**2. Results**

In our lab, we were working on developing relative green methods for 1-thioglycosides by avoiding the use of odorous thioacetic acids and alkylthiols [28–30]. We noticed a report where NaBH4 and disulfides were used instead of sodium arylthiolates in the synthesis of 1 thioglycosides [31]. It was observed that phenylselenolate and phenylthiolate were quickly generated by mixing diselenide or disulfide precursors with a stoichiometric amount of NaBH4 in acetonitrile (Reaction formula shown in Figure 3a,b). This inspired us to explore whether a system of disulfides and NaBH4 could be used to improve the synthesis of **1** [26,27] starting from glucal **2**.

Thus, 1,2-anhydro glucose **3** was first prepared by oxidation of glycal **2** with oxone in acetone, and then, its crude crystals were directly reacted with 0.7 equiv of phenyl disulfide and 1.5 equiv of NaBH4 (equivalent to 1.4 equiv of NaBH3SPh) at rt in acetonitrile for 1 h to yield **1** in 72% yield, yielding **1** in 75% yield when the reaction was performed at 0 ◦C for 4 h (entry 1 in Table 1). Due to concerns about direct hydrogenation reduction of NaBH4 to **3**, we first allowed NaBH4 to react with phenyl disulfide at 50 ◦C in acetonitrile for 1 h and then added crude crystalline **3** to the reaction mixture (entry 2). Yielding **1** in 73% yield indicated that we had been overly concerned about the possible side effects caused by NaBH4. Reducing the amount of NaBH4 to 1.0 equiv (equivalent to 1.0 equiv of NaBH3SPh and 0.4 equiv of HSPh) resulted in a decrease in the yield of **1** to 68%, and reducing the amount of NaBH4 to 0.7 equiv (equivalent to 0.7 equiv of NaBH3SPh and 0.7 equiv of

HSPh) resulted in a decrease in the yield of **1** to 60% (entry 3). The use of 1.0/2.0 equiv of NaBH4 and 0.5/1.0 equiv of phenyl disulfide (equivalent to 1.0/2.0 equiv of NaBH3SPh) led to 55%/65% yield of **1** (entry 4). The use of 1.2 equiv of NaBH4 and 0.6/0.8 equiv of phenyl disulfide led to 65%/69% yield of **1** (entry 5). These results suggested that 1.5 equiv of NaBH4 and 0.7 equiv of phenyl disulfide should be the optimal conditions. We also examined the effect of solvents (acetone, DMF, MeOH, and DCM) on the reaction (entries 6 and 7). These results suggested that acetonitrile should be the optimal solvent. As a comparison, we allowed **3** to react with 1.5 equiv of NaSPh at rt in acetonitrile, which gave **1** in 43% yield after 36 h, indicating the low reactivity of this reaction (entry 8).

**Figure 3.** Proposed reaction mechanism.

**Table 1.** Comparison of results by variation of reaction conditions a.


<sup>a</sup> Reagents and conditions: substrate **2** (0.1 mmol), solvents (1 mL), yields based on **2**. <sup>b</sup> Treatment of PhSSPh with NaBH4 in acetonitrile at 50 ◦C for 1 h, then cooling to rt, and adding crude substrate **3**. <sup>c</sup> Large scale.

We proposed the mechanism of the reaction between **3** and NaBH3SPh in Figure 3c and the mechanism of the reaction between **3** and NaSPh in Figure 3d. The coordination of the boron atom of borane instead of Na+ (or H+) to the 1,2-anhydro oxygen atom may greatly enhance the nucleophilic attack activity of −SPh towards the 1-position of **3**, which

explains the results shown in entries 1, 2, and 8 in Table 1. The results shown in entry 3 in Table 1 suggested that NaBH3SPh may catalyze the reaction of **3** with HSPh. A possible catalytic mechanism is shown in Figure 3c,e where NaBH3SPh reacts with **3** to form **1a** (Figure 3c) and regenerates (Figure 3e) from the exchange of [NaBH3] <sup>+</sup> and H<sup>+</sup> (Na+) between **1a** and HSPh (or NaSPh). Compared to the result (**1**, 42%, 36 h) shown in entry 8, the result (**1**, 55%, 4 h) shown in entry 9 showed that the use of 0.1 equiv of NaBH4 and 0.1 equiv of phenyl disulfide (equivalent to 0.1 equiv of NaBH3SPh and 0.1 equiv of HSPh) in the presence of 1.2 equiv of NaSPh (1.4 equiv of −SPh existing in the system) led to higher reactivity. The optimal conditions were the use of 0.3 equiv of NaBH4, 0.3 equiv of phenyl disulfide and 0.8 equiv of NaSPh (1.4 equiv of −SPh existing in the system also), by which 72% yield of **1** was obtained after 4 h' reaction (entry 10); continuing to increase the amount of NaBH4 and phenyl disulfide to 0.5 equiv (using 0.4 equiv of NaSPh in order to keep 1.4 equiv of −SPh present in the system) instead reduced the yield of **1** to 65% (entry 11). Since aryl disulfides are generally more commercially available reagents than sodium arylthiolates, the conditions shown in entries 1–2 are obviously more practical than that shown in entry 10.

With the optimized conditions in hand, we next set out to evaluate this method using phenyl disulfide with various glycals as substrates (Figure 4). As can be seen, phenyl-2- OH-1-thio-β-D-glucopyranosides **4**–**11** and phenyl-2-OH-1-thio-β-D-galactopyranosides **12**–**14** were efficiently synthesized in 50–70% yields starting from the corresponding glucals and galactals with various protecting groups. For compounds **4**, **5**, **6**, **13**, and **14**, the TBS, acetyl, or benzoyl can be removed orthogonally in the presence of benzyl-protecting group under corresponding acid–base conditions. Thus, these compounds can be used as building blocks for the elongation of sugar chains and the synthesis of branched oligosaccharides. Phenyl-2-OH-3,4-di-OBn-1-thio-β-D-xylopyranoside **15** was synthesized in 65% yield from 3,4-di-OBn xylal, and phenyl-2-OH-1-thio-β-D-lactoside **16** was synthesized in 56% yield from per-benzylated lactal. These results suggested that this method should be applicable to various glycals.

**Figure 4.** Synthesis of 1-thiophenyl glycosides with 2-OH starting from corresponding glycals.

We next evaluated this method using various disulfides with glucal **2** as the substrate (Figure 5). As can be seen, aryl disulfides worked well in this method, leading to 2-OH, β-D-thioglucosides **17**–**22** in 70–76% yields, but non-aryl disulfides did not. The 2-OH, β-D-thioglucosides **23**–**25** could not be obtained by this method. Hydroreduction product **27** was isolated in 26–37% yield in the reaction with non-aryl disulfides, indicating that NaBH4 had not been consumed by the reaction with non-aryl disulfides. Further experiments indicated that NaBH4 could not reduce non-aryl disulfides even at 50 ◦C.

**Figure 5.** Evaluation of reactions between various disulfides and glucal 2.

Phenyl diselenide also worked well in this method, leading to 2-OH, β-D-selenoglucoside **26** in 61% yield. However, this reaction took a long time due to the low reactivity for reduction of diselenide by NaBH4. In light of the mechanism shown in Figure 3c, we speculated that **1a** should be able to react directly with RX (X represents −Cl or −Br) in the present of NaH to form various thioglycoside donors containing "NGP" group at their 2-positions. This speculation was supported by further experiments and a one-pot method was developed by us (Figure 6). Once the TLC plate showed complete consumption of 1,2-anhydro sugar, NaH and RX were added to the reaction mixture, and the reaction proceeded at rt for 1–4 h, leading to thioglycoside donors **28**–**34** in 48–68% yields based on glycals, respectively. It has been reported that 2-Pic STaz-donors exhibited good reactivity and steroselectivity in glycosylation with Cu(OTf)2 as promoter (2-Pic glucoside STaz-donor was obtained in 60% yield over four steps from orthoester) [10], while 2-Pic glucoside SEtdonor exhibited no reactivity with NIS/TfOH as promoter [10b]. We then evaluated the glycosylation between 2-Pic SPh-donors **28**/**29** and various acceptors with NIS/TfOH as promoter (Figure 7). As can be seen, disaccharides **35**–**41** with absolute β-configuration were obtained in 50–86% yields.

**Figure 6.** One-pot synthesis of various thioglycoside donors.

**Figure 7.** Application of this method in glycosylation.
