Stereocontrolled Synthesis of α-3-Deoxy-d-manno-oct-2-ulosonic Acid (α-Kdo) Glycosides Using C3-p-Tolylthio-Substituted Kdo Donors: Access to Highly Branched Kdo Oligosaccharides
Ao Sun
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Investigation (lead), Methodology (lead), Writing - original draft (lead)
Search for more papers by this authorZipeng Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Investigation (supporting), Methodology (supporting), Validation (lead)
Search for more papers by this authorYuchao Wang
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Investigation (supporting), Methodology (supporting), Visualization (supporting)
Search for more papers by this authorDr. Shuai Meng
Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, College of Marine Science, Hainan University, Haikou, 570228 China
Contribution: Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorDr. Xiao Zhang
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorProf. Dr. Xiangbao Meng
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorDr. Shuchun Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Dr. Zhongtang Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Software (lead)
Search for more papers by this authorCorresponding Author
Prof. Dr. Zhongjun Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Conceptualization (lead), Funding acquisition (lead), Project administration (lead), Resources (lead), Supervision (lead), Writing - review & editing (lead)
Search for more papers by this authorAo Sun
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Investigation (lead), Methodology (lead), Writing - original draft (lead)
Search for more papers by this authorZipeng Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Investigation (supporting), Methodology (supporting), Validation (lead)
Search for more papers by this authorYuchao Wang
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Investigation (supporting), Methodology (supporting), Visualization (supporting)
Search for more papers by this authorDr. Shuai Meng
Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, College of Marine Science, Hainan University, Haikou, 570228 China
Contribution: Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorDr. Xiao Zhang
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorProf. Dr. Xiangbao Meng
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorDr. Shuchun Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Dr. Zhongtang Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Software (lead)
Search for more papers by this authorCorresponding Author
Prof. Dr. Zhongjun Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191 China
Contribution: Conceptualization (lead), Funding acquisition (lead), Project administration (lead), Resources (lead), Supervision (lead), Writing - review & editing (lead)
Search for more papers by this authorGraphical Abstract
A modified donor has been developed for the glycosylation of 3-deoxy-d-manno-2-octulosonic acid (Kdo). The high reactivity and wide substrate scope of the donor enabled the synthesis of a range of Kdo-containing glycosides with complete α-stereoselectivity without the formation of 2,3-ene by-products. Several natural oligosaccharides were synthesized by a stepwise or one-pot process, including a highly branched Kdo pentasaccharide.
Abstract
3-Deoxy-d-manno-oct-2-ulosonic acid (Kdo) is an eight-carbon monosaccharide found widely in bacterial lipopolysaccharides (LPSs) and capsule polysaccharides (CPSs). We developed an indirect method for the stereoselective synthesis of α-Kdo glycosides with a C3-p-tolylthio-substituted Kdo phosphite donor. The presence of the p-tolylthio group enhanced the reactivity, suppressed the formation of elimination by-products (2,3-enes), and provided complete α-stereocontrol. A variety of Kdo α-glycosides were synthesized by our method in excellent yields (up to 98 %). After glycosylation, the p-tolylthio group can be efficiently removed by free-radical reduction. Subsequently, the orthogonality of the phosphite donor and thioglycoside donor was demonstrated by the one-pot synthesis of a trisaccharide in Helicobacter pylori and Neisseria meningitidis LPS. Moreover, an efficient total synthesis route to the challenging 4,5-branched Kdo trisaccharide in LPSs from several A. baumannii strains was highlighted. To demonstrate the high reactivity of our approach further, the highly crowded 4,5,7,8-branched Kdo pentasaccharide was synthesized as a model molecule for the first time. Additionally, the reaction mechanism was investigated by DFT calculations.
Conflict of interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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