Chemical Synthesis of Saponins

ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL.
71
CHEMICAL SYNTHESIS OF SAPONINS
You Yanga,1, Stephane Lavalb, and Biao Yub,1
a
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and
Technology, Shanghai, PR China
b
State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, PR China
I. Introduction 138
II. General Considerations on Saponin Synthesis 141
1. Synthesis of Aglycones 141
2. Synthesis of Carbohydrate Building Blocks 144
3. Assembly Strategies 151
4. Protecting-Group Strategies 153
III. Synthesis of Plant Saponins 159
1. Steroid Saponins 159
2. Triterpene Saponins 183
IV. Synthesis of Marine Saponins 207
V. Summary and Outlook 211
Acknowledgments 213
References 213
Abbreviations
2,2-DMP, 2,2-dimethoxypropane; Ac, acetyl; AIBN, azobisisobutyronitrile; All,

allyl; AZMB, 2-(azidomethyl)benzoyl; BAIB, [bis(acetoxy)iodo]benzene; Bn, ben-
zyl; Boc, tert-butoxycarbonyl; Bu, butyl; Bz, benzoyl; CA, chloroacetyl; CBS,
Corey–Bakshi–Shibata; CNS, central nervous system; DABCO, 1,4-diazabicyclo
[2.2.2]octane; D-Api, D-apiose; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; D-Dig,
D-digitoxose; DEAD, diethyl azodicarboxylate; D-Fuc, D-fucose; D-Gal, D-galactose;
D-Glc, D-glucose; D-GlcA, D-glucuronic acid; D-GlcNAc, N-acetyl-D-glucosamine;
1
Corresponding authors: E-mail: yangyou@ecust.edu.cn; byu@mail.sioc.ac.cn
ISBN: 978-0-12-800128-8
http://dx.doi.org/10.1016/B978-0-12-800128-8.00002-9. 137 # 2014 Elsevier Inc. All rights reserved.
138 Y. YANG, S. LAVAL, AND B. YU
DIAD, diisopropylazodicarboxylate; DIBAL, diisobutylaluminum hydride; dios,

diosgenin; DIPEA, N,N-diisopropylethylamine; DIPT, diisopropyl tartrate; DMAP,
4-dimethylaminopyridine; DMF, N,N-dimethylformamide; DMP, Dess–Martin peri-
odinane; DMSO, dimethyl sulfoxide; D-Qui, D-quinovose; DtBMP, di-tert-butyl-4-
methylpyridine; D-Xyl, D-xylose; EDCI, N-ethyl-N’-(3-dimethylaminopropyl)
carbodiimide; EDTA, ethylenediaminetetraacetic acid; Et, ethyl; GOTCAB, Glucur-
onide oleanane-type triterpene carboxylic acid 3,28-O-bidesmoside; imid, imidazole;
L-Ara, L-arabinose; LDA, lithium diisopropylamide; Lev, levulinoyl; LG, leaving
group; LiDBB, lithium 4,40 -di-tert-butylbiphenyl; L-Rha, L-rhamnose; MBz,
p-methoxybenzoyl; mCPBA, m-chloroperoxybenzoic acid; Me, methyl; MOM, meth-
oxymethyl; Ms, methanesulfonyl; MS, molecular sieves; NBS, N-bromosuccinimide;
NBSH, o-nitrobenzenesulfonylhydrazide; NBz, p-nitrobenzoyl; NGP, neighboring-
group participation; NIS, N-iodosuccinimide; NMO, N-methylmorpholine N-oxide;
NMP, N-methyl-2-pyrrolidinone; P, permanent protecting group; PCC, pyridinium
chlorochromate; PDC, pyridinium dichromate; Penno, pennogenin; Ph, phenyl; Phth,
phthaloyl; Piv, pivaloyl; PMB, p-methoxybenzyl; PPTs, pyridinium p-toluenesulfo-
nate; Pr, propyl; pyr., pyridine; SAR, structure–activity relationship; T, temporary
protecting group; TBAB, tetrabutylammonium bromide; TBAF, tetrabutylammonium
fluoride; TBAI, tetrabutylammonium iodide; TBDPS, tert-butyldiphenylsilyl; TBS,
tert-butyldimethylsilyl; TEMPO, (2,2,6,6-tetramethylpiperidin-1-yl)oxy; TES,
triethylsilyl; Tf, trifluoromethanesulfonyl; TFA, trifluoroacetic acid; THF, tetrahy-
drofuran; tigo, tigogenin; TIPS, triisopropylsilyl; TMS, trimethylsilyl; TMU, tetra-
methylurea; Tr, trityl; Ts, p-toluenesulfonyl
I. Introduction
Naturally occurring saponins constitute a structurally diverse class of glycosides

that are composed of one or more sugar chains and aglycones linked via glycosidic
bonds.1 As secondary metabolites, these natural products are widely distributed in
terrestrial plants as well as in some marine species, such as starfish and sea cucum-
bers.2–4 The name saponin is originated from the Latin word sapo meaning soap.
Indeed, because of the amphiphilic nature that stems from the combination of
hydrophilic sugar chains and a lipophilic sapogenin, saponins can act as surfactants
and produce soapy foams when shaken with water.1,5 For example, saponin-
containing plant extracts from soapwort (Saponaria officinalis) and soapbark (Quil-
laja saponaria) have been used as natural soaps and detergents for hundreds of years.
In Nature, plants protect themselves from the attack of pathogens, pests, and
herbivores by secreting various saponins that possess antimicrobial, fungicidal, insec-
ticidal, molluscicidal, and antiparasitic activities.6 Besides their role in plant-defense
CHEMICAL SYNTHESIS OF SAPONINS 139
systems, saponins also exhibit a variety of biological and pharmacological properties,

including hemolytic, cytotoxic, immunomodulatory, anti-inflammatory, and antitu-
mor effects.2,7–10 Since ancient times, a wide range of saponins have served as key
ingredients in plant drugs and folk medicines, especially in traditional Chinese
medicines.11,12 Ginseng (Panax ginseng), which contains saponins as major active
components, is one of the most widely used plants in traditional Oriental medicines.13
In addition, the major active principles of more than half of such traditional Chinese
medicines as “Sanqi,” “Chaihu,” “Diwu,” “Chonglou,” “Xiebai,” and “Maidong” are
recognized to be saponins.11,12,14 Furthermore, saponins have also found many other
applications, from adjuvants in vaccine formulation to foaming agents and emulsifiers
in the food and cosmetic industries.15
The multifaceted properties of saponins are primarily attributed to their aglycone
skeleton, which can be modified by various degrees of glycosylation. From the
viewpoint of biosynthesis, this class of glycosylated isoprenoids is derived from the
mevalonate pathway via the common precursor 2,3-oxidosqualene, which is then
cyclized into different aglycone skeletons.16 Further decorations of the skeletons
involve glycosylations by glycosyltransferases and trans-glycosidases, as well as
some postmodifications such as oxidation, rearrangement, and acylation, thus leading
to extensive structural diversity of saponins.16,17 After the biosynthetic pathways are
fulfilled, the “finished” saponins can be considered to have two independent parts: the
aglycone core and the sugar moiety. In many cases, both the aglycone and the sugar
chain are crucial for activities of the saponins. However, in other cases, the sugar
chain merely enhances the pharmacokinetic properties by increasing the hydrophilic-
ity of the saponin.18
Based on the structures of the aglycone skeletons, saponins can usually be divided
into two main groups, namely, steroid saponins and triterpene saponins.1,3,19 Steroid
saponins, which occur almost exclusively in the monocotyledonous angiosperms,
comprise four representative types of steroid skeletons, namely, hexacyclic spiros-
tane, pentacyclic furostane, tetracyclic cholestane, and lactone-containing cardeno-
lide types (Fig. 1).
Fig. 1. Representative aglycone skeletons of steroid saponins.

Triterpene saponins, which are widely distributed in the dicotyledonous angio-

sperms, include four representative types of triterpene skeletons, namely, pentacyclic
oleanane, ursane, and lupane, as well as tetracyclic dammarane types (Fig. 2).
In addition, the number of saccharide chains attached to the aglycone core can vary
from one to three, giving rise to another dimension of nomenclature, that is, mono-
desmosides, bidesmosides, and tridesmosides, respectively. The sugar units most fre-
quently linked are D-glucose (D-Glc), L-rhamnose (L-Rha), D-glucuronic acid (D-GlcA),
D-xylose (D-Xyl), L-arabinose (L-Ara, in both pyranose and furanose forms), and
D-galactose (D-Gal), while relatively rare sugar residues include N-acetyl-D-
glucosamine (D-GlcNAc), D-fucose (D-Fuc), D-quinovose (D-Qui), D-digitoxose
(D-Dig), and D-apiose (D-Api) (Fig. 3).1,3
To date, a wide range of chemical structures and biological activities of saponins
have been reported; however, the structure–activity relationships (SARs) and the
mechanisms of action of saponins are still poorly understood.9,20 The isolation of
pure saponins from crude plant extracts, especially in appreciable amounts, is
extremely tedious and difficult because of the microheterogeneity of these complex
molecules. Chemical synthesis therefore serves as a powerful tool for accessing
Fig. 2. Representative aglycone skeletons of triterpene saponins.
Fig. 3. Representative sugar units found in naturally occurring saponins.

homogeneous saponins, as well as their congeners, in sufficient amounts to facilitate

SAR studies and accelerate the discovery of optimal saponin structures for potential
commercial applications. To address the synthesis of saponins, two different research
fields of organic chemistry—carbohydrate chemistry (the sugar part) and steroid/
triterpene chemistry (the aglycone)—need to be combined in a cooperative manner.21
With the discovery of a range of efficient glycosylation protocols and protecting-
group strategies in the past three decades,22 it has become feasible to access complex
naturally occurring saponins by installing various sugar chains on the sophisticated
skeletons of steroids and triterpenes.
In 2004, Pellissier exhaustively reviewed the glycosylation of steroids.23 In 2007,
Yu and coworkers summarized the synthesis of saponins with a major emphasis on
steroid saponins; the synthesis of triterpene saponins was discussed in 2009.24
Recently, Gauthier and coworkers focused on progress in the synthesis of triterpene
saponins, especially oleanane and lupane types.25 Herein, we present a comprehen-
sive account on the chemical synthesis of saponins, including both steroid and
triterpene saponins. The general considerations in saponin synthesis, such as assembly
strategies and protecting-group strategies, are highlighted in the following section.
Subsequently, the chemical synthesis of each type of plant and marine saponin,
classified by the nature of the aglycone skeletons, is described in detail, with partic-
ular focus on saponins having potent biological and pharmacological activities.
II. General Considerations on Saponin Synthesis
1. Synthesis of Aglycones
In Nature, two types of aglycone are present in saponins: steroids and triterpenes.3
Steroid skeletons generally include (a) spirostane, (b) furostane, (c) cholestane, and
(d) cardenolide types, while triterpene cores comprise mainly (a) oleanane, (b) ursane,
(c) lupane, and (d) dammarane types (Figs. 1 and 2). Such aglycones as diosgenin,
cholesterol, and oleanolic acid can be obtained in large amounts by direct extraction
from natural sources. However, in most cases, complex aglycones have to be synthe-
sized from commercially available precursors. Practical methods for synthesis rely
principally on the structural modification of commercially available steroid and
triterpene skeletons.24,26 Aiming at providing the reader with a general understanding
of the aglycone synthesis, we introduce herein with three representative examples the
preparation of coupling-ready aglycones belonging to the saponin family.
In the total synthesis of pavoninin-4, a steroid saponin, the steroid core (6) was
prepared from diosgenin 1, a spirostan that is commercially available (Scheme 1).27 The
Pd-catalyzed hydrogenation of the double bond in 1, followed by spirocycle ring
opening using zinc and hydrochloric acid, furnished 3,16,26-cholestanetriol (2) in
84% yield. Chemoselective protection of the less sterically hindered 3-OH and 26-OH
groups and inversion of the 3-OH group from β to α were achieved in one step under
Mitsunobu conditions,28 affording the 3,26-dibenzoate 3 in 85% yield. Next, an efficient
Scheme 1. Synthesis of the steroid core (6) of pavoninin-4.

five-step procedure was employed to convert compound 3, containing a 16β-ΟΗ group,

into the target steroid 6, bearing a 15α-ΟΗ group. This sequence involves (1) regios-
pecific dehydration of the sterically hindered 16β-ΟΗ group using Ms protection,
followed by Kim’s methodology using NaI in DMF29; (2) introduction of the hydroxyl
group at the C-15α position by allylic oxidation and subsequent Luche reduction; and
(3) Pd-catalyzed hydrogenation of the double bond. This protocol provides the steroid
(6) of pavoninin-4 in eight steps and 41% overall yield from diosgenin 1.
The first total synthesis of the steroid saponin OSW-1 was completed by Deng and
coworkers in 1999, in which the steroid backbone (13) was obtained from the
commercially available dehydroisoandrosterone 7 (Scheme 2).30 Wittig alkenation
of 7 followed by protection of the 3-OH group with TBDPSCl yielded compound 8 in
78% yield over two steps. Next, an ene reaction of 8 with paraformaldehyde under the
Scheme 2. Synthesis of the steroid backbone (13) of OSW-1.

promotion by BF3OEt2 generated the homoallylic alcohol, which was further oxi-
dized with Dess–Martin periodinane31 to give aldehyde 9 (65%). This aldehyde was
then transformed into 11 via the ketone intermediate 10 in five steps, including (1)
Grignard addition with (3-methylbutyl)magnesium bromide; (2) PDC oxidation; (3)
protection of the ketone at the C-22 position with ethylene glycol; (4) and (5)
substitution of the 3-OTBDPS group by 3-OTBS. Subsequently, regioselective dihy-
droxylation of diene 11 with OsO4 afforded the 16α,17α-diol 12, which was subjected
to Swern oxidation and subsequent Luche reduction in order to furnish the desired
16β,17α-diol 13 (30% yield over three steps). This synthetic approach provides the
cholestan core (13) of steroid saponin OSW-1 in 12 steps (10% overall yield) from
dehydroisoandrosterone 7.
The synthesis of the oleanane (21) component of the triterpene saponin lobatoside
E started from oleanolic acid 14, which is the most abundant triterpene in Nature
(Scheme 3).32 Oleanolic acid 14 was first converted into the 3-oxime 15 in 82% yield
over three steps: (1) benzylation of 28-CO2H; (2) oxidation of the 3-OH group under
Jones’ conditions; and (3) subsequent oxime formation. The equatorial methyl group at
the C-4 position was then selectively hydroxylated using Baldwin’s method33 to
produce compound 16 in 72% yield. This method involves (1) cyclopalladation of
the equatorial methyl group in oxime 15 with Na2PdCl4; (2) protection of the oxime
hydroxyl group with an acetyl group; and (3) oxidation with Pb(OAc)4 followed by
reductive workup using NaBH4. After hydrolysis of compound 15 with Na2CO3–
MeOH and then TiCl3–NH4OAc, the 23-OH group was protected as the benzyl ether
to yield compound 17 (86%). Thereafter, Rubottom oxidation,34 involving the forma-
tion of a silyl enol ether, oxidation by mCPBA, and removal of the silyl group, was
employed to introduce the 2α-OH group of intermediate 18 (84%). Isomerization of
the 3-one-2α-ol 18 into 2-one-3β-ol 19 was achieved under acidic conditions. Next,
acetylation of the 3-OH group and reduction of the resultant 2-ketone by NaBH4
provided the 2β,3β-diol derivative 20 in 79% yield. Finally, fine-tuning of the protect-
ing groups in 20, that is, benzylation of the 2β-OH group, removal of the 3-O-acetyl
group, and cleavage of the 28-benzyl ester yielded the oleanane scaffold 21 in 91%
yield. By following this synthetic route, the triterpene core (21) of lobatoside E was
realized from natural oleanolic acid (14) in 19 steps with a 30% overall yield.
2. Synthesis of Carbohydrate Building Blocks
Carbohydrate building blocks, including both donors and acceptors, are generally
derived from commercially available sugar sources.24 Alternatively, de novo synthesis
Scheme 3. Synthesis of the triterpene core (21) of lobatoside E.

can be used to access carbohydrate building blocks that are orthogonally protected,
especially for naturally occurring rare sugars.35 By introducing a suitable set of
protecting and leaving groups, carbohydrate components can be efficiently attached
to the aglycones. To date, a wide range of glycosyl donors have been successfully
applied to the synthesis of saponins.21,23–25 These donors may be categorized
by their leaving groups and include glycosyl halides,36 trichloroacetimidates,37
N-phenyl trifluoroacetimidates,38 thioglycosides,39 sulfoxides,40 glycals,41 phosphate
derivatives,42 1-acyl sugars,43 1-hydroxyl sugars,44 1,2-anhydro sugars,45 orthoesters,46
and ortho-alkynylbenzoates.47 In order to describe the synthesis of carbohydrate
building blocks involved in the total synthesis of complex saponins, the preparation
of some typical sugar units, including both donors and acceptors, is presented in the
following section.
In the first reported synthesis of goniopectenoside B, a starfish saponin, the
preparation of the D-xylose donor (25) commenced from the commercially available
1,2-O-isopropylidene-α-D-xylofuranose 22 (Scheme 4).48 Preliminary functional-
group manipulation on 22 by trityl protection of the primary alcohol, benzyl protec-
tion at the C-3 position, and removal of the trityl group provided compound 23 in
Scheme 4. Preparation of the D-xylose building block (25) for the synthesis of goniopectenoside B.
81% yield. Exposure of 23 to acetic acid at elevated temperature led to cleavage of

the isopropylidene group and simultaneous equilibration to its pyranose form, which
was acetylated to afford compound 24 in 85% yield. The anomeric acetyl group of
24 was selectively removed in the presence of ethylenediamine, and the correspond-
ing hemiacetal intermediate was allowed to react with CCl3CN to yield the target
trichloroacetimidate donor 25 in 78% yield. This approach provides the D-xylose
donor 25 from the commercially available D-xylofuranose derivative 22 in seven
steps (54% overall yield).
For the synthesis of lobatoside E, the L-arabinose building block (29) was prepared
from L-arabinose 26 (Scheme 5).32 Peracetylation followed by bromination at the
anomeric position and subsequent orthoester formation yielded the fully protected
L-arabinose derivative 27. Substitution of the 3,4-O-Ac group by 3,4-O-Bn furnished
compound 28 in high yield. This compound was finally converted into the target
glycosyl bromide (29) in three steps, involving acidic cleavage of the orthoester, 2-O-
acetylation, and anomeric bromination employing the TMSBr reagent. This synthetic
route started from the parent L-arabinose (26) and led to the L-arabinose donor 29 in
46% overall yield over eight steps.
Scheme 5. Preparation of the L-arabinose building block (29) for the synthesis of lobatoside E.
To construct the architecture of QS-21Aapi, D-fucose (30) was used as the starting
material for synthesis of the D-fucose acceptor 33 (Scheme 6).49 The parent D-fucose
(30) was first transformed into the 2,4-diol 31 by anomeric allylation and regioselec-
tive benzylation via the stannylene acetal intermediate. The equatorial 2-OH group of
31 was masked as its TBS ether, while the 4-OH group was acetylated, thus yielding a
fully orthogonally protected intermediate 32. Subsequent allyl-group removal
(Pd(PPh3)4, Et2Zn), TBS cleavage (TBAF), and anomeric silylation (TIPSCl) pro-
vided the D-fucose acceptor 33 in a modest (29%) yield over three steps. Following
this approach, the D-fucose building block 33 was obtained in seven steps from
D-fucose (30) in 16% overall yield.
D-Quinovose (37) is a key acceptor intermediate in the synthesis of an
asterosaponin, and it can be prepared from commercially available 1,2:5,6-
di-O-isopropylidene-α-D-glucofuranose (34, Scheme 7).50 Compound 34 was first
converted into the 6-deoxy-5-ol 35 via an efficient four-step procedure involving
3-O-benzylation, regioselective cleavage of the 5,6-isopropylidene group, and
tosylation of the primary 6-OH followed by reductive cleavage with LiAlH4.
Acidic treatment of intermediate 35 removed the 1,2-isopropylidene group and
allowed equilibration of 35 into its pyranose form, resulting in the formation of
3-O-benzyl-D-quinovopyranose 36 (94% yield). Finally, selective TBS protection
Scheme 6. Preparation of the D-fucose building block (33) for the synthesis of QS-21Aapi.
Scheme 7. Preparation of the D-quinovose building block (37) toward the synthesis of an asterosaponin.
of the anomeric alcohol followed by acetylation of the 2-OH and 4-OH groups and
removal of the 3-benzyl group by hydrogenolysis furnished the D-quinovose
acceptor 37 in 62% yield (three steps). This approach enabled synthesis of the
D-quinovose acceptor 37 from the glucofuranose diacetal 34 in eight steps and
35% overall yield.
To date, a number of D-digitoxose donors, such as compounds 42, 45, and 50, have
been successfully applied to the synthesis of digitoxin, relying on de novo synthesis or
structural modification of available sugars. As an example, McDonald and coworkers
reported in 2000 a de novo method to access the D-digitoxose glycal 42
(Scheme 8A).51 Starting from ketoeneyne 38, enantioselective 1,2-reduction followed
by epoxidation provided the epoxyalkynol 39 in 69% yield. Then, regioselective anti-
addition of benzoic acid and subsequent desilylation with TBAF afforded diol 40 in
almost quantitative yield. Silylation of diol 40 with TBSCl, followed by DIBAL
reduction of the ester group, yielded intermediate 41. The targeted glycal 42 was
finally obtained by cycloisomerization of 41 in the presence of W(CO)6 under light
irradiation at 350 nm. This procedure provides the D-digitoxose glycal donor 42 from
38 in 63% yield over seven steps.
Scheme 8. Preparation of D-digitoxose building blocks 42, 45, and 50 for the synthesis of digitoxin.
In 2006, another de novo approach was developed by O’Doherty’s group to access

the D-digitoxose donor 45 (Scheme 8B).52 Their synthesis started with the acylfuran
43, which was converted into pyranone 45 via a efficient three-step sequence: (1)
enantioselective Noyori reduction; (2) Achmatowicz oxidation using NBS; and (3)
Boc protection at elevated temperature.53 Thus, this de novo approach was quite
effective for synthesis of the D-digitoxose building block 45 in only three steps and
in high yield.
In 2011, Ma and colleagues prepared the D-digitoxose o-alkynylbenzoate donor 50
through structural modification of methyl α-D-glucopyranoside (46, Scheme 8C).54
First, a four-step sequence, comprising (1) 4,6-O-benzylidene protection, (2) 2,3-di-
O-tosylation, (3) 2,3-anhydro-allopyranoside formation, and (4) reduction by LiAlH4,
provided the 2-deoxy-glucopyranoside intermediate 47. Then, protection of 3-OH as
the 3-OMBz derivative, followed by treatment with NBS/AIBN, afforded the
6-bromide derivative 48 in high yield. Simultaneous reductive cleavage of the
CdBr bond at C-6 and reduction of the two ester groups of 48 with LiAlH4, followed
by 3,4-O-silylation with TBDPSCl, provided the D-digitoxose framework in product
49 in an excellent yield. Finally, the o-alkynylbenzoate donor 50 was obtained by
successive acidic hydrolysis of the glycoside and subsequent esterification at C-1.
This synthetic route provides the D-digitoxose building block 50 from methyl α-D-
glucopyranoside (46) in 47% yield over 10 steps.
As part of the synthetic effort toward QS-21, D-xylose (51) was selected as the
starting material for access to the 1-thio-D-apiose donor 54 (Scheme 9).55 Acid-
catalyzed acetonation of D-xylose (51) with 2,2-dimethoxypropane followed by an
aldol-Cannizzaro reaction led to the diol 52. Then, selective acidic hydrolysis and
oxidative cleavage with NaIO4 furnished the hemiacetal intermediate 53. This com-
pound was finally converted into the acetylated ethyl 1-thio-D-apiofuranose donor 54,
with the concomitant formation of the isomeric L-apiose derivative 55, in three steps
involving removal of the isopropylidene group, acetylation, and thioglycoside forma-
tion. Based on this method, the D-apiose building block 54 was synthesized from
D-xylose 51 in 12% yield over seven steps.
3. Assembly Strategies
One of the key steps in the synthesis of saponins is the stereoselective construction
of the glycosidic linkage between the carbohydrate component and the agly-
cone.21,23–25 Depending on which step the glycosidic linkage is introduced, two
basic tactics can be established for the synthesis of a monodesmosidic saponin
(Fig. 4).
Scheme 9. Preparation of the D-apiose building block (54) for the synthesis of QS-21.
The most straightforward way to synthesize monodesmosides is a convergent tactic

that couples a full-length sugar chain with a prefabricated aglycone (Tactic I, Fig. 4).
This convergent tactic is favored when the aglycone is of difficult access, or is
sensitive to the reagents and conditions involved in further elongation of the sugar
chain. The other strategy is the linear tactic, which attaches the carbohydrate building
blocks to the aglycone in a stepwise manner (Tactic II, Fig. 4). This linear tactic
ensures stereospecific formation of the naturally occurring 1,2-trans-glycosidic link-
age between the sugar unit and the aglycone by employing the neighboring-group
participation (NGP) effect. This tactic is thus especially useful for the construction of
an array of saponins bearing (1 ! 2)-linkage at the reducing end of the sugar chain,
Fig. 4. Two general tactics used for the synthesis of monodesmosidic saponins.
where the NGP effect can always be exploited at each glycosylation step to avoid the
formation of anomeric mixtures.
Furthermore, both convergent and linear tactics for the preparation of monodesmo-
sides can be applied for the synthesis of bidesmosides. When a monodesmoside is
synthesized via the convergent Tactic I or the linear Tactic II, it can be further
extended to a bidesmoside by either a convergent or a linear approach.
It is important to note that there is not a universal tactic that can ensure the efficient
assembly of a saponin. All of the aforementioned tactics have advantages and
drawbacks, and the choice of the tactic is highly dependent on the specific structures
of the saponins.
4. Protecting-Group Strategies
The manipulation of protecting groups for the alcohol, amine, and carboxylic acid
functions present in sugars constitutes an indispensable part of contemporary carbo-
hydrate chemistry.22 The protecting-group pattern employed in oligosaccharide syn-
thesis not only serves for orthogonal application of the different functional groups, but
it also exerts drastic influence on the yields and the α/β selectivities of the glycosyl-
ation reactions in terms of match/mismatch between donors and acceptors.
Because of the multiple functional groups present in carbohydrates, especially
hydroxyl groups, a large range of protecting groups are required for full
differentiation and to permit the manipulation of one or more functional groups in a

single step. In the synthesis of saponins, two types of protecting groups, namely,
temporary and permanent, are frequently used to differentiate alcohols, carboxylic
acids, and amines. Temporary protecting groups need to be introduced easily and be
removed selectively without affecting the other protecting groups. Ideally, they
should be orthogonal to each other, and be stable under the reaction conditions used
for modification of sugars. Permanent protecting groups need to withstand all of the
glycosylation conditions and functional-group transformations until their cleavage at
a late stage of the synthesis. In addition, their installation and deprotection need to be
performed under mild conditions in high yields. As exemplified in Scheme 10, the
temporary protecting groups T1, T2, and T3 are removed to generate the corresponding
glycosyl acceptors used for the subsequent glycosylation. In this step, T2 and T3
should be orthogonal to permit the synthesis of branched oligosaccharides. After
constructing the protected skeleton of the saponin, all permanent protecting groups
are then cleaved to furnish the target saponin.
Scheme 10. Schematic protecting groups manipulation in saponin synthesis.

In the past several decades, a large collection of protecting groups has been used as
temporary and permanent protecting groups in the production of a variety of sapo-
nins.21,23–25 Temporary protecting groups generally include those of the ester-type
(Lev, ClAc, Ac, Bz, NBz, and AZMB), ether-type (Tr, PMB, MOM, All), silyl ether-
type (TBS, TES, TIPS, and TBDPS), and acetal-type (isopropylidene, benzylidene),
whereas permanent protecting groups consist mainly of ester-type (Ac, Bz, MBz, and
Piv), ether-type (Bn, PMB, Tr, All, Me), silyl ether-type (TBS, TES, and TBDPS),
and acetal-type (isopropylidene, benzylidene) groups as well as amino protecting
groups (N-Phth, N3) (Fig. 5). It is noteworthy that some protecting groups (such as Ac,
Bz, PMB, All, Tr, TBS, TES, TIPS, TBDPS, isopropylidene, and benzylidene) can
serve as either temporary or permanent protecting groups, according to the particular
situation.
Appropriate choice of the protecting pattern is important and crucial for the success
of the synthesis, since it can significantly affect the stereo-, chemo-, and regioselec-
tivity, as well as the yield of the glycosylations.56 It is of particular note that ester-type
Fig. 5. Commonly used temporary and permanent protecting groups in saponin synthesis.
protecting groups, such as Ac, Bz, Lev, and AZMB, introduced at C-2 in a glycosyl
donor, can ensure the formation of a 1,2-trans-glycosidic linkage because of the NGP
effect, whereas the coupling of an aglycone with a glycosyl donor containing a
nonparticipating C-2 substituent at the reducing end often leads to α/β-anomeric
mixtures. A representative example is depicted in Scheme 11. When the aglycone
acceptor 57 was coupled with the perbenzoylated L-rhamnopyranosyl-(1 ! 3)-L-
arabinopyranosyl imidate 56, bearing 2-benzoyl group (NPG) at the L-arabinose
residue, the 1,2-trans glycoside 59 was formed exclusively.57 In contrast, coupling
of aglycone acceptor 57 with the perbenzoylated L-rhamnopyranosyl-(1 ! 2)-L-
arabinopyranosyl imidate (58) bearing a nonparticipating C-2 substituent under the
same conditions led to an α/β-mixture of glycosides 60 in 89% yield, in which the 1,2-
cis anomer was the major product.57
In addition to affecting the outcome of the glycosylation step, the overall choice
of the protecting-group pattern is also critical to success in the synthesis of saponins.
Scheme 11. Influence of NPG and nonparticipating (1 ! 2)-linkage on the stereoselectivity of the
glycosylation reaction.
The synthesis of saponins in an efficient and robust manner requires optimal

selection of protecting groups, based on a thorough understanding of the properties
of each one. Sometimes, only one inappropriate protecting group can ruin an entire
synthetic plan. As an example, in the synthesis of ginsenoside Ro, it was found that
TEMPO-based oxidation of the bidesmoside 61, containing a 30 -OAc group in the
middle glucose residue, gave a complex mixture, presumably attributable to migra-
tion of the acetyl group to the adjacent hydroxyl groups (Scheme 12).58 However,
when the 30 -OAc group was replaced by a 30 -OBz group (which is less prone to
acyl-group migration under basic conditions), the TEMPO-based oxidation of 62
proceeded smoothly and led to the desired carboxylic acid derivative 63 in 89%
yield.59
In 2006, Gin and coworkers reported that global deprotection of the QS-21Aapi
skeleton 64 under various conditions of acidic hydrolysis–hydrogenolysis yielded
only trace amount of QS-21Aapi (66) because the acid-mediated cleavage of the
isopropylidene group installed in the apiose moiety could not be effected without
compromising the glycosidic linkages (Scheme 13).49 However, when the isopropy-
lidene group was substituted by a benzylidene group (compound 65), the synthesis of
QS-21Aapi could be successfully completed.
Scheme 12. Protecting groups effective in the synthesis of ginsenoside Ro.

Scheme 13. Protecting groups effective in the total synthesis of QS-21Aapi (66).
III. Synthesis of Plant Saponins
1. Steroid Saponins
a. Spirostan Type.—Spirostan-type saponins are the most common steroid sapo-

nins in plants. They possess a hexacyclic aglycone, such as diosgenin or tigogenin, in
which the 3-OH group is usually decorated with an oligosaccharide chain.
Dioscin (67), one of the most widely distributed steroid saponins in plants, exhibits
antitumor, antiviral, antifungal, anti-inflammatory, and immunostimulatory activities
and has been found in a number of traditional Chinese herbal medicines.60 A variety
of approaches have been developed to produce dioscin (67),61–67 among which the
most straightforward and efficient one was achieved in five steps from diosgenin 1
(Scheme 14).63 The synthesis started with the TMSOTf-catalyzed glycosylation
reaction between diosgenin (1) and the perbenzoylated glucopyranosyl N-phenyl
trifluoroacetimidate donor 69. This reaction afforded the corresponding 3-O-β-
glycoside 70 in 92% yield. Then, sequential removal of benzoyl groups and selective
30 ,60 -OPiv protection provided the 20 ,40 -diol acceptor 71 in 60% yield. Coupling of 71
Scheme 14. Efficient syntheses of dioscin (67) and polyphyllin D (68).

with peracetylated L-rhamnopyranosyl N-phenyl trifluoroacetimidate (72) furnished

the desired monodesmosidic trisaccharide derivative in 66% yield, global deprotec-
tion of which provided dioscin (67).
Polyphyllin D (68) is a congener of dioscin (67) and is found in various Paris
species. Among the spirostan-type saponins, it demonstrates the most potent
antitumor effects.68 Its synthesis shares the same 20 ,40 -diol acceptor 71
(Scheme 14).61,62,69 This acceptor was first subjected to a selective rhamnosylation
at the 20 -OH position with perbenzoylated L-rhamnopyranosyl bromide (73), in the
presence of AgOTf, followed by a second glycosylation with peracetylated
L-arabinofuranosyl trichloroacetimidate (74), which took place at the remaining
40 -OH group under the promotion of BF3OEt2. A global deprotection of the ester
groups generated the target polyphyllin D (68).
To further investigate the SARs and the mechanisms of action of diosgenyl
saponins, especially dioscin analogues, a collection of diosgenyl glycosides (75–96)
bearing different sugar units and branched structures has been synthesized, using
similar methods (Fig. 6).70–72
Recently, such dioscin bioisosteres as solamargine (97) and 26-thio- and
26-seleno-dioscins (102, 103) have attracted attention because of their good antican-
cer activities.73–76 As an example, solamargine (97), a major glycoalkaloid found in
Solanum species, is a 26-amino-dioscin. Its amino-aglycone, also called solasodine
(98), can be elaborated from diosgenin (1) in nine steps and with a 25% overall yield
(Scheme 15).74 Then, glycosylation promoted by NIS/AgOTf of solasodine (98) with
the partially protected thioglycoside donor 99 led to the 3-O-β-glycoside 100 in 65%
yield. Coupling of 100 with peracetylated L-rhamnopyranosyl bromide (101) under
AgOTf-promotion afforded the desired 20 ,40 -O-branched trisaccharide saponin in
81% yield. Finally, sequential PMB-removal/deacetylation provided solamargine
(97) in 80% yield.
Diosgenin (1) was also selected as the starting material in the synthesis of 26-thio-
and 26-seleno-dioscins (102 and 103) in order to prefabricate their steroid cores,
compounds 104 and 105, respectively (Scheme 16).75 Interestingly, couplings of the
trisaccharide trichloroacetimidate donor 106 with aglycone acceptors 104 and 105
were catalyzed by HB(C6F5)4 in a solvent mixture of PhCF3 and t-BuCN–CH2Cl2. In
this manner, the corresponding 3-O-glycosides 107 and 108 were obtained in good to
excellent yields, with the β anomers predominating.77 Finally, full removal of the
ester protecting groups under Zemplén conditions generated the 26-thio- and
26-seleno-dioscins 102 and 103 in 95% and 78% yields, respectively.
Desgalactotigonin (109) is a monodesmosidic spirostan saponin isolated from the
purple foxglove (Digitalis purpurea L.), which has long found a wide range of
Fig. 6. A collection of synthetic diosgenyl saponins (75–96) for SAR studies (Odios ¼ 3-O-diosgenin).
medicinal uses.78 Its synthesis started from tigogenin (111), a spirostan aglycone
(Scheme 17).79 The 1,2-anhydro galactose derivative 110 was glycosylated with
tigogenin (111) under promotion by ZnCl2 to provide the 3-O-β-glycoside 112 in
89% yield. After converting glycoside 112 into the 40 -OH acceptor 113 via a
standard six-step manipulation, the tri-n-butylstannyl ether of 113 was coupled
in situ with the disaccharide 1,2-epoxide 114, mediated by zinc triflate. The corre-
sponding trisaccharide bearing a 200 -OH group was then condensed with the glucosyl
fluoride derivative 115 under promotion by stannous triflate, thus affording the 200 -
O-branched tetrasaccharide 116 in 56% yield. Final global deprotection of the
benzoyl, benzyl, and benzylidene groups furnished desgalactotigonin (109) in excel-
lent yield.
Scheme 15. Synthesis of solamargine (97).
Recently, based on a one-pot strategy, Gu and coworkers achieved the synthesis of

the tigogenin triglycoside (117) and several analogues (117a–c), with the aim of
evaluating their antitumor activities (Fig. 7).80
In addition, a concise synthesis of triglycosides (118–120) of sarsasapogenin,
bearing a rare 40 ,60 -dibranched oligosaccharide structure, was also reported, employ-
ing a direct transglycosylation reaction (Fig. 8).81
The pennogenin glycoside (121), first isolated from the rhizome of Paris species,
has been prescribed in such traditional Chinese medicines as Chonglou, since it
displays potent antitumor properties.82 Its first synthesis was achieved in 2012 via a
convergent tactic comprising assembly of the trisaccharide trichloroacetimidate 122
with the pennogenin aglycone 123 under catalysis by TMSOTf (Scheme 18).83
Surprisingly, this coupling gave rise to the 3-O-β-glycoside 124 in 87% yield as the
predominant anomer, even though the trisaccharide donor 122 lacked a participating
neighboring group. Final acidic cleavage of the benzylidene group followed by
deacetylation furnished the fully deprotected glycoside 121 in 84% yield.
Xiebai saponin I (125), which occurs in the bulbs of Allium chinense, is the main
active principle of the traditional Chinese medicine “Xiebai” for treating chest pain
and heart asthma.14,84 The aglycone of Xiebai saponin I, laxogenin (126), was readily
prepared from diosgenin (1) in a short four-step procedure in 69% overall yield
(Scheme 19).63 Glycosylation of laxogenin (126) with the benzoylated glucose
N-phenyl trifluoroacetimidate 69 led to the 3-O-β-glycoside 127 in excellent yield,
and this was then transformed into the 40 ,60 -diol acceptor 128 in four steps (78%).
Scheme 16. Convergent synthesis of 26-thio- and 26-seleno-dioscins (102 and 103).
Scheme 17. Synthesis of desgalactotigonin (109).
Fig. 7. Synthetic tigogenin triglycoside (117) and analogues (117a–c) (Otigo ¼ 3-O-tigogenin).
Fig. 8. Synthetic sarsasapogenin triglycosides (118–120).
The final three steps comprised (1) regioselective glycosylation at the 60 -OH position
with L-arabinopyranosyl N-phenyl trifluoroacetimidate 129; (2) coupling at the
remaining 40 -OH position with the D-xylopyranosyl trifluoroacetimidate 130; and
(3) removal of the benzoyl groups, to provide the target Xiebai saponin I (125).
Maidong saponin C (131), isolated from the tuber of Liriope muscari, shows strong
anti-inflammatory and immunopharmacological activities and is considered as the
major active ingredient of the traditional Chinese medicine “Maidong”.85 The con-
vergent synthesis of Maidong saponin C (131) relied on (25R)-ruscogenin derivative
(132) as the key intermediate, which can be prepared from diosgenin (1) in 8% yield
over six steps (Scheme 20).86 The coupling of 132 with the trisaccharide imidate 133
under a “normal procedure”—promoter being added slowly to a mixed solution
of donor and acceptor—produced only a trace amount of the desired product,
Scheme 18. Synthesis of pennogenin glycoside (121).
Scheme 19. Synthesis of Xiebai saponin I (125).
Scheme 20. Synthesis of Maidong saponin C (131).
attributable to hindrance of the 1-β-OH group in 132. However, under an “inverse

procedure” wherein 133 was slowly added to a mixed solution of acceptor 132 and
promoter, the target 1-O-glycoside 134 was obtained as the major β anomer, in 56%
yield. Finally, removal of the TBS group in 134 with TMSOTf (2 equiv., 78 C),
followed by saponification of ester groups with sodium methoxide furnished Maidong
saponin C (131) in 85% yield.
b. Furostan Type.—From the viewpoint of biosynthesis, furostan-type saponins
are thought to be the precursors of the corresponding spirostan-type saponins in
plants.1 Furostan saponins of natural occurrence are bidesmosides in which a glucose
monosaccharide is attached at the 26-OH group of the aglycone (with few excep-
tions), and an oligosaccharide chain is usually connected at 3-OH.
In 2001, Liao and colleagues developed the first synthetic route to furostan
saponins by stepwise introduction of the sugar moieties at the C-3 and C-26 posi-
tions.87 After this work, Cheng and coworkers completed the synthesis of methyl
protodioscin (135),88 isolated from fresh rhizomes of Dioscorea gracillima MiQ. This
compound displays a similar level of antitumor activities to that of dioscin (67), but
without hemolytic effects.89 Its aglycone core was synthesized from diosgenin (1),
which was transformed after four steps into an equilibrium mixture of spiroketal 136a
and dione 136b in which the key stage is the oxidative opening of the spirostan E and
F rings (Scheme 21). An attachment of the sugar at the C-26 position of the aglycone
was realized with the aforementioned equilibrium mixture and glucopyranosyl tri-
chloroacetimidate 137, thus furnishing 26-O-β-glucoside 138 in 62% yield. After
TBDPS deprotection, the 3-OH aglycone acceptor 139 was glycosylated with the
trisaccharide thioglycoside 140 under promotion by NIS and TfOH, which fortunately
yielded the desired 3-O-β-glycoside (52%). Finally, selective reduction of the
16-ketone with NaBH4 and removal of ester groups with sodium methoxide provided
methyl protodioscin (135) in 58% yield (two steps).
In 2006, Li and Yu developed a facile approach for converting spirostan saponins
into furostan saponins, as exemplified by the transformation of the readily available
dioscin pivalate (141) to methyl protodioscin (135) in six steps and a 21% overall
yield (Scheme 22).90 The advantage of this approach is in avoiding the stereocon-
trolled installation of the chacotriosyl moiety, which lacks a neighboring participatory
group, onto the steroidal 3-OH at a late stage. The E and F rings of the readily
available dioscin pivalate (141), which already contains the chacotriosyl moiety at the
3-OH position, were oxidatively opened in order to install the glucose residue at the
26-OH position.
Cyclic ether mimetics of methyl protodioscin (135) that are more stable, such as
compounds 144–147, were concisely synthesized for antitumor assessment (Fig. 9).91
Scheme 21. Synthesis of methyl protodioscin (135).
Furthermore, such monodesmosidic furostan saponins as icogenin and its analogues

(which bear the same steroidal aglycone as 135 but different branched sugar chains
attached either at the 3-OH or at the 22-OH group) were synthesized in order to
evaluate their cytotoxic effects.92
Timosaponin BII (148), isolated from the rhizomes of Anemarrhena asphodeloides
Bunge, is claimed to have pharmaceutical activities against dementia and stroke, and
the abilities to lower blood-sugar levels and capture free radicals.93 In 2009, Du and
colleagues reported its synthesis, starting from the readily available sarsasapogenin
aglycone 149 (Scheme 23).94 In a two-step procedure involving (1) 3-OTBS protec-
tion and (2) oxidative opening of the E and F rings, spirostan 149 was transformed
into an equilibrium mixture of spirostan (150a) and cholestan (150b). Catalyzed
by TMSOTf, this equilibrium mixture was glycosylated with donor 137, leading to
26-O-glycoside 151 in 80% yield. After removal of the silyl group at the C-3 position
Scheme 22. Facile conversion of dioscin pivalate (141) to methyl protodioscin (135).
Fig. 9. Synthetic mimics (144–147) of methyl protodioscin (135).
using BF3OEt2, the 3-OH acceptor 152 was sequentially coupled with the partially
protected thioglycoside 153 and peracetylated imidate 154. The fully protected
bidesmosidic cholestan 155 was obtained after acetylation of the 400 -OH position of
the galactose moiety. Construction of the furostan core was achieved after conversion
of dione 155 into the hemiketal with NaBH4, saponification of the ester groups, and
Scheme 23. Synthesis of timosaponin BII (148).
boiling under reflux in a mixture of acetone and water, thus furnishing timosaponin
BII (148) in 65% yield (three steps).
c. Cholestan Type.—Cholestan-type saponins, an important class of steroid sapo-
nins in plants, contain a tetracyclic cholesterol skeleton, generally decorated with
sugar moieties at the C-3, C-16, and/or C-26 positions.
Sashida and coworkers in 1992 isolated OSW-1 (156) from the bulbs of Ornitho-
galum saudersiae cultivated in southern Africa.95 It possesses a unique 16β,17α-
dihydroxycholest-22-one aglycone and an acylated disaccharide moiety attached to
the 16β-OH group and displays exceptionally potent antitumor activity that is 10–100
times more potent than such clinically used anticancer drugs as cisplatin and
taxol.96,97 As a consequence, considerable effort has been devoted toward its
synthesis.96
In 1999, Deng and coworkers completed the first total synthesis of OSW-1 (156),
starting from the commercially available dehydroisoandrosterone 7 (Scheme 24).30
Dehydroisoandrosterone 7 was first transformed into the cholestan aglycone 13
(Scheme 2), which was then glycosylated with the disaccharide trichloroacetimidate
157 under promotion by TMSOTf, thus producing the protected OSW-1 158
Scheme 24. First total synthesis of OSW-1 (156).
(69% yield). Subsequent removal of the protecting groups (TBS, TES, and ethylene
glycol ketal) was achieved smoothly with Pd(MeCN)2Cl2 without affecting the acetyl
and MBz groups, thus providing the target OSW-1 (156) in 79% yield. Subsequent to
this work, other approaches have been developed for synthesizing OSW-1, wherein
the glycosylations were realized in a similar manner.98–103
Numerous analogues of OSW-1 (156) have been chemically synthesized for SAR
and mechanism of action studies of OSW-1.96 As depicted in Fig. 10, four types of
analogues were designed. The first type comprises only modification of the carbon
chain at the C-17 position of the steroid skeleton of OSW-1 (analogue 159).104 The
second type of analogues bears the same cholestan core as OSW-1, but with a
modified sugar chain at the C-16 position (analogue 160).104c,d Analogues of the
third family contain the same sugar chain, as well as the same carbon chain at C-17 as
OSW-1, but with a modified cholestan parent nucleus (analogue 161).105 In the fourth
class, the original sugar chain of OSW-1 is attached to different aglycone cores
(analogue 162).106
Candicanoside A (163) belongs to a group of minor cholestan glycosides bearing a
rearranged steroidal side chain.107 It was isolated from the bulbs of Galtonia candi-
cans and has shown remarkable antitumor activities, comparable to the clinical
anticancer agents etoposide and methotrexate.107,108 As illustrated in Scheme 25,
Tang and Yu accomplished its total synthesis in 2007, employing dehydroisoandros-
terone (7) to construct the steroid scaffold 164 in 23 steps.109 Under promotion by
Fig. 10. Four types of synthetic analogues (159–162) of OSW-1.
TfOH, the coupling of 164 with glucosyl imidate 165 (containing the neighboring
participating 2-O-AZMB group) generated the corresponding 3-O-β-glycoside 166 in
excellent (96%) yield. Then, deprotection of the 20 -O-AZMB under Staudinger
conditions provided acceptor 167, which was condensed with the L-rhamnosyl imi-
date 168 under catalysis by TfOH in toluene, thus leading to disaccharide 169 in 81%
yield. Finally, full deprotection of the ester groups with sodium methoxide afforded
candicanoside A (163) in 90% yield.
Osladin (170), isolated from the rhizome of the European fern Polypodium
vulgare, is a bidesmosidic saponin 500 times sweeter than sucrose.110 In 1995, its
total synthesis was completed by sequential attachment of the sugar moieties
(Scheme 26).111 Starting from steroidal aldehyde 171, the cholestan aglycone 172
was constructed in seven steps (45% overall yield). It was then glycosylated with
the partially protected glucosyl chloride 173 in the presence of TfOH and tetra-
methylurea (TMU), in boiling 1,2-dichloroethane. The resulting 3-O-β-glycoside
174 (57%), bearing a free hydroxyl group at the C-2 position of the saccharide,
was then condensed with the benzylated L-rhamnosyl chloride 175 in neat TMU at
Scheme 25. Total synthesis of candicanoside A (163).
80 C to give the monodesmosidic disaccharide 176 in 81% yield. Reduction of

lactone 176 by DIBAL, followed by basic treatment, led to formation of the more
stable equatorial 25-methyl product 177. Glycosylation between hemiacetal acceptor
177 and donor 175 under AgOTf/TMU conditions produced the desired bidesmosi-
dic trisaccharide derivative 178 stereoselectively in 61% yield. Next, sequential
hydroboration–PDC oxidation transformed the 5,6-double bond into the 6-ketone,
and finally, hydrogenolytic removal of the benzyl protecting groups yielded the
target osladin (170).
Scheme 26. Total synthesis of osladin (170).
In addition, other cholestan-type bidesmosides, such as kryptogenyl saponins (179)

and aethioside C (180) bearing an aromatic E ring, have also attracted the attention of
carbohydrate chemists (Fig. 11).112,113
d. Cardenolide Type.—Cardenolide saponins constitute a class of cardiac glyco-
sides used for more than 200 years for the treatment of heart failure and abnormal
heart rhythms. They typically bear a five-membered unsaturated lactone ring, such as
butenolide, at the C-17 position of the steroid core, and a mono- or oligo-saccharide,
consisting mostly of deoxy sugars, at the C-3 position.114
Digitoxin (181), usually extracted from the leaves of D. purpurea (purple fox-
glove), is a structural prototype of the cardenolide saponins widely prescribed for
treating congestive heart failure and cardiac arrhythmias, since it can inhibit the
enzyme Na+/K+-ATPase in myocardiac cells.115 In addition, digitoxin exhibits anti-
cancer activity and it could be a potential neuroprotective agent.116 Syntheses of
digitoxin and its congeners bearing various sugar moieties have attracted great
Fig. 11. Other synthetic cholestane-type bidesmosides (179 and 180).
interest and have provided a deep understanding of the structural requirements for
biological activity in the cardiac glycosides.52,54,117–121 Among these extensive
efforts, the synthesis of natural digitoxin (181) has been accomplished by five
research groups.52,54,117–119
In 1985, the Wiesner group reported the first synthesis of digitoxin (181) via a
linear tactic, starting from the furyl precursor 182 of digitoxigenin (Scheme 27).117
Glycosylation of 182 with the hemiacetal 183 under promotion by p-TsOH gave the
3-O-glycoside 184 as an anomeric mixture (β/α ¼ 3) in modest (48%) yield. Replace-
ment of the protecting group at the C0 -3 position, followed by benzyl-group depro-
tection, yielded the 40 -OH acceptor 185, ready to couple with thioglycoside 186
under promotion by HgCl2 and CdCO3. The resulting disaccharide 187 was obtained
in 61% yield, with a preponderance for the β anomer, presumably attributable to a
remote 1,3-participation effect. After removal of the 400 -p-nitrobenzyl group using a
saturated solution of ammonia–methanol, elongation of the sugar chain was realized
by using thioglycoside 189 under similar conditions of HgCl2/CdCO3 promotion: the
protected β-linked trisaccharide 190 was obtained selectively in moderate (58%)
yield. Digitoxin (181) was finally isolated after a three-step procedure involving (1)
MBz deprotection using LiAlH4; (2) oxidation of the furyl residue with
m-chloroperoxybenzoic acid; and (3) reduction by NaBH4 in order to generate the
butenolide moiety of the cardenolide backbone.
The second synthesis of digitoxin (181) was completed by the McDonald group in
2001 using a de novo approach for constructing the sugar chain (Scheme 28).118 Thus,
acid (Ph3P–HBr)-catalyzed glycosylation of glycal 42 with alkynyl alcohol 191 gave
the 2-deoxyglycoside 192 with high β-selectivity. Debenzoylation of 192 with
DIBAL and subsequent tungsten-catalyzed, endoselective cycloisomerization of the
Scheme 27. First synthesis of digitoxin (181) by the Wiesner group.
Scheme 28. Synthesis of digitoxin (181) by the McDonald group.
alkynol generated disaccharide glycal 194, which was further elaborated into glycal
195. By employing an iterative acid-catalyzed glycosylation and tungsten-catalyzed
alkynol cycloisomerization, the trisaccharide glycal 198 was efficiently obtained from
glycal 195 in 56% yield (four steps). Acid-catalyzed coupling of 198 with digitoxi-
genin (199) afforded the protected product 200 in 82% yield as an anomeric mixture,
with the β anomer as the major product (β/α ¼ 3/2). Finally, global deprotection of the
silyl and acetyl groups provided the target digitoxin (181).
In 2006, O’Doherty’s group developed a different de novo approach for the linear
construction of the sugar chain of digitoxin (Scheme 29).52 Digitoxigenin (199) was
first coupled with the pyranone 45β under palladium-catalyzed conditions to afford
stereoselectively the corresponding 3-O-β-glycoside 201 (86%). Following a five-step
procedure including (1) Luche reduction, (2) Myers’ reductive 1,3-allylic
transposition,122 (3) diastereoselective dihydroxylation, and (4) a two-step regiose-
lective protection, glycoside 201 was converted into the 40 -OH acceptor 202.
Scheme 29. Synthesis of digitoxin (181) by the O’Doherty group.
Elongation of the sugar chain from the monosaccharide of 202 to the trisaccharide of
digitoxin (181) was achieved by iterative application of this procedure.
In 2011, Ma and coworkers disclosed a route for assembly of digitoxin (181) by
gold(I)-catalyzed glycosylation with glycosyl o-alkynylbenzoate donors
(Scheme 30).54 Thus, gold-catalyzed glycosylation of digitoxigenin (199) with the
digitoxosyl o-cyclopropylethynylbenzoate derivative 50, containing the bulky axial
3-OTBDPS group, led to glycoside 206 almost quantitatively, with the β anomer as
the major product. Unmasking of the TBDPS groups in 206 followed by selective
protection of the axial 3-OH with an acetyl group gave 40 -OH acceptor 207, ready for
coupling with another o-alkynylbenzoate donor. Elongation of the sugar chain was
achieved by repetition of the Au(I)-catalyzed glycosylation-protecting group manip-
ulation, leading to the final digitoxin (181) in good overall yield and complete β
selectivity. It is noteworthy that changing the glycosylation solvent from CH2Cl2 to
toluene avoided side reactions, thus allowing formation of the β-glycoside in nearly
quantitative yield.
In 2013, the Zhu group described a synthesis of digitoxin (181) that employed
sequential rhenium(V)-catalyzed glycosylations with glycal donors to elaborate the
sugar chain (Scheme 31).119 The Re(V)-catalyzed glycosylation of 6-deoxy D-allal
derivative 211 with the thioglycoside acceptor 212 having 4-OH free, followed by
removal of the TBS group with TBAF generated the disaccharide 213 having 40 -OH
free in 64% yield (β/α ¼ 8.3). This compound was then ready for glycosylation by
another molecule of the glycal donor 211. By repeating a similar procedure,
Scheme 30. Synthesis of digitoxin (181) by the Yu group.
Scheme 31. Synthesis of digitoxin (181) by the Zhu group.
trisaccharide thioglycoside 214 was synthesized in 77% yield with the β anomer as the
major product (β/α ¼ 7). Then, reductive debenzylation and concomitant reductive
lithiation–elimination with LiDBB, followed by TBS protection afforded the new
trisaccharide glycal donor 215 in 63% yield. Because of the poor solubility of
digitoxigenin (199) in benzene, the glycosylation to couple 215 and 199 was
Scheme 32. Synthesis of Purpurea glycoside A (216) by catalyst-controlled, regioselective glycosyl-

ation of digitoxin (181).
performed in CHCl3 under promotion by Ph3P–HBr, thus generating digitoxin (181)

with modest β-selectivity (β/α ¼ 1.4) and in 48% yield after global deprotection.
Taylor and coworkers have described a catalyst-controlled, regioselective glyco-
sylation approach for access to congeners of digitoxin from digitoxin (181) itself,
enabling the synthesis of novel analogues of cardiac glycosides.121e As illustrated
in the synthesis of Purpurea glycoside A (216), glycosylation between glucosyl
bromide 217 and digitoxin (181), catalyzed by borinic ester 218 and in the presence
of silver oxide as a halide-abstracting agent, proceeded cleanly and regioselectively at
the 4000 -OH position, providing the β-(1 ! 4)-linked tetrasaccharide glycoside 219 in
77% yield (Scheme 32). Finally, all acetyl groups were removed with lithium
hydroxide in order to furnish the naturally occurring Purpurea glycoside A (216) in
73% yield.
Fig. 12. Synthetic cardenolide saponins rhodexin A (220) and ouabain (221).
Other cardenolide saponins, such as rhodexin A (220) and ouabain (221), have also
received attention (Fig. 12).123 Specifically, rhodexin A (220), isolated from the
leaves and roots of the Japanese evergreen Rhodea japonica, possesses potent anti-
proliferative activity. Ouabain (221), isolated from the bark of the African ouabio tree
(Acokanthera ouabio), acts as an endogenous digitalis.
Moreover, cardenolide saponins can also be used as intermediates or precursors in
the synthesis of other steroid saponins. As an example, digoxin (222), a cardenolide
saponin, was employed as the starting material for the assembly of pregnane glycoside
P57 (223), an appetite suppressant isolated from Hoodia plants (Scheme 33).124,125
The advantage of this approach is the use of digoxin, which is commercially available,
and in which the 12β,14β-OH groups are already present on the aglycone. These
groups are usually difficult to install from other steroid sources. After a 16-step
manipulation, digoxin (222) was transformed into hoodigogenin A 224 (11% overall
yield). Coupling of 224 with the cymarosyl o-hexynylbenzoate derivative 225 under
catalysis by Ph3PAuOTf (0.2 equiv.) afforded an α/β-mixture of 3-O-glycoside 226 in
75% yield (β/α ¼ 3.5). The 40 -O-acetyl group of 226β was selectively cleaved by using
Na2CO3–MeOH to give the β-acceptor 227. Under promotion by Ph3PAuOTf, com-
pound 227 was condensed with the disaccharide o-hexynylbenzoate 228 in toluene,
providing monodesmosidic trisaccharide 229 as a mixture of the α and β anomers
(70%, β/α ¼ 1). Finally, removal of the acetyl groups of 229β with KOH in a mixture
of methanol and benzene furnished saponin P57 (223) in 90% yield.
2. Triterpene Saponins
a. Oleanane Type.—Oleanane-type saponins constitute more than half of the

known triterpene saponins. Typically, oleanolic acid and its derivatives are the most
Scheme 33. Total synthesis of saponin P57 (223).
common aglycones, and the sugar chains are attached at the 3-OH and/or 28-CO2H
positions of these pentacyclic triterpenes.1 In the past few decades, most of the
synthetic efforts in the area of triterpene saponins have been directed toward
oleanane-type saponins.24,25a
Oleanane saponins bearing an L-arabinose moiety at the 3-OH position are fre-
quently found in Nature. As an example, ciwujianoside C3 (230), isolated from
leaves of the Chinese medicinal herb Acanthopanax senticosus,126 was synthesized
in 1999 employing a one-pot glycosylation protocol: it constitutes the first synthetic
example of a bidesmosidic triterpene saponin (Scheme 34).127 The fully protected
saponin 235 was efficiently assembled by a one-pot glycosylation protocol (62%
yield), involving (1) coupling of oleanolic 28-trityl ester 231 with the
L-arabinopyranosyl imidate 232, as catalyzed by TMSOTf; (2) cleavage of the trityl
group upon warming up to room temperature; (3) attachment of the glucopyranosyl
imidate 233 to the 28-CO2H position of the aglycone; and (4) addition of in situ-
generated disaccharide thioglycoside 234 to the solution under promotion by NIS and
TMSOTf. The last step is the removal of the ester protecting groups with NaOMe–
MeOH, leading to ciwujianoside C3 (230) in 73% yield.
Another representative example is the oleanane saponin 236, a monodesmosidic
pentasaccharide saponin, isolated from the roots of Pulsatilla chinensis, which dis-
plays potent cytotoxic activity against HL-60, with an IC50 of 2.7 μg/mL.128 Its
Scheme 34. First synthesis of a bidesmosidic triterpene saponin, ciwujianoside C3 (230).
synthesis also employed a one-pot sequential glycosylation as the key stage

(Scheme 35).129 The disaccharide imidate 237 was first glycosylated with the
1-thioglycoside acceptor 238 under TMSOTf catalysis. The resulting trisaccharide
thioglycoside was coupled directly, in one-pot procedure, with the saponin acceptor
239 under promotion by NIS–TMSOTf, to provide the fully protected tetrasaccharide
saponin 240 in 76% yield. Following removal of the 30 ,40 -isopropylidene group in
240, the resulting diol acceptor (which adopted a 1C4 conformation) was condensed
regioselectively at the 4-OH position with glucopyranosyl imidate 137, thus affording
pentasaccharide glycoside 241 in 86% yield. Finally, hydrogenolysis of 241 over
Pd/C, followed by saponification with sodium methoxide, furnished the desired
monodesmosidic pentasaccharide saponin 236 (76% yield, two steps), in which the
4
L-arabinose residue had returned to the normal C1 chair conformation. It should be
noted that numerous analogues of L-arabinose-containing oleanane saponins have also
been synthesized for biological investigations.57,130
Oleanane saponins bearing a D-xylose residue at the 3-OH position also constitute
an important class of triterpene saponins in plants. Flaccidoside II (242), isolated from
the alcohol extracts of Anemone flaccida Fr. Schmidt, is a bioactive component of
Chinese folk medicine “Diwu” used for detoxication.131 In 2008, Du and coworkers
completed the synthesis of flaccidoside II (242) by employing a partially protected
thioglycoside 243 as a key building block (Scheme 36).132 In this work, glycosylation
Scheme 35. Synthesis of monodesmosidic oleanane saponin 236.
of the oleanolic ester 231 with a partially protected thioglycoside (243) promoted by
NIS and TMSOTf gave the saponin acceptor 244 in 70% yield. This compound was
coupled with the L-rhamnopyranosyl imidate 245 under catalysis by TMSOTf to
produce disaccharide glycoside 246 in 75% yield. Successive acid-catalyzed cleavage
of the 28-trityl group in 246 with 80% aqueous acetic acid, TMSOTf-catalyzed
coupling of the resulting acceptor 247 with trisaccharide imidate 248, and subsequent
removal of acetyl and benzoyl groups with sodium methoxide produced flaccidoside
II (242) in 69% yield over three steps.
One year later, the Li group reported a synthesis of flaccidoside II (242) by using a
one-pot sequential glycosylation procedure (Scheme 37).133 The oleanolic ester 231
Scheme 36. Synthesis of flaccidoside II (242) by the Du group.
Scheme 37. Synthesis of flaccidoside II (242) by the Li group.
was first glycosylated with D-xylopyranosyl imidate 249 under promotion by

TMSOTf, providing the corresponding 3-O-monodesmoside. Warming the reaction
mixture to room temperature cleaved the trityl group, leading to the 28-CO2H
acceptor, which was then coupled with trisaccharide imidate 250 to provide the
3,28-O-bidesmosidic saponin 251 in 65% yield. After removal of the Lev group,
acceptor 252 was glycosylated with L-rhamnopyranosyl imidate 245 under TMSOTf
promotion to yield the fully protected flaccidoside II. Removal of the ester protecting
groups gave flaccidoside II (242) (73% yield, two steps). In addition, a range of
analogues of D-xylose-containing oleanane saponins were synthesized for SAR
studies.134
Oleanane saponins containing an N-acetylglucosamine residue at the 3-OH position
are rare in Nature. However, they have been shown to exhibit remarkable cytotoxic
activities and, as a consequence, have attracted attention. For example, the saponin
253, isolated from the rainforest plants Acacia tenuifolia and Albizia subdimidiata in
Suriname, shows significant cytotoxic activity against the A2780 and M109 lung
cancer cell lines, with IC50 values of 0.8 and 1.0 μg/mL, respectively.135
The synthesis was achieved in 2003 by employing a stepwise glycosylation strategy
(Scheme 38).136 Glycosylation of oleanolic ester 254 with the 2-N-
Phth-glucopyranosyl N-phenyl trifluoroacetimidate 255, promoted by TMSOTf, led
to the 3-O-β-glycoside 256 in quantitative yield. The 60 -O-Ac group of the glucos-
amine residue in 256 was then replaced by 60 -O-trityl group in a two-step procedure,
affording the trityl ether 257. Coupling of 257 with the L-arabinopyranosyl thioglyco-
side 258, promoted by NIS/TMSOTf, furnished the desired (100 ! 60 )-linked disac-
charide, which was subjected to selective removal of the Lev group using hydrazine
acetate, and consequently providing the 200 -OH acceptor 259 (68% yield over two
Scheme 38. Synthesis of N-acetylglucosamine-containing saponin 253.

steps). Thereafter, condensation of 259 with the perbenzoylated L-arabinopyranosyl

N-phenyl trifluoroacetimidate 129 under TMSOTf promotion afforded trisaccharide
glycoside 260 in 76% yield. Finally, global deprotection involving (1) conversion of
the 20 -N-Phth group into 20 -N-Ac, (2) removal of the 28-allyl ester group with PdCl2,
and (3) saponification with sodium methoxide led to the target saponin 253.
Moreover, in order to study the SAR of N-acetylglucosamine-containing triterpene
saponins, a library of oleanane saponins having (1 ! 3)-, (1 ! 4)-, or (1 ! 6)-linked
N-acetylglucosamine oligosaccharide moieties has been synthesized by several
groups.137
A typical class of oleanane saponins is represented by the glucuronide oleanane-
type triterpenecarboxylic acid 3,28-O-bidesmosides (GOTCABs), and considerable
efforts have been devoted to their synthesis.49,138–140
The saponin 261, isolated from Aralia dasyphylla, a Chinese medicinal plant for
treating hepatitis and diabetes, is claimed to be highly cytotoxic against the KB and
HeLa-S3 human cancer cell lines, with IC50 values of 1.2 and 0.02 μg/mL, respec-
tively.141 As a typical member of the family, this saponin (261) was efficiently
synthesized in 2004 (Scheme 39).138 Glycosylation of oleanolic acid (14) with the
glucopyranosyl bromide 262 under phase-transfer conditions provided the corre-
sponding oleanolic 28-glucosyl ester, which was then coupled with the disaccharide
N-phenyl trifluoroacetimidate 263 to afford 3β,28-O-bidesmoside 264 in excellent
yield. Removal of the AZMB group under Staudinger conditions provided acceptor
265 (90%), which was coupled with the galactosyl N-phenyl trifluoroacetimidate 266
under promotion by TBSOTf, affording the β-glycoside 267 in 90% yield. After
removal of the 40 ,60 -acetyl groups in 267 with acetic chloride in methanol, TEMPO-
mediated oxidation of the resulting primary 60 -OH group to the carboxylic acid and
subsequent treatment with CH2N2 produced the glucosiduronate 268 in 63% yield.
Finally, cleavage of benzoyl groups and the methyl ester under basic conditions was
performed selectively in the presence of the 28-glucosyl ester, thus furnishing the
desired saponin (261) in 66% yield (two steps).
Betavulgaroside III (269), present in Beta vulgaris and Achyranthes fauriei plants,
is a representative triterpene seco-glycoside which possesses a glucosiduronic acid
residue appended with a terminal seco-saccharide, which is itself presumed to come
from the oxidative cleavage of a monosaccharide unit.142 It is noteworthy that
triterpene seco-glycosides are capable of mimicking the structure of sialyl Lewis
X (sLex), a cell-surface tetrasaccharide epitope that regulates the cell–cell recognition
processes.143
In 2008, Zhu and coworkers reported the synthesis of betavulgaroside III (269) via a
convergent four-step approach, using oleanolic acid (14) as the starting material
Scheme 39. Synthesis of the glucuronide-containing saponin 261.
Scheme 40. Synthesis of betavulgaroside III (269).
(Scheme 40).139 Glycosylation of oleanolic acid (14) at the carboxyl group with the
acetylated glucopyranosyl bromide 217 under phase-transfer conditions provided
28-O-monodesmoside 270 in 78% yield. Compound 270 was then coupled with the
quasi-disaccharide imidate 271 which had been prefabricated by oxidative cleavage of
the corresponding disaccharide diol precursor. Promoted by TBSOTf, the glycosylation
reaction proceeded smoothly to afford the corresponding 3-O-β-bidesmosidic glucosi-
duronate 272 in 75% yield. Finally, full deprotection involving (1) Pd-catalyzed
hydrogenolysis of the three benzyl groups and (2) removal of acetyl and benzoyl
groups with lithium hydroxide furnished betavulgaroside III (269) in 85% yield.
The triterpene saponins QS-21 were extracted from the tree bark of Q. saponaria in
South America and were isolated in the 21st fraction of an HPLC separation. In 1991,
they were found to be the most promising adjuvants for immune-response potentiation
and dose sparing in vaccine therapy.144
QS-21Aapi (66), which belongs to this class of saponins, is a typical example. It is
composed of a quillaic acid aglycone which bears a glucosiduronic acid-containing
trisaccharide at its 3-OH position and a linear tetrasaccharide extended with an
L-arabinofuranose-terminated fatty acyl chain at its 28-CO2H group. Its total syn-
thesis was accomplished in 2006 by Gin and coworkers, relying on a convergent
modular assembly strategy (Scheme 41).49 Coupling of the quillaic allyl ester 273
with the branched trisaccharide imidate 274 under promotion by B(C6F5)3 produced
the corresponding 3-O-monodesmosidic glycoconjugate 275 in 59% yield, with the β
anomer as the major product (β/α ¼ 7). Trisaccharide 275 was then transformed into
the 28-carboxylic acid 276 in four steps with 75% yield, involving (1) cleavage of
Scheme 41. Synthesis of QS-21Aapi (66).
the acetyl, benzoyl, and methyl ester groups; (2) masking of the glucuronic acid
carboxylate group as its benzyl ester; (3) protection of the remaining hydroxyl
groups as TES-ethers; and (4) cleavage of the 28-allyl ester group. Afterward,
BF3OEt2-promoted coupling of 276 with the trichloroacetimidate 277 that had
been prefabricated by condensation of the linear tetrasaccharide with the glycosy-
lated fatty acid under Yamaguchi conditions proceeded smoothly to furnish the fully
protected QS-21Aapi 65 in 70% yield. Finally, removal of the silyl (TBS and TES)
and isopropylidene groups in 65 with trifluoroacetic acid, followed by hydrogeno-

lysis of all benzyl and benzylidene groups over Pd/C, provided bidesmoside
QS-21Aapi 66 in 75% yield.
Oleanane saponins bearing a cyclic acetal glycosidic linkage, or a macrocyclic
lactone, have also attracted interest on account of their biological significance as well
as the synthetic challenges arising from their unique structural features.
Anemoclemoside B (278), bearing an open-chain cyclic acetal glycosidic linkage,
was identified from the roots of Anemoclema glaucifolium, a Chinese folk medicinal
plant.145 The unique cyclic acetal glycosidic linkage in 278 may imply a new, but yet
unknown, biosynthetic pathway.146 As depicted in Scheme 42, the synthesis of
anemoclemoside B (278) relied on the open-chain alcohol 280, which had been
obtained from the known L-arabinose derivative 279 in five steps (42% overall
yield).147 The TMSOTf-catalyzed glycosylation of 280 with the L-rhamnopyranosyl
N-phenyl trifluoroacetimidate 72 afforded disaccharide derivative 281 in 88% yield.
Sequential desilylation of 281 with 80% aqueous acetic acid and Dess–Martin oxi-
dation of the resulting primary alcohol generated aldehyde 282 (79%). Afterward,
acetalization of 282 with hederagenin 3,23-diol (283) was effected with TMSOTf
Scheme 42. Synthesis of anemoclemoside B (278).

in the presence of 4 Å MS in CH2Cl2 at room temperature. The desired equatorial

(10 R)-acetal product 284 was obtained in excellent (92%) yield as the single isomer.
Finally, removal of acetyl groups in 284 with sodium hydroxide, followed by hydro-
genolysis of the benzyl groups over Pd/C, produced anemoclemoside B (278) in
50% yield.
Lobatoside E (285), isolated from the Chinese medicinal plant Actinostemma
lobatum, is a cyclic bidesmoside that features two oligosaccharide chains attached
at the 3-OH and 28-CO2H groups of a bayogenin scaffold, and linked together with a
3-hydroxyl-3-methyl glutarate bridge.148 Among its analogues, lobatoside E (285)
displays the most potent antitumor activities against the lung cancer cell A549, colon
cancer cell SW-620, and melanoma SK-MEL-5, exhibiting GI50 values in the range of
0.14–0.36 μM.149
In 2008, Zhu, Tang, and Yu accomplished its total synthesis, based on a linear
assembly strategy that started from bayogenin derivative 21 (Scheme 43).32 Conden-
sation of this aglycone (21) with the L-arabinopyranosyl bromide 29 under phase-
transfer conditions provided the desired monodesmoside 28-arabinosyl ester, which
was subsequently glycosylated at the 3-OH position with the glucosyl imidate 286,
under TMSOTf promotion. The corresponding 3,28-O-bidesmoside 287 was obtained
in excellent yield. After selective removal of the CA (ClAc) protecting group with
DABCO, the resulting acceptor 288 was coupled with galactosyl imidate 289 under
activation by TMSOTf, leading to the β-glycoside 290 in good yield (65%). Removal
of the acetyl group with DBU furnished acceptor 291, which was glycosylated with
disaccharide thioglycoside 292 under promotion by NIS–TMSOTf to produce the
bidesmosidic pentasaccharide 293 (81% yield). Then, substitution of the benzoyl
group in 293 by a benzyl group and deprotection of the TBDPS group provided the
corresponding primary alcohol, which was condensed with carboxylic acid 294 under
Yamaguchi conditions. Subsequent removal of the PMB groups with TFA, followed
by intramolecular macrolactonization under Yamaguchi conditions, resulted in the
formation of two cyclic C-30 epimers 295 in almost equal amounts. After separation of
the two epimers by column chromatography on silica gel, the desired epimer 30 (S)-
295 was cleanly debenzylated under hydrogenolytic conditions using Pd(OH)2, thus
furnishing the target lobatoside E (285) in 80% yield.
b. Ursane Type.—Ursane saponins are quite rare in Nature and have thus
received relatively less attention compared to oleanane saponins. They usually feature
a ursolic acid scaffold decorated with sugar chains at the 3-OH and/or 28-CO2H
positions.
As an example, the L-arabinose-containing saponin 296, isolated from Fagonia
arabica and Aralia decaisneana, is a ursane saponin claimed to possess anticancer
Scheme 43. Total synthesis of lobatoside E (285).

Scheme 44. Synthesis of the bidesmosidic ursane saponin 296.
and anti-inflammatory properties.150 In 2005, Li and coworkers described its syn-

thesis, starting from ursolic acid (297, Scheme 44).151 Condensation of ursolic acid
(297) with the glucosyl bromide 217 under phase-transfer conditions generated the
monodesmoside 28-glucosyl ester 298 in almost quantitative yield. Then, TMSOTf-
catalyzed glycosylation between the 3-OH acceptor 298 and the disaccharide imidate
299 afforded the 3,28-O-bidesmoside 300 in 96% yield. After removal of the Lev
protecting group in 300 with hydrazine acetate, the resulting alcohol 301 was
glycosylated with the D-xylopyranosyl imidate 302 to provide the corresponding
protected bidesmosidic pentasaccharide. Finally, full deprotection of the ester groups
was effected by sodium methoxide in methanol, thus yielding the target ursane
saponin 296.
Neosaponin (303) is a glucuronide-containing ursane saponin that was synthesized
in order to study its anticancer activity (Scheme 45).140d In a convergent approach,
the ursolic 28-benzyl ester 304 was glycosylated with disaccharide imidate 305 under
promotion by TMSOTf, followed by removal of the silyl group with HFpyridine
to afford the 3-O-β-glycoside 306 (86% yield). Subsequently, elaboration of the
glucosiduronic moiety as well as full deprotection was achieved in a one-pot, four-
step procedure involving (1) TEMPO-mediated oxidation of the primary 60 -OH to
60 -CO2H; (2) removal of benzoyl groups with sodium methoxide in a mixture of
MeOH and CH2Cl2; (3) formation of the methyl ester using methyl iodide; and (4)
hydrogenolysis of the benzyl group over Pd/C.
Scheme 45. Synthesis of neosaponin (303), a glucosiduronic acid-containing ursane saponin.
A series of N-acetylglucosamine-containing ursane saponins were also synthesized,

in order to assess their cytotoxic activities in cancer cell lines.137b
c. Lupane Type.—Lupane saponins have attracted detailed attention in the
past decade because of their multiple biological properties, including anticancer,
anti-inflammatory, and pancreatic-lipase inhibitory activities.25 Lupane saponins are
composed essentially of a lupeol, betulin, or betulinic acid aglycone, linked by sugar
chains attached at the 3-OH and/or 28-OH/28-CO2H positions.
As an example, the saponin 307 is an L-arabinose-containing monodesmosidic
lupane saponin isolated from the roots of Pulsatilla koreana, a plant used in tradi-
tional Chinese medicine for the treatment of malaria, amebic dysentery, and various
cancers.152 In 2008, Gauthier and coworkers reported a synthesis of this saponin
(307), starting from the allyl ester 308 of betulinic acid (Scheme 46).153 Glycosylation
of 308 with the L-arabinopyranosyl imidate 232 under TMSOTf catalysis, followed by
manipulation of the protecting groups, provided the 3-O-β-glycoside 309 in 50%
yield. Acceptor 309 was then coupled with L-rhamnopyranosyl imidate 245 under
promotion by BF3OEt2, to afford disaccharide glycoside 310 in almost quantitative
yield. Cleavage of the isopropylidene group under acidic conditions furnished the
corresponding 30 ,40 -diol, which was directly glycosylated with the glucosyl imidate
137 to produce regioselectively the branched trisaccharide 311 (35%), in which the
1
L-arabinose moiety favored the C4 conformation. Finally, removal of the allyl group
in 311 with Pd(PPh3)4 and subsequent saponification under basic conditions furnished
the desired monodesmosidic lupane saponin 307 in 60% yield.
Scheme 46. Synthesis of monodesmosidic lupane saponin 307.
Scheme 47. Synthesis of bidesmosidic lupane saponin (312).
The aforementioned intermediate 310 was also used by the same authors to
synthesize the L-arabinose-containing bidesmosidic saponin 312, which was obtained
by extraction from the aerial parts of Schefflera rotundifolia, a plant used in Asian
countries for treating pain, rheumatoid arthritis, and lumbago (Scheme 47).153,154
After removal of the 28-allyl ester group of intermediate 310 in the presence of
Pd(PPh3)4, the resulting carboxylic acid was coupled with glucosyl bromide 262
under phase-transfer conditions, thus leading to the bidesmoside 313 (66% yield
over two steps). Finally, cleavage of the isopropylidene group, followed by deben-
zoylation, yielded the target bidesmosidic lupane saponin 312.
On account of the promising anticancer activities of such chacotrioside-containing
saponins as dioscin and solamargine, concise syntheses of chacotrioside lupan-type
neosaponins (314–316) were undertaken, employing a stepwise glycosylation
Scheme 48. Synthesis of chacotrioside-containing lupane saponins (314–316).
strategy (Scheme 48).155 Thus, TMSOTf-promoted glycosylation of lupeol (317),

28-O-pivaloyl betulin (318), or betulinic allyl ester (308) with glucosyl imidate 137,
followed by basic hydrolysis and regioselective pivaloylation at the 30 -OH and 60 -OH
positions of the sugar unit afforded the diols 319–321 in moderate yields (41–54%).
Subsequently, the 20 -OH and 40 -OH groups of 319–321 were simultaneously coupled
with the rhamnosyl imidate 245, under the promotion of TMSOTf and a reverse
Schmidt procedure, to produce the chacotrioside saponins (314–316) in 48–75%
yields, after full deprotection. It is noteworthy that an excess of the Lewis acid
(such as 0.5 equiv. TMSOTf ) used to promote the inverse glycosylation led to a
Wagner–Meerwein rearrangement of the acid-labile betulin and betulinic acid deriv-
atives. This side reaction led to formation of their corresponding germanicane-type
products, thus diminishing the yields of the desired lupane saponins.156
In order to avoid glycosylation of betulin and betulinic acid derivatives under acidic
conditions, the gold(I)-catalyzed glycosylation method was employed to achieve
synthesis of the glucuronide-containing lupane-type saponin 322, which is the pro-
posed betulinic acid trisaccharide from Bersama engleriana (Scheme 49).157,158
Gold(I)-catalyzed glycosylation of the 28-OTBDPS betulinate 323 with the glucosyl
Scheme 49. Synthesis of glucuronide-containing lupane saponin 322.
ortho-hexynylbenzoate derivative 324 proceeded smoothly to furnish the 3-O-β-

glucoside 325 in 93% yield. After cleavage of the benzoyl and TBDPS groups
under basic conditions, the resulting 20 -OH-28-CO2H-acceptor 326 was simulta-
neously coupled with glucosyl ortho-hexynylbenzoate 327 under promotion by
Ph3PAuNTf2 (0.5 equiv.), thus affording bidesmoside 328 in excellent (92%) yield.
Then, protecting-group manipulation of the sugar chain linked at the C-3 position of
the aglycone led to the primary alcohol 329 in 75% yield. Successive oxidations by
PCC and NaClO2, followed by treatment with MeI, yielded the corresponding glucur-
onate intermediate that was fully deprotected, thus providing the glucuronide-
containing lupane-type saponin 322 in 53% yield (four steps).
Furthermore, a series of lupane saponins bearing various sugar moieties have been
synthesized in the quest for understanding the role of the sugar units in the pharma-
cological and pharmacokinetic properties of saponins.156,159
d. Dammarane Type.—Tetracyclic dammarane-type saponins are mainly ginse-
nosides. These are found in plants (ginseng) of the Panax genus and have been widely
used for over 2000 years in traditional Chinese medicine as effective tonics.160
Ginsenosides are the major active principles of ginseng and possess a variety of
pharmacological properties including immunostimulatory, anticarcinogenic, anti-
atherosclerotic, and antihypertensive effects, as well as CNS-protective activities.161
Structurally, ginsenosides can be divided into two major categories related to the
triterpene scaffold: the protopanaxadiol and the protopanaxatriol glycosides. The
former lack a hydroxyl group at the C-6 position of the aglycone compared to the
latter.
Ginsenoside Rh2 (330), a minor protopanaxadiol glycoside identified from red
ginseng, shows inhibitory activities against the growth of Lewis lung, Morris
hepatoma B16, and HeLa cells.162 In 1997, Elyakov and coworkers described its
synthesis, starting from the 12-O-acetyl-20(S)-protopanaxadiol aglycone 332,
obtained in three steps from betulafolienetriol (331) (Scheme 50A).163 Glycosylation
of 332 with glucosyl bromide 217 in the presence of silver oxide gave the 3-O-β-
glycoside 333 in 48% yield, which was subjected to deacetylation with sodium
methoxide to afford ginsenoside Rh2 (330). In 2011, Liao and coworkers reported
a different synthesis of ginsenoside Rh2 (330), employing a gold(I)-catalyzed gly-
cosylation (Scheme 50B).164 Starting from protopanaxadiol (334), the hydroxyl
group at the C-12 position was selectively protected with PivCl to give the 3,20-
diol 335 in 76% yield. Then, glycosylation of 335 with the glucosyl ortho-
hexynylbenzoate 327, promoted by Ph3PAuNTf2, took place regioselectively at the
3-OH group, affording the 3-O-β-glucoside 336 in 82% yield. Finally, effective
removal of all ester groups (Bz and Piv) using potassium hydroxide yielded the
target ginsenoside Rh2 (330) (76%).
Furthermore, three protopanaxadiol galactosides (337–339), congeners of ginseno-
side Rh2, were concisely synthesized for SAR studies among dammarane saponins
(Fig. 13).165
Ginsenoside Rb2 (340), which constitutes the most complex protopanaxadiol
ginsenoside, exhibits potent immunosuppressive and antidiabetic activities.166 In
2013, the Yu group completed its synthesis by employing gold(I)-catalyzed glyco-
sylation procedures (Scheme 51).167 The advantage of these glycosylations is the
activation under neutral conditions, which overcomes the difficulties caused by the
acid-labile 20-OH group of the dammarane scaffold. The glycosylation between
12-O-allyl-3-O-chloroacetyl-protopanaxadiol (341) and the glucosyl alkynylbenzo-
ate 342 under Ph3PAuNTf2 catalysis furnished the corresponding 20-O-glucoside
343 in 75% yield. Replacement of the 12-O-allyl group in 343 by an acetyl group
and subsequent selective removal of the 60 -OTBDPS group generated the 60 -OH
acceptor 344, which was thus set up to couple with the L-arabinopyranosyl
Scheme 50. Synthesis of ginsenoside Rh2 (330).

Fig. 13. Synthetic protopanaxadiol galactosides (337–339).
alkynylbenzoate 345 in the presence of Ph3PAuNTf2, providing disaccharide 346 in

almost quantitative yield. After removal of the chloroacetyl (CA) group with
DABCO, gold(I)-catalyzed coupling of the resulting 3-OH acceptor 347 with the
glucosyl alkynylbenzoate 348 afforded the 3,20-O-bidesmoside derivative 349
(83%). Cleavage of the AZMB group under Staudinger conditions produced the
C2000 -alcohol 350, which was glycosylated with glucosyl alkynylbenzoate 327 under
the standard gold(I)-catalyzed conditions, leading to the bidesmosidic tetrasacchar-
ide 351 in 84% yield. Finally, a three-step global deprotection, including removal of
1 allyl, 1 benzylidene acetal, 1 acetyl, and 10 benzoyl groups, furnished ginsenoside
Rb2 (340) in 63% yield.
Synthetic routes have also been developed for access to all five types of proto-
panaxatriol glycosides, namely, ginsenoside F3 (20-O-glycoside 352), chikusetsusa-
ponin L10 (12-O-glycoside 353), ginsenoside Rh1 (6-O-glycoside 354), ginsenoside
Rg1 (6,20-O-bisglycoside 355), and ginsenoside Ia (3,20-O-bisglycoside 356), by
convenient full differentiation of the four C-3, C-6, C-12, and C-20 hydroxyl groups
of protopanaxatriol (357) (Scheme 52).161,167 It was demonstrated that the reactivity
sequence of the four hydroxyl groups is 12-OH > 3-OH > 6-OH 20-OH. This work
permitted control of the protecting pattern of the aglycone, and thus enabled synthesis
of various alcohols (358–362) in two to four steps, with 61–85% yields. By employing
gold(I)-catalyzed glycosylations with glycosyl alkynylbenzoates as donors, alcohols
358–362 were successfully elaborated into the representative natural protopanaxatriol
glycosides (352–356) in 25–70% yields over two to five steps.
Chikusetsusaponin-LT8 (363), isolated from Panax japonicas C. A. Meyer in 1978,
is the 12-keto derivative of the corresponding protopanaxadiol glycoside. It displays
anticancer activity more potent than its 12-OH congener.168 Atopkina and coworkers
reported the synthesis of chikusetsusaponin-LT8 (363) employing Koenigs–Knorr
Scheme 51. Synthesis of ginsenoside Rb2 (340).

Scheme 52. Synthesis of natural protopanaxatriol glycosides (352–356), based on the full differentia-
tion of the four hydroxyl groups present in protopanaxatriol (357).
Scheme 53. Synthesis of chikusetsusaponin-LT8 (363).
glycosylations with a glycosyl bromide as donor (Scheme 53A).169 The 3,12-

dione-20-OH 364 was first condensed with glucosyl bromide 217 in the presence of
silver oxide to yield the 20-O-glycoside 365. Selective reduction of the 3-ketone with
NaBH4 then afforded the 3-alcohol 366 (84% yield), ready for coupling with glucosyl
bromide 217 under promotion with silver oxide. The resulting 3,20-O-bidesmoside
was fully deprotected with sodium methoxide to yield chikusetsusaponin-LT8 (363).
In 2011, Liao and coworkers described the synthesis of chikusetsusaponin-LT8
(363) via a gold(I)-catalyzed glycosylation with a glycosyl alkynylbenzoate as donor
(Scheme 53B).164 After a four-step manipulation of protopanaxadiol 334 to transform
the 12-OH group into the 12-ketone (42% yield), the 3,20-diol 367 was glycosylated
with two equivalents of the glucosyl alkynylbenzoate 327 under gold(I) catalysis to
yield the corresponding 3,20-O-bidesmoside (70%). Global debenzoylation using
KOH furnished the target chikusetsusaponin-LT8 (363) in 80% yield.
IV. Synthesis of Marine Saponins
Saponins from such marine sources as starfish and sea cucumbers are commonly
identified as secondary metabolites.170 Although they are relatively rare compared to
plant saponins, marine saponins display a wide range of biological and pharmacolog-
ical activities.170 To date, most of the synthetic efforts in the area of marine saponins
have been directed toward steroid glycosides, that is, shark-repelling saponins and
starfish saponins.
Shark-repelling saponins that are secreted by the Red Sea Moses sole Pardachirus
marmoratus and Pardachirus pavoninus are steroid glycosides named mosesins and
pavoninins, respectively.171 They are believed to be potent cell disrupters and there-
fore might have important pharmacological properties.172
As an example, mosesin-4 (369) having shark-repellent activity was synthesized in
1989 by the Nakanishi group (Scheme 54).173 Starting from commercially available
cholic acid (370), a seven-step manipulation led to the steroid aglycone 371 (14%
overall yield). Next, glycosylation of 371 with D-galactose pentaacetate (372) pro-
moted by TMSOTf gave the 7-O-β-glycoside 373 in 40% yield. Afterward, a series of
functional-group transformations, including (1) alkaline hydrolysis of ester and car-
bonate groups, (2) TBS protection of the free alcohols, (3) cleavage of the 26-benzyl
group as well as reduction of the double bond under H2–Pd conditions, (4) acetylation
Scheme 54. Synthesis of mosesin-4 (369).

Scheme 55. Synthesis of pavoninin-1 (374).
of the 26-OH group, and (5) deprotection of the TBS groups, were effectively
performed to provide the target mosesin-4 (369) (57% yield, five steps).
In 1997, the synthesis of pavoninin-1 (374) was achieved by Ohnishi and Tachibana,
using a sulfoxide-activated glycosylation as the key step (Scheme 55).174 Starting
from the commercially available chenodeoxycholic acid (375), an eight-step trans-
formation provided the 7-OH aglycone acceptor 376 in 26% overall yield. Then,
the sterically hindered 7-OH group was efficiently coupled with the
2-azido-glucosyl phenyl sulfoxide 377 in the presence of Tf2O and DtBMP. The
glycosylation proceeded smoothly to form the desired 7-O-β-glycoside 378 in
excellent (97%) yield. Glycoside 378 was further elaborated into compound 379
in five steps, involving (1) removal of the TBDPS group with hydrogen fluoride,
(2) oxidation of the resulting 3-OH group by PDC to the 3-ketone, (3) protection
of the 3-ketone as its dimethyl acetal, (4) simultaneous azide reduction–removal of
the carbonate group with LiAlH4, and (5) acetylation of the resulting 20 -NH2 and
26-OH groups. Finally, the intermediate 379 was subjected to (1) debenzylation
under hydrogenolytic conditions, (2) acidic hydrolysis of the acetal, and (3)
formation of the 4β-selenenylated ketone, followed by (4) cis-elimination with
hydrogen peroxide, thus providing the target marine saponin pavoninin-1 (374) in
21% yield.
In 2005, Williams and coworkers reported the synthesis of pavoninin-4 (380)
employing a stereospecific glycosylation with 2-acetamido-3,4,6-tri-O-benzyl-2-
deoxy-D-glucosyl fluoride (381) as donor (Scheme 56).27 The 3,26-OBz-15-OH
cholestan aglycone 6 was prepared from diosgenin 1 in 41% yield over eight steps
(Scheme 1). It was then glycosylated with the fluoride 381 under activation by
AgClO4–SnCl2 to yield the 15-O-β-glycoside 382 (72%). After removal of the
benzoyl groups at the C-3 and C-26 positions with potassium hydroxide, selective
acetylation of the resulting primary 26-OH was performed with vinyl acetate under
distannoxane catalysis. Finally, global debenzylation under hydrogenolytic condi-
tions furnished the target pavoninin-4 (380) (69% yield over three steps).
Starfish saponins have been identified from nearly 100 starfish species and exhibit
a broad spectrum of pharmacological properties, such as antitumor and antibacterial
activities. They have proven to be defensive agents against parasites and predators in
many cases.170 Among the steroid glycosides found in starfish, asterosaponins are the
Scheme 56. Synthesis of pavoninin-4 (380).

Scheme 57. Synthesis of forbeside E1 (383).
most representative and are composed of a steroid aglycone sulfated at the C-3
position and with a sugar chain attached at the C-6 position.170,175 In the past few
decades, total syntheses of starfish saponins and their analogues have attracted much
interest from carbohydrate chemists.48,50,176–178
In 1993, the Schmidt group reported the synthesis of sulfated steroid glycoside
forbeside E1 (383), isolated from the starfish Asterias forbesi Desor
(Scheme 57).176,179 11-Oxoprogesterone (384) was transformed into the
3-OTBS-6-OH aglycone acceptor 385 in eight steps and 14% overall yield. Next,
compound 385 was glycosylated with the D-quinovosyl imidate 386 under catalysis
by TMSOTf to furnish the 6-O-β-glycoside 387 in 76% yield. Removal of the TBS
group at the C-3 position with TBAF was followed by sulfation with the SO3pyridine
complex. Treatment with ion-exchange resin (Na+ form) resulted in the formation of
the corresponding sulfated saponin as its sodium salt. Finally, sequential NaBH4
reduction of the 20-ketone to the 20-alcohol and deacetylation with sodium methox-
ide provided the target forbeside E1 (383) (40% yield over four steps).
Recently, Xiao and Yu completed the synthesis of starfish saponin goniopecteno-
side B (388), isolated from a large pinkish starfish Goniopecten demonstrans
(Scheme 58).48,180 In a convergent manner, the 6,20-OH aglycone 390 was synthe-
sized from adrenosterone (389, 17 steps and 9% overall yield) and the pentasaccharide
Scheme 58. Total synthesis of goniopectenoside B (388).
ortho-hexynylbenzoate 391 was prefabricated by sequential assembly of the corre-

sponding D-quinovosyl, D-xylosyl, and D-fucosyl building blocks. Glycosylation
between acceptor 390 and donor 391 proceeded smoothly under promotion by
Ph3PAuOTf and took place regioselectively at the 6-OH position to afford the fully
protected steroid pentasaccharide 392 in 80% yield. Removal of the TBS group under
acidic conditions was followed by selective sulfation of the resulting 3-OH, using the
SO3pyridine complex. The corresponding pyridinium salt was converted into the
sodium salt by Na+ ion-exchange resin. Finally, debenzoylation with sodium methox-
ide in methanol furnished goniopectenoside B (388) in 61% yield over three steps.
V. Summary and Outlook
Saponins constitute a large class of diverse amphiphilic steroid and triterpene

glycosides identified as secondary metabolites of terrestrial plants and some marine
species. Members of this class are known to exhibit a broad spectrum of biological
and pharmacological activities, including cytotoxic, immunostimulatory, anticancer,
and antimicrobial effects. Because of their high toxicity to various pathogens but low
oral toxicity to mammals,181 saponins are considered to be the major active principles
of traditional Chinese medicines, as well as some other folk medicines that have been
used for thousands of years to prevent and treat various diseases. Consequently,
saponins have attracted detailed attention by chemists and other scientists.
Because the isolation of homogeneous saponins from natural resources is difficult
or even impossible due to the microheterogeneity of these complex molecules,
chemical synthesis has emerged as an alternative and powerful tool for access
to saponins having well-defined structures. Their chemical synthesis involves
both steroid and triterpene chemistry for elaboration of the sophisticated aglycone
skeleton, and carbohydrate chemistry for access to the sugar units and construction of
the glycosidic linkage. It requires the establishment of an appropriate synthetic tactic
as well as judicious choice in the arrangement of protecting groups.
As illustrated earlier, a wide variety of plant and marine saponins have been
successfully synthesized during the past three decades, with the main objective
being to study their SARs and to understand their mechanisms of action. Within
this range of examples, it is evident that construction of the glycosidic bond consti-
tutes the most challenging step. Clearly, the glycosylation has to be performed
chemo-, regio-, and stereoselectively, in good yield, and under reaction conditions
that do not affect the aglycone. These factors are largely influenced by the choice of
the saccharide donor (leaving group) and the associated activation conditions, as well
as the pattern of protecting groups. The examples presented here demonstrate the host
of different glycosylation protocols that have been applied for the synthesis of
saponins. These include the frequently used trichloroacetimidate, N-phenyl trifluor-
oacetimidate, thioglycoside, glycosyl halide, ortho-alkynylbenzoate, and glycal
donors, as well as such donors as glycosyl 1,2-epoxides, 1-hydroxyl, sulfoxide,
aldehyde, and acetate that have been employed occasionally. Among these methods,
the use of ortho-alkynylbenzoate donors activated under neutral gold(I) conditions is
particularly attractive for glycosylations with such acid-labile aglycones as lupanes
and dammaranes. Moreover, the pattern of protecting groups plays an important role
in the glycosylation reactions, and many different protecting groups have been
devised. They can be temporary, permanent, and orthogonal to each other for control
of the regio- and stereoselectivity of the glycosylation. In addition, choice of suitable
protecting groups can have a profound impact on the efficiency of the synthesis; one
unwisely selected group can ruin an entire synthetic plan.
To sum up, the success of a saponin synthesis depends mainly on the choice of
tactics, selection of protecting groups, and the glycosylation conditions employed for
constructing the glycosidic linkages. Unfortunately, there is no universal method that
can ensure the success of the synthesis, and the selection of these various
methodologies is highly dependent on the specific structures of the particular sapo-

nins. Intensive research efforts have been devoted during the past three decades to
develop efficient and concise syntheses of many plant and marine (steroid and
triterpene) saponins, and these successes reflect important advances of modern
synthetic methods in carbohydrate chemistry and in steroid/triterpene chemistry.
Nevertheless, numerous other saponins, such as marine saponins featuring cyclic or
polyhydroxylated steroid glycosides, remain as challenging targets awaiting the
attention of synthetic chemists.1,2,175 Although SAR studies of synthetic saponins
have now provided better insight into the structural requirements for biological
activity among the saponins,72c,96,134b,156a,182 there remains a great need for further
research. By combining the efforts of chemists, biologists, and pharmacologists, we
look to decipher the saponin code underlying the bioactivities of folk medicines and
permit new saponin-based drugs to become commercially available in the future.
Acknowledgments
Financial support from the Ministry of Science and Technology of China (2012ZX09502-002),
the National Natural Science Foundation of China (91213301), and the Chinese Academy of
Sciences is gratefully acknowledged.
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Chemical Synthesis of Saponins

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ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, VOL.

CHEMICAL SYNTHESIS OF SAPONINS

You Yanga,1, Stephane Lavalb, and Biao Yub,1

2,2-DMP, 2,2-dimethoxypropane; Ac, acetyl; AIBN, azobisisobutyronitrile; All,

DIAD, diisopropylazodicarboxylate; DIBAL, diisobutylaluminum hydride; dios,

Naturally occurring saponins constitute a structurally diverse class of glycosides

systems, saponins also exhibit a variety of biological and pharmacological properties,

Fig. 1. Representative aglycone skeletons of steroid saponins.

Triterpene saponins, which are widely distributed in the dicotyledonous angio-

Fig. 2. Representative aglycone skeletons of triterpene saponins.

Fig. 3. Representative sugar units found in naturally occurring saponins.

homogeneous saponins, as well as their congeners, in sufficient amounts to facilitate

II. General Considerations on Saponin Synthesis

Scheme 1. Synthesis of the steroid core (6) of pavoninin-4.

five-step procedure was employed to convert compound 3, containing a 16β-ΟΗ group,

Scheme 2. Synthesis of the steroid backbone (13) of OSW-1.

2. Synthesis of Carbohydrate Building Blocks

Scheme 3. Synthesis of the triterpene core (21) of lobatoside E.

81% yield. Exposure of 23 to acetic acid at elevated temperature led to cleavage of

In 2006, another de novo approach was developed by O’Doherty’s group to access

The most straightforward way to synthesize monodesmosides is a convergent tactic

differentiation and to permit the manipulation of one or more functional groups in a

Scheme 10. Schematic protecting groups manipulation in saponin synthesis.

The synthesis of saponins in an efficient and robust manner requires optimal

Scheme 12. Protecting groups effective in the synthesis of ginsenoside Ro.

III. Synthesis of Plant Saponins

a. Spirostan Type.—Spirostan-type saponins are the most common steroid sapo-

Scheme 14. Efficient syntheses of dioscin (67) and polyphyllin D (68).

with peracetylated L-rhamnopyranosyl N-phenyl trifluoroacetimidate (72) furnished

Scheme 15. Synthesis of solamargine (97).

Recently, based on a one-pot strategy, Gu and coworkers achieved the synthesis of

Fig. 8. Synthetic sarsasapogenin triglycosides (118–120).

attributable to hindrance of the 1-β-OH group in 132. However, under an “inverse

Scheme 21. Synthesis of methyl protodioscin (135).

Furthermore, such monodesmosidic furostan saponins as icogenin and its analogues

Fig. 9. Synthetic mimics (144–147) of methyl protodioscin (135).

Scheme 23. Synthesis of timosaponin BII (148).

Scheme 24. First total synthesis of OSW-1 (156).

Fig. 10. Four types of synthetic analogues (159–162) of OSW-1.

Scheme 25. Total synthesis of candicanoside A (163).

80 C to give the monodesmosidic disaccharide 176 in 81% yield. Reduction of

Scheme 26. Total synthesis of osladin (170).

In addition, other cholestan-type bidesmosides, such as kryptogenyl saponins (179)

Fig. 11. Other synthetic cholestane-type bidesmosides (179 and 180).

Scheme 28. Synthesis of digitoxin (181) by the McDonald group.

Scheme 29. Synthesis of digitoxin (181) by the O’Doherty group.

Scheme 30. Synthesis of digitoxin (181) by the Yu group.

Scheme 31. Synthesis of digitoxin (181) by the Zhu group.

Scheme 32. Synthesis of Purpurea glycoside A (216) by catalyst-controlled, regioselective glycosyl-

performed in CHCl3 under promotion by Ph3P–HBr, thus generating digitoxin (181)

a. Oleanane Type.—Oleanane-type saponins constitute more than half of the

Scheme 33. Total synthesis of saponin P57 (223).

Scheme 34. First synthesis of a bidesmosidic triterpene saponin, ciwujianoside C3 (230).

synthesis also employed a one-pot sequential glycosylation as the key stage

Scheme 35. Synthesis of monodesmosidic oleanane saponin 236.

Scheme 36. Synthesis of flaccidoside II (242) by the Du group.

Scheme 37. Synthesis of flaccidoside II (242) by the Li group.