Total Synthesis of Linckosides A and B, the Representative Starfish Polyhydroxysteroid Glycosides with Neuritogenic Activities

Article abstract of DOI:10.1021/jacs.5b11276

Linckosides A and B, two starfish metabolites with promising neuritogenic activities, are synthesized in a longest linear sequence of 32 steps and 0.5% overall yield; this represents the first synthesis of members of the polyhydroxysteroid glycoside family, which occur widely in starfishes.

Full text of DOI:10.1021/jacs.5b11276

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Communication
Total Synthesis of Linckosides A and B, the Representative Starfish
Polyhydroxysteroid Glycosides with Neuritogenic Activities
Dapeng Zhu, and Biao Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11276 • Publication Date (Web): 23 Nov 2015
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Total Synthesis of Linckosides A and B, the Representative Starfish
Polyhydroxysteroid Glycosides with Neuritogenic Activities
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Dapeng Zhu and Biao Yu*
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China.
Supporting Information Placeholder
tions8 would be reliable tasks. A late-stage glycosylation at C3-
ABSTRACT: Linckosides A and B, two starfish metabolites
OH with 2-O-methyl donor 5 was straightforward, however, the
required -selectivity would require scrutiny of the glycosylation
conditions.9 Given the dense functionality of the substrates, a
successful sequence of transformations can only be determined by
trial-and-error.
with promising neuritogenic activities, are synthesized in a long-
est linear sequence of 32 steps and 0.5% overall yield; this repre-
sents the first synthesis of members of the polyhydroxysteroid
glycoside family which occur widely in starfishes.
R =
24
16
Linckosides A (1) and B (2) were identified from an Okinawan
starfish namely Linckia laevigata in 2002 during a screening for
neuritogenic natural products, which could be candidates for the
prevention and treatment of neurodegenerative diseases.1a The
promising results led to further isolation and characterization of
over twenty minor congeners, and the majority of these
O
OH
8
OH
15
29
O
HO
1''
HO
HO
OR
1''
3
OH
HO
OH
O
6
OH
HO
HO
O
Linckoside A (1)
Linckoside B (2)
1'
OH
MeO
O
OH
OAc
O
O
S
N
S
MBzO
MBzO
O
O
linckosides share
a
common cholesta-3,6,8,15,16-
OAc
OMe
O
pentahydroxy nucleus and a 2-O-methyl--D-xylopyranose resi-
due at C3.1 In fact, polyhydroxysteroid glycosides relevant to
linckosides are common and characteristic metabolites in starfish-
es, in which hydroxyl groups commonly occur at C6, C8, and C15
besides the biogenetic hydroxyl group at C3.2 These metabolites
of the slow-moving starfishes are believed to be the defense
chemicals against parasites and predators, therefore are expected
to possess a variety of pharmacological activities, such as anti-
tumor and antibacterial activities. However, the poor accessibility
of these molecules from natural sources has retarded in-depth
studies on their activities. Chemical synthesis to attain these high-
ly polar, fragile, and complex steroid glycosides poses also a for-
midable challenge;3,4 to the best of our knowledge, none of the
starfish polyhydroxysteroid glycosides has ever been synthesized
to date.4,5
MOMO
3
4
5
HO
nBu
OH
OTBDPS
O
O
O
O
BzO
BzO
O
O
BzO
OBz
O
O
BzO
OBz
nBu
AcO
nBu
8
6
7
Figure 1. Linckosides A (1) and B (2) and a retrosynthetic plan.
The synthesis commenced with preparation of lactone 8 from
the cheap industrial material diosgenin (4 steps, 53% yield; Sup-
porting Information) (Scheme 1). Regioselective allylic bromina-
tion of 8 led to the corresponding C7-bromide as a mixture of
epimers, which were in equilibrium in the presence of excess LiBr;
subsequent treatment with p-toluenethiol and Et3N provided -
sulfide 9 (79%).10 The 3-O-acetyl group in 9 was replaced by a
methoxymethyl group, which was found appropriate in the fol-
lowing transformations. The resulting 10 was then subjected to
reduction (of the lactone); selective protection of the nascent 22-
OH with a tert-butyldiphenylsilyl (TBDPS) group and oxidation
of the 16-OH (with Dess-Martin periodinane) furnished C16-
ketone 11 smoothly (85%). Treatment of 11 with a EtOAc solu-
tion of oxaziridine 12 resulted in an epimeric mixture of the corre-
sponding sulfoxide, which underwent cis-elimination at 80 °C to
yield the desired 5,7-diene 13 (80%).10 Addition of oxaziridine 12
to a THF solution of ketone 13 and LiHMDS at -78 °C, a protocol
We envisioned the assembly of linckoside A/B from four
pieces (Figure 1), including a polyhydroxysteroid C22 aldehyde
(e.g., 3), a side chain derivative (e.g., 4), a 2-O-methyl-D-
xylopyranosyl donor (e.g., 5), and an L-arabinofuranosyl/D-
xylopyranosyl donor (e.g., 6/7). The polyhydroxysteroid aldehyde
(3) could be elaborated from the easily accessible vespertilin ace-
tate 86 by exploiting the inherent functional groups at C3, C5/6,
C16, and C22. Both the installation of the side chain onto the C22
aldehyde via a Julia olefination (3+4)7 and the stereoselective
glycosylation at C29-OH with donors (6/7) bearing a neighboring
participating ester group under the mild gold(I)-catalyzed condi-
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developed by Davis et al,11 gave a satisfactory conversion, en-
followed by oxidation of the sulfide with ammonium molybdate
sured by a relatively high concentration (ca. 0.3 M) of the lithium
enolate and careful workup. Immediate reduction of the resultant
acyloin with NaBH(OAc)3 delivered the required 15,16-diol 14
in a decent 42% yield, without detection of the possible diastereo-
isomers.12,13 The 15,16-OHs were masked with acetyl groups to
give 15. Selective epoxidation of the 5,6-ene in diene 15 was
achieved with methyltrioxorhenium (VII) and urea hydrogen per-
oxide.14 Successive hydrolysis with an aqueous NaH2PO4 solution
in THF afforded 5,6-diol 16 in a good 71% yield.15
tetrahydrate and H2O2 afforded sulfone 4 smoothly (88%). The
condensation of sulfone 4 and aldehyde 3 was realized under the
modified Julia olefination conditions,7 which necessitated
LiHMDS (9.2 equiv) as a base and TMEDA (18.4 equiv) as an
additive. Nevertheless, besides the desired adducts 23 (48%, E/Z
= 1:1), adducts 22 (30%, E/Z = 1:1) were obtained in that the
5,6-diol was converted into 5,6--epoxide via seemingly an
SN2 substitution of the sterically hindered 6-OH by the anti-
perpendicular 5-OH which is much easier to be deprotonated. It
was noticed that condensation with the corresponding 6-O-acetyl
derivative led to the epoxide predominantly. All these products
were separated; and the epoxide 22E/22Z could be converted
into 5,6-diol 23E/23Z in ~50% yield (Supporting Infor-
mation).19 Surprisingly, the double bond in 23 was found to be
inert toward hydrogenation under various conditions (Supporting
Information), that might be attributable to its crowded surround-
ing. Therefore, after blocking the 6-OH with an acetyl group
(while the tertiary 5,8-OHs were inert toward acetylation), the
bulky TBDPS group was removed to give 24. Subjection of
24E/24Z to hydrogenation in the presence of Crabtree’s cata-
lyst20 afforded the saturated aglycon 25 quantitatively.
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In was noted that few literatures have documented the instal-
lation of the steroidal C8-OH, which involved either dihydroxyla-
tion or epoxidation of 7,8-ene derivatives.16 We failed at numer-
ous attempts on substrates either before or after introduction of
the 15,16/5,6 diols. Fortunately, application of the Mukaiyama
hydration conditions17 onto the advanced 7,8-ene 16 led to the
desired 8-ol 17 in appreciable yields. Under the optimized condi-
i
tions (1.1 equiv Co(acac)2, 9.5 equiv PhSiH3, O2, PrOH, 50 °C)
17 was readily isolated in 46% yield. The downfield shift of the
angular methyl H18 and H19 resonances in 17 compared to those
in 16 (by 0.30 and 0.24 ppm, respectively) is consistent with a β
configuration at C8.16c,d Removal of the silyl group provided
tetraol 18; selective oxidation of the resulting primary C22-OH
was achieved with TEMPO and PhI(OAc)2,18 affording the de-
sired aldehyde 3 in an excellent 91% yield. The structure of 3 was
confirmed by an X-ray diffraction analysis (CCDC 1433646;
Supporting Information).
Scheme 2. Synthesis of the aglycon derivative 25.
N
S
SH
DIAD, PPh3,
S
1) DIBAL-H, CH2Cl2;
HO
COOtBu
20
N
S
COOtBu
2) NaBH4, MeOH, 99%
THF, 90%
19
Scheme 1. Synthesis of steroidal aldehyde 3.
O
O
1) TBDPSCl, DMAP
CH2Cl2;
TBDPSO
S
S
O
LiHMDS, 3, TMEDA, THF
OH
1) NBS, AIBN, CCl4;
N
S
1) LiAlH4, THF;
N
S
O
2) (NH4)6Mo7O24-4H2O,
H2O2 (30% aq.),
EtOH, 88%
8
OTBDPS
O
2) LiBr, TolSH,
Et3N, toluene,
actetone, 79%
2) TBDPSCl, DMAP,
21
4
CH2Cl2
;
RO
STol
3) DMP, NaHCO3,
CH2Cl2, 85%
MOMO
STol
OTBDPS
9 R = Ac
11
OTBDPS
+
1) K2CO3, MeOH/CH2Cl2;
2) MOMCl, DIPEA, CH2Cl2, 79%
10 R = MOM
1) Ac2O, DMAP
CH2Cl2;
TBDPSO
nBu
O
TBDPSO
O
OH
OAc
OAc
OH
OAc
OAc
2) HF-pyridine
MeOH; ~94%
N
1) EtOAc,
1) LiHMDS, 12, THF;
S
O
OR
MOMO
MOMO
O
O
HO
12
OH
23 (48%, E/Z = 1:1)
2) NaBH(OAc)3,
OR
2) Et3N, toluene,
THF, 42%
MOMO
22 (30%, E/Z = 1:1)
MOMO

80 C, 80%
13
14 R = H
Ac2O, DMAP, CH2Cl2, 86%
1) HClO4, acetone/H2O;
15 R = Ac
2) TBDPSCl, DMAP, CH2Cl2; ~50%
OH
OH
OTBDPS
Co(acac)2, PhSiH3,
O2, iPrOH, 46%
1) UHP, MTO, pyridine, THF;
Crabtree's catalyst,
H2 (1 atm), CH2Cl2, 99%
OAc
OAc
16
2) aq. NaH2PO4 (1 N),
THF, 71%
OH
OAc
OAc
25
OH
OAc
OAc
24
MOMO
HO
OH
R
MOMO
MOMO
HO
HO
OAc
OAc
OTBDPS
OAc
OH
OAc
OH
HF-py, MeOH, 76%
OAc
OAc
17
MOMO
As expected, glycosylation of 25 at 29-OH with o-
hexynylbenzoate donor 6 proceeded smoothly under the catalysis
of PPh3AuNTf2 (0.2 equiv);8 subsequent removal of the 3-O-
MOM group with HCl in THF/H2O facilitated the purification of
the product to provide -L-arabinofuranoside 26 in a good 72%
yield (Scheme 3). Oxidation of the 3-OH (in triol 26) with pyri-
dinium chlorochromate in CH2Cl2 followed by treatment with
HCl in dioxane led to the corresponding 4,5,3-one derivative,21
which was subjected to Luche reduction to afford 4,5,3-ol 27
HO
MOMO
OH
HO
OH
18 R = CH2OH
3 R = CHO
TEMPO, PhI(OAc)2, CH2Cl2, 91%
Preparation of the side chain derivative 4 was straightfor-
ward (Scheme 2). Indeed, Mitsunobu substitution of the readily
available chiral alcohol 197d with 2-mercaptobenzothiazole pro-
vided sulfide 20 (90%). The ester residue in 20 was reduced into
alcohol by DIBAL-H and subsequently NaBH4 (99%). Protec-
tion of the resulting hydroxyl group (in 21) with a TBDPS group
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(64%).22 It was noted that direct dehydration of the 5-OH in 17
after acetylation of 6-OH was not successful.
Corresponding Author
byu@mail.sioc.ac.cn
7
8
Scheme 3. Completion of the synthesis of linckoside A (1).
ACKNOWLEDGMENT
9
Financial support from the Ministry of Science and Technology of
China (2013AA092903), the National Natural Science Foundation
of China (21432012), and the E-Institutes of Shanghai Municipal
Education Commission (E09013) is acknowledged. We are also
grateful to Prof. Ojika for providing the NMR spectra of the
authentic linckoside B and Mrs. Yanqing Gong for the analysis of
X-ray diffraction data of compound 3 which were collected on the
BL17B1 beamline at the Shanghai Synchrotron Radiation Facility.
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1) PPh3AuNTf2 (0.2 eq),
4A MS, CH2Cl2, rt;
OH
OAc
25
+
6
O
OAc
2) HCl, THF/H2O, 72%
O
HO
HO
OBz
OAc
26
BzO
OBz
5
, PPh3AuNTf2 (0.2 eq),

4A MS, CH2Cl2, -10 C,
> 20:1
1) PCC, Al2O3, CH2Cl2;
2) HCl, dioxane;
OH
OAc
/

93%,
a
O
OAc
BzO
3) CeCl3-7H2O, NaBH4,
THF/MeOH, 64%
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HO
OBz
OAc
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27
OBz
OH
OAc
KOH, MeOH,
50 C, 98%
O

1
OAc
BzO
O
O
MBzO
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OMe
OBz
OAc
28
OBz
The glycosylation of 27 with 3,4-di-O-p-methoxybenzoyl-2-
O-methyl-D-xylopyranosyl o-hexynylbenzoate (5, / = 1:2.4)
under the catalysis of PPh3AuNTf2 (0.2 equiv) in CH2Cl2 at -10
oC was proven to be optimal (see Supporting Information for
model studies), affording the desired 3-O--glycoside 28 in an
excellent 93% yield, with the -anomer hardly detectable.
Nevertheless, further studies are required to understand the
mechanism behind this unusually high -selectivity.8d,9 Finally, all
the acyl groups on 28 were cleaved cleanly with KOH in
methanol at 50 oC, furnishing linckoside
quantitatively. By the same token, linckoside
synthesized starting from glycosylation of 25 with D-
xylopyranosyl o-hexynylbenzoate 7 (Supporting Information).
The analytic data of the synthetic 1 and 2 are identical to those
reported for the natural products (Supporting Information).
A
(1) nearly
(2) was
B
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Summarizing, the total synthesis of linckoside A/B (1/2) has
been achieved from readily available materials in a modular
sequence, which requires a longest 32 linear operations (in a total
of 44 steps) and proceeded with 0.5% overall yield. The synthesis
is easily adaptable to the synthesis of analogs, and thus shall
facilitate in-depth studies on the promising neuritogenic effects of
linckosides. In addition, the present synthesis represents the first
synthesis of members of the polyhydroxysteroid glycosides,
which occur ubiquitously in starfishes, and thus demonstrates the
feasibility of synthetic access to this type of complex marine
metabolites with a wide spectrum of biological activities.
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ASSOCIATED CONTENT
Supporting Information
Synthetic procedures, characterization data, and NMR spectra for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Linckoside A
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