A method for the synthesis of l-fucose

Abstract

The application discloses a synthesis method of L-fucose, which comprises the following eight steps: D-galactose is used as raw material, and is subjected to acetone acetal protection, benzyl protection, hydrolysis and acetone acetal removal, dithioacetal reaction, acetyl protection, reduction and desulfurization and debenzyl, oxidation of alcohol into aldehyde, and deacetylation, so as to synthesize L-fucose. The synthesis process of the application does not involve complex chiral carbon inversion, the reaction route and total time are short, the condition is simple and easy to operate, and the method is environment-friendly and efficient.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis technology, and specifically relates to a method for synthesizing sugars. Background Technology

[0002] L-fucose, also known as 6-deoxygalactose, is a rare sugar that exists naturally in its L-isomer form (structural formula shown in Formula I). ​​It is found in nature, mainly in oligosaccharides, polysaccharides, and glycosides in bacteria and plants, as well as in glycoesters and glycoproteins in the human body. It plays an important role in physiological and biological functions and is widely used in chemical analysis, bioengineering, cell engineering, and glycoengineering.

[0003]

[0004] Formula I: Structural formula of L-fucose

[0005] Currently, the main methods for producing L-fucose fall into the following categories: natural extraction, microbial fermentation, enzyme-catalyzed synthesis, and chemical synthesis. For chemical synthesis, readily available monosaccharides (such as L-arabinose, L-rhamnose, and D-galactose) are typically used for chemical modification to synthesize L-fucose. However, current synthesis methods either have stringent reaction temperature requirements, complex synthetic routes leading to high costs, or involve the generation of epimers, making separation difficult, thus rendering them unsuitable for large-scale industrial production. Therefore, further research on the synthesis of L-fucose is necessary. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for synthesizing L-fucose. Using D-galactose as a raw material, L-fucose is synthesized through eight steps including acetone fork protection, benzyl protection, selective deprotection, reduction, and deoxygenation. The reaction process does not involve complex chiral carbon inversions, has a shorter reaction route and total time, is simple and easy to implement, and is environmentally friendly and efficient.

[0007] The technical solution adopted by this invention to solve its technical problem is:

[0008] A method for synthesizing L-fucose, comprising:

[0009] 1) 1,2,3,4-O-diisopropylidene-D-galactose (compound 1) was synthesized by protecting D-galactose with a 1,2,3,4-hydroxyacetone fork.

[0010] 2) 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2) was synthesized by protecting 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 1) with 6-hydroxybenzylation.

[0011] 3) 6-O-benzyl-D-galactose (compound 3) was synthesized from 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2) by acetone deprotection.

[0012] 4) 1,1-S,S'-diethyl-6-O-benzyl-D-galactose (compound 3) was synthesized by dithioacetalization.

[0013] 5) 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 4) was synthesized by acetylation of the 2,3,4,5-hydroxyl group to form 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 5).

[0014] 6) 2,3,4,5-Tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 5) was reduced to synthesize 2,3,4,5-tetra-O-acetyl-L-fucoitol (compound 6).

[0015] 7) 2,3,4,5-Tetra-O-acetyl-L-fucoitol (compound 6) was oxidized to an aldehyde via an alcohol hydroxyl group to synthesize 2,3,4,5-tetra-O-acetyl-L-fucoitol (compound 7).

[0016] 8) L-fucose (compound 8) was synthesized from 2,3,4,5-tetra-O-acetyl-L-fucose (compound 7) by deacetylation.

[0017] The synthetic route of this invention is shown in Formula II.

[0018]

[0019] Formula II: Synthetic route of the present invention

[0020] Further, in step 1), D-galactose, acetone and concentrated sulfuric acid react at room temperature, and the reaction is neutralized with alkali in the post-treatment to obtain 1,2,3,4-O-diisopropylidene-D-galactose (compound 1).

[0021] Step 1) uses acetone as the protecting agent to introduce the acetone fork protecting group. When acetone is used as the protecting agent and concentrated sulfuric acid is used as the catalyst, fewer byproducts are generated. If other protecting agents are used, such as 2,2-dimethoxypropane, more byproducts are generated, or even none are generated.

[0022] Preferably, in step 1), the feed ratio of D-galactose, acetone, and concentrated sulfuric acid is 0.8–1.2 g: 9–11 mL: 0.8–2 mL. More preferably, the feed ratio of D-galactose, acetone, and concentrated sulfuric acid is 0.8–1.2 g: 9–11 mL: 1–1.5 mL, resulting in a higher yield.

[0023] Preferably, in step 1), the base used is an organic base. Using an organic base ensures effective dissolution in the reaction solution and prevents anhydrous formation, thus avoiding product decomposition. The organic base is triethylamine.

[0024] In one embodiment, in step 1), the base used is an inorganic base, and the post-treatment involves adding the reaction solution dropwise into the base solution for neutralization, so that the neutralization reaction can proceed fully and the product decomposition can be avoided.

[0025] Further, in step 2), 1,2,3,4-O-diisopropylidene-D-galactose (compound 1), benzyl chloride and sodium hydride react at room temperature to obtain 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2).

[0026] Step 2) uses inexpensive and readily available benzyl chloride as the benzylating agent and sodium hydride as the catalyst, which can shorten the reaction time.

[0027] Further, in step 3), 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2), dilute sulfuric acid and dioxane are refluxed at 75-85 °C to obtain 6-O-benzyl-D-galactose (compound 3).

[0028] In step 3), dilute sulfuric acid is used for hydrolysis to protect the benzyl group from detachment; dioxane promotes the dissolution of the raw materials and accelerates the reaction process.

[0029] Preferably, in step 3), the dilute sulfuric acid is 0.8%–2.5% sulfuric acid; the feed ratio of 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2), 0.8%–2.5% sulfuric acid, and dioxane is 0.8–1.2 g: 7–8 mL: 2–3 mL. This achieves a better balance between shortening the reaction time and ensuring the yield.

[0030] Preferably, in step 3), the concentration of sulfuric acid is 1.8-2.2%.

[0031] Further, in step 4), 6-O-benzyl-D-galactose, concentrated hydrochloric acid, and ethanethiol react at -5 to 5°C to obtain 1,1-S,S'-diethyl-6-O-benzyl-D-galactose thioacetal (compound 4).

[0032] In step 4), concentrated hydrochloric acid is used as a catalyst to prevent benzyl group loss and ensure yield.

[0033] Further, in step 5), 1,1-S,S'-diethyl-6-O-benzyl-D-galactosylthioacetal (compound 4), acetic anhydride and pyridine react at room temperature to obtain 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 5).

[0034] Step 5) introduces an acetylation protecting group using acetic anhydride and pyridine, and the subsequent deprotection process is simple.

[0035] Preferably, in step 5), anhydrous acetic anhydride and anhydrous pyridine are used to avoid product decomposition.

[0036] Further, in step 6), 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 5), Raney nickel, and ethanol are refluxed in hydrogen at 65–75 °C to give 2,3,4,5-tetra-O-acetyl-L-fucoitol (compound 6).

[0037] Further, in step 7), 2,3,4,5-tetra-O-acetyl-L-fucoitol (compound 6), dimethyl sulfoxide and acetic anhydride (i.e., acetic anhydride) react at room temperature to obtain 2,3,4,5-tetra-O-acetyl-L-fucoitol (compound 7).

[0038] In step 7), the alcohol is oxidized to an aldehyde using the dimethyl sulfoxide / acetic anhydride oxidation method, resulting in fewer byproducts.

[0039] Further, in step 8), 2,3,4,5-tetra-O-acetyl-L-fucose (compound 7), sodium methoxide and methanol react at -5 to 5 °C to obtain L-fucose (compound 8).

[0040] In step 8), the sodium methoxide / methanol method is used for deacetylation, which is simple and fast.

[0041] In a preferred embodiment, the method for synthesizing L-fucose includes:

[0042] 1) D-galactose, acetone, and concentrated sulfuric acid were reacted at room temperature, and then neutralized with the organic base triethylamine to obtain 1,2,3,4-O-diisopropylidene-D-galactose (compound 1); the feed ratio of D-galactose, acetone, and concentrated sulfuric acid was 0.9–1.1 g: 9.5–10.5 mL: 1.1–1.3 mL;

[0043] 2) 1,2,3,4-O-diisopropylidene-D-galactose (compound 1), benzyl chloride and sodium hydride react at room temperature to give 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2).

[0044] 3) 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2), 1.8–2.2% sulfuric acid, and dioxane were refluxed at 78–82 °C to yield 6-O-benzyl-D-galactose (compound 3); the feed ratio of 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2), 1.8–2.2% sulfuric acid, and dioxane was 0.9–1.1 g: 7.4–7.6 mL: 2.4–2.6 mL;

[0045] 4) 6-O-benzyl-D-galactose (compound 3), concentrated hydrochloric acid and ethanethiol were reacted at -2 to 2℃ to give 1,1-S,S'-diethyl-6-O-benzyl-D-galactose thioacetal (compound 4).

[0046] 5) 1,1-S,S'-diethyl-6-O-benzyl-D-galactosylthioacetal (compound 4), acetic anhydride and pyridine were reacted at room temperature to give 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 5).

[0047] 6) 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 5), Raney nickel, and ethanol were refluxed in hydrogen at 68–72 °C to give 2,3,4,5-tetra-O-acetyl-L-fucoitol (compound 6).

[0048] 7) 2,3,4,5-Tetra-O-acetyl-L-fucoitol, dimethyl sulfoxide and acetic anhydride were reacted at room temperature to give 2,3,4,5-tetra-O-acetyl-L-fucose (compound 7).

[0049] 8) 2,3,4,5-tetra-O-acetyl-L-fucose (compound 7), sodium methoxide and methanol are reacted at -2 to 2℃ to give L-fucose (compound 8).

[0050] In this invention, unless otherwise specified or generally understood, % refers to mass percentage.

[0051] In this invention, "room temperature" or "room temperature" refers to the normal ambient temperature, which can be 10 to 30 °C.

[0052] In this invention, the concentrated sulfuric acid is commercially available sulfuric acid with a mass fraction of 96-98%, and the concentrated hydrochloric acid is commercially available hydrochloric acid with a mass fraction of 36-38%.

[0053] Unless otherwise specified, the equipment, reagents, processes, parameters, etc. involved in this invention are all conventional equipment, reagents, processes, parameters, etc., and no further examples will be provided.

[0054] All ranges listed in this invention include all point values ​​within that range.

[0055] Compared with the prior art, this technical solution has the following advantages:

[0056] This invention synthesizes the rare sugar L-fucose from D-galactose through eight steps: acetone protection, benzyl protection, hydrolysis to remove the acetone, dithioacetal reaction, acetyl protection, Raney nickel reduction to desulfurize and debenzylate, oxidation of alcohol to aldehyde, and deacetylation. The overall yield is 12.4%. This route has not been reported in the literature. The method is simple and efficient, does not involve complex chiral carbon inversion, and uses inexpensive and readily available reagents, greatly saving time and cost. Attached Figure Description

[0057] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0058] Figure 1 The compound is 1,2,3,4-O-diisopropylidene-D-galactose (compound 1). 1 H-NMR spectrum.

[0059] Figure 2 The compound is 1,2,3,4-O-diisopropylidene-D-galactose (compound 1). 13 C-NMR spectrum.

[0060] Figure 3 The compound is 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2). 1 H-NMR spectrum.

[0061] Figure 4 The compound is 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2). 13 C-NMR spectrum.

[0062] Figure 5 The compound is 1,1-S,S'-diethyl-6-O-benzyl-D-galactosylthioal (compound 4). 1 H-NMR spectrum.

[0063] Figure 6 The compound is 1,1-S,S'-diethyl-6-O-benzyl-D-galactosylthioal (compound 4).13 C-NMR spectrum.

[0064] Figure 7 The compound is 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 5). 1 H-NMR spectrum.

[0065] Figure 8 The compound is 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 5). 13 C-NMR spectrum.

[0066] Figure 9 It is 2,3,4,5-tetra-O-acetyl-L-fucoidol (compound 6). 1 H-NMR spectrum.

[0067] Figure 10 It is 2,3,4,5-tetra-O-acetyl-L-fucoidol (compound 6). 13 C-NMR spectrum.

[0068] Figure 11 For L-fucose (compound 8) 1 H-NMR spectrum.

[0069] Figure 12 For L-fucose (compound 8) 13 C-NMR spectrum. Detailed Implementation

[0070] The present invention will be specifically illustrated below through examples:

[0071] The method for synthesizing L-fucose in this embodiment includes:

[0072] 1) Synthesis of 1,2,3,4-O-diisopropylidene-D-galactose (compound 1) from D-galactose, as shown in Formula III, and the specific method is as follows:

[0073]

[0074] Synthesis of Formula III 1,2,3,4-O-diisopropylidene-D-galactose (compound 1)

[0075] Scheme A: Using acetone as a protective agent and concentrated sulfuric acid as a catalyst. Specifically: Add 100 mL of acetone and 10 g of D-galactose to a 250 mL three-necked flask equipped with a thermometer and magnetic stirrer. Control the temperature below 5 °C, and slowly add 9 mL of concentrated sulfuric acid while stirring. React at room temperature for 3–4 h. Monitor the reaction by TLC (thin-layer chromatography) until complete (developing solvent: ethyl acetate: petroleum ether = 1:2). Slowly add the reaction solution dropwise to sodium hydroxide solution under ice bath, stir until neutral, filter, concentrate the filtrate under reduced pressure, evaporate to dryness, dissolve in 50–80 mL of dichloromethane, wash with 100 mL of water, extract the aqueous layer with dichloromethane (50 mL × 2), combine the dichloromethane layers, wash with water (100 mL × 3), and dry overnight with anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, and separate by silica gel column chromatography to obtain compound 1.

[0076] Option b: Change the amount of concentrated sulfuric acid used in option a to 12 mL, and keep the rest the same as option a.

[0077] Option c: Change the amount of concentrated sulfuric acid used in option a to 18 mL, and keep the rest the same as option a.

[0078] In contrast, scheme d uses acetone as a protective agent, concentrated sulfuric acid as a catalyst, and anhydrous copper sulfate as a desiccant. Specifically, 100 mL of acetone and 10 g of anhydrous copper sulfate are added to a 250 mL three-necked flask equipped with a thermometer and magnetic stirrer. After stirring for half an hour, 10 g of D-galactose is added. The temperature is controlled below 5 °C, and 2 mL of concentrated sulfuric acid is slowly added while stirring. The reaction is carried out at room temperature for 6 h, and the reaction is monitored by TLC until complete (evolving solvent: ethyl acetate: petroleum ether = 1:2). The reaction solution is slowly added dropwise to sodium hydroxide solution under ice bath, neutralized to neutral, filtered, and the filtrate is concentrated under reduced pressure. After evaporation to dryness, it is dissolved in 50 mL–80 mL of dichloromethane, washed with 100 mL of water, and the aqueous layer is extracted with dichloromethane (50 mL × 2). The dichloromethane layers are combined, washed with water (100 mL × 3), and dried overnight with 10 g of anhydrous sodium sulfate. The filtrate is filtered and concentrated under reduced pressure. Compound 1 is obtained by silica gel column chromatography.

[0079] In contrast, scheme e uses 2,2-dimethoxypropane as a protecting agent and concentrated sulfuric acid as a catalyst. Specifically, 10 g of D-galactose and 100 mL of 2,2-dimethoxypropane are added to a 250 mL round-bottom flask. The temperature is controlled below 5°C. While stirring, 12 mL of concentrated sulfuric acid is slowly added. After reacting at room temperature for 4 h, the reaction is monitored by TLC until complete (evolving solvent: ethyl acetate: petroleum ether = 1:2). The reaction solution is then slowly added dropwise to sodium hydroxide solution under ice bath to neutralize to neutral. The solution is filtered, the filtrate is concentrated under reduced pressure, evaporated to dryness, dissolved in 100 mL of dichloromethane, and washed with water (100 mL × 3). The solution is dried over anhydrous sodium sulfate overnight. The filtrate is filtered and concentrated under reduced pressure. Compound 1 is obtained by silica gel column chromatography.

[0080] In contrast, scheme f used 2,2-dimethoxypropane as a protecting agent and anhydrous zinc chloride as a catalyst. Specifically, 10 g of D-galactose, 100 mL of 2,2-dimethoxypropane, and 10 g of dry zinc chloride were added to a 250 mL round-bottom flask. The mixture was reacted at room temperature for 24 h, and multiple TLC monitoring (eluent: ethyl acetate: petroleum ether = 1:2) showed no product formation.

[0081] In contrast, scheme g used 2,2-dimethoxypropane as a protecting agent and p-toluenesulfonic acid as a catalyst. Specifically, 10 g of D-galactose, 100 mL of 2,2-dimethoxypropane, and 10 g of p-toluenesulfonic acid were added to a 250 mL round-bottom flask, and the reaction was carried out at room temperature for 24 h. Multiple TCL analyses (developing solvent: ethyl acetate: petroleum ether = 1:2) showed no product formation.

[0082] In contrast, scheme h uses 2,2-dimethoxypropane as a protecting agent and boron trifluoride diethyl ether as a catalyst. Specifically, 10 g of D-galactose, 100 mL of 2,2-dimethoxypropane, and 5 mL of boron trifluoride diethyl ether solution are added to a 250 mL round-bottom flask. The mixture is stirred at room temperature for 12 h, and the reaction is monitored by TLC until complete (evolving solvent: ethyl acetate: petroleum ether = 1:2). The reaction solution is then slowly added dropwise to a triethylamine solution under ice bath, neutralized to neutral, filtered, and the filtrate is concentrated under reduced pressure. After evaporation to dryness, the filtrate is dissolved in 100 mL of dichloromethane and washed with water (100 mL × 3). The solution is dried over anhydrous sodium sulfate overnight. The filtrate is then filtered and concentrated under reduced pressure. The solution is separated by silica gel column chromatography and concentrated to obtain compound 1.

[0083] Option i: Replace the alkaline solution in Option b with the organic base triethylamine, and keep the rest the same as Option b.

[0084] NMR analysis of compound 1:

[0085] 1¹H-NMR (500 MHz, CDCl₃) δ: 1.31 (s, 6H, CH₃), 1.42 (s, 3H, CH₃), 1.50 (s, 3H, CH₃), representing the hydrogens on the four methyl groups of the acetone ion, i.e., the hydroxyl groups at positions 1, 2, 3, and 4 of D-galactose are protected by isopropylidene groups; 2.58 (m, OH), 3.69 (m, 1H, H-4), 3.81 (m, 2H, H-6), 4.245 (dd, J=1.0 Hz, 8.0 Hz, 1H, H-5), 4.31 (t, 1H, H-2), 4.25 (dd, J=1.5 Hz, 8.0 Hz, 1H, H-3), 5.53 (m, 1H, H-1).

[0086] 13 The C-NMR signal assignments are shown in Table 1. 1 H-NMR and 13 The C-NMR spectra are shown below. Figure 1 and Figure 2 .

[0087] Table 1. Compound 1 13 C-NMR signal attribution

[0088] Monosaccharides are polyhydroxy compounds. If a single hydroxyl group is to be structurally modified or its functional group to be transformed, the other hydroxyl groups must first be protected. This invention aims to oxidize the 6-hydroxyl group on D-galactose, therefore the 1-, 2-, 3-, and 4-hydroxyl groups must be protected first. The 1- and 2-, 3-, and 4-hydroxyl groups of D-galactose constitute cis-ortho-dihydroxy groups, which are protected using ketals (isopropylidene). Commonly used protecting agents for introducing isopropylidene protecting groups include acetone and 2,2-dimethoxypropane, and the reaction is carried out under acid catalysis.

[0089] When 2,2-dimethoxypropane is used as a protecting agent, a product is generated under concentrated sulfuric acid catalysis (Scheme e), but three byproducts are generated. When zinc chloride (Scheme f) and p-toluenesulfonic acid (Scheme g) are used as weak acid catalysts, no product is generated. Boron trifluoride (Scheme h) also has more side reactions and lower yield, as shown in Table 2.

[0090] When acetone is used as a protective agent and concentrated sulfuric acid as a catalyst, fewer byproducts are produced (schemes a–d, scheme i). Further comparisons of the amount of concentrated sulfuric acid used were made (schemes a–c), as shown in Table 2. The results show that the highest yield is achieved when the amount of concentrated sulfuric acid is 12% of the solvent, i.e., the reaction feed ratio of 1 g D-galactose, 10 mL acetone, and 1.2 mL concentrated sulfuric acid (scheme b) yields the best results.

[0091] The ketal reaction is reversible; it can be catalyzed by acid, and the product can be decomposed by dilute acid. A small amount of water is generated during the reaction, causing the reaction to proceed in the reverse direction. Since concentrated sulfuric acid can act as both a catalyst and a dehydrating agent, the amount of concentrated sulfuric acid used in the reaction can be appropriately increased, but not excessively, otherwise it will lead to sugar carbonization. If anhydrous copper sulfate is added as a dehydrating agent (scheme d), the yield does not increase, possibly because copper sulfate is less effective at absorbing water than concentrated sulfuric acid. See Table 2.

[0092] Diacetone galactose is relatively stable under alkaline conditions. In most existing technologies, neutralization is achieved by adding sodium hydroxide solution or solid sodium hydroxide dropwise to the reaction solution at low temperatures during post-processing. However, this neutralization process generates water, leading to product decomposition and affecting the yield. Therefore, this embodiment uses dropwise addition of the reaction solution to an equivalent amount of alkaline solution for neutralization. Since the protective reaction solution is mostly composed of organic phases, it does not disperse well in the dilute alkaline water after addition, mostly existing as small droplets and not being immediately neutralized. Therefore, the stirring speed needs to be increased and the addition slowed during neutralization to ensure the neutralization reaction proceeds fully. After adding the solution, stirring continues until the pH remains constant. At this point, the organic phase cannot be directly extracted with dichloromethane because acetone in the reaction solution dissolves in both water and dichloromethane phases; therefore, concentration is required before extraction. The yield is 42.5% (Scheme b).

[0093] Considering that the reaction solution is mostly composed of organic phases, triethylamine, an organic base, was used for neutralization (Scheme i), which is both effectively soluble in the reaction solution and produces no water. After neutralization, the solution was concentrated, extracted with dichloromethane, and washed with water. The yield increased by 48.5% compared to Scheme b, which used sodium hydroxide treatment. See Table 2.

[0094] Table 2. Effects of different protective agents, catalysts, and alkaline post-treatment on yield and by-products.

[0095] This step is the first step in the synthetic route, and its yield directly affects the smooth progress of the entire synthesis. Furthermore, the synthetic yields of existing similar compounds are generally low. This step ensures a high yield by comprehensively controlling various factors affecting the yield.

[0096] 2) 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2) was synthesized from 1,2,3,4-O-diisopropylidene-D-galactose (compound 1). The reaction formula is shown in Formula IV, and the specific method is as follows:

[0097]

[0098] Synthesis of Formula IV 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2)

[0099] 26 g of compound 1, 300 mL of N,N-dimethylformamide, and 15 mL of benzyl chloride were added to a 500 mL round-bottom flask. 3.6 g of sodium hydride was slowly added under ice bath conditions. The mixture was stirred at room temperature and monitored by TLC until complete (electrolyte: ethyl acetate: petroleum ether = 1:2). The reaction was quenched by slowly adding ice water under ice bath conditions. The mixture was extracted with dichloromethane (300 mL × 2), and the organic layers were combined and washed with water (300 mL × 3). The organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by silica gel column chromatography to obtain compound 2. The reaction was relatively fast, with almost no byproducts, and the yield was 97.4%.

[0100] NMR analysis of compound 2:

[0101] 1 ¹H-NMR (CDCl₃) δ: 1.36 (s, 3H, CH₃), 1.37 (s, 3H, CH₃), 1.48 (s, 3H, CH₃), 1.57 (s, 3H, CH₃), representing hydrogen signals from the four methyl groups on the acetone fork; 3.70 (m, 2H, Ph-CH₂), 7.34 (m, 5H, Ph-H), representing hydrogen signals from the benzyl group; 4.05 (ddd, J=1.5 Hz, 6.5 Hz, 13.0 Hz, 1H, H-5), 4.31 (dd, J=2 Hz, 8 Hz, 1H, H-4), 4.34 (dd, J=2.5 Hz, 5 Hz, 1H, H-2), 4.59 (d, J=12Hz, 1H, H-6), 4.64 (d, J=12.5 Hz, 1H, H⁻⁶), 4.63 (d, J=2 Hz, 8 Hz, 1H, H⁻³), 5.58 (d, J=5 Hz, 1H, H⁻¹). Similar to compound 1. 1 Compared with H-NMR, there is a characteristic peak of benzene ring at δ 7.34 ppm with 5 H, and 2 more hydrogens (Ph-CH2) at 3.70 ppm. The 6-hydroxyl group H disappears, indicating that the 6-hydroxyl group has been protected by benzyl, and the product is the target compound.

[0102] 13 The C-NMR signal assignments are shown in Table 3. 1 H-NMR and 13 The C-NMR spectra are shown below. Figure 3 and Figure 4 .

[0103] Table 3. Compound 2 13 C-NMR signal attribution

[0104] In this step, the 6-hydroxyl group is protected. Since the acetone protecting group is stable under basic conditions, the Williamson synthesis method is used to ensure the acetone protecting group in compound 1 remains unaffected. This involves O-benzylating sodium alkoxide with benzyl chloride or benzyl bromide. The benzyl ether product exhibits stability under both acidic and basic conditions (the subsequent acetone-ide acid hydrolysis and potassium borohydride reduction have little effect on it), and the benzyl group can be easily removed by catalytic hydrogenolysis without affecting other groups. These two points are crucial in the synthesis of carbohydrate compounds.

[0105] In this step, inexpensive and readily available benzyl chloride is used as the benzylating agent, avoiding the use of expensive, highly toxic, and more potent benzyl bromide.

[0106] In this step, the catalyst used is sodium hydride, a strong base, which greatly shortens the reaction time compared to sodium hydroxide. However, sodium hydride is flammable when it comes into contact with water, so it should be kept away from water and added slowly in multiple portions under an ice bath. When quenching the reaction, ice water should be added slowly to avoid splashing.

[0107] 3) 6-O-benzyl-D-galactose (compound 3) was synthesized from 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2). The reaction formula is shown in Formula V, and the specific method is as follows:

[0108]

[0109] Synthesis of Formula V 6-O-benzyl-D-galactose (compound 3)

[0110] Scheme a. Add 2 g of compound 2 and 20 mL of 80% acetic acid solution to a 50 mL round-bottom flask, reflux at 80 °C, monitor the reaction by TLC until complete (evolving solvent: ethyl acetate: petroleum ether = 1:1), concentrate under reduced pressure, and dry under vacuum to obtain a crude product containing compound 3.

[0111] Option b. Add 2 g of compound 2 and 20 mL of 1% sulfuric acid solution to a 50 mL round-bottom flask, reflux at 80 °C, and monitor by TLC (developing solvent: ethyl acetate: petroleum ether = 1:1) until no product is formed.

[0112] Scheme c. Add 50 mL of 1,4-dioxane and 150 mL of 1% sulfuric acid aqueous solution to a 500 mL round-bottom flask, stir well, then add 20 g of compound 2, reflux at 80 °C, and monitor the reaction with TLC (electrolyte: ethyl acetate: petroleum ether = 1:1) every half hour. After 6 h, the reaction is complete. Place the reaction solution in an ice bath until the system temperature drops below 10 °C, add barium carbonate in small amounts several times to neutralize, stir until neutral, filter, and concentrate the filtrate under reduced pressure to obtain a crude product containing compound 3.

[0113] Scheme d. Add 50 mL of 1,4-dioxane and 150 mL of 2% sulfuric acid aqueous solution to a 500 mL round-bottom flask. After stirring thoroughly, add 20 g of compound 2. Reflux at 80 °C. Monitor the reaction by TLC (electrolyte: ethyl acetate: petroleum ether = 1:1) every half hour. The reaction is complete in 4 h. Place the reaction solution in an ice bath to lower the system temperature to below 10 °C. Add barium carbonate in small amounts several times to neutralize the solution, stirring until neutral. Filter the solution, concentrate the filtrate under reduced pressure to obtain a crude product containing compound 3.

[0114] Scheme e. In a 500 mL round-bottom flask, add 50 mL of 1,4-dioxane and 150 mL of 3% sulfuric acid aqueous solution. After stirring thoroughly, add 20 g of compound 2 and reflux at 80 °C. Monitor the reaction by TLC (electrolyte: ethyl acetate: petroleum ether = 1:1) every half hour until the reaction is complete in 2.5 h. Place the reaction solution in an ice bath to lower the system temperature to below 10 °C. Add barium carbonate in small amounts several times to neutralize the solution, stirring until neutral. Filter the solution, concentrate the filtrate under reduced pressure to obtain a crude product containing compound 3.

[0115] Compound 3 has four hydroxyl groups and is highly polar, making it impossible to effectively separate by silica gel column chromatography. Furthermore, the crude product does not affect the next step of the reaction. Therefore, the crude product, including compound 3, was directly added to the next step of the reaction without purification.

[0116] This step is the deprotection reaction of acetone ions, which is generally carried out under dilute acidic conditions. Commonly used acidic catalysts include trifluoroacetic acid, acetic acid, dilute sulfuric acid, and acidic resins. When there are other acidic protecting groups or acid-sensitive groups in the raw materials, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is also a relatively practical deprotection catalyst.

[0117] Using an 80% acetic acid aqueous solution (Scheme a), hydrolysis was found to be very slow, requiring overnight reflux, and acetic acid was expensive, making it unsuitable for industrial production. A dilute sulfuric acid aqueous solution was then used for acetone removal. Considering the presence of a benzyl group in the product structure from the previous step, excessive acidity might cause the benzyl group to detach; therefore, a 1% dilute sulfuric acid aqueous solution was first used for hydrolysis (Scheme b), heated to 80°C, and reacted for 8 hours, with no product formation. When a certain amount of dioxane was added (Scheme c), the reaction was completed in 6 hours. This is presumably because the starting material is insoluble in water, and dioxane increases its solubility, thus accelerating the reaction process.

[0118] The effects of different concentrations of dilute sulfuric acid on reaction time and yield were compared (schemes c, d, and e). The results (as shown in Table 4) indicate that the yields are similar when the concentrations of dilute sulfuric acid are 1% and 2%. Appropriately increasing the sulfuric acid concentration can shorten the reaction time, but the sulfuric acid concentration should not be too high, otherwise, although the reaction time will be shortened, the yield will decrease significantly.

[0119] After the reaction was complete, barium carbonate was used to neutralize the sulfuric acid in the reaction solution. First, the reaction solution was cooled to room temperature, and then excess barium carbonate was added. The solution remained acidic, but after appropriate heating, it became neutral. This is because barium carbonate is poorly soluble in water, and heating increases its solubility, thus accelerating the reaction rate. Once the solution became neutral, the barium sulfate precipitate was removed by filtration, and the solution was concentrated under reduced pressure to obtain the crude product containing compound 3.

[0120] Table 4 Effect of catalyst concentration on the reaction

[0121]

[0122] 4) 1,1-S,S'-diethyl-6-O-benzyl-D-galactose (compound 4) was synthesized from 6-O-benzyl-D-galactose (compound 3). The reaction formula is shown in Formula VI, and the specific method is as follows:

[0123]

[0124] Synthesis of Formula VI 1,1-S,S'-diethyl-6-O-benzyl-D-galactosylthioal (compound 4)

[0125] Scheme a. Add 20 g of the crude product (including compound 3) obtained in step 3) and 100 mL of ethanethiol to a 250 mL round-bottom flask. Add a few drops of concentrated sulfuric acid under ice bath conditions and stir the reaction. A white precipitate continuously forms. Monitor the reaction by TLC (developing solvent: petroleum ether: ethyl acetate = 1:3). After the reaction is complete, wash three times with ice water and crystallize from ethanol to obtain compound 4.

[0126] Scheme b. Add 20 g of the crude product containing compound 3 obtained in step 3) to a 500 mL round-bottom flask. Add 100 mL of concentrated hydrochloric acid under ice bath conditions. After the raw material dissolves, add 100 mL of ethanethiol and stir the reaction. After about 10 min, a white precipitate continuously forms. Monitor the reaction by TLC (developing solvent: petroleum ether: ethyl acetate = 1:3). Under ice bath conditions, add ammonia water in portions to neutralize the concentrated hydrochloric acid until neutral. Concentrate under reduced pressure at 40 °C. Add 50 mL of anhydrous ethanol to the concentrate to dissolve it. Continue distillation under reduced pressure at 40 °C for 3 times. Evaporate to dryness to obtain crude product 4. Crystallize from ethanol to obtain compound 4.

[0127] NMR analysis of compound 4:

[0128] 1H-NNR (CDCl3) δ: 1.19 (t, J=7.6 Hz 6H, Et-CH3), representing the methyl hydrogens on the two ethylthio groups; 2.63 (m, 4H, Et-CH2), representing the two methylene hydrogens, indicating the formation of thioacetal; 7.24 (m, 5H, Ph-H), representing the benzyl hydrogen signal; 3.16 (d, J=2.0 Hz, 3H, Ph-CH2, H-3), 3.79 (d, J=8.0 Hz, 1H, H-5), 3.89 (dd, J=8.4 Hz, 3.2 Hz, 2H, H-6), 4.03 (s, 1H, H-1), 4.48 (t, J=12.8 Hz, 2H, H-2, H-4).

[0129] 13 The C-NMR signal assignments are shown in Table 5. 1 H-NMR and 13 The C-NMR spectra are shown below. Figure 5 and Figure 6 .

[0130] Table 5. Compound 4 13 C-NMR signal attribution

[0131]

[0132] The purpose of this step is to synthesize dithioacetals, preparing for the deoxygenation of the 1-position aldehyde group. Because the sulfur atom is more nucleophilic than the oxygen atom, sugars and thiols can react at room temperature or lower. The main product is a straight-chain dialkyl dithioacetal, which is relatively stable under both acidic and alkaline conditions, but is easily hydrolyzed in the presence of mercury salts.

[0133] The starting compound 3 contains a benzyl protecting group, which may detach if the acidity is too strong. Therefore, an ice bath was used with ethanethiol as the solvent and a few drops of concentrated sulfuric acid added as a catalyst (Scheme A). A white solid precipitated out, which was washed several times with ice water and recrystallized from ethanol to obtain the product with a yield of 20%. Due to the low yield, concentrated hydrochloric acid was tried as a catalyst (Scheme B). It was found that the benzyl protecting group of the product did not detach and the yield was higher, at 75.1%.

[0134] 5) 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 5) was synthesized from 1,1-S,S'-diethyl-6-O-benzyl-D-galactosylthioacetal (compound 4). The reaction formula is shown in Formula VII, and the specific method is as follows:

[0135]

[0136] Synthesis of Formula VII 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioal (compound 5)

[0137] In a 500 mL dry round-bottom single-necked flask, add 10 g of compound 4, 100 mL of pyridine, and 200 mL of anhydrous acetic anhydride. Stir the mixture overnight at room temperature until the solution changes from turbid to clear. Monitor the reaction by TLC until complete (eluent: ethyl acetate: petroleum ether = 1:1). Pour the reaction mixture into 200 mL of ice water, extract with dichloromethane (100 mL × 2), combine the dichloromethane layers, wash with water (200 mL × 3), dry with anhydrous sodium sulfate, filter, recover the solvent under reduced pressure, and crystallize from ethanol to obtain compound 5.

[0138] NMR analysis of compound 5:

[0139] 1 ¹H-NMR (CDCl₃) δ: 1.25 (m, 6H, Et-CH₃), 2.66 (m, 4H, Et-CH₂), hydrogens on the two ethylthio groups; 2.06 (s, 3H, Ac-CH₃), 2.124 (s, 3H, Ac-CH₃), 2.14 (s, 3H, Ac-CH₃), 2.16 (s, 3H, Ac-CH₃), i.e., acetylation of the hydroxyl groups at positions 2,3,4,5; 3.50 (m, 2H, Ph-CH₂), 7.34 (m, 5H, Ph), benzyl hydrogen signals; 3.87 (d, J=7.6 Hz, 1H, H-5), 4.44 (d, J =11.6 Hz, 1H, H-4), 4.52 (d, J=12 Hz, 1H, H-2), 4.58 (d, J=12 Hz, 1H, H-6), 5.18 (m, 2H, H-6), 5.36 (m, 1H, H-3), 5.80 (d, J=9.2 Hz, 8 Hz, 1H, H-1).

[0140] 13 The C-NMR signal assignments are shown in Table 6. 1 H-NMR and 13 The C-NMR spectra are shown below. Figure 7 and Figure 8 .

[0141] Table 6. Compound 5 13 C-NMR signal attribution

[0142]

[0143] This step protects the 2, 3, 4, and 5-hydroxyl groups, preparing for the subsequent oxidation of the 6-hydroxyl group. An ester-type protecting group was used, with acetic anhydride as the reaction reagent and pyridine as the catalyst. The resulting product was deprotected in sodium methoxide / methanol solution within 10 minutes under mild conditions, with a simple operation and a yield of 93.6%. Pyridine and acetic anhydride must be dried before the reaction because acetic acid is generated during the reaction, and acetate ester products are not very stable in acidic aqueous solutions.

[0144] 6) 2,3,4,5-Tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal (compound 5) was synthesized into 2,3,4,5-tetra-O-acetyl-L-fucoitol (compound 6). The reaction formula is shown in Formula VIII, and the specific method is as follows:

[0145]

[0146] Synthesis of Formula VIII 2,3,4,5-tetra-O-acetyl-L-fucoitol (compound 6)

[0147] 10 g of compound 5 and 100 mL of ethanol were added to a 250 mL dry round-bottom flask. The mixture was refluxed at 70 °C, and 5 g of Raney nickel was added in portions. Hydrogen gas was introduced, and the reaction was monitored by TLC until it was complete (evolving solvent: petroleum ether: ethyl acetate = 1:1). The mixture was filtered, the solvent was recovered under reduced pressure, and the ethanol was crystallized to obtain compound 6.

[0148] When reducing compound 5, Raney nickel catalyst was added, and some palladium on carbon was also added to accelerate the reaction, finally yielding 2,3,4,5-tetra-O-acetyl-L-fucoitol in 70.4% yield.

[0149] NMR analysis of compound 6:

[0150] 1 ¹H-NMR (CDCl₃) δ: 1.16 (d, J=6.4 Hz, 3H, H-6), indicating that thioacetal was reduced to methyl; 2.05 (s, 3H, Ac-CH₃), 2.08 (s, 3H, Ac-CH₃), 2.13 (s, 3H, Ac-CH₃), 2.15 (s, 3H, Ac-CH₃), representing the four acetyl hydrogen signals; 3.88 (dd, J =7.6 Hz, 10.0 Hz, 1H, H-5), 4.30 (dd, J=4.4 Hz, 11.6 Hz, 1H, H-2), 5.09 (m, 1H, H-4), 5.20 (d, J=10.0 Hz, 1H, H-3), 5.38 (m, 2H, H-1).

[0151] 13 The C-NMR signal assignments are shown in Table 7. 1 H-NMR and 13 The C-NMR spectra are shown below. Figure 9 and Figure 10 .

[0152] Table 7 Compound 6 13 C-NMR signal attribution

[0153]

[0154] If the dithioacetal of compound 4 is first reduced, then protected, and finally debenzylated to obtain compound 6 (planned route as shown in formula IX), when using this route, the benzyl group can also be removed when reducing the dithioacetal (compound 4) with Raney nickel, resulting in two byproducts (as shown in formula X): one where only one ethylthio group is removed (byproduct a), and the other where both ethylthio groups and the benzyl group are removed (byproduct b). Therefore, in steps 5) and 6), compound 4 needs to be acetylated to obtain compound 5 first, and then compound 5 needs to be reduced to obtain compound 6. The order of these steps cannot be changed.

[0155]

[0156] Formula IX is the planned route for obtaining compound 6 from compound 4 via reduction-acetylation protection-debenzylation.

[0157]

[0158] Byproducts obtained from the planned routes of Formula X and Formula IX

[0159] 7) 2,3,4,5-Tetra-O-acetyl-L-fucoitol (compound 6) was synthesized into 2,3,4,5-tetra-O-acetyl-L-fucoitol (compound 7). The reaction formula is shown in Formula XI, and the specific method is as follows:

[0160]

[0161] Synthesis of Formula XI 2,3,4,5-tetra-O-acetyl-L-fucose (compound 7)

[0162] Add 5g of compound 6, 50 mL of dimethyl sulfoxide, and 30 mL of acetic anhydride to a 250 mL round-bottom flask. React at room temperature for 24 h. Monitor the reaction by TLC until complete (eluent: ethyl acetate: petroleum ether = 1:1). Pour the reaction solution into 50 mL of ice water and extract with dichloromethane (50 mL × 2). Combine the dichloromethane layers, wash with water (100 mL × 3), dry with anhydrous sodium sulfate, filter, and recover the solvent under reduced pressure to obtain a crude product containing compound 7.

[0163] This step involves the oxidation of the 1-hydroxyl group of an alcohol to an aldehyde using a dimethyl sulfoxide / acetic anhydride oxidation method. The reaction is complete after stirring at room temperature for 24 hours. This method is simple, economical, and yields few byproducts as detected by TLC. When purified by silica gel column chromatography, the product is highly susceptible to degradation, resulting in significant losses over prolonged processing. Therefore, the crude product, including compound 7, was directly added to the next reaction step without further separation and purification. The yield was 69.8%.

[0164] 8) L-fucose was synthesized from 2,3,4,5-tetra-O-acetyl-L-fucose (compound 7) according to the reaction formula shown in formula XII. The specific method is as follows:

[0165]

[0166] Synthesis of Formula XII L-fucose (Compound 8)

[0167] 2 g of the crude product containing compound 7 and 20 mL of anhydrous methanol were added to a 50 mL round-bottom flask. The pH was adjusted to 11 by adding a saturated sodium methoxide solution. The reaction was carried out in an ice bath and monitored by TLC until the reaction was complete (eluent: ethyl acetate: petroleum ether = 1:1). The sodium ions in the reaction solution were removed by passing the solution through a cation exchange resin column. The solution was concentrated under reduced pressure and the solvent was recovered to obtain compound 8.

[0168] This step uses the sodium methoxide / methanol method for deacetylation, with methanol as the solvent, sodium methoxide to adjust the pH to 11, and stirring in an ice bath for about 10 minutes to obtain the product, with a yield of 82.3%.

[0169] NMR analysis of compound 8:

[0170] 1 H-NNR (D2O) δ: 1.12 (d, J=6.4 Hz, 3H), 1.16 (d, J=6.4 Hz, 4H), 3.36 (t, 1H), 3.56 (d, J=10.0 Hz, 1H), 3.67~3.76 (m, 6H), 4.10~4.15 (m, 1H), 4.47 (d, J=7.6 Hz, 1H), 5.12 (s, 1H). The presence of both α and β configurations in L-fucose makes 1H spectrum assignment difficult, but it is generally consistent with literature reports. Therefore, this product is identified as the target product.

[0171] 13 The C-NMR signal assignments are shown in Table 8, which are consistent with the literature reports. 1 H-NMR and 13 The C-NMR spectra are shown below. Figure 11 and Figure 12 .

[0172] Table 8. Compound 813 C-NMR signal attribution

[0173]

[0174] Take compound 8 and dissolve it in distilled water to prepare a 0.01 g / mL solution. Filter the solution through filter paper to ensure it is clear and transparent. Rinse the solution in small amounts several times with the test solution in a clean test tube. Fill the tube with the test solution, ensuring there are no air bubbles. Place the tube in a polarimeter and record the optical rotation α. ​​Perform this operation in triplicate and take the average value. [α] t D Specific rotation is calculated as α / l*c.

[0175] The optical rotation α measured three times was -0.750, -0.745, and -0.742, with an average of -0.746. The tube length was 1 dm, the temperature was 20℃, and the solution concentration was 0.01 g / mL. The calculated specific rotation was -74.6°, which is basically consistent with the literature report, proving that the target product L-fucose was obtained.

[0176] The optimal synthesis steps for this route are:

[0177] Using D-galactose as the raw material, the feed ratio was 1 g D-galactose, 10 mL acetone, and 1.2 mL concentrated sulfuric acid. The post-treatment was carried out by neutralization with the organic base triethylamine to selectively protect the 1,2,3,4-hydroxyl groups, thus synthesizing 1,2,3,4-O-diisopropylidene-D-galactose (compound 1).

[0178] ② Using compound 1 as a raw material, benzyl chloride as a reaction reagent, and sodium hydride as a catalyst, 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose (compound 2) was synthesized by protecting the 6-hydroxyl group.

[0179] ③ Using a feed ratio of 1 g (compound 2), 2.5 mL of dioxane, and 7.5 mL of 2% sulfuric acid solution, reflux at 80°C to selectively hydrolyze the acetone ions, thereby synthesizing 6-O-benzyl-D-galactose (compound 3).

[0180] ④ Using compound 3 as a raw material, concentrated hydrochloric acid as a solvent and catalyst, and ethanethiol as a reaction reagent, the reaction was carried out under ice bath conditions to synthesize 1,1-S,S'-diethyl-6-O-benzyl-D-galactosylthioal (compound 4).

[0181] ⑤ Using compound 4 as a raw material, acetic anhydride as a protecting agent, and pyridine as a catalyst, 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioal (compound 5) was synthesized by protecting the 2,3,4,5-hydroxyl groups.

[0182] ⑥ Using compound 5 as a raw material, Raney nickel as a catalyst, and ethanol as a solvent, hydrogen gas was introduced for reduction to synthesize 2,3,4,5-tetra-O-acetyl-L-fucoitol (compound 6).

[0183] ⑦ Using compound 6 as a raw material, the 6-hydroxyl group was oxidized by dimethyl sulfoxide / acetic anhydride method to synthesize 2,3,4,5-tetra-O-acetyl-L-fucose (compound 7).

[0184] ⑧ Compound 7 was deacetylated with methanol to synthesize L-fucose (compound 8). The overall yield was 12.4%.

[0185] The above description is merely a preferred embodiment of the present invention, and therefore should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made in accordance with the scope of the patent and the contents of the specification should still fall within the scope of the present invention.

Claims

1. A method for synthesizing L-fucose, characterized in that: include: 1) Synthesis of 1,2,3,4-O-diisopropylidene-D-galactose from D-galactose; 2) Synthesize 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose from 1,2,3,4-O-diisopropylidene-D-galactose; 3) Synthesize 6-O-benzyl-D-galactose from 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose; 4) Synthesis of 1,1-S,S'-diethyl-6-O-benzyl-D-galactose thioacetal from 6-O-benzyl-D-galactose; 5) Synthesize 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal from 1,1-S,S'-diethyl-6-O-benzyl-D-galactosylthioacetal. 6) Synthesize 2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal from 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal; 7) Synthesize 2,3,4,5-tetra-O-acetyl-L-fucoitol; 8) Synthesis of L-fucose from 2,3,4,5-tetra-O-acetyl-L-fucose; In step 1), D-galactose, acetone, and concentrated sulfuric acid react at room temperature, and the reaction is neutralized with alkali in the post-treatment to obtain 1,2,3,4-O-diisopropylidene-D-galactose; the feed ratio of D-galactose, acetone, and concentrated sulfuric acid is 0.8-1.2 g: 9-11 mL: 0.8-2 mL. In step 2), 1,2,3,4-O-diisopropylidene-D-galactose, benzyl chloride, and sodium hydride react at room temperature to obtain 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose. In step 3), 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose, dilute sulfuric acid, and dioxane are refluxed at 75–85 °C to obtain 6-O-benzyl-D-galactose; the dilute sulfuric acid is 0.8%–2.5% sulfuric acid; the feed ratio of 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose, 0.8%–2.5% sulfuric acid, and dioxane is 0.8–1.2 g: 7–8 mL: 2–3 mL; In step 4), 6-O-benzyl-D-galactose, concentrated hydrochloric acid and ethanethiol react at -5 to 5°C to obtain 1,1-S,S'-diethyl-6-O-benzyl-D-galactose thioal. In step 5), 1,1-S,S'-diethyl-6-O-benzyl-D-galactosylthioacetal, acetic anhydride and pyridine react at room temperature to obtain 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal. In step 6), 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal, Raney nickel, and ethanol are refluxed in hydrogen at 65–75 °C to give 2,3,4,5-tetra-O-acetyl-L-fucoitol.

2. The method for synthesizing L-fucose according to claim 1, characterized in that: In step 1), the alkali used is an organic alkali.

3. The method for synthesizing L-fucose according to claim 1, characterized in that: In step 3), the sulfuric acid concentration is 1.8–2.2%.

4. The method for synthesizing L-fucose according to claim 1, characterized in that: In step 7), 2,3,4,5-tetra-O-acetyl-L-fucoitol, dimethyl sulfoxide, and acetic anhydride react at room temperature to obtain 2,3,4,5-tetra-O-acetyl-L-fucoitol.

5. The method for synthesizing L-fucose according to claim 1, characterized in that: In step 8), 2,3,4,5-tetra-O-acetyl-L-fucose, sodium methoxide, and methanol react at -5 to 5 °C to obtain L-fucose.

6. The method for synthesizing L-fucose according to claim 1, characterized in that: include: 1) D-galactose, acetone, and concentrated sulfuric acid were reacted at room temperature, and then neutralized with the organic base triethylamine to obtain 1,2,3,4-O-diisopropylidene-D-galactose; the feed ratio of D-galactose, acetone, and concentrated sulfuric acid was 0.9–1.1 g: 9.5–10.5 mL: 1.1–1.3 mL; 2) 1,2,3,4-O-diisopropylidene-D-galactose, benzyl chloride, and sodium hydride react at room temperature to give 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose; 3) 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose, 1.8–2.2% sulfuric acid, and dioxane were refluxed at 78–82 °C to obtain 6-O-benzyl-D-galactose; the feed ratio of 1,2,3,4-O-diisopropylidene-6-O-benzyl-D-galactose, 1.8–2.2% sulfuric acid, and dioxane was 0.9–1.1 g: 7.4–7.6 mL: 2.4–2.6 mL; 4) 6-O-benzyl-D-galactose, concentrated hydrochloric acid and ethanethiol react at -2 to 2℃ to give 1,1-S,S'-diethyl-6-O-benzyl-D-galactose thioacetal; 5) 1,1-S,S'-diethyl-6-O-benzyl-D-galactosylthioacetal, acetic anhydride and pyridine react at room temperature to give 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal. 6) 1,1-S,S'-diethyl-2,3,4,5-tetra-O-acetyl-6-O-benzyl-D-galactosylthioacetal, Raney nickel, and ethanol were refluxed in hydrogen at 68–72 °C to give 2,3,4,5-tetra-O-acetyl-L-fucoitol. 7) 2,3,4,5-Tetra-O-acetyl-L-fucoitol, dimethyl sulfoxide, and acetic anhydride react at room temperature to give 2,3,4,5-tetra-O-acetyl-L-fucoitol; 8) 2,3,4,5-tetra-O-acetyl-L-fucose, sodium methoxide, and methanol are reacted at -2 to 2°C to obtain L-fucose.

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