Total Synthesis of Marine Glycosphingolipid Vesparioside B

Article abstract of DOI:10.1021/jacs.5b12589

The first total synthesis of a major component of marine glycolipid vesparioside B (Scheme 1, 1, R₁ = n-C₂₂H₄₅, R₂ = n-C₁₄H₂₉) has been accomplished through a convergent [4 + 3] coupling strategy. Key steps included stereoselective installment of a set of challenging 1,2-cis-glycoside bonds. A 2-quinolinecarbonyl-assisted α-galactosylation and a novel β-arabinosylation were developed, respectively, to synthesize the α-galactofuranosidic and the β-arabinopyranosidic linkages. Furthermore, a 4,6-O-benzylidene-controlled α-galactopyranosylation reaction allowed the efficient connection of the left tetrasaccharide donor 2 with the right disaccharide lipid acceptor 3, hence leading to the total synthesis of 1.

Full text of DOI:10.1021/jacs.5b12589

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Article
Total Synthesis of Marine Glycosphingolipid Vesparioside B
Peng-Cheng Gao, San-Yong Zhu, Hui Cao, and Jin-Song Yang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b12589 • Publication Date (Web): 19 Jan 2016
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Total Synthesis of Marine Glycosphingolipid Vesparioside B
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Peng-Cheng Gao,a,‡ San-Yong Zhu,a,§,‡ Hui Cao,a and Jin-Song Yang*ab
aDepartment of Chemistry of Medicinal Natural Products, and Key Laboratory of Drug Targeting, Ministry of Edu-
cation, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
bState Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
ABSTRACT: The first total synthesis of a major component of marine glycolipid vesparioside B (Scheme 1, 1, R1 = n-C22H45,
R2 = n-C14H29) has been accomplished through a convergent [4+3] coupling strategy. Key steps included stereoselective
installment of a set of challenging 1,2-cis-glycoside bonds. A 2-quinolinecarbonyl-assisted α-galactosylation and a novel β-
arabinosylation were developed, respectively, to synthesize the α-galactofuranosidic and the β-arabinopyranosidic linkag-
es. Furthermore, a 4,6-O-benzylidene-controlled α-galactopyranosylation reaction allowed the efficient connection of the
left tetrasaccharide donor 2 with the right disaccharide lipid acceptor 3, hence leading to the total synthesis of 1.
INTRODUCTION
assisted 1,2-cis-α-galactofuranosylation strategy and a
new 1,2-cis-β-arabinopyranosylation method were devel-
oped to assemble the α-galactofuranoside and the β-
arabinopyranoside scaffolds, respectively.
Glycosphingolipids (GSLs) from marine sponges often
have interesting immunomodulating activities.1 In 2008,
Mangoni and co-workers reported the isolation of ves-
parioside B (Scheme 1), a novel hexaglycosylated GSL,
from Caribbean sponge Spheciospongia vesparia.2 This
natural product exists as a mixture of congeners, which
differs from the length and the terminus of the alkyl
chains of the hydrophobic ceramide part. On the other
hand, the hydrophilic part of vesparioside B has been so
far the most structurally complex carbohydrate chain of
GSLs isolated from marine sponges. The unique structural
features of the glycan motif of vesparioside B include: 1) it
is rich in furanose, which is rarely found in natural GSLs.
2) it possesses multiple types of 1,2-cis glycosidic linkages,
including two α-D-galactofuranose (α-D-Galf), one α-D-
Scheme 1. Structure and Retrosynthetic Analysis of
Vesparioside B
galactopyranose
(α-D-Galp),
and
one
β-D-
arabinopyranose (β-D-Arap) moieties. Syntheses of 1,2-cis
glycosides in a stereoselective manner are usually consid-
ered as significantly challenging tasks in carbohydrate
chemistry.3 3) it contains a 2,3-branched trisaccharide
fragment at the non-reducing end and two adjacent 1,2-cis
glycosidic bonds with high hindrance between the D-Galp
and D-Arap units. The presence of these frameworks
brings extra difficulties in generating the molecule. We
chose vesparioside B as a synthetic target due to the chal-
lenge posed by its intricate oligosaccharide architecture.
Furthermore, the chemical synthesis may help promote
the discovery of its unknown biological activities. In this
paper, we describe the total synthesis of the most abun-
dant component of vesparioside B (Scheme 1, 1, R1 = n-
C22H45, R2 = n-C14H29). In the event, a 2-quinolinecarbonyl-
As retrosynthetically showed in Scheme 1, we anti-
cipated that 1 could arise in a highly convergent manner
from a [4 + 3] glycosylation between two advanced inter-
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NMR spectroscopy in CDCl3. For the α-anomer, the 3JH1/H2
value is 4.0-4.5 Hz, while, for the β-anomer, the JH1/H2 is
mediates, i.e., the left tetrasaccharide donor 2 and the
right disaccharide lipid alcohol 3. The construction of the
critical 1,2-cis-α-galactopyranosidic bond linking both
portions could in turn rely on a 4,6-O-benzylidene-
controlled α-selective galactopyranosylation approach. In
addition, the key route to compound 2 would involve the
stereoselective formation of two challenging 1,2-cis-α-
3
0-2.0 Hz.6i As illustrated in Table 1, entries 1-6, the glyco-
sylation of both donors showed α-stereoselectivity in all
cases, but the 5-O-Quin carrying 4a is superior to the 6-
O-Quin carrying analog 4b as the former generally led to
higher levels of chemical yields and α:β ratios than the
latter, regardless of the structure of the acceptor (entries 1
vs 2, 3 vs 4, and 5 vs 6, respectively). Next, the reaction of
5-O-quinoline-2-carbonylated 4a was further investigated.
We were pleased to find that a broad range of carbohy-
drate acceptors including D-manno-, L-rhamnopyranosyl,
as well as D-galactofuranosyl nucleophiles 8,11 9,12 10,13 11,14
and 12 all glycosylated smoothly with 4a, furnishing the
corresponding disaccharide products 7g-k in good-to-
excellent yields either as predominantly or as exclusively
α-isomers (Table 1, entries 7-11).
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galactofuranosyl linkages via
a
2-quinolinecarbonyl
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(Quin)-assisted α-galactofuranosylation approach. On the
other hand, the 1,2-cis-β-D-arabinopyranosyl unit within
compound 3 would be introduced by taking advantage of
a 3,4-di-O-Bz carrying D-Arap thioglycoside donor.
RESULTS AND DISCUSSION
The total synthesis of 1 commenced with the development
of a new method for stereoselective synthesis of 1,2-cis-α-
galactofuranoside which is found in a number of bacterial
and fungal glycoconjugates.4 In fact, a few strategies have
been employed for this in the past.5,6 Among them, the 2’-
carboxybenzyl (CB) glycoside method, developed by Kim
and co-workers, has proved to be useful for direct α-
galactofuranosylation.6d,e Besides, the 2,3-anhydro-D-
gulofuranosyl thioglycoside and sulfoxide activators, re-
ported by Lowary et al., have also shown validity in stere-
ocontrolled preparation of α-D-Galf-containing oligosac-
charides, but the regioselective opening of the 2,3-epoxide
ring structure increases the synthetic steps.6f,g
Table 1. Glycosylation of D-Galf thioglycoside Donors
4a-ba
Recently, an elegant hydrogen-bond-mediated aglycone
delivery (HAD) strategy was disclosed by Demchenko et
al.7 to stereoselectively synthesize diverse glycosides in
particular the 1,2-cis-pyranosides including α-gluco-, β-
manno-, as well as β-rhamnosides. Key to the high stere-
oselectivity of this glycosylation method is that the inter-
molecular hydrogen bonding formed between the donor
and acceptor can guide the attack of the acceptor to one
specific side of the donor ring.7a Based on such a concept,
our laboratory developed a reliable Quin-assisted 1,2-cis-
glycosylation methodology for efficiently preparing β-
arabinofuranosides.8 The Quin functionality, acting as a
H-bond acceptor, displays a strong β-stereocontrolling
effect in the glycosylation of both D- and L-
arabinofuranosyl thioglycoside donors with various ac-
ceptors. Here, we sought to extend such Quin-mediated
1,2-cis-furanosylation chemistry to the synthesis of the α-
linked galactofuranosides. In order to achieve the re-
quired α-stereocontrol, the Quin directing group should
be incorporated on the α-face of the Galf ring. Thus, the
5- and 6-O-Quin substituted Galf ethyl thioglycoside do-
nors 4a-b were synthesized (Table 1, see Supporting In-
formation) and their glycosylation behavior was first
evaluated by reaction with simple benzylalcohol, glucose
6-OH, and galactose 4-OH acceptors 59 and 610 under the
promotion of N-iodosuccinimide (NIS) and catalytic tri-
fluoromethanesulfonic acid (TfOH) in 1,2-dichloroethane
(DCE) at –30 → 0 °C for half an hour. The anomeric con-
a Glycosylations were performed with donor 4a (1.2 equiv,
7 mM, for entries 1, 3, 5, and 7-11) or 4b (1.2 equiv, 7 mM,
for entries 2, 4, and 6), acceptor (1 equiv), NIS (2
equiv)/TfOH (0.2 equiv), 4 Å molecular sieves (MS) in
DCE at –30 → 0 °C for 0.5 h. b Yield of the major α-isomer
1
unless otherwise noted. c Determined by H NMR of the
corresponding isomer mixture. d Yield of the inseparable
mixture of α/β-isomers.
Having established a high-yielding and selective means
to the synthesis of 1,2-cis-D-galactofuranoside, we
1
figuration of the products was deduced based on the H
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planned to apply it as a key step for creating the left tetra-
ing Information). After extensive screening studies, we
found that the glycosylation worked well when 17 was
coupled with an excess of 18 (17/18, ca. 1:3) upon activa-
tion with catalytic amounts of TMSOTf at –40 °C to room
temperature in toluene, delivering the required tetrasac-
charide thioglycoside 2 in 55% yield as a single β-isomer
(δH1’ = 5.34 ppm, s) ready for direct condensation with the
right fragment. The high selectivity of the coupling is pre-
sumably attributed to the shielding of the bottom face of
substrate 17 by its 2-O-Galf residue, therefore favoring the
approach of the nucleophile from the β-face.
saccharide sequence 2 (Scheme 2). To this end, the readily
available D-galactofuranose derivative 13 (see Supporting
Information) was galactofuranosylated with the 5-O-Quin
equipped building block 4a under the similar conditions
as above to obtain solely the α-galactosyl disaccharide 14
(JH1’/H2’ = 4.4 Hz) in excellent yield (95%). Removal of the
2-O-TBS group of 14 by treatment with TBAF buffered
with HOAc in THF15 afforded the corresponding glycoside
15 (75% yield). However, the stereoselective assembly of
the second α-Galf residue on the C2 position of this (1→
3)-linked digalactoside alcohol turned out to be more
challenging. Both the newly developed glycosyl donors 4a
and 4b were examined for the glycosylation with 15 under
the promotion of NIS/TfOH (cat.) in DCE. Surprisingly,
the 5-O-Quin substituted 4a was labile during the glyco-
sylation since unreacted acceptor 15 and hemiacetal of the
donor were notably found at the end of the reaction peri-
od by TLC analysis. In contrast, the coupling of the 6-O-
Quin substituted 4b with 15 proceeded straightforwardly
and the trisaccharide glycoside 16 was accordingly ob-
tained in 85% combined yield as a separable 6:1 α/β mix-
ture in favor of the desired α-isomer.
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Scheme 3. Synthesis of the Ceramide Building Block
23
Then, our attention was directed to the synthesis of the
disaccharide lipid portion 3. First, the route to ceramide
building block 23 began from commercially available phy-
tosphingosine 19 (Scheme 3). On reaction with 1 equiv of
tert-butyldiphenylsilyl chloride (TBDPSCl) in pyridine,
the primary hydroxyl group of 19 was selectively protected
to give a silyl ether. Then, this intermediate was con-
densed with chiral α-hydroxyl fatty acid 2019 in the pres-
ence of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide
hydrochloride (EDC·HCl) to obtain the protected
ceramide derivative 21. Conversion of 21 to the required 23
involved (i) benzoylation of the secondary alcohols of 21
with benzoyl chloride (BzCl), forming 22 (80%), and (ii)
desilylation of 22 with TBAF in acidic THF solution, giv-
ing rise to the corresponding 23 (90% yield).
Scheme 2. Synthesis of the Left Tetrasaccharide Do-
nor 2
The next objective was to explore appropriate condi-
tions for stereoselective construction of 1,2-cis-β-D-
arabinopyranoside. Previously, during the total synthesis
of marine natural product eleutherobin, both Nicolaou
and Danishefsky groups have surveyed the glycosylation
method for stereoselective attachment of a β-D-Arap unit
to the core aglycons. Nicolaou et al.20 utilized 2-O-PMB-
3,4-di-O-TBS protected D-Arap trichloroacetimidate as
donor and found that the glycosylation selectivity greatly
depended on the experimental conditions. On the other
hand, the glycosylation of the 2-O-TBS-3,4-O-acetonide
protected 1-thioarabinopyranoside, presented by Dan-
ishefsky et al,21 showed slight anomeric selectivity. In our
study, we found that the protecting group pattern of the
D-arabinopyranosyl donor significantly influenced the
anomeric stereochemistry of the glycosylation product.
Table 2 summarized the reaction outcomes of D-Arap-
derived ethyl thioglycosides 24a-c having different pro-
tecting groups such as an isopropylidene acetal, benzyl
ethers, or benzoate esters on the C3 and C4 positions
Oxidative cleavage of the C1 p-methoxyphenyl (PMP)
group of pure α-16 with ceric ammonium nitrate (CAN) in
aqueous acetonitrile at 0 °C gave an intermediate hemiac-
etal (Scheme 2). Activation of the anomeric hydroxyl
group through the reaction of trichloroacetonitrile
(CCl3CN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)16
readily gave the trisaccharide trichloroacetimidate 17 as a
single β-diastereomer (65% yield, two steps from α-16).
Then, 17 was subjected to chemoselective glycosylation17
with the known thiogalactoside alcohol 1818 (see Support-
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(Supporting Information) with glucosyl 6-OH substrate
pound to 3 equiv of DDQ in wet CH2Cl2 liberated the 2’’-
OH to form the alcohol 3 (90% yield), which completed
the preparation of the required right part.
25.22 The NIS/TfOH (cat.)-activated coupling of 24a pos-
sessing a 3,4-O-acetonide group with 25 displayed poor β-
selectivity, affording a 1:2 α/β mixture of disaccharides
26a in 72% yield (entry 1), which is analogous to the find-
ings reported by Danishefsky et al.21 Upon switching the
promoter system to NIS/AgOTf, no significant improve-
ment was obtained in yield or selectivity (entry 2). A simi-
lar result was observed in the reaction of 3,4-di-O-Bn pro-
tected 24b (entry 3). To our delight, successful β-D-
arabinopyranosylation of 25 was achieved when it was
glycosylated with 3,4-di-O-benzoylated donor 24c using
NIS/AgOTf (cat.) as activating agent in Et2O at –17 °C,
yielding disaccharide 26c in 95% yield with a complete
1,2-cis-β-selectivity (entry 4). No α-stereoisomer was
found even after chromatographic isolation in the glyco-
Scheme 4. Synthesis of the Right Disaccharide Lipid
Acceptor 3
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3
1
sylation. The JH1/H2 coupling constant (J = 3.6 Hz) in H
Finally, we aimed for the connection of the key precur-
sors 2 and 3 and elaboration of the resulting product to
natural vesparioside B. Scheme 5 shows how the assembly
of the α-(1→2)-galactopyranosyl linkage between the left
and the right parts was achieved. The C2 hydroxyl group
of the β-D-Arap residue in 3 is very crowded since it is cis
to the bulky aglycone on the neighboring anomeric cen-
ter. Indeed, owing to the severe hydrolysis of the donor 2,
the NIS/TfOH-mediated coupling of 2 to 3 provided only
16% yield of the desired hexasaccharide lipid 29. This
prompted us to carry out the reaction using an inverse
glycosylation protocol,12,15b,23 i.e., the acceptor 3 was pre-
mixed with the NIS/TfOH promoter system in CH2Cl2
prior to the slow addition of a CH2Cl2 solution of the do-
nor 2 at 0 °C. As a result, decomposition of the donor was
effectively suppressed and 29 was obtained in a consider-
ably elevated 80% yield as a single diastereomer.24 None
of the corresponding β-glycoside counterpart was detect-
ed by TLC. The α-configuration of the newly formed ga-
lactopyranoside bond was unambiguously verified by the
expected doublet for anomeric signal of the α-Galp moie-
ty (δH1 = 5.0 ppm, d, JH1/H2 = 3.6 Hz). Global deprotection
of 29 was performed in the following order (Scheme 5):
Zemplén deacylation with NaOMe in MeOH/CH2Cl2 (4:1),
deprotection of the Bn ethers and the benzylidene acetal
by catalytic hydrogenolysis, and finally cleavage of the
isopropylidene acetal under acidic conditions. Purifica-
tion of deprotected glycolipid was completed using chro-
matography on silica gel with CH2Cl2-MeOH (1:2) as elu-
ent to give the target 1 as a white solid in 60% yield over
three steps. Synthetic 1 was found to be identical with the
natural isolate2 based on 1H and 13C NMR spectral compar-
ison (see Supporting Information). The free 1 was further
acylated with acetic anhydrate (Ac2O) in pyridine to pro-
duce the corresponding peracetylated derivative 30 (93%
yield). The NMR data (1H and 13C NMR spectra) and spe-
cific rotation of this material are in full agreement with
those of the peracetate substance derived from naturally
occurring vesparioside B,2 thereby further confirming the
structure of the synthetic molecule.
NMR spectrum of 26c clearly indicated the β-anomeric
1
configuration of the 6-O-D-Arap residue adopting a C4
conformation. Changing the promoter system to
NIS/TfOH (cat.) and the solvent to CH2Cl2 also led to sim-
ilar results (entry 5). At present, we are unsure about the
origin of the high β-stereoselectivity with the glycosyl
substrate 24c.
Table 2. Glycosylation of D-Arap thioglycoside Do-
nors 24a-ca
a
Glycosylations were carried out with donor 24a-c (1.2
equiv), acceptor (1 equiv), NIS (2 equiv)/TfOH (0.2 equiv) or
AgOTf (0.2 equiv), 4 Å molecular sieves (MS) at –17 °C for 3
b
h. Yield of the inseparable mixture of α/β-isomers unless
c
1
otherwise noted. Determined by H NMR of the corre-
sponding isomer mixture. d Yield of the β-isomer.
The C1 position of 26c was then unmasked via a PdCl2-
catalyzed deallylation protocol (Scheme 4). As before, the
resulting crude hemiacetal was converted easily to disac-
charide trichloroacetimidate 27 (65% yield over two
steps). Upon activation with TMSOTf, 27 underwent an
efficient glycosylation with ceramide acceptor 23 to give
disaccharide lipid 28 (70% yield). Exposure of this com-
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Scheme 5. Completion of Total Synthesis of Vespario-
side B (1)
Present Address
§651 W Hancock St. APT205, Detroit, MI, 48201, United
States
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Author Contributions
‡These authors contributed equally.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
This work was supported by the NSFC (21372166, 21172156,
21321061), the 973 program (2010CB833202), and the Ministry
of Education (20100181110082) of China.
REFERENCES
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CONCLUSIONS
In conclusion, we have developed a convergent strategy
for the total synthesis of a major congener of structurally
unusual vesparioside B. Our synthesis highlights an effi-
cient 4,6-O-benzylidene-directed α-galactopyranosylation
method for forging the left and the right fragments to-
gether to build the whole hexasaccharide glycolipid back-
bone. Moreover, the difficult-to-obtain 1,2-cis-α-
galactofuranoside and β-arabinopyranoside were effi-
ciently assembled through the use of 5- or 6-O-Quin sub-
stituted D-Galf thioglycoside and 3,4-di-O-Bz protected
D-Arap thioglycoside donors, respectively. These glycosyl
donors exhibited excellent glycosylation yields and selec-
tivity. Research is in progress to study the biological func-
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ASSOCIATED CONTENT
Supporting Information. Experimental details, H and 13C
NMR spectra for all new compounds, and 2D NMR spectra
for 2, α-16, β-16, 26c, 28, and 29. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
AUTHOR INFORMATION
Corresponding Author
*yjs@scu.edu.cn
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