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Chemical synthesis of marine saponins

Cite this: Nat. Prod. Rep., 2019, 36, 769 Guozhi Xiao, *a Xiaofei Shao,b Dapeng Zhub and Biao Yu *b

Covering: 1989–2017

Received 11th October 2018
DOI: 10.1039/c8np00087e
rsc.li/npr
Saponins are characteristic metabolites of starfish and sea cucumbers, and occasionally are also found in
sponges, soft coral, and small fish. These steroid or triterpenoid glycosides often show remarkable
biological and pharmacological activities, such as antifungal, antifouling, shark repellent, antitumor and
anti-inflammatory activities. Over one thousand marine saponins have been characterized; the majority
of them can be categorized into three major structural types, i.e., asterosaponins, polyhydroxysteroid
glycosides, and holostane glycosides. Thus far, only 12 marine saponins have been synthesized; those
representing the major types were successfully synthesized recently. The syntheses involve preparation
of the aglycones from the terrestrial steroid or triterpene materials, installation of the carbohydrate units,
and manipulation of the protecting groups. Herein, we provide a comprehensive review on these syntheses.

1. Introduction are found mainly from starsh and sea cucumbers, and occa-
2. General considerations on the syntheses of marine sionally from certain sponges, so coral, and sh.2–12 Over one
saponins thousand marine saponins have been characterized. Those
3. Synthesis of shark-repelling saponins from star sh are steroid glycosides, which can be classied into
3.1 Synthesis of mosesin-4 two major structural types, i.e., the asterosaponins and poly-
3.2 Synthesis of pavoninin-1 hydroxysteroid glycosides.4–7 The asterosaponins contain
3.3 Synthesis of pavoninin-4 a D9(11)-3b,6a-dihydroxysteroidal nucleus with a sulfate residue
4. Synthesis of starsh saponins at C3 and a glycan at C6. The glycans are mostly penta- or
4.1 Synthesis of forbeside E1 and E3 hexasaccharides with all 1,2-trans-pyranosidic linkages and
4.2 Synthesis of goniopectenoside B a (1 / 2) branching point at the second sugar unit. Gonio-
4.3 Synthesis of astrosterioside A pectenoside B (6) and astrosterioside A (7) are two representa-
4.4 Synthesis of linckosides A and B tive asterosaponins (Fig. 1). The polyhydroxysteroid glycosides
5. Synthesis of sea cucumbers saponins possess hydroxyl groups commonly at C6, C8, and C15 besides
5.1 Synthesis of echinoside A, ds-echinoside A and echinoside B the biogenetic hydroxyl group at C3, which is oen attached
6. Conclusions with a 2-O-methyl-b-D-xylopyranose residue. Linckoside A and B
7. Conicts of interest (8 and 9) represent two such congeners. In contrast, all of the
8. Acknowledgements saponins from sea cucumbers are triterpenoid saponins, with
9. References the majority bearing lanostane-18,20-lactones (namely holo-
stane) as aglycones.8–12 The glycans are attached exclusively at
the lanostane C3-OH, which start mostly with D-xylose (Xyl) and
1. Introduction is elongated via its 2-OH. Echinoside A, B and ds-echinoside A
(10–12) are typical examples.
Saponins, the glycosides of steroids or triterpenes, occur widely Marine saponins are produced as chemical weapons of those
and oen abundantly in terrestrial plants.1 In marine, saponins slow moving marine species to attack prey or to defense against
predators, parasites, and microorganisms. Behaving as attrac-
a
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming tants to insure symbiosis was also disclosed.13 Thus, not
Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of surprisingly, marine saponins are oen found as active
Sciences, 132 Lanhei Road, Kunming 650201, China. E-mail: xiaoguozhi@mail.kib.
components in various bio-assays, such as in the assays for
ac.cn
b
antifungal, antibacterial, antimicrobial, anti-fouling, antitumor
State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, and anti-inammatory activities.2–12 However, in-depth studies
University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 on the structure–activity relationships (SAR), the mechanism of
Lingling Road, Shanghai 200032, China. E-mail: byu@sioc.ac.cn

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action, and the pharmacological properties are hampered by
the poor accessibility of these marine metabolites, which are
highly polar, fragile, and complex, and occur in the precious
marine species and oen in a heterogeneous manner.
Synthetic approaches to the terrestrial saponins have been
well developed, allowing ready access to a large number of those
biologically interesting nature products and their analogs.14–18
In contrast, only 12 marine saponins (i.e., 1–12) have been
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2. General considerations on the
syntheses of marine saponins
Structurally, marine saponins are clearly different from the
terrestrial saponins.1–12 The aglycones are usually further
oxidized from the basic steroid and triterpene structures of the
terrestrial origins; sulfonate group is commonly present, either

at the carbohydrate units or at the aglycone. The added

synthesized through 2018 (Fig. 1 and Table 1); those repre-
senting the major types (6–12) were successfully synthesized
only recently.19–26 In those syntheses, elaboration of the multi-
functional marine aglycones from the basic steroid or tri-
terpene materials (of the terrestrial origins) is always a difficult
task, and installation of the carbohydrate units and the addi-
tional substituents (e.g., the acetyl and sulfonate groups)
demands sophisticated arrangement of protecting groups and
the transformation sequence. The early synthesis of shark
repelling saponins (i.e., 1–5) has been briey summarized in
2004.27 Herein, we provide a comprehensive review on the
syntheses of marine saponins through 2018, covering litera-
tures from 1989–2017.
complexity makes marine saponins more challenging synthetic
targets than many of the terrestrial saponins. General consid-
erations on the synthesis of a marine saponin usually include:
(1) the assembly strategy, (2) the arrangement of protecting
groups, (3) the glycosylation method, (4) the synthesis of the
aglycone, and (5) the preparation of the carbohydrate building
blocks.
The assembly strategy concerns mainly the stage at which
the carbohydrate units are attached onto the aglycone.15,28 The
convergent one involves a later-stage glycosylation of the agly-
cone with a wholly prefabricated saccharide donor (Tactic I).
Otherwise, the sugar units can be attached to the aglycone in

Guozhi Xiao received his B.S. in Dapeng Zhu received his B.S. in
Chemistry from Sun Yat-sen Chemistry from the University of
University in 2008 and his Science and Technology of
Ph.D at Shanghai Institute of China in 2011 and his Ph.D.
Organic Chemistry, Chinese from Shanghai Institute of
Academy of Sciences (CAS) Organic Chemistry, CAS, in
under the supervision of Prof. 2016 (with Prof. Biao Yu). He
Biao Yu. Aer postdoctoral stays as a research associate in
research at Max Planck Institute the Yu group.
of Colloids and Interfaces with
Prof. Peter H. Seeberger (2013–
2015) and at the University of
Wisconsin–Madison with Prof.
Weiping Tang (2015–2017), he was appointed as a research
professor at Kunming Institute of Botany (KIB), CAS, in 2017. His
research interests include carbohydrate chemistry and
carbohydrate-based therapeutics.

Xiaofei Shao received his B.S. in Biao Yu received his B.S. in

Chemistry from East China Radiochemistry from Peking
University of Science and Tech- University in 1989 and his Ph.D.
nology in 2011. He is now a Ph.D (with Prof. Y. Hui) from
candidate at Shanghai Institute Shanghai Institute of Organic
of Organic Chemistry, CAS, Chemistry (SIOC), CAS, in 1995.
under the supervision of Prof. Aer a one-year postdoctoral
Biao Yu. stay at New York University, Dr
Yu returned to SIOC as an
Assistant Professor, and became
Professor in 1999. His labora-
tory is dedicated to the total
synthesis, synthetic method-
ology, and chemical biology of
glycans and glycoconjugates.

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Fig. 1 Marine saponins synthesized up to 2017.
a stepwise manner (Tactic II). When the glycosylation of the
aglycone, even with a compromised monosaccharide donor, is
unsuccessful, then this glycosidic linkage has to be built before
elaboration of the full aglycone (Tactic III). The nal alternative
involves elaboration of both the aglycone and the glycan aer
construction of the glycosidic linkage (Tactic IV).
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The protecting groups strategy considers rstly the choice of
the permanent protecting groups, which can be taken off,
usually at the last step, without affecting all the functional
groups of the target molecule. Then, the temporary protecting
groups are arranged, which can be selectively removed in
a sequential manner.
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Table 1 The occurrence, bioactivities and synthesis of marine saponins 1–12
Marine Saponins Occurrence
Mosesin-4 (1) Red sea moses sole Pardachirus marmoratus
Pavoninin-1 & -4 (2 & 3) Peacock sole Pardachirus pavoninus
Forbeside E1 & E3 (4 & 5) Starsh Asterias forbesi
Goniopectenoside B (6) Starsh Goniopecten demonstrans
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Astrosterioside A (7) Starsh Astropecten monacanthus
Linckoside A & B (8 & 9) Starsh Linckia laevigata
Echinoside A, B & Sea cucumber Actinopyga echinites etc.
ds-echinoside A (10–12)
For the glycosylation method, a special concern is given to
the reaction which connects the carbohydrate unit with the
aglycone.29,30 Given the multifunctional steroid and triterpene
scaffolds of the marine saponins, an effective glycosylation
reaction under mild conditions is usually required.31 In addi-
tion, the a/b stereoselectivity of the glycosylation requires
a special device.32,33
For the synthesis of the aglycone, the synthetic approaches
depend on the choice of starting materials.34 In fact, many
steroid or triterpene compounds (of the terrestrial origins) are
produced in large quantities and are commercially available,
which might possess the basic skeleton and necessary func-
tional groups for the desired transformations.35–37
The carbohydrate building blocks can be prepared from
common sugars, each requires installation of a suitable pro-
tecting group pattern and a functional group at the anomeric
position to facilitate the sequential assembly.38,39
These general considerations are reected in each of the
synthesis described in the following sections.
3. Synthesis of shark-repelling
saponins
3.1 Synthesis of mosesin-4
In 1988, Tachibana and Gruber characterized ve mono- or di-
O-acetylated steroid 7-O-galactosides, namely mosesins (1 and
13–16, Fig. 2), from the ichthyotoxic secretion of the Red Sea
Moses sole Pardachirus marmoratus.40 Shortly, Nakanishi et al.
Fig. 2 Mosesins 1–5 (1 and 13–16).
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Bioactivities Synthesis19–26
Ichthyotoxic and shark repellent Nakanishi et al., 1989
Ichthyotoxic and shark repellent Tachibana et al., 1997 &
Williams et al., 2005
Not reported Schmidt et al., 1993
Antifouling Yu et al., 2013
Anti-inammatory Yu et al., 2015
Neuritogenic Yu et al., 2015
Antitumor and antifungal Yu et al., 2017
achieved the chemical synthesis of mosesin-4 (1),19 this repre-
sents the rst synthesis of a marine saponin.
The synthesis used cholic acid (17) as starting material,
which possesses the requisite steroidal cis-A,B ring junction and
the 3a, 7a, and 12a hydroxyl groups (Scheme 1). Modication of
the side chain and glycosylation of the 7a-OH would lead to
mosesin-4 (1) readily. Thus, cholic acid (17) was subjected to
acetylation followed by photochemical decarboxylation and
iodination to give iodide 18.41 Hydrolysis of the iodide followed
by oxidation led to aldehyde 19. The desired side chain was then
installed via a Wittig reaction with ylide 20, affording Z-olen
21. Removal of the acetyl groups on 21 and selective protection
of the most reactive 3a-OH with ethyl chloroformate provided
22 (7 steps and 18% overall yield from cholic acid 17), which is
ready for the attachment of the galactose residue. Indeed,
glycosylation of 7a,12a-diol 22 with galactose peracetate 23
under optimized conditions (TMSOTf, ClCH2CH2Cl,
20  C)
provided the desired 7a-O-b-glycoside 24 regio- and stereo-
selectively in 40% yield. To furnish the target mosesin-4 (1),
ve more steps were used (58% overall yield), including (1)
removal of the cathyl and acetyl groups, (2) protection of the
resultant hydroxyl groups with TBS groups, (3) removal of the
26-O-benzyl ether (via hydrogenolysis) and concurrent satura-
tion of the 23,24-double bond, (4) acetylation of the resulting 26-
OH, and (5) global removal of the TBS groups.
3.2 Synthesis of pavoninin-1
In 1984, Tachibana et al. characterized a group of ichthyotoxic
and shark repellent steroid glycosides, namely pavoninins 1–6
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Scheme 1 Synthesis of mosesin-4 (1).

(2, 3 & 26–29, Fig. 3), from the peacock sole Pardachirus pav- The cholestane aglycone of pavoninin 1 and 2 (2 & 26) could
oninus.42,43 These cholestane saponins have a N-acetylglucos- be prepared readily from the abundant diosgenin (40).44
amine (GlcNAc) residue at the 7a- or 15a-OH and an acetyl Nevertheless, Tachibana and Ohnishi envisioned an early stage
residue at the 26-OH. glycosylation in the synthesis of pavoninin-1 (2) to avoid the

Fig. 3 Pavoninins 1–6 (2, 3 & 26–29).

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possible problems derived from the acid labile enone func-
tionality in the A ring (Scheme 2).20 The synthesis used the
commercially available chenodeoxycholic acid (30) as starting
material, which possesses the hydroxyl groups at C-3 and C-7a.
A similar approach as that in the synthesis of mosesin-4 (1) was
employed to elaborate the side chain (30 / 32). Reductive
cleavage of the acetyl groups in 32 gave 3a,7a-diol 33, which was
subjected to selective protection of the more reactive 3a-OH
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with TBDPS group. Subsequent hydrogenolysis led to cleavage
Scheme 2 Total synthesis of pavoninin-1 (2).
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of the 26-O-benzyl ether and saturation of the 23,24-double
bond. The resultant 26-OH was then protected as a methyl
carbonate to provide 34, which was subjected to glycosylation.
Indeed, employing Kahne's glycosylation method,45 condensa-
tion of the hindered 7a-OH on 34 with 2-azido-3,4,6-tri-O-ben-
zylglucosyl sulfoxide 35 in the presence of Tf2O/DtBMP (2,6-di-
tertbutyl-4-methylpyridine) at low temperature provided the
desired b-glycoside 36 in an excellent 97% yield. This unusual
formation exclusively of the 1,2-trans-b-glycoside in the absence
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of a neighbouring participation in the glycosylation might be
attributed to the matching stereochemistry of the coupling
partners.
The nal stage involved elaboration of functional groups.
Compound 36 was subjected to selective removal of the 3-O-
TBDPS group; oxidation of the resulting hydroxyl group and
protection of the nascent ketone as dimethyl acetal provided 37.
Reduction of the azide and methoxycarbonyl group in 37 (with
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LiAlH4) followed by acetylation afforded 38. Hydrogenolysis of
the benzyl groups on the sugar residue and subsequent acidic
hydrolysis of the ketal led to dihydropavoninin-1 (39). Final
introduction of the 4,5-double bond was realized via seleneny-
lation (albeit with a poor 2,4-regioselectivity) and oxidative
elimination,46 thus leading to pavoninin-1 (2) in a moderate
yield of 24% (for 2 steps).
3.3 Synthesis of pavoninin-4
In 2005, Williams et al. accomplished the total synthesis of
pavoninin-4 (3), using diosgenin (40) as starting material
(Scheme 3).21,47 Thus, diosgenin (40) was subjected to catalytic
Scheme 3 Synthesis of pavoninin-4 (3).
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hydrogenation to saturate the 5,6-double bond and Clem-
mensen reduction to open the spiroketal, providing triol 41.
Mitsunobu reaction of triol 41 led to 3a,26-dibenzoate 42 in
high yield, with the C3 conguration being inverted. Regio-
selective dehydration of the 16b-OH (in 42) via a mesyl deriv-
ative gave 16,17-olen 43.48 Allylic oxidation of 43 (with CrO3)
followed by Luche reduction of the resulting enone provided
15a-ol 44. Hydrogenation of the 16,17-double bond in 44
furnished aglycone derivative 45, in which and the previously
Luche reduction step, the stereochemistry is completely
controlled by the substrates. Employing Mukaiyama's glyco-
sylation method,49 coupling of 45 with 3,4,6-tri-O-benzyl-N-
acetylglucosaminosyl uoride 46 in the presence of AgClO4/
SnCl2 provided the desired b-glycoside 47 in a satisfactory 72%
yield.
Finally, the 3,26-O-benzoyl groups (in 47) were cleaved; the
resultant 26-OH was selectively acetylated under Otera's
trans-esterication conditions (vinyl acetate, Bu8Sn4Cl4O2)50
to provide 48 in good yield. Hydrogenolysis of the benzyl
groups on the sugar residue (in 48) furnished pavoninin-4 (3)
cleanly.
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4. Synthesis of starfish saponins
4.1 Synthesis of forbeside E1 and E3
In the late 1980s, Findlay et al. identied four sterol glycosides,
namely forbeside E, E1, E2 and E3 (49, 4, 50 & 5, Fig. 4), from the
starsh Asterias forbesi.51,52 These compounds bear a truncated
steroidal side chain, a b-quinovose (6-deoxy-glucose) residue at
the 6a-OH, and one sulfonate group or two at the 3b-OH and the
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4-OH of the sugar residue.
Fig. 4 Forbeside E and E1–E3 (49, 4, 50 & 5).
Scheme 4 Synthesis of forbeside E1 (4) and E3 (5).
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The synthesis of forbeside E1 (4) and E3 (5) was achieved in
1993 by Schmidt et al. (Scheme 4),22 as a progress toward
synthesis of the complex asterosaponins.53,54 The synthesis
chose the commercially available but expensive 11a-hydrox-
yprogesterone (51) as starting material, which was converted
into the desired D9,11,3b,6a-diol 55 adopting modication of
a previously known procedure (9 steps and 18% overall yield).55
Selective protection of the more reactive 3b-OH with TBS group
led to 56. Using Schmidt's glycosylation method,56 coupling of
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56 with peracetyl quinovosyl imidate 57 in the presence of
TMSOTf led to the desired b-glycoside 58 in a good 76% yield.
Removal of the 3-O-TBS group (in 58) followed by sulfonation
(with SO3$pyridine), aer ion exchange with Na+ resin, provided
59. Finally, deprotection of the acetyl groups in the sugar
residue (in 59) furnished forbeside E3 (5) cleanly. Alternatively,
reduction of the 20-carbonyl group in 59 with NaBH4 followed
by removal of the acetyl groups provided forbeside E1 (4).
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(62), aglycone derivative 74, which is ready for installation of the
glycan, was prepared in total 17 steps and 9% overall yield.
The glycosylation of 74 was achieved with Yu's glycosylation
method,31,64 using pentasaccharide ortho-hexynylbenzoate 75 as
donor and Ph3PAuOTf as catalyst (0.2 eq.), to afford the desired
steroid 6a-O-b-pentasaccharide 76 in an excellent 80% yield.
Finally, selective removal of the 3-O-TBS group, sulfonation of
the resulting 3-OH, and global deprotection of the benzoyl

groups furnished goniopectenoside B (6) cleanly.

4.2 Synthesis of goniopectenoside B

4.3 Synthesis of astrosterioside A
Goniopectenoside A–C (60, 6 & 61, Fig. 5) was identied by Zollo
In 2013, astrosterioside A–D (Fig. 6) were isolated by Kim et al.
et al. in 2000 from a large pinkish starsh, namely Goniopecten
from the edible Vietnamese starsh Astropecten monacanthus.65
demonstrans, in deep waters of the Gulf of Mexico.57 These
Astrosterioside A and D (7 and 79) showed potent inhibitory
asterosaponins were found to inhibit signicantly the settle-
activities against the production of pro-inammatory cytokines
ment of the biofouling marine brown macroalga Hincksia
IL-12 p40, IL-6, and TNF in LPS-stimulated bone marrow-
irregularis. In 2013, Xiao and Yu achieved the total synthesis of
derived dendritic cells, whereas congeners astrosterioside B
Goniopectenoside B (6), which represents the rst synthesis of
and C (77 and 78) were much less active. This result indicates
an asterosaponin or a marine steroid oligosaccharide.23
that the steroidal side chain are crucial for the anti-
The commercially available adrenosterone (62) was
inammatory activities of these compounds. In 2015, Dai and
employed as starting material (Scheme 5). Thus, trisketone 62
Yu reported the synthesis of astrosterioside A (7),24 which
was subjected to selective enol acetylation and ketal formation
features a 20(22)E-ene-23-one motif in the steroidal side chain
to give 63.58 Treatment of 63 with Ca(BH4)2 in EtOH led to the
and a terminal L-arabinofuranose residue in the glycan.
corresponding 3,11-diol, which was protected with TBS groups
Following the previous procedures for the synthesis of gonio-
to give 64.59 Hydroboration–oxidation of the 5,6-double bond
pectenoside B (Scheme 5), adrenosterone 62 was converted similarly
yielded 6a-ol 65. Removal of the C17 ethylene ketal and subse-
into ketone 70 (13 steps and 21% overall yield) (Scheme 6). Elabo-
quent protection of the 6a-OH with TBS group gave 66.60 Ketone
ration of the side chain from 70 required stepwise transformations,
66 was subjected to Wittig reaction to provide Z-olene 67.
i.e., HWE reaction with phosphonate 80 gave nitrile 81,66 and
Treatment of 67 with 9-BBN followed by oxidation afforded the
subsequent addition with iso-butylmagnesium bromide afforded
desired 20-ol,61 which was converted to ketone 68 via the Ley
the desired a,b-unsaturated ketone 82.67 Removal of the two TBS
oxidation.62 Subjection of ketone 68 to HClO4 in HOAc at 100  C
groups (in 82) followed by selective TBS protection led to 6a-ol 83.
resulted in complete removal of the TBS groups, acetylation of
Glycosylation of 83 with hexasaccharide ortho-cyclo-
the equatorial 3b,6a-OHs and dehydration of the axial 11b-OH,
propylethynylbenzoate 84 proceeded smoothly under the
furnishing the D9,11 derivative 69 in good yield.55 Before elon-
catalysis of Ph3PAuNTf2 (0.2 eq.), affording the desired 6a-O-b-
gation of the side chain, the incompatible acetyl groups (in 69)
glycoside 85 in an excellent 83% yield. Finally, removal of the 3-
was replaced with TBS groups to give 70. Addition of ketone 70
O-TBS group (in 85), sulfonation of the resulting C3-OH, and
with 2-lithio-2-isopentyl-1,3-dithiane (71) was then succeeded to
global deprotection of the acetyl and benzoyl groups furnished
provide the desired 20(R)-hydroxydithiane 72 as a single
astrosterioside A (7) in overall 69% yield over 3 steps.
stereoisomer in 83% yield.63 Aer removal of the TBS groups in
72, the S,S-acetal was taken off under optimized conditions
(Hg(ClO4)2, CaCO3, MeOH,
80  C) to avoid degradation of the 4.4 Synthesis of linckosides A and B
resultant hydroxyl ketone 73. Selective TBS protection of the In 2002, linckoside A and B (8 & 9) were identied as active
most reactive 3b-OH in triol 73 led to 74. From adrenosterone components from the blue Okinawan starsh Linckia laevigata

Fig. 5 Goniopectenoside A–C (60, 6 & 61).

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Scheme 5 Synthesis of goniopectenoside B (6).
by Ojika et al. in the search of neuritogenic natural products.68
The encouraging results led to further isolation and character-
ization of linckosides C–K and M–Q (Fig. 7).69–72 From the
Vietnamese L. laevigata, Kicha et al. isolated new congeners,
named linckosides L1–L7.73–75 Using dehydroisoandrosteron as
starting material, Li et al. reported in 2013 the synthetic studies
toward linckoside B.76 In 2015, the synthesis of linckoside A and
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B (8 and 9) was accomplished by Zhu and Yu,25 which employed
diosgenin as starting material.
Diosgenin (40) was converted readily to lactone 107 following
a known procedure (Scheme 7).77,78 Regioselective allylic
bromination of 107 followed by epimerization (with excess LiBr)
led to the desired C7a bromide; subsequent treatment with p-
toluenethiol yielded b-sulde 108.79 Replacing the 3-O-acetyl
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Fig. 6 Astrosterioside A–D (7 & 77–79).

group in 108 with MOM group, reduction of the lactone, Subjection of 109 to oxaziridine 110 yielded the sulfoxide,
selective protection of the resultant primary hydroxyl group which underwent cis-elimination at 80  C to provide 5,7-diene
with TBDPS ether, and oxidation of the remaining 16-OH 111. 16-Ketone 111 was treated with oxaziridine 110 and
afforded ketone 109. LiHMDS at
78  C;80 reduction of the resultant acyloin with

Scheme 6 Synthesis of astrosterioside A (7).

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Fig. 7 Linckosides (8, 9 & 86–106).
NaBH(OAc)3 (ref. 81 and 82) followed by acetylation of the
resultant 15a,16b-diol provided 112. Selective epoxidation of
the 5,6-double bond (over the less accessible 7,8-double bond)
in diene 112 was realized;83 hydrolysis of the resultant epoxide
afforded 5a,6b-diol 113 in good yield.84 Few methods were
available for the introduction of the steroidal C8-OH, which
used either dihydroxylation or epoxidation of the 7,8-ene
derivatives. Such attempts were unsuccessful on substrates
either before or aer installation of the 15,16- or 5,6-diols.
Luckily, using Mukaiyama's hydration method (Co(acac)2,
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PhSiH3, O2, iPrOH),85 7,8-ene 113 was converted to the desired
8b-ol 114 in 46% yield. Removal of the TBDPS group followed by
selective oxidation of the resultant primary alcohol gave the
desired aldehyde 115.86 Julia olenation of aldehyde 115 with
sulfone 116 provided 117.87 Aer removal of the bulky TBDPS
group in 117, the proximal double bond was successfully satu-
rated via hydrogenation over Crabtree's catalyst,88 furnishing
the advanced aglycone derivative 119.
Glycosylation of 119 with L-arabinofuranosyl o-hex-
ynylbenzoate 120 proceeded smoothly under the catalysis of
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Scheme 7 Synthesis of an advanced aglycone precursor (119) of linckosides.
Ph3PAuNTf2 (0.2 eq.); subsequent removal of the 3-O-MOM
group provided the desired 29-O-glycoside 121 in 72% yield over
two steps (Scheme 8). Oxidation of the 3-OH in 121, dehydration
of the 5-OH,89 and subsequent Luche reduction led to the
desired allylic alcohol 122.90 Glycosylation of 122 with 2-O-
methyl-D-xylopyranosyl o-hexynylbenzoate 123 under the
optimal conditions (0.2 eq. PPh3AuNTf2, CH2Cl2, -10  C)
provided the desired b-glycoside 124 (93%) in an unusually high
b selectivity without presence of a neighbouring participation
group in the glycosyl donor. Finally, removal of the acyl groups
furnished linckoside A (8) cleanly. Similarly, linckoside B (9)
was synthesized, using xylosyl o-hexynylbenzoate 125 as the
donor in the rst glycosylation step.
5. Synthesis of sea cucumbers
saponins
5.1 Synthesis of echinoside A, ds-echinoside A and echinoside B
In 1980, echinoside A and B (10 and 12) were isolated by Kita-
gawa et al. from an Okinawa sea cucumber Actinopyga echinites
as potent antifungal compounds.91,92 Where aer, echinoside A
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was also isolated from other sea cucumber species together with
a series of congeners (Fig. 8), including holothurin A (129) from
Bohadschia argus,93 Holothurin A1 (130), ds-echinoside A (11)
and 24-dehydroechinoside A (128) from Pearsonothuria graef-
fei,94 Holothurin A (129), A1 (130), B (134), B4 (135), scabraside B
(131), D (132), 24-dehydroechinoside A (128) and HS-1 (133)
from Holothuria scabra.95 Biological studies showed that echi-
noside A exhibited potent antitumor activities in vitro and in
vivo.94–96 In 2017, Yu et al. reported the synthesis of echinoside
A, B and ds-echinoside A.26 Besides these echinosides, holotoxin
and philinopside E of the sea cucumber saponins have also
been synthetic targets.97,98
The successful synthesis of echinosides (10–12) used the
commercially available lanosterol (136) as starting material
(Scheme 9). Thus, degradation of the side chain in lanosterol
(136) led to 20-ketone 139 over 6 steps in overall 22% yield.
Reduction of ketone 139 with L-selectride afforded alcohol 140,
which was subjected to the radical C-H functionalization reac-
tion followed by oxidation to give 18-iodo-20-ketone 141
(44%).99–101 Hydrolysis of the iodide led to hemiketal 142, which
was converted to 18-silyloxy-20-ketone 143 via reduction,
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Scheme 8 Completion of the synthesis of linckoside A and B (8 and 9).
selective protection, and re-oxidation. Introduction of the 17-
OH in 143 was realized with Gardner's procedure;102 the nascent
hydroxyl group was protected as a TMS-ether to give 144.103 The
requisite side chain was then installed in a stepwise manner to
secure the desired conguration at C20. Thus, ketone 144 was
alkylated with isopentyl iodide, aer removal of the TMS group,
to provide 145,104 which was subjected to addition with MeLi.
Aer cleavage of the TBDPS group, the desired triol 146 was
obtained in good yield.105 A selective oxidation of the primary
18-OH in 146 was succeeded with the Swern reaction, further
oxidation with PCC led to lactone 147. The transposition of the
8,9-double bond was effected following an oxidative procedure
(with CrO2Cl2) reported by Staliński and Paryzek,106 affording
the desired D9(11)-7-oxo derivative 148, which bears the desired
conguration at C8. The C7-carbonyl group was reduced by the
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Barton–McCombie sequence in three steps, giving 149. Allylic
oxidation of C12 was achieved with CrO3-DMP, concurrently the
3-O-benzyl group was oxidized into a benzoyl group; subsequent
removal of the benzoyl group furnished aglycone derivative
150.107,108
To secure the stereoselective formation of the 1,2-trans-
glycosidic linkages in echinosides, a stepwise glycosylation
sequence was implemented. Thus, aglycone 150 was rstly
coupled with xylosyl o-hexynylbenzoate 151 which was equipped
with a participating Azmb group at O2; subsequent removal of
the Azmb group led to 3-O-b-glycoside 152 (73%). Mono-
saccharide 152 was then condensed with trisaccharide o-hex-
ynylbenzoate 153 to provide tetrasaccharide 154 (85%). Finally,
reduction of the 12-carbonyl group,109 acetylation of the resul-
tant hydroxyl group, and subsequent removal of the Nap group
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Fig. 8 Echinoside A, B and congeners (10, 12 and 128–135).

Scheme 9 Synthesis of an advanced aglycone derivative (150) of echinosides.

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Scheme 10 Completion of the synthesis of echinoside A (10), B (12) and ds-echinoside A (11).
led to 155. Sulfonation of the nascent 40 -OH, exchange with
sodium ion, and removal of all the acyl groups on the glycan
furnished echinoside A (10). Removal of the acyl groups in 155
provided ds-echinoside A (11). Alternatively, glycosylation of 152
with quinovosyl o-hexynylbenzoate 156 led to disaccharide 157,
which was converted readily into echinoside B (12), following
a similar sequence as that for the synthesis of echinoside A (10)
from tetrasaccharide 154.
6. Conclusions
Over one thousand saponins have been characterized from
starsh, sea cucumber, sponges, so coral, and small sh.
These metabolites show various biological and pharmacological
784 | Nat. Prod. Rep., 2019, 36, 769–787
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activities, however, are poorly accessible. This poor accessibility
is partly due to the heterogeneous occurrence of these mole-
cules in the marine species, as highlighted here by the many
congeners of linckoside A and B (8, 9 and 86–106, Fig. 7) and of
echinoside A and B (10, 12 and 128–135, Fig. 8). Thus far, only
12 marine saponins (1-12) have been synthesized. Nevertheless,
the chemical synthesis has shown a realistic alternative to
provide these marine natural products. Especially, the synthe-
sized goniopectenoside B (6) and astrosterioside A (7) repre-
sents typical members of the asterosaponins, linckoside A and B
(8 and 9) typical members of the polyhydroxysteroid glycosides,
and echinoside A (10) a typical member of the sea cucumber
saponins. The majority of marine saponins can be categorized
into these three structural types.
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The synthesis of marine saponins involve preparation of the
multi-functionalized steroid or triterpenoid aglycones from the
commercially available, and oen inexpensive, steroid or tri-
terpene materials of the terrestrial origins, such as cholic acid
(17), chenodeoxycholic acid (30), diosgenin (40), 11a-hydrox-
yprogesterone (51), adrenosterone (62), and lanosterol (136).
Degradation of the original side chain and elaboration of a new
one, and selective introduction of hydroxyl groups onto the
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nucleus are the major tasks. The glycans are introduced oen at
a late stage of the synthesis. To ensure the stereoselective
formation of the glycosidic linkage, which is always 1,2-trans in
marine saponins, the whole glycan can be installed in a step-
wise manner, as in the synthesis of echinosides (Scheme 10).
Thus, the glycosylation can be facilitated by a neighbouring
participating group at O2 of the glycosyl donor. Otherwise,
stereoselective glycosylation is also possible in the absence of
a neighbouring participating group employing optimal condi-
tions, as in the synthesis of pavoninin-1 (Scheme 2) and
linckosides (Scheme 8). The protecting group strategy plays
a crucial role in the successful synthesis of marine saponins. A
particular attention is given to the permanent protecting
groups, which have to be taken off, usually at the nal steps,
without affecting all the functional groups of the target mole-
cule. Thus, the protecting groups on the glycans are oen
synchronized before attachment to the aglycone (e.g., in oligo-
saccharide donors 75, 84, and 153).
These successful synthetic approaches are adaptable to the
synthesis of many congeners and analogs, thus will facilitate the
detailed SAR studies on marine saponins. However, it is note-
worthy that the current synthesis, employing conventional
transformations, require long steps and are in low overall
yields. Selective functionalization reactions on complex steroid
and triterpenoid scaffolds as well as innovative methods for the
synthesis of carbohydrates need to be developed and imple-
mented in the future synthesis.110–112
7. Conflicts of interest
There are no conicts to declare.
8. Acknowledgements
B. Y. acknowledges the National Key Research & Development
Program of China (2018YFC0310900), the National Natural
Science Foundation of China (21432012 & 21621002), the Stra-
tegic Priority Research Program of the Chinese Academy of
Sciences (XDB20020000), and the K. C. Wong Education Foun-
dation for nancial support on the relevant researches. G. X.
thanks nancial support from the CAS Pioneer Hundred
Talents Program (No. 2017-128) and the Start-up funding of
Kunming Institute of Botany for the relevant research program.
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