CN113234113B

CN113234113B - Method for constructing 1, 2-cis-2-nitro-glucoside and galactose glucoside

Info

Publication number: CN113234113B
Application number: CN202110598797.XA
Authority: CN
Inventors: 张庆举; 林希锷; 薛云霞; 孙建松; 王黎明; 万勇勇; 吴晓培
Original assignee: Jiangxi Normal University
Current assignee: Jiangxi Normal University
Priority date: 2021-05-31
Filing date: 2021-05-31
Publication date: 2023-09-01
Anticipated expiration: 2041-05-31
Also published as: CN113234113A

Abstract

The application discloses a method for efficiently constructing 1, 2-cis-2-nitro-glucoside and 1, 2-cis-2-nitro-galactose glucoside, and belongs to the technical field of organic synthesis. The preparation method provided by the application can be used for efficiently preparing the 1, 2-cis-2-nitro-glucoside and the 1, 2-cis-2-nitro-galactose glucoside through one-step synthesis. The application successfully applies the organic catalytic stereoselective glycosylation method in the total synthesis of sugar chemistry, solves the problem of constructing 1, 2-cis-glycosidic bonds among the most critical sugar units, and lays a foundation for the completion of the subsequent total synthesis of poly-O-antigen. These efforts have important reference values for future related immunological research and vaccine development.

Description

Method for constructing 1, 2-cis-2-nitro-glucoside and galactose glucoside

Technical Field

The application belongs to the field of organic synthesis, and particularly relates to a method for efficiently constructing 1, 2-cis-2-nitro-glucoside and galactose glucoside.

Background

Although a large amount of polysaccharides exist in living bodies, it is difficult to directly extract high purity polysaccharides from living bodies because of the variety of polysaccharides in living bodies, and the direct biological purification often results in sugar chains of different lengths. Thus, currently, the main methods for obtaining polysaccharides in organisms are synthesized in vitro, and there are two main methods for synthesis: biosynthesis and chemical synthesis. The biosynthesis method is obtained through a series of separation after enzyme catalysis synthesis under in vitro biological culture conditions, but the method has the advantages of poor substrate universality, sensitivity to external environment, great culture cost, high cost of industrial production and high operation difficulty. Therefore, the chemical synthesis method with convenient production, controllable conditions and lower cost is still a main means for synthesizing polysaccharide compounds. Chemical synthesis research of sugar vaccines has been carried out for decades, new glycosylation methods and sugar chain assembly strategies are continuously presented under the continuous efforts of sugar chemists, the technical difficulties of sugar vaccine research and development are continuously overcome, more and more sugar chemists are put into the synthesis research of sugar vaccines, the chemical synthesis technology of sugar vaccine antigens is mature, and the method has wide development space and good development prospect.

Proteus enterobacteriaceae is one of three major 'key priority' antibiotic drug-resistant pathogens listed in 2017 of world health organization, wherein Proteus mirabilis and general Proteus are zoonotic pathogens with important public health significance. Because they are widely distributed in nature, exist in soil, sewage and animals and plants, meat products, aquatic products and bean products are extremely susceptible to infection, and the sensory and character of the polluted foods are not obviously changed in general, so that the food is easy to be poisoned by people eating by mistake. They also exist in iatrogenic and secondary infections, especially Proteus mirabilis, often associated with urinary tract and traumatic infections, and can even cause high mortality sepsis. The widespread use of antibiotics has long made them more resistant to antibiotics, so there is an urgent need to find new means to combat these pathogens, and vaccine development against these pathogens has become critical.

Lipopolysaccharide of Proteus is its main surface antigen and important virulence factor, which is important for vaccine development. The lipopolysaccharides of Proteus mirabilis OE and Proteus vulgaris TG 103 were found to have identical trisaccharide repeat units {. Fwdarw.6) - α -D-GlcpNAc- (1. Fwdarw.3) - β -D-Galp- (1. Fwdarw.3) - α -D-GalpNAc- (1. Fwdarw.) which may be a suitable common epitope for vaccines, and are of considerable value for immunoassays and vaccine development.

The core structure of the common O-antigen (trimer to dodecamer) of Proteus mirabilis OE and Proteus vulgaris TG 103 is a trisaccharide unit which can be obtained by reducing nitro groups and then acetylating after the connection of trisaccharide 1 and Linker 5, and the core trisaccharide 1 can be split into nitroglucene 2 as a donor, galactoalkene 4 as a receptor and galactosulfan 3 at intermediate connection 2 and 4. The difficulty with the synthesis of this trisaccharide unit is the stereoselective glycosylation of the nitro-glucosene 2 and the trisaccharide nitro-glucosene 1. Galan and McGarrigle and colleagues have reported emerging methods for highly stereoselective 1, 2-cis glycosylation using organic catalysts; high alpha-selective glycosylation of 4, 6-di-t-butylsiloxane galactose by the Kiso team is a powerful means of synthesizing 1, 2-cis-galactoside. However, the above-mentioned method is complicated in reaction product and not high in yield.

Disclosure of Invention

The application aims to provide a method for efficiently constructing 1, 2-cis-2-nitro-glucoside and galactose glucoside.

Based on the above purpose, the application adopts the following technical scheme:

1, 2-cis-2-nitro-glucoside and 1, 2-cis-2-nitro-galactose glucoside have the following specific structures:

wherein Cy is cyclohexyl, ac is acetyl, bn is benzyl, bz is benzoyl, ⁱ pr is isopropyl, lev is levulinyl, ^t bu is tert-butyl and Fmoc is +.>AII is->

The high-efficiency construction method of the 1, 2-cis-2-nitro-glucoside and the 1, 2-cis-2-nitro-galactose glucoside comprises the following synthetic routes:

PG is a protecting group, and the PG is a protecting group,

the synthesis steps are as follows:

will beAdding H-OR and catalyst into a reaction bottle, adding solvent toluene OR fluorobenzene under nitrogen atmosphere, reacting at 80deg.C, concentrating by rotary evaporation, purifying by silica gel column chromatography to obtain target compound, wherein the #>The molar ratio of H-OR to the catalyst is 1:1.5 (0.1-0.2).

Further, the method comprises the steps of,in particular +.>H-OR is specifically

Preferably, the method comprises the steps of,in particular +.>When the solvent is fluorobenzene, +.>H-OR and the molar ratio of the catalyst is 1:1.5:0.1; />In particular +.>In the process, the solvent is toluene,the molar ratio of H-OR to catalyst is 1:1.5:0.2.

Wherein the compound isThe synthetic route of (2) is as follows:

the synthesis process is as follows:

s1, adding a compound 8 and imidazole into a reaction bottle, adding DMF (dimethyl formamide), adding tert-butyldimethyl chlorosilane under ice bath, then heating to room temperature for reaction, detecting complete reaction of a substrate by TLC (thin layer chromatography), adding DCM into a reaction system for dilution, extracting with water, extracting with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and concentrating by rotary evaporation to obtain a crude product of the compound 15;

s2, adding the crude product of the compound 15 and DMAP into a reaction bottle, adding DCM, adding levulinic acid and EDCl under ice bath, adding DIPEA, then heating to room temperature for reaction, detecting that the substrate is completely reacted by TLC, adding DCM into a reaction system for dilution, extracting with water, extracting with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and concentrating by rotary evaporation to obtain the crude product of the compound 16;

s3, adding the crude product of the compound 16 into a reaction bottle, adding THF, adding tetrabutylammonium fluoride under ice bath, then heating to room temperature for reaction, detecting that the substrate is completely reacted by TLC, performing rotary evaporation concentration on the reaction system, and purifying by silica gel column chromatography to obtain a compound 17;

s4, adding the compound 17 and imidazole into a reaction bottle, adding DMF, dropwise adding 1, 3-dichloro-1, 3-tetraisopropyl disiloxane under ice bath, then heating to room temperature for reaction, detecting that a substrate is completely reacted by TLC, adding DCM into a reaction system for dilution, extracting with water, extracting with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating by rotary evaporation, and purifying by silica gel column chromatography to obtain a compound 12;

s5, placing the compound 12, tetrabutylammonium nitrate and 4-methyl 2, 6-di-tert-butylpyridine in a reaction bottle, adding DCM, dropwise adding trifluoroacetic anhydride into a reaction system at-70 ℃ for reaction, detecting that the substrate is completely reacted by TLC, heating the reaction system to 0 ℃, adding pyridine and acetic anhydride in a volume ratio of 2:1, then heating to room temperature for reaction, detecting that the reaction is completely reacted by TLC, extracting the reaction system by 1M hydrochloric acid, drying by anhydrous sodium sulfate, filtering, concentrating by rotary evaporation, and purifying by silica gel column chromatography to obtain the compound 2.

Further, the mol ratio of the compound 8, the imidazole and the tertiary butyl dimethyl chlorosilane in the S1 is 1:4:2.2; the mol ratio of the compound 15, DMAP, levulinic acid, EDCl and DIPEA in the S2 is 1:0.2:2:2.4:2.8; compound 16 in S3, tetrabutylammonium fluoride 1:2.4; the mol ratio of the compound 17 to the imidazole to the 1, 3-dichloro-1, 3-tetraisopropyl disiloxane in the S4 is 1:4:1.1; the molar ratio of the compound 12, tetrabutylammonium nitrate, 4-methyl 2, 6-di-tert-butylpyridine and trifluoroacetic anhydride in the S5 is 1:2:4:2, and 2mL of pyridine is required to be added for each 7.2mmol of the compound 12.

Wherein the compound isThe synthetic route of (2) is as follows:

the synthesis process is as follows:

(1) Compound S1, bu ₂ Mixing SnO and TBAB, adding DIPEA, bnBr, N at 70deg.C ₂ Under the protection of complete reaction, cooling to room temperature after the reaction is finished, adding methanol for quenching reaction, spin drying, and separating by column chromatography to obtain a compound S15;

(2) Dissolving compound S15 in DMF, adding pyridine, stirring, adding tert-Bu at-20deg.C ₂ Si(OTf) ₂ N ₂ The reaction is complete under the protection, DCM extraction, water washing, saturated salt water washing and anhydrous Na ₂ SO ₄ Drying, suction filtering, spin drying the solvent, column layerSeparating to obtain white solid 2-7;

(3) Dissolving compound 2-7, TBAN and DTBMP in dry DCM, adding to the systemMolecular sieve, nitrogen protection, stirring at room temperature for 25-35 min, adding Tf into the reaction system at-30 deg.c ₂ O reaction, TLC monitoring reaction is complete; adding pyridine and acetic anhydride in a volume ratio of 2:1, reacting for 2 hours at room temperature, diluting the reaction system with DCM, filtering, washing with hydrochloric acid and saturated salt water, and anhydrous Na ₂ SO ₄ Drying, suction filtering, spin drying the solvent, and purifying by column chromatography to obtain the compound 2-9.

Wherein in the step (1), the compounds S1 and Bu ₂ SnO, TBAB, DIPEA and BnBr in a molar ratio of 1:0.1:0.3:2:2; in step (2), compound S15, pyridine, tert-Bu ₂ Si(OTf) ₂ The molar ratio of (2) is 1:4:1.1; compounds 2-7, TBAN, DTBMP and Tf in step (3) ₂ The molar ratio of O is 1:2:2:4, and 2mL of pyridine is required to be added per 0.8mmol of compound 2-7.

The application successfully applies the organic catalytic stereoselective glycosylation method in the total synthesis of sugar chemistry, solves the problem of constructing 1, 2-cis-glycosidic bonds among the most critical sugar units, and lays a foundation for the completion of the subsequent total synthesis of poly-O-antigen. These efforts have important reference values for future related immunological research and vaccine development.

Detailed Description

The technical scheme of the present application will be further described in detail with reference to specific examples, but the scope of the present application is not limited thereto.

Example 1

TABLE 1 screening of catalysts

As can be seen from the reaction results of Table 1, although the reaction yield using the catalyst 28 was the highest up to approximately 50%, the stereoselectivity was not particularly good (Entry 1). The reaction yields of catalysts 29, 31-38 are all low, but the alpha stereoselectivity is quite good; wherein the reaction yields of catalysts 29 and 36 are relatively high (Entry 2, 9). Whereas catalysts 30 and 39 gave the beta stereoselective product most (Entry 3, 12). Under the condition of various catalysts, the reaction yield is mostly 20% -30%, and the reason for the lower yield is that a plurality of raw materials remain; the reaction yield was only 10.7% (Entry 13) without catalyst in the blank. Based on the results of Table 1, the present application conducted further condition investigation on the catalysts 29 and 36.

TABLE 2 investigation of solvent types and concentrations of catalyst 29

As seen from the results of Table 2, the yield of the reaction was significantly improved by using the catalyst 29 with toluene and fluorobenzene as solvents, and the yield of fluorobenzene as a solvent was slightly higher than that of toluene; the alpha stereoselectivity was somewhat reduced and the stereoselectivity of toluene as solvent was slightly higher than that of fluorobenzene (Entry 3, 4). Then the concentration of the reaction substrate is increased from 0.2M to 0.5M, and the reaction yield is increased by about 20 percent; the stereoselectivity is further reduced and the stereoselectivity of toluene as a solvent becomes inferior to that of fluorobenzene (Entry 5, 6).

TABLE 3 investigation of solvent species for catalyst 36

From the results of Table 3, when catalyst 36 was used, the reaction yield and the alpha stereoselectivity were the best when fluorobenzene was used as the solvent (Entry 4), but the reaction effect of catalyst 36 was significantly inferior to that of catalyst 29 of Table 2 under the same solvent conditions. After that, we studied the effect of temperature on the reaction result, and decreasing the reaction temperature not only slows down the reaction rate, resulting in a decrease in the reaction yield per unit time, but also decreases the alpha stereoselectivity (Table 4). Based on the above results, catalyst 29 is the best choice for the subsequent glycosylation reaction; although the concentration increase can reduce the residual raw material and increase the yield, the alpha stereoselectivity of the reaction is reduced, the raw material can be reacted completely under the condition of lower concentration by prolonging the reaction time to increase the yield, and meanwhile, the better stereoselectivity is kept; the reaction results of toluene and fluorobenzene as solvents are good and bad, and considering that the toluene as the solvent has better alpha stereoselectivity at lower concentration and the fluorobenzene has larger toxicity, the toluene is considered to be more suitable as the solvent in the synthesis of trisaccharide; the reaction temperature is preferably 80 ℃. In addition, the increase in catalyst equivalent accelerates the reaction and does not affect the stereoselectivity.

TABLE 4 influence of temperature on the reaction

Based on the above results, the present application extends the glycosylation reaction substrate somewhat with some common sugars and alcohols as acceptors. From the results in table 5, it can be seen that the method has better yields and alpha stereoselectivity for most substrates; wherein the reaction has good yields and excellent stereoselectivity when compounds 43,44,48,49 and 50 act as glycosylation acceptors (Entry 4,5,9, 10, 11); compounds 45, 47 and 52 as glycosylation acceptors gave good reaction yields and poor stereoselectivity (Entry 6,8, 13); since galactoalkene 4 may be structurally unstable under this condition, the reaction system is confused (Entry 1); the lack of reaction of compound 42 as the glycosylation acceptor and the low reaction yields of compounds 41,46 and 51 as the glycosylation acceptor may be due to the weak activity of the acceptor hydroxyl groups (Entry 2,3,7, 12).

TABLE 5 development of glycosidated substrates

The structural formula of each receptor in table 5 is as follows:

compound 6 (25 g,64 mmol) was placed in a 500mL round bottom flask, 250mL of dry DCM was added, 33% HBr/AcOH (60 mL) was slowly dropped into the flask with a constant pressure dropping funnel under ice-bath, then slowly warmed to room temperature for 3h, TLC detected the completion of the substrate reaction, and concentrated by rotary evaporation to give a crude bromoglycoside solution. Zinc powder (30 g,459 mmol), anhydrous sodium acetate (27 g,329 mmol) and anhydrous copper sulfate (0.7 g,4.4 mmol) were placed in a 500mL round bottom flask, 100mL glacial acetic acid and 60mL water were added, the crude bromoglycoside product solution was quickly dropped into the flask with a constant pressure dropping funnel under ice bath, then slowly warmed to room temperature for 7h, TLC detection substrate reaction was complete, the reaction system was diluted with ethyl acetate, suction filtration was performed with celite, the filter residue was washed 3 times with ethyl acetate, then the filtrate was extracted 3 times with water, saturated sodium bicarbonate solution was extracted until no large amount of bubbles were generated, saturated sodium chloride solution was extracted 1 time, anhydrous sodium sulfate was dried, concentrated by rotary evaporation after filtration, and compound 7 (13.8 g,50.7mmol, 84%) was obtained after purification by silica gel column chromatography (PE/EA=5:1), concretely reference was made to R.Ashique, R.V.Chirakal, D.W.Hughes, G.J.Schrobilgen, carbohydr.Res.2006,341,457-466.

Compound 7 (13.8 g,50.7 mmol) and potassium carbonate (0.74 g,5.35 mmol) were placed in a 250mL round bottom flask, 100mL anhydrous methanol was added, reaction was performed at room temperature for 4h, TLC was used to detect completion of the substrate reaction, the reaction system was concentrated by rotary evaporation and purified by silica gel column chromatography (DCM/MeOH=5:1→3:1) to give compound 8 (7.2 g,49.3mmol, 97%) as a white solid, see V.D.Bussolo, M.Caselli, M.Pineschi, P.Crotti, org.Lett.2003,5,2173-2176 for a specific procedure.

Compound 8 (2.92 g,20 mmol) and imidazole (5.44 g,80 mmol) were placed in a 100mL round bottom flask, 25mL dry DMF was added, tert-butyldimethylsilyl chloride (6.88 g,44 mmol) was added under ice-bath, followed by slow warming to room temperature for 3h, TLC checked for completion of the substrate reaction, the reaction system was diluted with DCM, extracted 8 times with water, 1 time with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to give the crude product of compound 15.

The crude product of compound 15 and DMAP (0.49 g,4 mmol) were placed in a 250mL round bottom flask, 100mL of dry DCM was added, levulinic acid (4.64 g,40 mmol) and EDCI (9.2 g,48 mmol) were added under ice-bath, DIPEA (10 mL,56 mmol) was added and allowed to react at room temperature for 5h, TLC detection of substrate reaction was complete, the reaction system was diluted with DCM, extracted 6 times with water, 1 time with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation after filtration to give the crude product of compound 16.

Crude yield of Compound 16The reaction was placed in a 250mL round bottom flask, 100mL of dry THF was added, tetrabutylammonium fluoride (12.55 g,48 mmol) was added under ice-bath, then slowly warmed to room temperature for 3h, tlc detected completion of the substrate reaction, the reaction system was concentrated by rotary evaporation and purified by silica gel column chromatography (PE/ea=2:1→1:2) to give compound 17 (3.66 g,15mmol,75%,3 steps) as a white solid. ¹ H NMR(400MHz,CD ₃ OD)δ6.31(dd,J＝6.1,1.5Hz,1H),4.71(dd,J＝6.1,2.3Hz,1H),4.42(dd,J＝12.0,2.3Hz,1H),4.30(dd,J＝12.0,5.6Hz,1H),4.11(dt,J＝7.0,1.8Hz,1H),3.90(ddd,J＝9.5,5.6,2.3Hz,1H),3.56(dd,J＝9.7,7.1Hz,1H),2.80(t,J＝6.4Hz,2H),2.59(t,J＝6.4Hz,2H),2.17(s,3H)； ¹³ C NMR(100MHz,CD ₃ OD)δ208.3,173.0,143.2,103.4,76.3,69.3,68.8,63.0,37.2,28.3,27.4.

Compound 17 (5.15 g,21.1 mmol) and imidazole (5.7 g,84.4 mmol) were placed in a 100mL round bottom flask, 25mL of dry DMF was added dropwise under ice-bath, 1, 3-tetraisopropyl disiloxane (7.4 mL,23.2 mmol) was then allowed to react slowly to room temperature for 1h, TLC detected substrate reaction was complete, the reaction system was diluted with DCM, extracted 8 times with water, 1 time with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by rotary evaporation after filtration, and purified by silica gel column chromatography (PE/EA=50:1) to give Compound 12 (9.8 g,20.1mmol, 95%) as a colorless oil.

/>

Compound 12 (3.5 g,7.2 mmol), tetrabutylammonium nitrate (4.4 g,14.4 mmol) and 4-methyl-2, 6-di-tert-butylpyridine (5.9 g,28.7 mmol) were placed in a 500mL round bottom flask, 180mL of dried DCM was added, trifluoroacetic anhydride (2.4 mL,14.4 mmol) was added dropwise to the reaction system at-70℃and reacted for 10min, TLC was allowed to detect completion of the substrate reaction, the reaction system was raised to 0℃and 2mL of dried pyridine and 1mL of acetic anhydride were added, followed by slow warming to room temperature and reaction for 3h, TLC was allowed to detect completion of the reaction, whereupon the reaction system was extracted 5 times with 1M hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated by spin evaporation, and purified by silica gel column chromatography (PE/EA=10:1) to give Compound 2 (3.2 g,6.0mmol, 83%) as pale yellow solid.

Compound 24 (2.5 g,7.5 mmol) and triphenylphosphine (2.6 g,9.8 mmol) were placed in a 250mL round bottom flask, nitrogen protection was performed in the flask after air-pumping and air-charging operation, 30mL of dry THF was injected with a syringe, diisopropyl azodicarboxylate (1.9 mL,9.4 mmol) was added dropwise under ice bath and reacted for 20min, diphenyl azide phosphonate (2 mL,9.0 mmol) was added dropwise, then the reaction system was warmed to room temperature and reacted overnight, TLC detection of substrate reaction was complete, 3mL of dry pyridine, 2mL of water and triphenylphosphine (8.1 g,30 mmol) dissolved in 10mL of THF were added to the reaction system, the reaction system was refluxed to 70℃for 5h, TLC detection was complete, the reaction system was cooled to room temperature, THF was removed by rotary evaporation, DCM was added, extracted 3 times with water, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation, and purified by silica gel column (DCM/MeOH/=100:2) to give compound (1.9.9 g,5.9 mmol) as white solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.74(d,J＝4.5Hz,1H),8.02(d,J＝9.2Hz,1H),7.62(s,1H),7.53(s,1H),7.37(dd,J＝9.2,2.5Hz,1H),5.78(ddd,J＝17.4,10.2,7.4Hz,1H),5.03(t,J＝13.5Hz,2H),4.70(d,J＝6.6Hz,1H),3.98(s,3H),3.89(s,3H),3.48–3.28(m,3H),3.10–2.86(m,2H),2.37(s,1H),1.64(t,J＝7.6Hz,1H),1.49(t,J＝9.9Hz,1H),1.30(t,J＝7.3Hz,1H),0.82(dd,J＝13.5,7.1Hz,1H)； ¹³ C NMR(100MHz,CDCl ₃ )δ＝157.9,147.8,146.1,144.60,140.59,131.7,128.4,121.5,115.1,101.8,61.7,55.8,55.5,45.9,41.0,39.0,27.3,27.2,25.5,9.1.

Compound 25 (157 mg,0.49 mmol) was placed in a 25mL round bottom flask, 3mL dry THF was added, and ice-bath addition3, 5-Ditrifluoromethylbenzyl isocyanate (26) (0.11 mL,0.61 mmol) and triethylamine (68. Mu.L, 0.49 mmol) followed by reaction at room temperature overnight, TLC detection of complete substrate reaction, concentration by rotary evaporation, purification by silica gel column chromatography (DCM/MeOH=30:1) gave compound 28 (189 mg,0.33mmol, 67%) as a white solid. ¹ H NMR(400MHz,CD ₃ OD)δ8.70(d,J＝4.6Hz,1H),8.01–7.92(m,3H),7.86(d,J＝2.2Hz,1H),7.61–7.52(m,1H),7.50–7.39(m,2H),6.00–5.81(m,1H),5.63(d,J＝8.2Hz,1H),5.05(dd,J＝19.2,13.9Hz,2H),4.03(s,3H),3.59–3.31(m,3H),2.92–2.76(m,2H),2.40(s,1H),1.79–1.52(m,4H),0.90(dd,J＝12.0,5.9Hz,1H)； ¹³ C NMR(100MHz,CD ₃ OD)δ158.5,155.2,146.9,146.0,143.8,141.8,141.0,132.2,131.9,131.5,131.2,130.0,128.6,127.4,124.7,122.4,122.0,119.3,117.6,114.2,113.9,101.7,67.5,59.3,55.4,54.9,40.9,39.2,27.4,26.9,26.1,25.1.

Specific procedures for this experiment refer to the synthesis of compound 28 from compound 25 (1.9 g,5.9 mmol) and 3, 5-bistrifluoromethylbenzothioisocyanate (27) (1.4 mL,7.1 mmol) to afford compound 29 (2.3 g,3.8mmol, 64%) as a white solid. ¹ H NMR(400MHz,CD ₃ OD)δ8.69(d,J＝4.7Hz,1H),8.10(s,3H),7.95(d,J＝9.2Hz,1H),7.60(s,1H),7.57(d,J＝4.7Hz,1H),7.45(dd,J＝9.2,2.7Hz,1H),6.36(d,J＝10.9Hz,1H),5.86(ddd,J＝17.5,10.3,7.5Hz,1H),5.08–5.01(m,1H),4.99(dd,J＝10.4,1.1Hz,1H),4.03(s,3H),3.68–3.53(m,1H),3.42(dd,J＝17.5,10.2Hz,1H),3.35–3.23(m,2H),2.96–2.73(m,2H),2.37(s,1H),1.75–1.59(m,3H),1.47(dd,J＝12.9,10.4Hz,1H),0.97–0.79(m,1H)； ¹³ C NMR(100MHz,CD ₃ OD)δ181.1,158.3,146.9,146.2,143.8,141.7,141.1,131.8,131.5,131.1,130.8,129.8,128.8,124.7,122.4,122.3,122.0,119.8,116.4,113.7,102.8,60.1,55.3,55.1,41.5,39.3,27.4,27.2,25.6,13.1.

The synthesis of compound 29 from compound 24 can be found in particular in Sandra Medina, matthew J.Harper, edward I.Balmond, silvia Miranda, giacomo E.M.Crisenza, diane M.Coe, eoghan M.McGarrigle, M.Carmen Galan, org.Lett.2016,18,4222-4225.

Compound 2 (64 mg,0.12 mmol) and compound 29 (7 mg,0.012 mmol) were placed in a Schlenk tube, the tube was evacuated by an oil pump for 1 hour and then subjected to nitrogen substitution protection, cyclohexanol (25. Mu.L, 0.24 mmol) and 0.6mL of dried fluorobenzene were added under nitrogen atmosphere, the reaction system was reacted at 80℃for 48 hours, then cooled to room temperature, concentrated by rotary evaporation, and purified by silica gel column chromatography (PE/EA=10:1) to give compound 40. Alpha./40. Beta (43 mg,0.068mmol,57%, α/beta=5.1:1) as a colorless oil. 40 alpha: ¹ H NMR(400MHz,Acetone-d ₆ )δ5.44(d,J＝4.2Hz,1H),4.81(dd,J＝9.9,4.2Hz,1H),4.70(dd,J＝9.8,8.2Hz,1H),4.51(dd,J＝11.8,2.1Hz,1H),4.16(dd,J＝11.8,5.8Hz,1H),4.03(ddd,J＝9.5,5.7,2.0Hz,1H),3.85(dd,J＝9.7,8.2Hz,1H),3.69–3.62(m,1H),2.77(t,J＝6.5Hz,2H),2.58–2.52(m,2H),2.13(s,3H),1.92–1.83(m,1H),1.75–1.56(m,3H),1.50–1.39(m,2H),1.38–1.22(m,4H),1.19–0.93(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.4,172.0,94.3,87.7,76.2,73.3,72.7,69.8,62.6,37.2,32.8,30.5,28.8,27.5,25.3,23.4,23.1,17.2,16.93,16.86,16.79,16.78,16.60,16.52,12.9,12.6,12.3,12.1.

40β: ¹ H NMR(400MHz,Acetone-d ₆ )δ5.16(d,J＝7.8Hz,1H),4.51–4.43(m,3H),4.24–4.17(m,1H),3.91–3.81(m,2H),3.77–3.68(m,1H),2.77(t,J＝6.5Hz,2H),2.63–2.47(m,2H),2.14(s,3H),1.90–1.80(m,1H),1.79–1.71(m,1H),1.70–1.57(m,2H),1.51–1.34(m,2H),1.33–1.18(m,4H),1.15–0.94(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.4,171.9,97.6,90.8,77.0,76.6,73.7,73.0,62.5,37.3,32.9,30.9,28.8,27.6,25.3,23.4,23.2,16.85,16.75,16.73,16.71,16.68,16.57,16.56,12.7,12.6,12.10,12.05.

compound 2 (133 mg,0.25 mmol) and compound 43 (77 mg,0.166 mmol) as well as compound 29 (10 mg,0.0166 mmol) were placed in a Schlenk tube, the tube was evacuated with an oil pump for 1 hour and then protected by nitrogen displacement, 0.5mL of dried fluorobenzene was added under nitrogen atmosphere, the reaction system was reacted at 80℃for 48 hours and then cooled to room temperature, concentrated by rotary evaporation, and purified by silica gel column chromatography (PE/EA=10:1) to give compound 43'α/43' β (121 mg,0.122mmol,73%, α/β=8.3:1) as a white solid. 43' alpha: ¹ H NMR(400MHz,Acetone-d ₆ )δ7.42–7.19(m,15H),5.45(d,J＝3.8Hz,1H),4.95(d,J＝11.2Hz,1H),4.90(d,J＝11.3Hz,1H),4.84–4.76(m,4H),4.73(s,2H),4.65(d,J＝11.4Hz,1H),4.51(dd,J＝11.7,2.0Hz,1H),4.13(dd,J＝11.8,5.4Hz,1H),4.00(ddd,J＝9.5,5.3,1.9Hz,1H),3.91–3.77(m,4H),3.70–3.63(m,1H),3.53(dd,J＝9.6,3.5Hz,1H),3.43(dd,J＝9.9,9.0Hz,1H),3.36(s,3H),2.76(t,J＝6.5Hz,2H),2.61–2.47(m,2H),2.12(s,3H),1.18–0.92(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.6,172.0,139.3,139.0,138.9,128.2,128.1,127.73,127.68,127.65,127.4,127.3,97.6,95.7,87.5,81.7,80.5,77.6,74.9,74.6,73.0,72.7,72.2,70.2,69.9,65.8,62.3,54.3,37.3,28.8,27.6,17.2,16.89,16.87,16.80,16.75,16.54,16.49,12.9,12.6,12.2,12.1.

specific procedures for this experiment refer to the synthesis of compound 43'α/43' β from compound 2 (140 mg,0.264 mmol) and compound 44 (89 mg,0.176 mmol) to give compound 44'α/44' β (128 mg,0.123mmol,70%, α/β=13.2:1) as a colorless oil. 44' alpha: ¹ H NMR(400MHz,Acetone-d ₆ )δ7.99–7.92(m,4H),7.91–7.85(m,2H),7.63–7.57(m,2H),7.53-7.41(m,5H),7.36(t,J＝7.7Hz,2H),6.12(t,J＝9.8Hz,1H),5.66(t,J＝9.9Hz,1H),5.46(d,J＝3.1Hz,1H),5.33(dd,J＝10.2,3.6Hz,1H),5.26(d,J＝3.6Hz,1H),4.94–4.82(m,2H),4.46(d,J＝9.6Hz,1H),4.35–4.27(m,1H),4.10–3.96(m,3H),3.87(t,J＝8.6Hz,1H),3.79(dd,J＝11.3,1.4Hz,1H),3.52(s,3H),2.79–2.72(m,2H),2.49(t,J＝6.4Hz,2H),2.14(s,3H),1.26–0.98(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.5,171.9,165.4,165.2,164.9,133.5,133.3,129.6,129.5,129.41,129.37,129.26,129.25,128.59,128.56,128.43,96.9,95.5,87.5,73.1,72.5,71.9,70.8,70.0,69.0,68.4,65.8,62.4,54.8,37.3,28.8,27.5,17.2,16.90,16.86,16.84,16.78,16.58,16.54,12.9,12.6,12.3,12.1.

specific procedures for this experiment refer to the synthesis of compound 43'α/43' β, from compound 2 (160 mg,0.301 mmol) and compound 45 (49 mg,0.201 mmol) compound 45'α/45' β (103 mg,0.133mmol,66%, α/β=2.7:1) was prepared as a colorless oil. 45' alpha: ¹ H NMR(400MHz,Acetone-d ₆ )δ5.94(ddd,J＝22.5,10.8,5.6Hz,1H),5.49(d,J＝4.1Hz,1H),5.34–5.26(m,1H),5.17(dd,J＝10.4,1.6Hz,1H),4.95(s,1H),4.86(dd,J＝10.0,4.1Hz,1H),4.71(dd,J＝9.9,8.3Hz,1H),4.59(dd,J＝11.9,2.2Hz,1H),4.24–4.09(m,5H),4.04–3.94(m,2H),3.58(dt,J＝12.5,6.2Hz,1H),3.37(dd,J＝10.0,6.4Hz,1H),2.78(t,J＝6.25Hz,2H),2.64–2.50(m,2H),2.14(s,3H),1.50(s,3H),1.33(s,3H),1.21–0.92(m,31H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.4,172.0,134.3,116.5,109.0,96.3,95.9,87.6,82.0,76.7,76.0,72.57,72.55,69.8,67.6,64.3,61.5,37.3,28.8,27.6,27.5,25.8,17.2,17.0,16.83,16.79,16.77,16.72,16.63,16.55,16.4,12.9,12.7,12.3,12.1.

45’β: ¹ H NMR(400MHz,Acetone-d ₆ )δ5.93(ddd,J＝22.5,10.8,5.6Hz,1H),5.51(d,J＝7.95Hz,1H),5.35–5.22(m,1H),5.16(dd,J＝10.4,1.5Hz,1H),4.97(s,1H),4.60(dd,J＝11.8,2.0Hz,1H),4.54–4.41(m,2H),4.24–4.08(m,3H),4.05–3.96(m,2H),3.94–3.86(m,1H),3.84–3.78(m,1H),3.68(dd,J＝9.9,7.3Hz,1H),3.59(dd,J＝10.0,6.1Hz,1H),2.78(t,J＝6.5Hz,2H),2.62–2.50(m,2H),2.14(s,3H),1.52(s,3H),1.32(s,3H),1.23–0.94(m,31H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.4,172.0,134.3,116.4,109.2,97.4,95.9,90.8,78.3,77.6,76.4,76.0,74.0,73.0,67.5,63.5,62.3,59.7,37.3,27.6,27.5,25.7,17.0,16.8,16.73,16.69,16.68,16.58,16.55,12.64,12.56,12.02,11.98.

specific procedures for this experiment refer to the synthesis of compound 43' α/43' β from compound 2 (137 mg,0.257 mmol) and compound 46 (77 mg,0.171 mmol) to afford compound 46' α (47 mg,0.048mmol, 28%) as a colorless oil. ¹ H NMR(400MHz,Acetone-d ₆ )δ7.48–7.44(m,4H),7.38–7.26(m,9H),7.18(d,J＝8.0Hz,2H),6.08(d,J＝4.0Hz,1H),5.72(s,1H),5.03(d,J＝11.1Hz,1H),4.90(dd,J＝10.2,4.1Hz,1H),4.78–4.71(m,2H),4.69(d,J＝9.7Hz,1H),4.38–4.27(m,2H),4.12(dd,J＝12.1,2.0Hz,1H),3.95–3.60(m,8H),2.69(t,J＝6.6Hz,2H),2.52–2.43(m,2H),2.10(s,3H),1.23–0.94(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.5,171.7,138.3,138.2,137.9,133.0,129.7,129.0,128.7,128.2,128.1,128.0,127.6,126.2,101.0,94.4,87.8,87.5,81.9,80.1,75.8,74.2,72.7,72.6,70.1,69.5,68.2,61.6,37.3,28.8,27.6,20.3,17.2,16.92,16.88,16.83,16.69,16.64,16.56,12.9,12.6,12.3,12.1.

Specific procedures for this experiment refer to the synthesis of compound 40 α/40 β from compound 2 (133 mg,0.25 mmol) and compound 47 (12 mg, 0.67 mmol) to yield compound 47'α/47' β (69 mg,0.114mmol,68%, α/β=2.2:1) as a colorless oil. 47' alpha: ¹ H NMR(400MHz,Acetone-d ₆ )δ5.78(ddt,J＝17.1,10.2,6.8Hz,1H),5.34(d,J＝4.1Hz,1H),5.08(dd,J＝17.2,1.7Hz,1H),5.01(dd,J＝10.3,0.8Hz,1H),4.83(dd,J＝9.9,4.1Hz,1H),4.70(dd,J＝9.8,8.1Hz,1H),4.52(dd,J＝11.8,1.9Hz,1H),4.16(dd,J＝11.8,5.5Hz,1H),4.00–3.94(m,1H),3.87(dd,J＝9.7,8.2Hz,1H),3.79(dt,J＝9.9,6.7Hz,1H),3.52(dt,J＝9.9,6.6Hz,1H),2.78(t,J＝6.5Hz,2H),2.56(td,J＝6.3,3.5Hz,2H),2.32(q,J＝6.6Hz,2H),2.13(s,3H),1.18–0.94(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.5,172.0,134.7,116.3,95.5,87.5,73.1,72.6,69.8,67.4,62.5,37.3,33.4,27.6,17.2,16.91,16.83,16.78,16.76,16.75,16.58,16.51,12.9,12.6,12.2,12.1.

47’β: ¹ H NMR(400MHz,Acetone-d ₆ )δ5.77(ddt,J＝17.1,10.3,6.7Hz,1H),5.12–5.04(m,2H),5.02–4.97(m,1H),4.56–4.43(m,3H),4.21(dd,J＝11.8,4.9Hz,1H),3.93–3.82(m,3H),3.63(dt,J＝9.9,6.8Hz,1H),2.78(t,J＝6.5Hz,2H),2.57(td,J＝6.4,3.9Hz,2H),2.30(q,J＝6.7Hz,2H),2.14(s,3H),1.19–0.91(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.6,172.0,134.6,116.2,99.1,90.5,76.5,73.8,72.9,68.9,62.4,37.3,33.6,27.6,16.82,16.72,16.70,16.68,16.65,16.53,12.7,12.6,12.1,12.0.

specific procedures for this experiment refer to the synthesis of compound 43'α/43' β from compound 2 (183 mg,0.344 mmol) and compound 48 (100 mg,0.229 mmol) to yield compound 48'α/48' β (162 mg,0.167mmol,73%, α/β=12.5:1) as a colorless oil. 48' alpha: ¹ H NMR(400MHz,Acetone-d ₆ )δ7.49(d,J＝7.0Hz,2H),7.45(d,J＝7.1Hz,2H),7.39–7.26(m,11H),5.72(d,J＝3.6Hz,1H),5.55(d,J＝1.3Hz,1H),4.97–4.81(m,4H),4.76(d,J＝11.8Hz,1H),4.68(d,J＝11.2Hz,1H),4.52–4.47(m,1H),4.35–4.29(m,1H),4.26(dd,J＝12.0,2.0Hz,1H),4.08–4.02(m,1H),3.99(dd,J＝12.0,4.4Hz,1H),3.91(dd,J＝9.5,8.1Hz,1H),3.86(dd,J＝9.2,2.7Hz,1H),3.57(t,J＝9.3Hz,1H),2.73(t,J＝6.5Hz,2H),2.52(t,J＝6.5Hz,2H),2.12(s,3H),1.31–0.92(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.4,171.9,138.7,138.3,134.3,131.6,129.1,128.4,128.2,128.0,127.54,127.48,127.35,92.7,87.4,84.0,80.1,79.2,74.9,73.3,72.8,72.5,71.8,70.1,69.0,62.1,37.3,27.6,17.3,16.96,16.95,16.92,16.89,16.71,16.55,16.51,13.0,12.7,12.3,12.2.

specific procedures for this experiment refer to the synthesis of compound 43' α/43' β from compound 2 (141 mg,0.266 mmol) and compound 49 (46 mg,0.177 mmol) to give compound 49' α (123 mg,0.155mmol, 88%) as a colorless oil. ¹ H NMR(400MHz,Acetone-d ₆ )δ5.45(d,J＝4.9Hz,1H),5.35(d,J＝3.9Hz,1H),4.82(dd,J＝9.9,3.9Hz,1H),4.73(dd,J＝9.9,8.2Hz,1H),4.63(dd,J＝7.9,2.4Hz,1H),4.49(dd,J＝11.7,1.9Hz,1H),4.34(dd,J＝4.9,2.4Hz,1H),4.23–4.16(m,2H),4.13(ddd,J＝9.6,4.8,1.8Hz,1H),3.98–3.93(m,1H),3.89(dd,J＝9.6,8.2Hz,1H),3.77(dd,J＝10.5,7.0Hz,1H),3.68(dd,J＝10.6,4.9Hz,1H),2.78(t,J＝6.6Hz,2H),2.57(td,J＝6.5,2.9Hz,2),2.14(s,3H),1.48(s,3H),1.37(s,3H),1.32(s,3H),1.30(s,3H),1.18–0.97(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.5,172.0,108.9,108.3,96.2,95.7,87.6,73.0,72.7,71.0,70.64,70.59,69.7,67.5,66.8,62.4,37.3,28.8,27.6,25.49,25.46,24.4,23.6,17.2,16.9,16.82,16.79,16.76,16.74,16.6,16.5,12.9,12.7,12.3,12.1.

Specific procedures for this experiment refer to the synthesis of compound 43' α/43' β from compound 2 (133 mg,0.25 mmol) and compound 50 (57 mg, 0.67 mmol) to afford compound 50' α (122 mg,0.14mmol, 84%) as a colorless oil. ¹ H NMR(400MHz,Acetone-d ₆ )δ7.87(d,J＝7.5Hz,2H),7.71(d,J＝7.4Hz,2H),7.42(t,J＝7.4Hz,2H),7.34(tt,J＝7.4,1.1Hz,2H),6.89(d,J＝8.4Hz,1H),5.40(d,J＝4.1Hz,1H),4.87(dd,J＝9.9,4.2Hz,1H),4.72(dd,J＝9.8,8.3Hz,1H),4.60–4.52(m,2H),4.41–4.23(m,3H),4.17(dd,J＝11.8,5.6Hz,1H),4.12–4.04(m,2H),3.94–3.84(m,2H),3.71(s,3H),2.76(t,J＝6.5Hz,2H),2.60–2.50(m,2H),2.11(s,3H),1.19–0.91(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.7,172.0,170.0,156.0,144.1,141.2,127.7,127.1,125.3,125.3,120.0,96.2,87.3,73.0,72.3,70.0,68.5,66.6,62.4,54.2,51.8,47.1,37.3,27.6,17.2,16.92,16.85,16.78,16.76,16.6,16.5,12.8,12.6,12.3,12.0.

Specific procedures for this experiment refer to the synthesis of compound 43' α/43' β from compound 2 (141 mg,0.266 mmol) and compound 51 (27 mg,0.177 mmol) to give compound 51' α (45 mg,0.066mmol, 37%) as a white solid. ¹ H NMR(400MHz,Acetone-d ₆ )δ5.70(d,J＝4.0Hz,1H),4.81–4.66(m,2H),4.49(d,J＝9.8Hz,1H),4.22–4.07(m,2H),3.81(dd,J＝9.3,8.0Hz,1H),2.77(t,J＝6.5Hz,2H),2.55(td,J＝6.4,3.0Hz,2H),2.13(s,3H),1.81(d,J＝11.4Hz,2H),1.75–1.57(m,13H),1.19–0.96(m,28H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.4,172.0,90.0,89.3,88.1,80.6,77.2,75.2,73.5,72.6,69.5,62.8,41.6,37.2,35.8,30.6,27.6,17.2,16.91,16.84,16.77,16.57,16.50,12.9,12.6,12.3,12.1.

Specific procedures for this experiment refer to the synthesis of compound 43'α/43' β from compound 2 (136 mg,0.256 mmol) and compound 52 (66 mg, 0.171mmol) to give compound 52'α/52' β (122 mg,0.133mmol,78%, α/β=3.5:1) as a white solid. 52' α: ¹ H NMR(400MHz,Acetone-d ₆ )δ5.48(d,J＝4.2Hz,1H),5.40(d,J＝5.2Hz,1H),4.83(dd,J＝9.9,4.2Hz,1H),4.69(dd,J＝9.9,8.2Hz,1H),4.54(dd,J＝11.7,2.0Hz,1H),4.17(dd,J＝11.7,6.0Hz,1),4.11–4.02(m,1H),3.85(dd,J＝9.7,8.2Hz,1H),3.49(ddd,J＝16.0,11.2,4.7Hz,1H),2.78(t,J＝6.7Hz,2H),2.56(t,J＝6.5Hz,2H),2.46–2.26(m,2H),2.14(s,3H),2.01–1.95(m,1H),1.90–1.82(m,2H),1.77(d,J＝12.5Hz,1H),1.64–1.26(m,16H),1.21–0.83(m,46H),0.72(s,3H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.4,172.0,140.3,122.0,94.6,87.8,78.9,73.3,72.7,69.8,62.7,56.7,56.2,50.2,42.2,39.7,39.7,39.4,37.3,36.8,36.5,36.1,35.7,31.8,31.7,28.8,28.0,27.8,27.6,27.3,24.1,23.7,22.2,21.2,20.9,18.8,18.3,17.2,16.9,16.84,16.77,16.6,16.5,12.9,12.6,12.3,12.1,11.4.

52’β: ¹ H NMR(400MHz,Acetone-d ₆ )δ5.36(d,J＝5.2Hz,1H),5.21(d,J＝7.8Hz,1H),4.51–4.39(m,3H),4.24–4.17(m,1H),3.9-3.84(m,2H),3.58(tt,J＝11.4,4.5Hz,1H),2.77(t,J＝6.5Hz,2H),2.63–2.48(m,2H),2.29(ddd,J＝12.8,4.6,2.0Hz,1H),2.14(s,3H),2.10(s,1H),2.00–1.81(m,4H),1.64–1.25(m,14H),1.24–0.84(m,48H),0.72(s,3H)； ¹³ C NMR(100MHz,Acetone-d ₆ )δ205.4,171.9,140.1,122.0,97.7,90.8,79.0,76.6,73.7,73.0,62.5,56.7,56.2,50.2,42.2,39.8,39.4,38.1,37.3,37.1,36.5,36.1,35.7,31.82,31.75,28.1,27.8,27.7,24.1,23.7,22.2,22.0,20.9,18.8,18.3,16.8,16.74,16.68,16.57,12.7,12.6,12.11,12.05,11.4.

compound S1 (5 g,34.2 mmol), bu ₂ SnO (851.4 mg,3.42mmol,0.1 eq), TBAB (3.3075 g,10.26mmol,0.3 eq), and the system was placed in a 70℃oil bath and DIPEA (11.3 mL,68.4mmol,2 eq), bnBr (8.1 mL,68.4mmol,2 eq), N were added ₂ The reaction was carried out for 7 hours under protection. After the reaction was completed, cooled to room temperature, quenched with methanol, dried by spin, and passed through a column (PE: ea=5:1-3:1) to give compound S15 as a white solid (5.4677 g, 72.5%). ¹ H NMR(400MHz,CDCl ₃ )δ7.35(d,J＝5.4Hz,5H),6.46(d,J＝6.3Hz,1H),4.73(dd,J＝4.5,1.8Hz,1H),4.63(d,J＝4.8Hz,2H),4.26–4.19(m,1H),4.12(d,J＝4.2Hz,1H),4.02(dd,J＝10.8,5.6Hz,1H),3.91(dd,J＝9.4,3.7Hz,2H).

Compound S15 (2 g,8.52 mmol) was dissolved in 10mL of DMF and pyridine (2.7 mL,34.08mmol,4 eq) was added and stirred well and placed at-20deg.C and tert-Bu was added ₂ Si(OTf) ₂ (3.1mL，9.37mmol，1.1eq)N ₂ The reaction was carried out for 1h under protection. DCM extraction, washing with a large amount of water, saturated brine, anhydrous Na ₂ SO ₄ Drying, suction filtration, spin-drying of the solvent and column chromatography (PE: ea=50:1) gave 2-7 (2.4867 g, 77.5%) as a white solid. [ alpha ]] _D ²⁵ ＝+71.5(c 1.0,CHCl ₃ ) ¹ H NMR(400MHz,CDCl ₃ )δ7.44–7.27(m,5H),6.35(dd,J＝6.4,2.0Hz,1H),4.80(d,J＝11.5Hz,1H),4.73(dt,J＝6.4,1.8Hz,1H),4.63(d,J＝3.5Hz,1H),4.57(d,J＝11.5Hz,1H),4.33–4.22(m,3H),3.85(s,1H),1.11(s,9H),1.05(s,9H). ¹³ C NMR(100MHz,CDCl ₃ )δ144.4,138.4,128.4,127.9,127.7,100.8,73.2,70.9,69.5,67.6,66.2,27.8,27.1,23.5,21.0.HRMS(ESI)calcd for C ₂₁ H ₃₂ O ₄ Si[M+K] ⁺ 415.1707,found 391.1700.

Compound 2-7 (300 mg,0.8 mmol), TBAN (485.1 mg,1.6mmol,2 eq) and DTBMP (657.1 mg,3.2mmol,4 eq) were dissolved in dry DCM and added to the systemStirring at room temperature for 30min under nitrogen protection, placing the reaction system at-30deg.C, adding Tf ₂ O (0.3 mL,1.6mmol,2 eq) was reacted for 5min. TLC monitoring the completion of the reaction, adding Py (2 ml), ac ₂ O (1 ml) was reacted at room temperature for 2 hours, the reaction was diluted with DCM, suction filtered, washed with 1N HCl, saturated brine washed with anhydrous Na ₂ SO ₄ Drying, suction filtration, spin-drying of the solvent, and column chromatography (PE: ea=20:1-8:1) gave compounds 2-9 as white solids (254.6 mg, 75.5%). ¹ H NMR(400MHz,CDCl ₃ )δ8.01(s,1H),7.48–7.43(m,2H),7.38–7.29(m,3H),4.85–4.77(m,2H),4.65(d,J＝4.9Hz,1H),4.55(d,J＝4.6Hz,1H),4.37(dd,J＝12.9,2.0Hz,1H),4.24(dd,J＝12.9,1.5Hz,1H),3.95(s,1H),1.08(s,9H),1.02(s,9H). ¹³ C NMR(100MHz,CDCl ₃ )δ154.5,137.9,132.5,128.6,128.3,128.1,72.6,69.8,66.9,66.1,27.7,27.1,23.5,21.0./>

A donor: compound 2-9 (0.12 mmol,1 eq), acceptor: HOR (1.5 eq) and catalyst 29 (0.2 eq) were placed in a sealed tube, purged, flushed with nitrogen, added with PhMe (7 mL) at 80℃for 24h, cooled to room temperature, the solvent was spun off, and passed through the column, with specific reference to the 43 'alpha/43' beta procedure.

Compound 31[ alpha ]] _D ²⁵ ＝+107.0(c 0.85,CHCl ₃ ) ¹ H NMR(400MHz,CDCl ₃ )δ7.45–7.27(m,5H),5.71(ddt,J＝17.0,10.2,6.7Hz,1H),5.35(d,J＝4.1Hz,1H),5.14–5.00(m,2H),4.91(dd,J＝10.5,4.2Hz,1H),4.72(s,2H),4.50(d,J＝2.8Hz,1H),4.32(dd,J＝10.5,3.1Hz,1H),4.20(ddd,J＝32.7,12.6,1.6Hz,2H),3.77–3.64(m,2H),3.50(dt,J＝9.8,6.6Hz,1H),2.28(q,J＝6.6Hz,2H),1.05(s,18H). ¹³ C NMR(100MHz,CDCl ₃ )δ137.9,134.2,128.7,128.2,128.1,117.3,96.3,83.5,73.8,71.9,69.9,68.1,67.6,67.0,33.6,29.8,27.7,27.4,23.56,20.8.HRMS(ESI)calcd for C ₂₅ H ₃₉ NO ₇ Si[M+K] ⁺ 532.2133,found 532.2128.

Compound 32[ alpha ]] _D ²⁵ ＝+86.8(c 0.4,CHCl ₃ ) ¹ H NMR(400MHz,CDCl ₃ )δ7.79(d,J＝7.5Hz,2H),7.62(dd,J＝7.3,2.9Hz,2H),7.46–7.39(m,4H),7.39–7.30(m,5H),5.75(d,J＝7.7Hz,1H),5.34(d,J＝4.2Hz,1H),4.91(dd,J＝10.5,4.2Hz,1H),4.72(s,2H),4.57–4.50(m,2H),4.47(dd,J＝10.5,7.1Hz,1H),4.36(dd,J＝10.5,7.2Hz,1H),4.29(dd,J＝10.5,3.0Hz,1H),4.24(t,J＝7.0Hz,1H),4.12(s,2H),4.01(dd,J＝10.3,2.4Hz,1H),3.92(dd,J＝10.3,3.3Hz,1H),3.80(s,3H),3.67(s,1H),1.05(d,J＝1.8Hz,18H). ¹³ C NMR(100MHz,CDCl ₃ )δ169.9,155.9,143.8,143.7,141.4,137.7,128.6,128.13,128.10,127.9,127.21,127.17,125.2,125.1,120.2,97.1,83.3,73.6,71.7,69.6,69.5,68.1,67.4,66.7,54.2,53.1,47.1,27.6,27.3,23.5,20.8.HRMS(ESI)calcd for C ₄₀ H ₅₀ N ₂ O ₁₁ Si[M+K] ⁺ 801.2821,found 801.2828.

Compound 33[ alpha ]] _D ²⁵ ＝+31.5(c 1.0,CHCl ₃ ) ¹ H NMR(400MHz,CDCl ₃ )δ7.41–7.27(m,17H),7.25–7.20(m,3H),5.42(d,J＝4.1Hz,1H),4.96(d,J＝11.0Hz,1H),4.92–4.83(m,2H),4.78(dd,J＝11.4,7.3Hz,2H),4.67(dt,J＝11.9,10.0Hz,3H),4.51(t,J＝7.1Hz,2H),4.42(d,J＝2.9Hz,1H),4.23(dd,J＝10.5,3.1Hz,1H),4.08(qd,J＝12.8,1.6Hz,2H),3.93(t,J＝9.3Hz,3H),3.73–3.57(m,2H),3.38–3.32(m,1H),3.31(s,3H),1.02(d,J＝5.5Hz,18H). ¹³ C NMR(100MHz,CDCl ₃ )δ138.9,138.5,138.3,137.8,128.7,128.6,128.5,128.3,128.2,128.1,128.0,127.9,127.7,127.7,98.1,96.8,83.5,81.9,80.2,75.7,75.0,73.7,73.4,71.6,70.2,69.7,67.4,66.9,66.2,55.2,27.7,27.4,23.5,20.8.HRMS(ESI)calcd for C ₄₉ H ₆₃ NO ₁₂ Si[M+K] ⁺ 924.3757,found 924.3762.

Compound 34[ alpha ]] _D ²⁵ ＝+103.6(c 0.85,CHCl ₃ ) ¹ H NMR(400MHz,CDCl ₃ )δ7.98(d,2H),7.92(d,2H),7.87(d,2H),7.53(dd,J＝15.2,7.6Hz,2H),7.47–7.27(m,12H),6.11(t,J＝9.9Hz,1H),5.49(t,J＝9.9Hz,1H),5.39(d,J＝4.1Hz,1H),5.25(dd,J＝10.2,3.6Hz,1H),5.17(d,J＝3.6Hz,1H),4.93(dd,J＝10.5,4.1Hz,1H),4.86–4.69(m,2H),4.51(d,J＝2.9Hz,1H),4.40(dd,J＝10.5,3.1Hz,1H),4.19–4.12(m,1H),4.05(ddd,J＝31.5,12.8,1.6Hz,2H),3.84(dd,J＝11.1,5.9Hz,1H),3.72(s,1H),3.57(dd,J＝11.1,1.8Hz,1H),3.42(s,3H),1.03(d,J＝8.2Hz,18H). ¹³ C NMR(100MHz,CDCl ₃ )δ165.90,165.89,165.5,137.8,133.8,133.5,133.2,130.1,129.9,129.8,129.3,129.1,128.8,128.7,128.6,128.5,128.4,128.3,128.1,96.9,96.5,83.4,73.6,72.1,71.8,70.5,69.7,69.2,68.3,67.7,66.8,66.4,55.6,27.7,27.4,23.5,20.8.HRMS(ESI)calcd for C ₄₉ H ₆₃ NO ₁₅ Si[M+K] ⁺ 966.3135,found 966.3134.

Compound 35[ alpha ]] _D ²⁵ ＝+80.2(c 1.0,CHCl ₃ ) ¹ H NMR(400MHz,CDCl ₃ )δ7.79(d,J＝7.5Hz,2H),7.69(dd,J＝7.3,2.9Hz,2H),7.44(dd,J＝9.7,5.0Hz,4H),7.40–7.29(m,5H),5.51(d,J＝4.2Hz,1H),5.40(d,J＝9.6Hz,1H),4.96(dd,J＝10.6,4.2Hz,1H),4.75(s,2H),4.56(d,J＝2.8Hz,1H),4.54–4.46(m,1H),4.42(dt,J＝6.7,5.0Hz,1H),4.38–4.28(m,3H),4.28–4.16(m,3H),3.77(s,1H),1.50(s,9H),1.29(d,J＝6.5Hz,3H),1.08(s,18H). ¹³ C NMR(100MHz,CDCl ₃ )δ169.0,156.8,144.,143.8,141.3,137.7,128.6,128.2,128.1,128.0,127.8,127.21,127.18,125.45,125.36,120.1,120.0,96.2,83.5,83.2,75.5,73.8,71.7,69.7,68.0,67.4,66.7,59.0,47.2,28.1,28.0,27.6,27.3,23.5,20.8,19.0.HRMS(ESI)calcd for C ₄₄ H ₅₈ N ₂ O ₁₁ Si[M+K] ⁺ 817.3737,found 817.3742.

Compound 36[ alpha ]] _D ²⁵ ＝+67.8(c 1.0,CHCl ₃ ) ¹ H NMR(400MHz,Acetone)δ7.33(ddt,J＝9.8,7.1,5.6Hz,5H),5.44(t,J＝4.3Hz,2H),4.89(dd,J＝9.4,5.3Hz,2H),4.82(d,J＝11.4Hz,1H),4.65(d,J＝11.4Hz,1H),4.61(dd,J＝8.0,2.4Hz,1H),4.45(dd,J＝10.6,3.1Hz,1H),4.39–4.32(m,2H),4.22–4.15(m,2H),4.04(s,1H),3.98–3.89(m,1H),3.75(dd,J＝10.5,6.9Hz,1H),3.67(dd,J＝10.5,5.5Hz,1H),1.47(s,3H),1.36(s,3H),1.32(s,3H),1.30(s,3H),1.07(d,J＝6.7Hz,18H). ¹³ C NMR(100MHz,Acetone)δ139.3,129.3,128.8,128.6,109.8,109.2,97.3,97.2,84.9,74.5,71.8,71.6,71.5,71.4,70.2,68.6,68.4,67.8,67.4,28.1,27.9,26.5,26.4,25.3,24.6,24.0,21.4.HRMS(ESI)calcd for C ₃₃ H ₅₁ NO ₁₂ Si[M+Na] ⁺ 704.3078,found 704.3068.

Compound 37[ alpha ]] _D ²⁵ ＝+70.7(c 0.35,CHCl ₃ ) ¹ H NMR(400MHz,CDCl ₃ )δ7.43–7.28(m,5H),5.97–5.81(m,1H),5.43(d,J＝4.1Hz,1H),5.29(dd,J＝17.2,1.5Hz,1H),5.22(dd,J＝10.3,1.1Hz,1H),4.97(s,1H),4.93(dd,J＝10.5,4.1Hz,1H),4.71(d,J＝1.8Hz,2H),4.54(d,J＝3.0Hz,1H),4.32(dd,J＝10.5,3.1Hz,1H),4.22(ddd,J＝13.7,12.6,1.6Hz,2H),4.12(dd,J＝14.4,5.5Hz,2H),4.04(t,J＝6.4Hz,2H),3.95(dd,J＝12.7,6.3Hz,1H),3.61(dq,J＝12.5,6.2Hz,1H),3.39(dd,J＝10.1,7.4Hz,1H),1.50(s,3H),1.29(s,3H),1.13(d,J＝6.3Hz,3H),1.05(s,18H). ¹³ C NMR(100MHz,CDCl ₃ )δ137.8,133.5,128.6,128.2,128.1,118.2,109.3,96.3,95.9,83.5,80.1,76.2,73.9,71.7,69.7,68.2,67.5,67.0,64.7,28.2,27.7,27.4,26.4,23.5,20.8,17.4.HRMS(ESI)calcd for C ₃₃ H ₅₁ NO ₁₂ Si[M+H] ⁺ 682.3259,found 682.3243.

Compound 38 ¹ H NMR(400MHz,CDCl ₃ )δ7.43–7.27(m,5H),5.71(d,J＝4.2Hz,1H),4.89(dd,J＝10.5,4.2Hz,1H),4.72(d,J＝1.8Hz,2H),4.52(d,J＝3.1Hz,1H),4.34(dd,J＝10.5,3.2Hz,1H),4.24(dd,J＝12.5,1.9Hz,1H),4.10(dd,J＝12.5,1.5Hz,1H),3.88(s,1H),2.12(s,3H),1.76–1.55(m,12H),1.05(s,18H). ¹³ C NMR(100MHz,CDCl ₃ )δ138.2,128.6,128.1,128.0,90.0,84.3,75.5,75.0,71.7,70.0,67.3,67.2,41.9,36.2,30.6,27.7,27.5,23.6,20.8.

Compound 39[ alpha ]] _D ²⁵ ＝+52.0(c 1.0,CHCl ₃ ) ¹ H NMR(400MHz,CDCl ₃ )δ7.44–7.27(m,5H),5.47(d,J＝4.3Hz,1H),5.32(d,J＝5.0Hz,1H),4.90(dd,J＝10.5,4.3Hz,1H),4.72(s,2H),4.50(d,J＝2.9Hz,1H),4.33(dd,J＝10.5,3.1Hz,1H),4.20(dd,2H),3.79(s,1H),3.51–3.37(m,1H),2.37–2.16(m,2H),2.11–1.90(m,3H),1.88–1.71(m,3H),1.66–1.08(m,24H),1.04(s,18H),0.96(s,4H),0.93–0.88(m,4H),0.86(dd,J＝6.6,1.7Hz,6H),0.66(s,3H). ¹³ C NMR(100MHz,CDCl ₃ )δ140.3,138.0,128.6,128.2,128.1,122.4,95.1,83.9,78.7,73.9,71.9,70.0,67.7,67.0,56.8,56.2,50.1,42.4,40.0,39.8,39.6,36.9,36.7,36.3,35.9,32.02,31.96,28.4,28.2,27.7,27.4,27.3,24.4,23.9,23.6,23.0,22.7,21.1,20.8,19.5,18.8,12.0.HRMS(ESI)calcd for C ₄₈ H ₇₇ NO ₇ Si[M+K] ⁺ 846.5106,found 846.5100.

While the foregoing is directed to the preferred embodiments of the present application, it will be appreciated by those skilled in the art that changes and modifications may be made without departing from the principles of the application, and such changes and modifications are intended to be included within the scope of the application.

Claims

1. The construction method of 1, 2-cis-2-nitro-glucoside or 1, 2-cis-2-nitro-galactose glucoside is characterized in that the specific structures of the 1, 2-cis-2-nitro-glucoside and the 1, 2-cis-2-nitro-galactose glucoside are as follows:

wherein Cy is cyclohexyl, ac is acetyl, bn is benzyl, bz is benzoyl, ⁱ pr is isopropyl, lev is levulinyl, ^t bu is tert-butyl and Fmoc is +.>AII is->The synthetic route is as follows:

PG is a protecting group, and the PG is a protecting group,

the synthesis steps are as follows:

will beAdding H-OR and catalyst 29 into a reaction bottle, adding solvent toluene OR fluorobenzene under nitrogen atmosphere, reacting completely at 80-85deg.C, concentrating by rotary evaporation, purifying by silica gel column chromatography to obtain target compound, (-) ->In particular +.>H-OR is specifically-> In particular +.>When the solvent is fluorobenzene, +.>H-OR and the molar ratio of the catalyst is 1:1.5:0.1; />In particular +.>In the process, the solvent is toluene,the molar ratio of H-OR to catalyst is 1:1.5:0.2.

2. The method for constructing 1, 2-cis-2-nitro-glucoside or 1, 2-cis-2-nitro-galacto-glucoside according to claim 1, wherein the compoundThe synthetic route of (2) is as follows:

the synthesis process is as follows:

s5, placing the compound 12, tetrabutylammonium nitrate and 4-methyl 2, 6-di-tert-butylpyridine in a reaction bottle, adding DCM, dropwise adding trifluoroacetic anhydride into a reaction system at-70 ℃ for reaction, detecting that a substrate is reacted completely by TLC, heating the reaction system to 0 ℃, adding pyridine and acetic anhydride in a volume ratio of 2:1, then heating to room temperature for reaction, detecting that the reaction is complete by TLC, extracting the reaction system by hydrochloric acid, drying by anhydrous sodium sulfate, filtering, concentrating by rotary evaporation, and purifying by silica gel column chromatography to obtain the compound 2.

3. The method for constructing 1, 2-cis-2-nitro-glucoside or 1, 2-cis-2-nitro-galactoside according to claim 2, wherein the molar ratio of compound 8, imidazole and tert-butyldimethylchlorosilane in S1 is 1:4:2.2; the mol ratio of the compound 15, DMAP, levulinic acid, EDCl and DIPEA in the S2 is 1:0.2:2:2.4:2.8; compound 16 in S3, tetrabutylammonium fluoride 1:2.4; the mol ratio of the compound 17 to the imidazole to the 1, 3-dichloro-1, 3-tetraisopropyl disiloxane in the S4 is 1:4:1.1; the molar ratio of the compound 12, tetrabutylammonium nitrate, 4-methyl 2, 6-di-tert-butylpyridine and trifluoroacetic anhydride in the S5 is 1:2:4:2, and 2mL of pyridine is required to be added for each 7.2mmol of the compound 12.

4. Root of Chinese characterThe method for constructing 1, 2-cis-2-nitro-glucoside or 1, 2-cis-2-nitro-galactoside according to claim 1, wherein said compoundThe synthetic route of (2) is as follows:

the synthesis process is as follows:

(2) Dissolving compound S15 in DMF, adding pyridine, stirring, adding tert-Bu at-20deg.C ₂ Si(OTf) ₂ N ₂ The reaction is complete under the protection, DCM extraction, water washing, saturated salt water washing and anhydrous Na ₂ SO ₄ Drying, suction filtering, spin-drying the solvent, and separating by column chromatography to obtain white solid 2-7;

5. The method for constructing 1, 2-cis-2-nitro-glucoside or 1, 2-cis-2-nitro-galactoside according to claim 4, wherein in step (1), the compounds S1 and Bu ₂ SnO, TBAB, DIPEA and BnBThe molar ratio of r is 1:0.1:0.3:2:2; in step (2), compound S15, pyridine, tert-Bu ₂ Si(OTf) ₂ The molar ratio of (2) is 1:4:1.1; compounds 2-7, TBAN, DTBMP and Tf in step (3) ₂ The molar ratio of O is 1:2:2:4, and 2mL of pyridine is required to be added per 0.8mmol of compound 2-7.