Efficient synthesis of lupane-type saponins via gold(I)-catalyzed glycosylation with glycosyl ortho-alkynylbenzoates as donors

Article abstract of DOI:10.1021/ol202232v

Glycosylation of the acid labile betulin and betulinic acid derivatives was achieved with glycosyl ortho-hexynylbenzoates as donors under the catalysis of PPh₃AuNTf₂; this enabled the efficient synthesis of lupane-type saponins, as e

Full text of DOI:10.1021/ol202232v

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5508–5511
Efficient Synthesis of Lupane-Type
Saponins via Gold(I)-Catalyzed
Glycosylation with Glycosyl ortho-
Alkynylbenzoates as Donors
Yan Li,†,‡ Jiansong Sun,*,† and Biao Yu*,†
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China and Department of Chemistry, University of Science and Technology of China,
Hefei, Anhui 230026, China
jssun@sioc.ac.cn; byu@mail.sioc.ac.cn
Received August 17, 2011
ABSTRACT
Glycosylation of the acid labile betulin and betulinic acid derivatives was achieved with glycosyl ortho-hexynylbenzoates as donors under the
catalysis of PPh3AuNTf2; this enabled the efficient synthesis of lupane-type saponins, as exemplified by the total synthesis of the proposed
betulinic acid trisaccharide from Bersama engleriana.
More than 70 lupane-type saponins have to date been
identified from plants;1 some of them show potent bioac-
tivities, including anticancer,2 anti-inflammatory,3 and
pancreatic lipase inhibitory activities.4 These plant glyco-
conjugates occur as minor components and in a hetero-
geneous manner, which makes them difficult to isolate in
sufficient quantities for biological and pharmacological
studies. Nevertheless, lupanes such as betulinic acid (which
is the most frequent aglycone) and betulin are abundantly
available from plants;5 attachment of sugars chemically
onto these aglycones would provide an easy access to the
diverse lupane-type saponins.1,6 Earlier efforts on the
glycosylation of betulinic acid and betulin relied on the
KoenigsꢀKnorr method with glycosyl bromides as donors
and a heavy metal salt (e.g., Ag2O) as a promoter to
provide simple glycosides in moderate yields.7 Recently,
higher glycosylation yields have been achieved with glyco-
syl trichloroacetimidates as donors under the catalysis of
TMSOTf or BF3 OEt2, which has enabled the synthesis of
3
a series of the lupane-type saponins.8,9 Withthese synthetic
compounds Pichette and co-workers found that some
members of the lupane-type saponins possessed good
anticancer activity while being devoid of hemolytic
† Chinese Academy of Sciences.
‡ University of Science and Technology of China.
(1) Gauthier, C.; Legault, J.; Pichette, A. Mini-Rev. Org. Chem. 2009,
6, 321.
(6) For reviews on the saponin synthesis, see: (a) Yu, B.; Sun, J.
Chem.;Asian J. 2009, 4, 642. (b) Yu, B.; Zhang, Y.; Tang, P. Eur. J.
Org. Chem. 2007, 5145. (c) Pellissier, H. Tetrahedron 2004, 60, 5123.
(7) (a) Odinokova, L. E.; Oshitok, G. I.; Denisenko, V. A.; Afufriev,
V. F.; Tolkach, A. M.; Uvarova, N. I. Khim. Prir. Soedin. 1984, 182.
Chem. Abstr. 1985, 102, 24940. (b) Odinokova, L. E.; Denisenko, M. V.;
Denisenko, V. A.; Uvarova, N. I. Khim. Prir. Soedin. 1988, 212. Chem.
Abstr. 1988, 109, 231406. (c) Klinotova, E.; Krecek, V.; Klinot, J.;
Endova, M.; Eisenreichova, J.; Budesinsky, M.; Sticha, M. Collect.
Czech. Chem. Commun. 1997, 62, 1776. (d) Samoshina, N. F.; Denisenko,
M. V.;Denisenko, V. A.; Uvarova, N. I. Chem. Nat. Compd. 2003, 39, 575.
(e) Ohara, S.; Ohira, T. J. Wood Sci. 2003, 49, 59.
(2) (a) Cioffi, G.; Braca, A.; Autore, G.; Morelli, I.; Pinto, A.;
Venturella, F.; De Tommasi, N. Planta Med. 2003, 69, 750. (b) Braca,
A.; Autore, G.; De Simone, F.; Marzocco, S.; Morelli, I.; Venturella, F.;
De Tommasi, N. Planta Med. 2004, 70, 960.
(3) Just, M. J.; Recio, M. C.; Giner, R. M.; Cuellar, M. J.; Manez, S.;
Bilia, A. R.; Rios, J.-L. Planta Med. 1998, 64, 404.
(4) Yoshizumi, K.; Hirano, K.; Ando, H.; Hirai, Y.; Ida, Y.; Tsuji, T.;
Tanaka, T.; Satouchi, K.; Terao, J. J. Agric. Food Chem. 2006, 54, 335.
(5) Krasutsky, P. A. Nat. Prod. Rep 2006, 23, 919.
r
10.1021/ol202232v
Published on Web 09/16/2011
2011 American Chemical Society

activity,8a,10 which is of particular interest for the develop-
ment of saponins as potential therapeutic agents.
During these syntheses, it was found that glycosylation
of the 28-OH of betulin derivatives and the 28-COOH of
betulinic acid derivatives proceeded with difficulty due to
WagnerꢀMeerwein rearrangements taking place easily
under the acidic glycosylation conditions (Scheme 1).8b,d
Herein we report an efficient solution to this problem by
glycosylation of betulin and betulinic acid derivatives
with our newly developed gold(I)-catalyzed glycosyla-
tion protocol.11
to the coupling product in only 63% yield. Moreover, no
coupling product was obtained when perbenzoyl glu-
copyranosyl trichloroacetimidate was used as the
donor.8d Gratifyingly, the coupling efficiency was sig-
nificantly enhanced when the corresponding glycosyl
ortho-hexynylbenzoates were used as donors under the
gold(I)-catalyzed conditions (entries 3ꢀ5). Thus, the
glycosylation of 2c with perbenzoyl rhamnosyl and
arabinopyranosyl ortho-hexynylbenzoates 1a and 1c
afforded the desired glycosides 5 and 6 in 90% and
84% yield, respectively. With perbenzoyl glucopyrano-
syl ortho-hexynylbenzoate 1d as the donor, the reaction
led only to the corresponding orthoester. Nevertheless,
upon raising the amount of PPh3AuNTf2 to 0.5 equiv,
the desired glycoside 78d could be obtained in a high
(83%) yield (entry 5).
Scheme 1. WagnerꢀMeerwein Rearrangements of Betulin and
Betulinic Acid Derivatives during Glycosylation
More difficult was the reported glycosylation of the 28-
OH of betulin and the 28-COOH of betulinic acid deriva-
tives, which undergo WagnerꢀMeerwein rearrangement
easily in the presence of Lewis acids.8b,d Especially, betulin
derivatives bearing a protected sugar residue at the 3-OH
(e.g., 2d) could not be glycosylated with glycosyl trichlor-
oacetimidates at all.8d In contrast to these precedents,
glycosylation of 2d with perbenzoyl rhamnosyl and arabi-
nopyranosyl ortho-hexynylbenzoates 1a and 1c under the
catalysis of PPh3AuNTf2 led to the corresponding glyco-
sides 8 and 10 in 83% and 87% yield, respectively (Table 2,
entries 1 and 3). The byproduct of the WagnerꢀMeerwein
rearrangement was not detected. Glycosylation of 2d with
perbenzoyl glucopyranosyl donor 1d again required 0.5
equiv of PPh3AuNTf2 to secure a satisfactory yield of
the product 12 (82%, entry 5). With the superarmed
glucopyranosyl ortho-hexynylbenzoate 1e14 as the do-
nor, 0.1 equiv of PPh3AuNTf2 was sufficient to yield
the coupled product 14 in a high 91% yield (entry 7).
Glycosylation of the 28-COOH of betulinic acid deri-
vative 2e8b with glycosyl ortho-hexynylbenzoates (1a,
1c, and 1d) met with no accident, leading to the desired
glycosyl betulinates (9, 11, and 13) in high yields
(entries 2, 4, and 6). Again, no product derived from
the WagnerꢀMeerwein rearrangement was detected.
With these glycoside derivatives of betulin and betulinic
acid easily available, access to lupane-type saponins be-
came an easy task. This is exemplified by our further
elaboration of the betulinic acid 3-O-glucoside 4 into the
trisaccharide 21, which was identified as a minor compo-
nent from Bersama engleriana (Scheme 2).15 Thus, the 28-
O-TBDPS and 20-O-benzoyl esters on 4 were cleaved under
A prominent feature of the gold(I)-catalyzed glycosyla-
tion protocol with glycosyl ortho-alkynylbenzoates as
donors is that the reaction proceeds under neutral condi-
tions. This point has been clearly proven by a recent
finding of the isochromen-4-yl-gold(I) intermediate and
the importance of its protodeauration for the catalytic
cycle of the glycosylation.12 Thus, extremely acid-labile
aglycones, such as the N-Boc-protected purine derivatives
and the dammarane derivatives, could be glycosylated
effectively with this method.13
Glycosylation of the 3-OH of betulin and betulinic acid
derivatives (i.e., 2a,8d 2b, 2c8d) was examined first with a
panel of the readily available glycosyl ortho-hexynylbenzo-
ates (1aꢀd)11,13,14 under normal conditions (0.1 equiv of
˚
PPh3AuNTf2, CH2Cl2, 4 A MS, rt). The results are sum-
marized in Table 1. Coupling of 28-O-TBDPS-betulin 2a
with perbenzoyl rhamnosyl ortho-hexynylbenzoate 1a gave
the desired 3-O-R-L-rhamnoside 38d in a good (83%)
yield (entry 1). Coupling of 28-O-TBDPS-betulinate
2b with the orthogonally protected glucopyranosyl ortho-
hexynylbenzoate 1b led to the desired 3-O-β-glucoside 4 in
an even higher yield (entry 2). It has been reported that
glycosylation of the betulinic acid derivative 2c, which
bears a perbenzoyl glucose residue on the 28-COOH, with
glycosyl trichloroacetimidates is problematic.8d A good
coupling yield (86%) was registered with perbenzoyl
rhamnosyl trichloroacetimidate as the donor; glycosylation
with perbenzoyl arabinopyranosyl trichloroacetimidate led
(10) Gauthier, C.; Legault, J.; Girard-Lalancette, K.; Mshvildadze,
V.; Pichette, A. Bioorg. Med. Chem. 2009, 17, 2002.
(11) (a) Li, Y.; Yang, Y.; Yu, B. Tetrahedron Lett. 2008, 49, 3604.
(b) Li, Y.; Yang, X.; Liu, Y.; Zhu, C.; Yang, Y.; Yu, B. Chem.;Eur. J.
2010, 16, 1871.
(12) Zhu, Y.; Yu, B. Angew. Chem., Int. Ed. 2011, 50, 8329.
(13) (a) Zhang, Q.; Sun, J.; Zhu, Y.; Zhang, F.; Yu, B. Angew. Chem.,
Int. Ed. 2011, 50, 4933. (b) Liao, J.; Sun, J.; Niu, Y.; Yu, B. Tetrahedron
Lett. 2011, 52, 3075.
(8) (a) Gauthier, C.; Legault, J.; Lebrun, M.; Dufour, P.; Pichette, A.
Bioorg. Med. Chem. 2006, 14, 6713. (b) Thibeault, D.; Gauthier, C.;
Legault, J.; Bouchard, J.; Dufour, P.; Pichette, A. Bioorg. Med. Chem.
2007, 15, 6144. (c) Gauthier, C.; Legault, J.; Lavoie, S.; Rondeau, S.;
Tremblay, S.; Pichette, A. Tetrahedron 2008, 64, 7386. (d) Gauthier, C.;
Legault, J.; Lavoie, S.; Rondeau, S.; Tremblay, S.; Pichette, A. J. Nat.
Prod. 2009, 72, 72.
(14) Yang, W.; Sun, J.; Lu, W.; Li, Y.; Shan, L.; Han, W.; Zhang,
W.-D.; Yu, B. J. Org. Chem. 2010, 75, 6879.
(9) Cmoch, P.; Pakulski, Z.; Swaczynova, J.; Strnad, M. Carbohydr.
Res. 2008, 343, 995.
(15) Tapondjou, A. L.; Miyamoto, T.; Lacaille-Dubois, M.-A. Phy-
tochemistry 2006, 67, 2126.
Org. Lett., Vol. 13, No. 20, 2011
5509

Table 1. Glycosylation of the 3-OH of Betulin and Betulinic
Acid Derivatives with Glycosyl ortho-Hexynylbenzoates as
Donorsa
Table 2. Glycosylation of the 28-OH of Betulin and the 28-
COOH of Betulinic Acid Derivatives with Glycosyl ortho-
Hexynylbenzoates as Donors
a A typical procedure: A solution of 2a (34 mg, 0.05 mmol) and 1a
(66 mg, 0.1 mmol) in anhydrousCH2Cl2 was stirred at room temperature
˚
in the presence of 4 A molecular sieves for 30 min. Then, Ph3PAuNTf2
(7 mg, 0.01 mmol) was added, and the resulting mixture was stirred for
another 1.5 h under an argon atmosphere at room temperature. Filtra-
tion through a pad of Celite and concentration yielded a residue, which
was purified by silica gel column chromatography (petroleum ether/
EtOAc, 15:1) to provide 3 (47 mg, 83%) as a white solid. b Isolated yield.
a Isolated yield.
basic conditions to afford 15 (86%), which was subjected
to glycosylation with perbenzoyl glucopyranosyl ortho-
hexynylbenzoate 1d (3.0 equiv). In the presence of 0.5
equiv of PPh3AuNTf2 under normal conditions, the 28-
COOH and 20-OH on 15 were glycosylated simultaneously
to afford trisaccharide 16 in an excellent 92% yield. The
30-O-allyl and 40,60-O-benzylidene groups on 16 were then
removed with PdCl2 and TsOH subsequently to provide
triol 17 in high yield (80% in two steps). At this stage we
attempted the selective oxidation of the primary 60-OH in
triol 17 via the modified Anelli oxidation (TEMPO, Ca-
(OCl)2, KBr, Bu4NBr).16 However, it was found that the
double bond in the betulinic acid aglycone did not survive
these conditions, and a complex mixture resulted.17 There-
fore, the 30,40-hydroxyls of 17 were blocked via a three-step
protecting group transformation, i.e., selective silylation of
the primary 60-OH, acetylation of the remaining 30,40-OH,
and selective removal of the 60-O-TBS group, to furnish 19
(95% in threesteps). Alcohol19was subjectedtooxidation
with PCC and NaClO2 subsequently to provide the corre-
sponding glucuronic acid derivative in good yield (64% in
two steps), which was further transformed into the methyl
ester 20 to facilitate purification and characterization.
During the PCC oxidation of the primary 60-OH in 19, it
was found that the oxidation proceeded sluggishly. Never-
theless, the reaction rate could be enhanced dramatically
(16) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559. (b) Lin, F.; Peng, W.; Xu, W.; Han, X.; Yu, B. Carbohydr.
Res. 2004, 339, 1219.
(17) Tojo, G.; Fernandez, M. In Oxidation of Primary Alcohols to
Carboxylic Acids: A Guide to Current Common Practice; Tojo, G., Ed.;
Springer: Berlin, 2007; p 79.
by the addition of activated 3 A MS.18 Finally, hydrolysis
˚
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Org. Lett., Vol. 13, No. 20, 2011

Unexpectedly, the physical and analytical data (13C
NMR and [R]D value) of 21 were not in agreement with
those reported for the natural product.15,19 To validate the
structure of the synthetic compound 21, this trisaccharide
was converted to the fully protected derivative 22, which
provided well assignable NMR spectra. Extensive NMR
analyses (1H, 13C, DEPT-135, COSY, NOESY, HMQC,
and HMBC) led to the conclusion of the structure of 22;
thus the structure of 21 was correct (Scheme 2). Additional
support was also obtained from the assignment of the
intermediate trisaccharide 16.19
Scheme 2. Synthesis of the Proposed Lupane-Type Saponin 21
from Bersama engleriana
In summary, taking advantage of the mild promotion
conditions associated with PPh3AuNTf2 as the catalyst,
glycosyl ortho-alkynylbenzoates have been successfully
applied to the glycosylation of betulin and betulinic acid
derivatives, which could otherwise undergo Wagnerꢀ
Meerwein rearrangement under the classical glycosylation
conditions with Lewis acids as promoters. The present
glycosylation method has enabled the facile synthesis of
lupane-type saponins, as exemplified by the efficient as-
sembly of the betulinic acid trisaccharide 21, which could
be conducted at a 5ꢀ10 g scale with excellent yields.
Acknowledgment. This work was financially supported
by the National Basic Research Program of China
(2010CB833202) and the National Natural Science Foun-
dation of China (90713003 and 20932009).
Supporting Information Available. Experimental details,
copies of 1H and 13C NMR spectra of all new compounds,
and 2D NMR spectra of compounds 16 and 22 are pro-
vided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Herscovici, J.; Antonakis, K. J. Chem. Soc., Chem. Commun.
1980, 561.
(19) See Supporting Information for details.
of all the ester protecting groups on 20 afforded the target
trisaccharide saponin 21 in a good 85% yield.
Org. Lett., Vol. 13, No. 20, 2011
5511