First synthesis of a bidesmosidic triterpene saponin by a highly efficient procedure [7]

Full text of DOI:10.1021/ja9926818

12196
J. Am. Chem. Soc. 1999, 121, 12196-12197
Scheme 1. Retrosynthesis of Saponin 1
First Synthesis of a Bidesmosidic Triterpene Saponin
by a Highly Efficient Procedure
Biao Yu,* Jianming Xie, Shaojiang Deng, and
Yongzheng Hui*
State Key Laboratory of Bioorganic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 354 Fenglin Road
Shanghai 200032, China
ReceiVed July 29, 1999
Saponins comprise a diverse class of plant glycosides which
possess a broad range of interesting biological activities.1 The
structural diversity of saponins lies mainly in their “glycoforms”
(a term which is used to describe a set of oligosaccharides of a
special pattern being attached to a same peptide chain). It is
noteworthy that more than half of the triterpene saponins are
glycosides of oleanolic acid or its derivatives, with one sugar chain
attached through an ether linkage at C-3 and another through an
ester linkage at C-28 (a so-called “bidesmosidic saponin”).1b The
isolation of individual saponins from a plant species presents a
formidable task, which hinders the further development of this
important group of natural products. Chemical synthesis could
remove this bottleneck; however, to date only a few studies on
the chemical synthesis of saponins have been reported, and none
of these addresses the construction of a bidesmosidic triterpene
saponin.2 Herein we report the first such synthesis of a bides-
mosidic triterpene saponin (1), a compound first isolated from
the leaves of a commonly used Chinese medicinal herb Acan-
thopanax senicosus.3
Scheme 2. Preparation of the Monosaccharide Building
Blocks 2, 4, and 5a
The recent development of glycosylation procedures and
sophisticated protecting group strategies has enabled the syntheses
of a number of naturally existing oligosaccharides and glyco-
conjugates.4 However, the laborious protecting group manipulation
required between each glycosylation step results in notorious low
efficiency. To address this problem, the “one-pot sequential
glycosylation” procedure has been developed, which depends on
sufficiently disparate reactivities of a set of carefully designed
carbohydrate building blocks.5 Most of the reported one-pot
protocols have been achieved by tuning the reactivities of the
glycosyl donors through selective introduction of different
protecting groups or leaving groups. Differences in reactivities
of the hydroxyl groups or their masked forms (silyl ethers and
trityl ethers) on the saccharide acceptors have also been exploited
to steer the sequential glycosylations,5a,f,6 in a strategy called “two-
a Conditions: (a) BzCl, pyridine, 0 °C, 96%; (b) 33% HBr/HOAc,
CH2Cl2, 1 h; (c) Ag2CO3, acetone, H2O, 89% (two steps); (d) Cl3CCN,
DBU, CH2Cl2, ∼90%; (e) TrCl, pyridine, 80 °C, 10 h, then BzCl, 0 °C,
96%; (f) H2NNH2‚HOAc, DMF, 79%; (g) Ac2O, pyridine, 100%; (h)
PhSH, SnCl4, CH2Cl2, 79%; (i) NaOMe, HOMe, 100%; (j) PhCH(OMe)2,
CSA (0.06 equiv), DMF; (k) Ac2O, pyridine; (l) 80% HOAc, 50 °C, 75%
(three steps); (m) BzCl, pyridine, -10 °C, 93%.
directional glycosylation”.6a-c Thus in designing our synthesis of
1 we planned to use both the one-pot glycosylation5 on the donor
side and the two-directional glycosylation6a-c on the acceptor side.
As shown in Scheme 1, saponin 1 was disconnected into five
readily accessible building blocks (2-6). The trityl ester 3 was
easily prepared in quantitative yield by treating oleanolic acid
with triphenylmethyl chloride (TrCl) and 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) in refluxing tetrahydrofuran (THF). 2,3,4-
Tri-O-benzoyl-â-L-arabinopyranosyl trichloroacetimidate (2), 2,3,4-
tri-O-benzoyl-6-O-trityl-R-D-glucopyranosyl trichloroacetimidate
(4), and phenyl 2,3-di-O-acetyl-6-O-benzoyl-1-thio-â-D-glucopy-
ranoside (5) were readily synthesized using routine transforma-
tions (Scheme 2). 2,3,4-Tri-O-acetyl-R-L-rhamnopyranosyl trichlo-
roacetimidate (6) is a known compound.7
(1) (a) Rouhi, A. M. Chem. Eng. News 1995, 73 (Sept 11), 28-35. (b)
Hostettmann, K.; Marston, A. Saponins; Cambridge University Press: Cam-
bridge, UK, 1995. (c) Saponins Used in Traditional and Modern Medicine;
Waller, G. R., Yamasaki, K., Eds.; Advances in Experimental Medicine and
Biology 404; Plenum Press: New York, 1996.
(2) For previous efforts on the total synthesis of saponins, see: (a)
Randolph, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 5693-
5700. (b) Nishizawa, M.; Yamada, H. Synlett 1995, 785-793. (c) Deng, S.;
Yu, B.; Hui, Y. Tetrahedron Lett. 1998, 39, 6511-6514. (d) Deng, S.; Yu,
B.; Lou, Y.; Hui, Y. J. Org. Chem. 1999, 64, 202-208.
(3) (a) Shao, C. J.; Kasai, R.; Xu, J. D.; Tanaka, O. Chem. Pharm. Bull.
1988, 36, 601-608. (b) Reference 1b, pp 337-341.
(4) (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-173. (b)
Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212-235. (c) Toshima,
K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531. (d) Boons, G.-J. Contemp.
Org. Synth. 1996, 173-200.
As shown in Scheme 3, assembly of the acyl-protected saponin
14 was achieved by four successive glycosylation steps: (1) The
(5) For “one-pot glycosylation”, see: (a) Raghavan, S.; Kahne, D. J. Am.
Chem. Soc. 1993, 115, 1580-1581. (b) Yamada, H.; Harada, T.; Takahashi,
T. J. Am. Chem. Soc. 1994, 116, 7919-7920. (c) Chenault, H. K.; Castro, A.
Tetrahedron Lett. 1994, 35, 9145-9148. (d) Ley, S. V.; Priepke, H. W. M.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2292-2294. (e) Zhang, Z.; Ollmann,
I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc.
1999, 121, 734-753. (f) Yamada, H.; Kato, T.; Takahashi, T. Tetrahedron
Lett. 1999, 40, 4581-4584.
(6) For “two-directional glycosylation”, see: (a) Zhu, T.; Boons, G.-J.
Angew. Chem., Int. Ed. Engl. 1998, 37, 1898-1900. (b) Zhu, T.; Boons, G.-
J. Tetrahedron Lett. 1998, 39, 2187-2190. (c) Zhu, T.; Boons, G.-J. J. Chem.
Soc., Perkin Trans. 1 1998, 857-861. (d) Boons, G.-J.; Bowers, S.; Coe, D.
M. Tetrahedron Lett. 1997, 38, 3773-3776. (e) Boons, G.-J.; Zhu, T. Synlett
1997, 809-811.
(7) Kitagawa, I.; Baek, N. I.; Ohashi, K.; Sakagami, M.; Yoshikawa, M.;
Shibuya, H. Chem. Pharm. Bull. 1989, 37, 1131-1133.
10.1021/ja9926818 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/10/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 51, 1999 12197
Scheme 3. Assembly of Saponin 1 by Successive
12. (3) In the second flask, the phenyl thio-disaccharide 13 had
been prepared during steps 1 and 2 by glycosylation of the
thioglycoside 5 (2.2 equiv) with trichloroacetimidate 6 (2.6 equiv)
under the promotion of TMSOTf (0.2 equiv).5b (4) Addition of
the mixture in the second flask into the first, followed by addition
of TMSOTf (1.5 equiv) and N-iodosuccinimide (NIS) (3.0 equiv)6d
at -15 °C and stirring at this temperature for 15 min, led to the
desired protected saponin 14 in 62% yield (after chromatography
on silica gel, based on the oleanolic ester 2). Remarkably, only
3 h was required to accomplish the four glycosylation steps and
one chromatographic purification, and a per glycosylation yield
of 89% was achieved. Selective removal of the acetate and
benzoate protections in the presence of the C-28 ester glycosidic
linkage (0.2% NaOMe/HOMe/CH2Cl2, room temperature) af-
forded the target saponin 1 in 73% yield.9 The physical data
obtained were essentially identical to those reported for the natural
product.3
Glycosylationa
Progress of the successive glycosylation was conveniently
monitored by thin-layer chromatography (TLC). On TLC plates,
each desired intermediate (10-14) appeared as the dominant spot
and was well separated from less mobile spots resulting from
decomposition of the excess donors (2, 4, 6, 13). The trityl group
(Tr), which has seldom been used to protect a carboxylic acid,10
appeared to have a pivotal role in the success of these transforma-
tions. Direct glycosylation of oleanolic acid (without the trityl
ester protection) with various glycosyl donors resulted in a mixture
of products, with the 13â,28-lactones being significant byproducts.
Other protecting groups were found to be either too labile (e.g.,
trimethylsilyl, triethylsilyl) or too robust (e.g., tert-butyldimethyl
silyl, allyl) for the protection of the 28-COOH, requiring an
additional step for deprotection. Finally, the trityl ether on
trichloroacetimidate 4 was stable under the conditions for the
coupling with acid 11, yet subsequently served as an acceptor
under stronger conditions (TMSOTf/NIS, Scheme 3, step e).6d
In conclusion, the first chemical synthesis of a bidesmosidic
triterpene saponin (1) was efficiently carried out using four
successive glycosylation steps. The method used represents a
conceptual advance in its use of two flasks11 and the combination
of one-pot glycosylation5 and two-directional glycosylation6
strategies. The present glycosylation procedure that has emerged
should provide an efficient entry into not only related bidesmosidic
saponins but also other complex glycoconjugates and their
libraries.
a The equivalents of the reactants and reagents were based on oleanolic
ester 3. Conditions: (a) TMSOTf (0.3 equiv), CH2Cl2, 4-Å MS, -60
°C, 20 min; (b) room temperature, 20 min; (c) 0 °C, 20 min; (d) TMSOTf
(0.2 equiv), CH2Cl2, 4-Å MS, -70 °C to room temperature; (e) TMSOTf
(1.5 equiv), NIS (3 equiv), CH2Cl2, 4-Å MS, -15 °C, 15 min, 62%
(overall yields based on 3); (f) 0.2% NaOMe, MeOH, CH2Cl2, room
temperature, 2 h, 73%.
Acknowledgment. This work is financially supported by the Ministry
of Science and Technology of China and the National Natural Science
Foundation of China. We thank Dr. P. R. Carlier and H. N. C. Wong for
critically reading the manuscript.
coupling of oleanolic ester 3 (1.0 equiv) with trichloroacetimidate
2 (1.15 equiv) was completed within 20 min in the presence of
a catalytic amount of trimethylsilyl trifluoromethanesulfonate
(TMSOTf) (0.3 equiv) at low temperature (-60 °C), providing
the desired glycoside 10,8 which was readily converted into the
acid 11 upon warming to room temperature for 20 min. (2)
Addition of a CH2Cl2 solution of the trichloroacetimidate 4 (1.5
equiv) into the above mixture at 0 °C resulted in the complete
consumption of the reactants (11 and 4) within 20 min, affording
Supporting Information Available: Experimental details and spec-
tral/ analytical data for all new compounds (2-14) and saponin 1 (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
JA9926818
(9) The ester glycosidic linkage at C-28 of a pentacyclic triterpene has
been found to be rather resistant to basic hydrolysis. See ref 1b, pp 185, and
references cited therein.
(10) (a) Murata, S.; Noyori, R. Tetrahedron Lett. 1981, 22, 2107-2108.
(b) Berlin, K. D.; Gower, L. H.; White, J. W.; Gibbs, D. E.; Sturm, G. P. J.
Org. Chem. 1962, 27, 3595-3597.
(11) Zhu and Boons also employed two flasks in their sequential glyco-
sylation, see ref 6e.
(8) The present conditions used for glycosylation of a sapogenin have been
found to be ideal, see: Deng, S.; Yu, B.; Xie, J.; Hui, Y. J. Org. Chem. 1999,
64, 7265-7266.