of the two triterpenoid glyco-
sides, anemoclemosides A and B (Figure 2; congener A lacks
the terminal R-rhamnopyranosyl residue in B), which they
had obtained from extracts of the roots of Anemoclema
glaucifolium, a folk medicinal plant distributed at an altitude
of 1600-3000 m in the Yangtse River valley region of
China.4 The unique structures of anemoclemosides A and B
make them chemotaxonomic markers of the native plant.
Herein, we report an effective approach to the synthesis of
open-chain cyclic acetal glycosidic linkages in the context
of a synthesis of anemoclemoside B 1.
the known L-arabinose derivative 25 into open-chain thioketal
3 and O-acetylated the primary OH of 3 selectively to obtain
4. Unfortunately, however, the subsequent glycosylation of
4 with 2,3,4-tri-O-acetyl-L-rhamnopyranosyl (N-phenyl)-
trifluoroacetimidate (8) using TMSOTf or BF3‚OEt2 as
promoters failed to afford the desired coupling product.6
Instead, intermolecular ethylthio transfer prevailed, and ethyl
2,3,4-tri-O-acetyl-1-thio-R-L-rhamnopyranoside was obtained
as the major reaction product.7
In light of this, we began investigating a new strategy that
did not involve us glycosylating with a thioketal present.
Accordingly, we converted the pyranose hemiacetal 2 into
linear alcohol 5 by reduction with NaBH4.8 Protection of
the vicinal 1,2-OHs as an O-isopropylidene acetal followed
by protection of the remaining 5-OH as an O-acetate
provided 6. The 1,2-O-isopropylidene on 6 was then removed
with 80% aq HOAc, and the resulting C1-OH was selec-
tively protected with a TBS group, giving 7 with its C2-
hydroxyl free. Coupling of 7 with the rhamnopyranosyl
trifluoroacetimidate 86 using 0.05 equiv of TMSOTf in CH2-
Cl2 in the presence of 4 Å MS at 0 °C afforded the desired
disaccharide 9 in a satisfactory 88% yield. The C1-OH
on 9 was then desilylated with 80% aq HOAc at 45 °C,9
and the resulting alcohol was oxidized with Dess-Martin
periodinane to give the desired disaccharide 10 in excellent
yield.
Figure 2.
To construct the targeted open-chain cyclic acetal linkage,
model reactions between 2,3,4,5-tetra-O-benzyl-L-arabinose
A major challenge in the synthesis of anemoclemoside B
1 is construction of the unique open-chain cyclic acetal
linkage between the 2-O-R-L-rhamnopyranosyl-(1f2)-L-
arabinose component and the 3,23-diol of hederagenin. A
suitably protected disaccharide derivative 10 having the
L-arabinose C1-aldehyde component in open-chain form was
synthesized as shown in Scheme 1. Initially, we converted
(5) Yang, G.; Kong, F. J. Carbohydr. Chem. 1994, 13, 909.
(6) (a) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405. (b) Yu, B.;
Tao, H. J. Org. Chem. 2002, 67, 9099.
(7) (a) Du, Y.; Lin, J.; Linhardt, R. J. J. Carbohydr. Chem. 1997, 16,
1327. (b) Yu, H.; Yu, B.; Wu, X.; Hui, Y.; Han, X. J. Chem. Soc., Perkin
Tran. 1 2000, 1445. (c) Leigh, D. A.; Smart, J. P.; Truscello, A. M.
Carbohydr. Res. 1995, 276, 417. (d) Belot, F.; Jacquinet, J.-C. Carbohydr.
Res. 1996, 290, 79. (e) Zhu, T.; Boons, G. J. Carbohydr. Res. 2000, 329,
709.
(3) Hindsgaul, O. Nature 1999, 399, 644.
(4) Li, X.-C.; Yang, C.-R.; Liu, Y.-Q.; Kasai, R.; Ohtani, K.; Yamasaki,
K.; Miyahara, K.; Shingu, K. Phytochemistry 1995, 39, 1175.
(8) Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1990, 55, 2776.
(9) Kawai, A.; Hara, O.; Hamada, Y.; Shiari, T. Tetrahedron Lett. 1998,
29, 6331.
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Org. Lett., Vol. 7, No. 10, 2005

Scheme 2
(12) and methyl 2,3-di-O-benzyl-R-D-glucopyranoside (13)
at -78 °C produced the desired 15 in only trace amount.
Nevertheless, upon raising the temperature to ∼15 °C, 15
was generated as a single isomer in 70% yield.14 Apparently,
the hindered 2-O-R-L-rhamnopyranosyl substituent discour-
aged formation of the corresponding axially (1′S) oriented
isomer.
were first examined (Scheme 2).10 Acetalization with diols
in the presence of an excess amount of an alkoxysilane and
a catalytic amount of TMSOTf11a has previously been
successfully applied for the effective condensation of sugar
lactones with pyranoside-4,6-diols.11b However, our applica-
tion of similar conditions as described in the literature
(TMSOMe (5∼10 equiv), TMSOTf (catalyst), CH2Cl2)11b
provided the acetalization product 14 in less than 46% yield.
The bulk of aldehyde 12 had been transformed mainly into
the corresponding dimethylacetal derivative, and diol 13 into
the 4,6-di-O-TMS product. Treatment of the 4,6-di-O-TMS
compound with aldehyde 12 under the catalysis of TMSOTf
led to 14 in only trace amounts.11b,c Replacing MeOTMS
with PhCH(OTMS)CH3 prevented formation of the alkyl-
acetal byproduct, but did not improve the yield of 14. We
also tried the condensation of dithioacetal 1112 and diol 13
under glycosylation conditions for thioglycosides (Tf2O,
1-benzensulfinylpiperidine (BSP))13 but failed to obtain the
desired adduct 14. Fortunately, acetalization between 12 and
13 could be achieved nicely under the action of 1.0-2.0
equiv of TMSOTf at low temperature (-78 °C) in the
presence of 4 Å MS; this afforded a pair of the diastereo-
isomers 14a and 14b in 50 and 20% yields, respectively.
Cyclic acetals 14a and 14b, with the open sugar chain in
equatorial (1′R) and axial (1′S) orientations, respectively,14
should be in a thermodynamic equilibrium favoring the
formation of the thermodynamically more stable 14a.
Evidently, treatment of 14b with TMSOTf at room temper-
ature produced an equilibrium in favor of 14a.
With an effective protocol for the construction of the open-
chain cyclic acetal glycosidic linkage now available, we set
about our final assembly of the target natural product,
anemoclemoside B 1 (Scheme 3). Hederagenin 16 was
converted into its 28-benzyl ester 17 in three convenient
steps, involving protection of the 3,23-di-OHs with an
O-isopropylidene acetal, C28-benzyl ester formation, and
cleavage of the 3,23-O-isopropylidene unit. Condensation
of hederagenin 3,23-diol 17 with disaccharide aldehyde 10
under conditions similar to those described above (2 equiv
of TMSOTf, -78 °C to rt) furnished 18 as a single isomer
in an excellent 92% yield. Removal of the acetyl group was
best achieved with NaOH at room temperature. This left the
28-benzyl ester group intact. Finally, all the benzyl groups
were removed by hydrogenolysis in the presence of Pd/C;
notably, the 12,13-double bond in the triterpenoid skeleton
was not affected.15 The sample of thus obtained synthetic 1
matched the natural product in every respect.4,16
In summary, an effective approach to the synthesis of the
open-chain cyclic acetal linkage, a new glycosidic linkage
in Nature, was developed. Acetalization of linear sugar
aldehyde with 1,3-diols proceeds smoothly under the action
(14) Acetal 14a was transformed into the corresponding 2,3,2′,3′,4′,5′-
hexa-O-acetyl derivative 19 via hydrogenolysis and acetylation (see
Supporting Information), which provided diagnostic NOE correlations
between the 1′-H and the 4-H and 6-H, thus confirming the 1′R configuration
in 14a. Similarly, compound 15 was converted into the corresponding
2,2′′,3,3′,3′′,4′,4′′,5′-octa-O-acetyl derivative 20 (see Supporting Informa-
tion). Compound 20 provided diagnostic NOE correlations between the 1′-H
and the 4-H and 6-H.
Treatment of diol 13 with disaccharide aldehyde 10 under
similar conditions (1.0 equiv of TMSOTf, 4 Å MS, CH2Cl2)
(10) Formation of methyl 4,6-D-glucosylidene-R-D-glucopyranoside de-
rivatives has been reported; see: Micheel, F.; Velker, E.; Witte, E. A.
Tetrahedron Lett. 1971, 12, 451.
(11) (a) Kurihara, M.; Miyata, N. Chem. Lett. 1995, 263. (b) Ohtake,
H.; Ichiba, N.; Shiro, M.; Ikegami, S. J. Org. Chem. 2000, 65, 8164. (c)
Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357.
(12) Thomas, S.; Andrea, V. HelV. Chim. Acta 1998, 81, 1896.
(13) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
(15) Hydrogenolysis of the diphenylmethyl oleanolate derivatives has
been performed; see: Seebacher, W.; Weis, R.; Jurenitsch, J.; Rauchen-
steiner, K.; Haslinger, E. Monatsh. Chem. 2000, 131, 985.
(16) For the preparation and characterization of all compounds mentioned
in the context, see Supporting Information.
Org. Lett., Vol. 7, No. 10, 2005
1937

Scheme 3
of 1-2 equiv of TMSOTf in the presence of 4 Å MS, leading
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds and
reproduction of 1H NMR spectra for compounds 1, 4-7, 9,
10, 14a/b, 15, and 17-20 and 13C NMR spectra for
compounds 10, 14a/b, 15, and 17-20. This material
is available free of charge via the Internet at http://
pubs.acs.org.
to the successful synthesis of anemoclemoside B 1, the first
natural product discovered to possess such a glycosidic
linkage.
Acknowledgment. This work is supported by the Na-
tional Natural Science Foundation of China (20321202 and
29925203), the Chinese Academy of Sciences (KGCX2-SW-
213), and the Committee of Science and Technology of
Shanghai (04DZ14901).
OL050324Y
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Org. Lett., Vol. 7, No. 10, 2005