TfOH = Trifluoromethanoic acid; DCE = 1,2-Dichloroethane; TBSOTf =tert - Butyldimethylsilyl trifluormethansulfonate;
AgNTf2 = Sliver bis(trifluoromethane sulfonimide); T =
temperature.
proven to be a powerful tool for constructing structurally complex
molecules.[32] Encouraged by these advances and in
order to improve the preparation efficacy of tetrasaccharide10 , we converted thioglycoside 14 into glycosylortho -hexnylbenzoate (OABz) donor 28 in 70% yield
through a two-step reaction sequence involving TCCA-mediate hydrolysis
of thioglycoside and subsequent DCC-promoted esterification of the
resultant hemiacetal with ortho -hexynylbenzoic acid (Scheme 5b).
The impact of various factors, including gold salts, silver salts, and
reaction temperature, was scrutinized on the outcome of glycosylation of28 with 13 . It was found that the reaction gave
Scheme 6 Synthesis of pentasaccharide 7
Reagents and conditions: (a) p -TsOH·H2O,
40 °C, CH2Cl2/MeOH; (b) TBSCl, DMAP,
pyridine, 89% over two steps; (c) 26 ,
BF3·Et2O, -40 °C,
CH2Cl2, 4 Å MS, 77%; (d) 13 ,
NIS, TBSOTf, 0 °C, PhMe, AW-300 MS, 65%; (e) 70% HF·pyridine,
pyridine, 93%; (f) TEMPO, BAIB,
CH3CN/H2O; (g) MeI,
NaHCO3, DMF, 89% over two steps; (h)
NH2·NH2·H2O (5.0 equiv),
AcOH (10.0 equiv), CH2Cl2, 97%; (i)9 , Cp2ZrCl2, AgOTf, -20 °C,
PhCF3, 4 Å MS, 90%; (j) LiOH·H2O, 30%
H2O2, THF/H2O, 92%; (k)
10% Pd/C, H2, 1 M HCl,
THF/i -PrOH/H2O, 74%.
Cp2ZrCl2 =
Bis(pentamethylcyclopentadienyl) zirconium dichloride.
tetrasaccharide 10 in the best yield of 37% under the
promotion of 0.75 equiv of (PhO)3PAuOTf, in situgenerated from equal molar units of (PhO)3PAuCl and
AgOTf. We attributed the unsatisfactory outcome mentioned above to the
low reactivity of uronic acid-based donors and weak nucleophilicity of
the C4’-OH due to steric hinderance resulting from the presence of the
adjacent 3’-O -L-rhaminosyl residue.
Basing on the observations of the Huang group that increasing the
reactivity of glycosyl donors favors the glycosylation of glycosyl
acceptors with weak nucleophilicity,[33] we moved
our focus to the construction of tetrasaccharide 11 following a
postglycosylation oxidation strategy. For this purpose, glucopyranosyl
thioglycoside acceptor 30 was made from29 [34] through hydrolysis of benzylidene
and regioselective TBS protection of the resulting primary hydroxy
group. Then thioglycoside 30 was subjected to glycosylation
with glucosyl TCAI donor 26 . Under the catalysis of
BF3·Et2O the reaction worked well and
afforded the expected disaccharide 15 in 77% yield.
With disaccharides 15 and 13 in hand, glycosylation
between them was executed (Scheme 6). To our delight, the reaction
efficiently proceeded and provided the desired tetrasaccharide11 in 65% yield when slowly adding a solution of 15to a flask charged with 13 , 2.5 equiv of NIS, and 0.2 equiv of
TBSOTf in toluene at 0 oC. The transformation of11 into the uronic acid-embedded counterpart 31 was
uneventfully achieved by the removal of TBS masking group, the oxidation
of primary hydroxy group, and methylation of the resulting carboxylic
acid. The orthogonal cleavage of Lev group with hydrazine acetate
furnished alcohol 32 that is ready for mannosylation viathe formation of α-glycosidic linkage.
After obtaining tetrasaccharide 32 and L-mannosyl fluoride9 , we proceeded to synthesize the desired pentasaccharide7 . (Scheme 6). Tetrasaccharide 32 was mannosylated
with glycosyl fluoride 9 under the action of 1.2 equiv of
Cp2ZrCl2 and 2.4 equiv of AgOTf to
afford the fully protected pentasaccharide 8 in a high yield of
90%. It should be noted that the coupling could also promoted with
(C6F5)3B·(H2O)nas the initiator.[35] However, the reaction
required 0.6 equiv of
(C6F5)3B·(H2O)nand pentasaccharide 8 was obtained in 59% yield in
PhCF3 in the presence of 4 Å MS.
With 8 successfully prepared, its deprotection was performed.
Pentasaccharide 8 was treated with LiOH·H2O in
the presence of H2O2 in a mixed solvent
of H2O and THF, resulting in concomitant hydrolysis of
one methyl ester and five benzoates to afford hexol S7 in 92%
yield (see the Supporting Information). Then, exposure of the hexolS7 to 1 atmosphere of dihydrogen in the presence of palladium
over charcoal and 1 M HCl resulted in hydrogenolysis of one benzylidene
and benzyl ethers as well as hydrogenation of azido substituent,
uneventfully affording the desired the target pentasaccharide 7in 74% yield.
Conclusions
We have developed an efficient protocol for synthesis of rare L-glycosyl
fluorides using a head-to-tail inversion strategy.
L-glucosyl/galactosyl/mannosyl fluorides were successfully prepared with
readily available 1-phenyl-2-(β-D-C -glucosyl, mannosyl, and
galactosyl)ethanone as the starting materials. The transformation
involves installing the anomeric hydroxymethyl group and switching the
sugar ring in a head-to-tail manner through radical oxidative
decarboxylative fluorination of uronic acids. To demonstrate the
practical application of our protocol, we successfully assembled the
pentasaccharide repeating unit of extracellular polysaccharide S-88 for
the first time. The synthesis is characterized by sugar chain extension
at a sterically hindered hydroxy group and the incorporation of a
L-mannosyl residue with L-mannosyl fluoride as the glycosylating agent.
Considering the challenges associated with accessing biologically
important oligosaccharides and glycoconjugates that contain L-sugar
residue(s), our work offers an additional tool for the synthesis of
these constructs.
Experimental
Experimental procedures and characterization data are available in
Supporting Information.
Supporting Information
The supporting information for this article is available on the WWW
under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
We are grateful for financial support from the Marine S&T Fund of
ShandongProvince for Pilot National Laboratory for Marine Science and
Technology (Qingdao) (No. 2022QNLM030003-2), the National Natural
Science Foundation of China (Nos. 21977088 and 21672194), and the
National Natural Science Foundation of China-Shandong Joint Fund (No.
U1906213).
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