Total synthesis of starfish saponin goniopectenoside B

Article abstract of DOI:10.1002/chem.201301186

Star quality: Goniopectenosidea...B, a minor asterosaponin from starfish Goniopecten demonstrans with antifouling activity, has been synthesized in a convergent 21a€...steps and in 4.3 % overall yield starting from adrenosterone. This represents the first synthesis of a complex asterosaponin, which are ubiquitous and characteristic in starfish as defense chemicals (see figure). Copyright

Full text of DOI:10.1002/chem.201301186

DOI: 10.1002/chem.201301186
Total Synthesis of Starfish Saponin Goniopectenoside B
Guozhi Xiao and Biao Yu*[a]
Steroid glycosides, which occur widely and abundantly in
been synthesized.[7] The synthesis of goniopectenoside B (1),
a typical asterosaponin, reported herein represents the first
synthesis of a marine steroidal oligosaccharide.
The penta- or hexasaccharides in asterosaponins invaria-
bly bear a free C2-OH at the first pyranose unit, this ena-
bled synthesis of asterosaponins in a convergent manner
through coupling of the fully fabricated aglycon and glycan
at a later stage (Figure 1).[5] Thus, in the synthesis of gonio-
terrestrial plants, are rarely found in the animal kingdom.
The only exception so far is in species belonging to Asteroi-
dea (starfish), in which steroid glycosides are ubiquitously
found.[1] Since the 1960s,[2] the investigation of nearly 100
starfish species collected in all climatic areas has led to the
identification of some 400 steroid glycosides.[3] With a few
exceptions, all the starfish saponins can be classified into
two structural groups, the asterosaponins and the glycosides
of polyhydroxysteroids. The asterosaponins, occurring in
almost all starfish species, possess well defined structural
characteristics.[3] They invariably contain a D9(11)-3b,6a-dihy-
droxysteroidal nucleus with a sulfate residue at C3 and a
glycan at C6. The glycans are mostly penta- or hexasacchar-
ides with all 1,2-trans-pyranosidic linkages and a (1!2)
branching point at the second sugar unit. An example in
point is goniopectenoside B (1). Goniopectenoside B, to-
gether with goniopectenosides A and C, was isolated from
Goniopecten demonstrans, a large pinkish starfish living in
deep waters of the Gulf of Mexico.[4] These three asterosa-
ponins, of which goniopectenoside B is the scarcest conge-
ner, differ only at the side chain and show similar antifoul-
ing activities.
Starfish are slow-moving animals, the metabolites of ste-
roid glycosides are therefore believed, and in many cases
have been proven, to be defense chemicals against parasites
and predators.[1] Accordingly, a variety of pharmacological
activities, such as antitumor and antibacterial activities, are
expected. Nevertheless, the poor accessibility of these mole-
cules has retarded in-depth studies on their activities. The
isolation of starfish saponins from natural resources is ex-
tremely difficult, because they are scarce, often vulnerable
toward acid and base, and occur as complex mixtures.
Chemical synthesis of these highly polar, fragile, and com-
plex natural products is also a formidable task.[5,6] In fact,
only two steroid monosaccharides from marine species have
Figure 1. Starfish saponin goniopectenoside B (1) and its retrosynthetic
analysis.
pectenoside B (1), the coupling of aglycon derivative 2 with
pentasaccharide donor 3 bearing the neighboring-participat-
ing benzoyl group at C2 would furnish the native 1,2-trans-
glycosidic linkage in a stereocontrolled manner. The aglycon
C3-OH in 2 was protected as a TBS ether (TBS=tert-butyl-
dimethylsilyl), which could be selectively replaced with the
destined sulfate residue, the hindered C20-OH was expected
to be innocent in the glycosylation with C6-OH. The penta-
saccharide donor 3 was activated with ortho-hexynylben-
[a] G. Xiao, Prof. B. Yu
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P.R. China)
Fax : (+86)21-64166128
E-mail: byu@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301186.
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COMMUNICATION
zoate at the anomeric C1, which would remain stable until
activation with a catalytic amount of a gold(I) complex
under mild conditions.[8,9] All other hydroxyl groups on pen-
tasaccharide 3 were synchronized with benzoyl protection,
which could be removed to furnish the target asterosaponin.
The cholestane aglycon 2 was expected to be derived from
the commercially available adrenosterone 4, through elabo-
ration of the D9(11)-3b,6a-dihydroxysteroidal core and instal-
lation of the side chain at C17.
ACHTUNGTRENNUNG
The pentasaccharide
3
was
planned to be assembled from
five monosaccharide building
blocks 5–9, in which trichloro-
ACHTUNGTRENNUNGacetimidate was employed as
the C1 leaving group and acetyl
as the temporary protecting
group. The 2-O-acetyl or -ben-
zoyl groups installed in the
donors (3 and 6–9) would
secure the formation of the 1,2-
trans-glycosidic
linkages
through neighboring-group par-
ticipation in the glycosylation
reactions.
Commencing with adrenos-
terone 4, compound 10 was pre-
pared conveniently in four steps
with 61% overall yield follow-
ing
literature
procedures
(Scheme 1).[10] Hydroboration–
oxidation of the steroidal D5(6)
derivative 10 provided the 6a-
ol
(73%).[10a] Treatment of 11 with
cerium ammonium nitrate
11
stereoselectively
(CAN) in a mixed solvent of
MeCN/THF/buffer (pH 8) at
608C led to cleavage of the C17
ethylene glycol ketal and unex-
pectedly the 3-O-TBS ether,[11]
subsequent protection of the
3,6-diol with TBS ethers
(TBSOTf, 2,6-lutidine, CH2Cl2,
08C; Tf=triflate) afforded 12
in high yield (88% over two
steps). It was noted that the
present conditions also trans-
formed the C17 ketone into a
silyl enol ether (intermediate
A), which was converted com-
pletely back to ketone during
chromatography on silica gel.
Wittig olefination of ketone 12
led to Z-olefin 13 highly stereo-
selectively (93%).[12] Treatment
of olefin 13 with 9-BBN (9-
BBN=9-borabicyclo-
Scheme 1. Synthesis of the aglycon 20 and its 3-O-TBS ether 2.
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7709

B. Yu and G. Xiao
a good 77% yield. Meanwhile, the corresponding C17 (R)-
epimer was isolated in roughly 10% yield.[15]
22 being hardly detectable (entry 5). Selective protection of
the 3b-OH on triol 20 with TBSCl (1.3 equiv.) furnished the
desired aglycon derivative 2 in a satisfactory 57% yield with
26% of 20 being recovered. To confirm the synthetic struc-
ture, especially the configuration at C20 that is assumed to
be R in all asterosaponins, we resorted to X-ray diffraction
of a single crystal of an advanced synthetic derivative. Fortu-
nately, suitable crystals of the 3,6-di-O-p-bromobenzoate
ester 21 was obtained for X-ray diffraction analysis, confirm-
ing unambiguously the synthetic structure.[21] Thus, the agly-
con derivative 2 was elaborated in 17 easily scalable steps
and 8.9% overall yield from the commercially available
adrenosterone (4).
Installation of the rest of the C17 side chain onto ketone
16 by a dithiane addition[16] was unsuccessful due to the de-
terioration of the 3,6-O-acetyl groups. This prompted us to
replace the acetyl group with TBS group. Thus, the acetyl
groups in 16 were removed cleanly (KOH, tBuOH/H2O,
308C).[17] The reaction in less steric alcoholic solvents (e.g.,
MeOH), however, resulted in a considerable amount of the
C17-epimerized product. Treatment of the resulting 3,6-diol
with TBSOTf in CH2Cl2 at ꢀ708C led to intermediate B, the
C20-ketone was transformed into a silyl enol ether besides
the 3,6-OHs being silylated (cf., 11!12). Nevertheless, the
desired ketone 17 was obtained in high yield (87% for two
steps) after silica gel column chromatography. Treatment of
ketone 17 with 2-lithio-2-isopentyl-1,3-dithiane in THF at
ꢀ258C furnished successfully the desired C20(R)-hydroxydi-
thiane 18 as a single stereo-isomer in 83% yield.[17,18]
Assembly of the pentasaccharide ortho-hexynylbenzoate 3
was carried out in an efficient and straightforward manner
(Scheme 3). Glycosylation of quinovoside C3-ol 5[6b] with xy-
Unexpectedly, removal of the S,S-acetal in 18 was not
trivial. Treatment of 18 with N-chlorosuccinimide[18b] or
[19]
PhIACHTUNGTRENNUNG(OCOCF3)2 under various conditions led to unavoida-
bly complex mixtures. This prompted us to remove the vul-
nerable TBS ether (70% HF·pyridine, THF, room tempera-
ture, 91%) in 18 before cleavage of the S,S-acetal. When
the resulting triol 19, which was easily soluble in polar sol-
vents (i.e., MeCN/THF/H2O), was treated with HgCl2/
CaCO3 at 658C;[18a] the desired hydroxyketone 20 together
with the degraded ketone 22 was obtained as a 3:1 mixture
in very low yield (9%); Scheme 2, entry 1). Exposure of 19
Scheme 3. Synthesis of the pentasaccharide o-hexynylbenzoate 3.
losyl trichloroacetimidate 6[22] under the catalysis of
TMSOTf (0.05 equiv.) provided the b-disaccharide 23 nearly
quantitatively. Removal of the 2’,4’-O-acetyl groups on 23
led to diol 24 (95%). It was known that the 4-OH was more
nucleophilic than the 2-OH in a b-d-xylopyranoside unit,[23]
therefore selective glycosylation of the 4-OH in diol 24 was
expected. Indeed, coupling of 24 (1.5 equiv.) with quinovosyl
imidate 7[22] under the action of TMSOTf (0.05 equiv.) at
ꢀ258C afforded the b-(1!4)-coupled trisaccharide 25 in a
good 82% yield, with the b-(1!2)-coupled trisaccharide
being isolated in only trace amount (c.a. 7%). The chemical
shifts of the three anomeric carbons in 25 were d=102.3
(C1), 104.1 (C1’), and 100.2 ppm (C1’’), respectively,[22] indi-
cating the b configurations. The glycosylation position (at 4’-
OH) in trisaccharide 25 was confirmed by 13C NMR compar-
Scheme 2. Optimization of the reaction conditions for conversion of S,S-
acetal 19 to ketone 20.
to HgACHTUNGTRENNUNG(ClO4)2 in THF/H2O at 08C afforded 20/22 (4.5:1) in a
better yield (32%) (entry 2).[20] To our delight, replacing the
solvent from THF/H2O to MeOH reduced greatly the degra-
dation of the a-hydroxyketone side chain, leading to 20/22
in 17:1 ratio, although the yield remained low (entry 3). For-
tunately, the yield of 20 was improved greatly upon lowering
the reaction temperature to ꢀ658C (84%, 20/22 22:1;
entry 4). We were finally satisfied with the reaction at
ꢀ808C; 20 was obtained in 91% yield with the side product
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Total Synthesis of Starfish Saponin Goniopectenoside B
COMMUNICATION
ison with its trifluoroacetate derivative 26, of which the
three anomeric carbon signals appeared at d=102.1 (C1),
99.6 (C1’), and 100.4 ppm (C1’’), respectively. The shift of
~
C1’ signal to high field (by 4.5 ppm) was in agreement with
the acylation at it neighboring 2’-OH.[24] The remaining
poorly reactive 2’-OH in 25 was then glycosylated with qui-
novosyl imidate 8[9b] under stronger reaction conditions
(3.0 equiv. 8, 0.05 equiv. TMSOTf, room temperature), lead-
ing to the desired tetrasaccharide 27 nearly quantitatively.
Selective removal of the 2’’-O-acetyl group in 27 (in the
presence of two benzoyl groups) was unsuccessful under
basic conditions (such as with DBU/MeOH; DBU=1,8-
diazabicycloACHTUNGTRENNUNG
[5.4.0]undec-7-ene),[25] nevertheless this was
achieved under acidic conditions (AcCl, MeOH, CH2Cl2,
room temperature),[26] providing tetrasaccharide mono-ol 28
in a good 70% yield with 12% recovery of 27. Glycosylation
of the resulting 2’’-OH (in 28) with perbenzoyl-fucosyl imdi-
ate 9[27] under the catalysis of TMSOTf (0.1 equiv.) in
CH2Cl2 afforded the desired pentasaccharide 29 in an excel-
lent 90% yield. Pentasaccharide 29 was then transformed
into ortho-hexynylbenzoate 3 in a four-step sequence, i.e.,
1) removal of the six benzyl groups by hydrogenolysis over
Pd(OH)2/C, 2) protection of the resulting hydroxyl groups
with benzoyl groups (77% for two steps), 3) selective re-
moval of the anomeric benzoyl group (NH2CH2CH2NH2,
HOAc, THF, room temperature, 78%+14% recovered
starting material),[28] and 4) condensation with ortho-hexy-
nylbenzoic acid (EDCI, DMAP, DIPEA, CH2Cl2, room tem-
perature, 91%).[8,9]
Scheme 4. Completion of the total synthesis of goniopectenoside B (1).
able to access many more members of this fascinating class
of marine natural products, thus facilitating in-depth studies
on their biological and pharmacological activities.
Acknowledgements
As expected, the coupling of aglycon derivative
(5.0 equiv.) with pentasaccharide ortho-hexynylbenzoate 3
proceeded smoothly under the catalysis of [Au(PPh3)(OTf)]
2
This work was financially supported by the Ministry of Science and Tech-
nology of China (2013AA092903) and the National Natural Science
Foundation of China (90713003 and 20932009). We are grateful to Profes-
sor Franco Zollo for communication on the structure of goniopecteno-
sides.
A
ACHTUNGTRENNUNG
(0.2 equiv.) in the presence of 5 ꢁ molecular sieves in
CH2Cl2 at room temperature, affording the desired steroid
pentasaccharide 30 in a good 80% yield, with the excess
aglycon 2 being fully recovered (Scheme 4). Removal of the
3-O-TBS group in 30 was effected with HOAc/THF/H2O
(3:1:1) at room temperature to provide 31 (88%). Selective
sulfation of the C3-OH on 31 with SO3·pyridine (5.0 equiv.)
in DMF at room temperature afforded the 3-O-sulfate deriv-
ative as a pyridinium salt, which was then transformed into
the sodium salt 32 by an ion exchange resin (Amberlite IR
120, Na+ form) in a good 86% yield. With a larger excess of
the sulfation reagent, the tertiary C20-OH in 31 was also
sulfated. Finally, the ten benzoyl groups on the glycan were
removed with NaOMe in MeOH, furnishing goniopectenosi-
de B (1) in a good 80% yield. The analytical data of 1 are in
good agreement with those reported for the natural prod-
uct.[4,22]
In summary, the total synthesis of goniopectenoside B has
been achieved in a total of 70 steps starting from cheap ma-
terials, with a convergent linear sequence of only 21 steps
and in 4.3% overall yield from adrenosterone. The present
work represents the first synthesis of a complex asterosapo-
nin, which are ubiquitous in starfish as defense chemicals.
Given the conservative nature of the structures of asterosa-
ponin, the present synthesis offers the prospect of being
Keywords: asterosaponin · glycosylation · gold · steroids ·
total synthesis
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The authors reported the synthesis of compound 16 from 11a-hy-
droxyprogesterone, which is a prohibited chemical in China.
Received: March 28, 2013
Published online: May 6, 2013
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Chem. Eur. J. 2013, 19, 7708 – 7712