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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