O-glycosides and N-glycosides play important roles in many life processes. Chemical synthesis is an effective and large-scale method to get the structure of the determined and pure carbohydrate compounds, so that we can understand their functions and develop new therapeutic drugs. However, it has been a long-standing chemical challenge to develop glycoside reaction which can be applied to the efficient synthesis of both oxyglycosides and nucleosides.
Fig. 1. Chemical synthesis of oxyglycoside and nucleoside pre glycosyl donor and present glycosyl PVB donor. Photo source: Nat. Commun
In 2008, Yu Biao research group of Shanghai Institute of organic chemistry developed ABZ as a novel glycosyl donor, which can realize the chemical synthesis of oxyglycosides and nucleosides, and it has been successfully applied to the synthesis of many complex natural sugars with important physiological activities. Now it is called Yu glycosylation in the world. At the beginning of 2019, Yu Biao's research group reported a new glycoside reaction based on ether bond type, which can also achieve efficient synthesis of oxyglycosides and nucleosides. Although important breakthroughs have been made in this field, challenges remain. For example, the method of glycosidization with easy preparation and stable glycosyl donor, cheap accelerant and mild reaction conditions is still very limited. The number of glycosyl donors that can combine for multi-step one pot glucosylation is still rare. In addition, there are few general glycoside reaction methods which can be used to synthesize oxyglycosides and nucleosides at low cost and high efficiency. Recently, Xiao Guozhi research group of Kunming Institute of Botany, Chinese Academy of Sciences reported a new general glycoside reaction method, which can realize the efficient synthesis of p-oxoside and nucleoside.
Figure 2. Chemical synthesis of oxyglycosides. Photo source: Nat. Commun
Firstly, the glycosidization of glycosyl PVB with alcohol receptors was investigated. It is found that glycosyl PVB can glycoside with various receptors in excellent yield. At the same time, various glycosyl PVB can react with the receptor to produce various glycosides efficiently (Fig. 2).
Next, the glycosidization of glycosyl PVB with pyrimidine was investigated. It was found that a variety of glycosyl PVB could react with uracil, thymine, n4-benzoylcytosine, fluorouracil, and trifluorothorazine to form nucleosides. Then, the glycoside reaction of glycosyl PVB with purine was investigated. Due to the regioselectivity of N9 and N7 in purine glycosidization, the glycosidization of purine has always been a difficult problem. Fortunately, the authors found that various glycosylated PVB can successfully glycoside with n6-bis (t-butyloxycarbonyl) adenine and n2-t-butyloxycarbonyl-2-amino-6-iodine to form N9 glycosylated nucleoside (Fig. 3).
Figure 3. Chemical synthesis of nucleosides. Photo source: Nat. Commun
Next, the activity of different glycosyl donors was investigated. When the glycosyl PVB was compared with glucosinoside, it was found that the donor could selectively glycoside with the receptor to generate disaccharide 3a, while the recovery of glucosinoside was 98%. When the glycosyl PVB was compared with the n-amyl glucoside, it was also found that the donor of p-benzoylglucosyl-pvb could selectively glycoside with the receptor to generate disaccharide 3a, while the p-benzoylglucosyl-n-amyl glucoside was almost immobile and recovered 99%. In view of the great difference in the activity of glycosyl PVB, glucoside and n-amyl glucoside, it is suggested that they can be combined for one pot of glucosylation reaction. Indeed, trisaccharide 13 can be produced in two steps and one pot with 89% yield by combining glycosyl PVB and glucosinolate. The yield of trisaccharide 14 was 73% in one pot in two steps. Furthermore, the authors found that glycosyl PVB can combine with Schmidt trichloroacetimide (TCAI) donor and glycosyl ABZ (Shu's glycoside reaction donor) to synthesize trisaccharide in three steps and one pot (Fig. 4).
Figure 4. One pot synthesis of oligosaccharides. Photo source: Nat. Commun
Fig. 5. Synthesis of capecitabine, deoxyfluuridine and garotabine. Photo source: Nat. Commun
Subsequently, the author used this glycoside reaction in the synthesis of nucleoside antibiotics capecitabine, deoxyfluorouridine and galotabine. It is worth mentioning that the current synthesis of the above nucleoside antibiotics route is much more efficient than the previous synthesis route (Figure 5).
Finally, the possible mechanism of this glycosidization reaction is proposed (Fig. 6).
Figure 6. Possible mechanism of PVB glycosidation. Photo source: Nat. Commun
summary
Xiao Guozhi research group of Kunming Institute of Botany, Chinese Academy of Sciences has developed a new and universal glycoside reaction method with high efficiency. In this method, simple and stable glycosyl PVB is used as novel glycosyl donor, n-iodobutylimide (NIS) and trimethylsilyl trifluoromethane sulfonate (TMSOTf) are cheap and easy to obtain accelerants. Meanwhile, the method has mild reaction conditions, wide substrate range, good to excellent yield of glycosidization reaction, and can be combined with other glycosyl donors for one pot glycosidization reaction Efficient synthesis of sugar compounds. The first authors of this research are Dr. Li Penghua, Dr. he Haiqing and Dr. Zhang Yunqin.
Original text (scan or long press QR code, and then go to the original page after identification): glycosyl ortho - (1-phenylvinyl) benzoates versatile glycosyl donors for highly efficient synthesis of both O-glycosides and nuclesides Penghua Li, Haiqing he, Yunqin Zhang, Rui Yang, Lili Xu, Zixi Chen, Yingying Huang, Limei Bao, Guozhi xiaonat. Commun., 2020, 11, 405, DOI: 10.1038/s41467-020-14295-z
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Xiao Guozhi https://www.x-mol.com/university/faculty/66063
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