Stereoselective Synthesis of 2-Deoxythiosugars from Glycals

2-deoxythiosugars are more stable than 2-deoxysugars occurring broadly in bioactive natural products and pharmaceutical agents. An effective and direct methodology to stereoselectively synthesize α-2-deoxythioglycosides catalyzed by AgOTf has been developed. Various alkyl thiols and thiophenols were explored and the desired products were formed in good yields with excellent α-selectivity. This method was further applied to the syntheses of S-linked disaccharides and late-stage 2-deoxyglycosylation of estrogen, L-menthol, and zingerone thiols successfully.


Introduction
2-deoxysugars occur broadly in bioactive natural products and pharmaceutical agents [1][2][3]. They have been applied as clinical drugs in treating various diseases, including heart failure, cancers, and bacterial and viral infections [4][5][6][7]. However, the glycosidic bond of 2-deoxysugar is easily hydrolyzed by enzymes or acids, resulting in a short half-life in vivo, which limits its application in drug development [8,9]. As sulfur is in the same group as oxygen, it is often used as a bioisostere to replace oxygen atoms in medicinal chemistry, indicating a longer half-life and better biological activity [10][11][12][13]. Stereoselective synthesis of 2-deoxythiosugar is quite challenging because there is no C2-group to direct the anomeric selectivity through the neighboring participation effect. Many efforts have been made to develop the strategies of 2-deoxythioglycosylation. Conventionally, 2-deoxysugar synthesis studies could be performed with saturated glycosyl donors, the high stereoselectivity of which relied on a specific structure of a well-assembled glycosyl donor [14,15]. On the other hand, unsaturated glycosyl donors (glycals) could be applied directly to construct 2-deoxysugars stereoselectively [16,17]. Toste and coworkers developed an effective synthesis of 2-deoxyglycosides from glycal donors mediated by a catalytic Re(V)-oxo complex [18]. Recently, Wan s group successfully achieved access to α-1,1 -2-deoxy thioglycosides stereoselectively catalyzed by ReOCl 3 (SMe 2 )(OPPh 3 ) as shown in Scheme 1a [19]. With the development of organocatalysis, Kancharla's group utilized a bulky pyridinium salt 2,4,6-tri-tert-butylpyridine-hydrochloric acid (TTBPy·HCl) to catalyze the reaction between glycals and thiols giving 2-deoxy-β-galactosides with an α/β ratio from 3.8:1 to β only (Scheme 1b) [20]. However, rhenium catalysts are quite expensive and the synthesis of organocatalysts is tedious. Therefore, the stereoselective synthesis of 2-deoxythioglycosides is still highly challenging. In view of our long-standing interest in exploring 3,4-O-carbonate-glycal donors [21][22][23][24][25][26][27], herein, we report an effective and stereoselective 2-deoxythioglycosylation catalyzed by the commercially available catalyst silver trifluoromethanesulfonate (AgOTf) as shown in Scheme 1c. The target α-2-deoxythiosugars were able to be obtained in good yields with high stereoselectivity under mild conditions.
With the optimized condition in hand, the substrate scope was first explored using thiophenols (Scheme 2). The aryl 2-deoxythioglycosides (3a-3c) were obtained using p-, mand o-thiocresols as acceptors in yields of 80-82% and with an α/β ratio from 15:1 to > 20:1 determined by 1 H NMR. Fortunately, the crystal of 3c was obtained and the configuration was confirmed as α-2-deoxy-D-galactoside by single-crystal X-ray diffraction. 3,4-Dimethylthiophenol also worked well giving 3d in an 82% yield and with a ratio of α/β = 20:1. Besides methyl substitution thiophenols, 4-methoxythiophenol reacted with 3,4-O-carbonate-D-galactal 1a to form 3e in a 73% yield with a ratio of α/β > 20:1. The bulkier substitute group on the phenyl ring also tolerated this method well. For example, 4-tert-butylthiophenol was applied to generate 3f in an 81% yield and with an α/β ratio of 18:1. Thiophenol 2-deoxysugar 3g was obtained stereoselectively (α/β > 20:1) in an 80% yield. When thiophenols were substituted by electron-withdrawing groups, the desired products (3h-3j) could still be formed in good yields but stereoselectivity decreased slightly. The 2-deoxythiosugar 3h was formed in a yield of 75% with a ratio of α:β = 11:1 using 4-bromothiophenol as the acceptor. 2-Bromothiophenol and 4-fluorothiophenol were examined and gave target products in a 71-74% yield at the ratios of α:β = 15:1 and α:β = 12:1, respectively.  Besides the substrate study of the thiophenol acceptors, the alkyl thiols were also employed to synthesize 2-deoxythioglycosides, including S-linked disaccharides. As shown in Scheme 3, two primary thiols ethyl and n-octyl mercaptan were utilized to react with glycal 1a to form 2-deoxythiosugars 5a and 5b in high yields (78-86%) with excellent stereoselectivity (α/β > 20:1). When n-butyl, iso-butyl, and sec-butyl mercaptan were employed, the corresponding α-2-deoxythioglycosides 5c-5e were all able to be generated in high yields (>80%). It is worth noting that the bulky tert-butyl mercaptan could also be well compatible with this method and gave 5f in an 80% yield with exclusive α-selectivity, indicating that the strategy was less affected by steric hindrance. Benzyl mercaptan was applied to form the 2-deoxythiogalactoside 5g in a yield of 82% with a ratio of α/β > 20:1. Methyl thioglycolate was also applied as a glycosyl acceptor and the desired product 5h was obtained in an 80% yield. Encouraged by these observations, we continued to study the synthesis of S-linked α-disaccharides. For example, 5i was achieved successfully from 3,4-O-carbonate-galactal 1 and 1,2:5,6-di-O-isopropylidene-α-D-allofuranose in a yield of 67% with exclusive α-selectivity. The α,β-1,1′-2-deoxythioglycosides 5j was obtained from glycal 1 and 1-thio-β-D-glucose tetraacetate in a yield of 69% with excellent stereoselectivity (α/β > 20:1). Besides the substrate study of the thiophenol acceptors, the alkyl thiols were also employed to synthesize 2-deoxythioglycosides, including S-linked disaccharides. As shown in Scheme 3, two primary thiols ethyl and n-octyl mercaptan were utilized to react with glycal 1a to form 2-deoxythiosugars 5a and 5b in high yields (78-86%) with excellent stereoselectivity (α/β > 20:1). When n-butyl, iso-butyl, and sec-butyl mercaptan were employed, the corresponding α-2-deoxythioglycosides 5c-5e were all able to be generated in high yields (>80%). It is worth noting that the bulky tert-butyl mercaptan could also be well compatible with this method and gave 5f in an 80% yield with exclusive α-selectivity, indicating that the strategy was less affected by steric hindrance. Benzyl mercaptan was applied to form the 2-deoxythiogalactoside 5g in a yield of 82% with a ratio of α/β > 20:1. Methyl thioglycolate was also applied as a glycosyl acceptor and the desired product 5h was obtained in an 80% yield. Encouraged by these observations, we continued to study the synthesis of S-linked α-disaccharides. For example, 5i was achieved successfully from 3,4-O-carbonate-galactal 1 and 1,2:5,6-di-O-isopropylidene-α-D-allofuranose in a yield of 67% with exclusive α-selectivity. The α,β-1,1 -2-deoxythioglycosides 5j was obtained from glycal 1 and 1-thio-β-D-glucose tetraacetate in a yield of 69% with excellent stereoselectivity (α/β > 20:1). Scheme 2. Substrate scope of aryl 2-deoxythioglycosides.  These successes stimulated us to further apply this 2-deoxythioglycosylation methodology to the modification of bioactive natural products (In the Supplementary Materials). Estrogen is a female sex hormone, one of the three main endogenous estrogens, which plays a vital role in human life and is also used as a medicine in clinical treatment [28][29][30]. S-Linked estrone 2-deoxygalactoside 7a was successfully achieved by AgOTf at room temperature with a 78% yield and excellent α-selectivity (Scheme 4). L-Menthol is the main component of peppermint and also demonstrates analgesic, antibacterial, and antiinflammatory effects [31]. L-Menthol-2-deoxythioglycoside 7b was generated in a 60% yield with high α-selectivity. Zingerone extracted from ginger indicates antioxidant, antiinflammatory and anti-cancer, and antibacterial bioactivity [32][33][34], and it was also converted to be a thiol to react with glycal 1a giving 2-deoxythiosugar 7c in a 72% yield with a ratio of α/β > 20:1. als). Estrogen is a female sex hormone, one of the three main endogenous estrogens, which plays a vital role in human life and is also used as a medicine in clinical treatment [28][29][30]. S-Linked estrone 2-deoxygalactoside 7a was successfully achieved by AgOTf at room temperature with a 78% yield and excellent α-selectivity (Scheme 4). L-Menthol is the main component of peppermint and also demonstrates analgesic, antibacterial, and anti-inflammatory effects [31]. L-Menthol-2-deoxythioglycoside 7b was generated in a 60% yield with high α-selectivity. Zingerone extracted from ginger indicates antioxidant, anti-inflammatory and anti-cancer, and antibacterial bioactivity [32][33][34], and it was also converted to be a thiol to react with glycal 1a giving 2-deoxythiosugar 7c in a 72% yield with a ratio of α/β > 20:1. Based on the results and literature research, a possible mechanism of AgOTf-catalyzed 2-deoxythioglycosylation was proposed as shown in Scheme 5. Silver triflate coordinated with the double bond of glycal from the bottom face to form intermediate A because of the steric effect [35,36]. After the pronation of the reactive olefin, the oxocarbenium ion B would be generated [1,4,37]. Alkylthio anion (RS -) would attack the anomeric position from the bottom face to yield α-2-deoxythioglycosides because the 3,4-O-carbonate ring would block the upper face.   [35,36]. After the pronation of the reactive olefin, the oxocarbenium ion B would be generated [1,4,37]. Alkylthio anion (RS -) would attack the anomeric position from the bottom face to yield α-2-deoxythioglycosides because the 3,4-O-carbonate ring would block the upper face.
plays a vital role in human life and is also used as a medicine in clinical treatment [28][29][30]. S-Linked estrone 2-deoxygalactoside 7a was successfully achieved by AgOTf at room temperature with a 78% yield and excellent α-selectivity (Scheme 4). L-Menthol is the main component of peppermint and also demonstrates analgesic, antibacterial, and anti-inflammatory effects [31]. L-Menthol-2-deoxythioglycoside 7b was generated in a 60% yield with high α-selectivity. Zingerone extracted from ginger indicates antioxidant, anti-inflammatory and anti-cancer, and antibacterial bioactivity [32][33][34], and it was also converted to be a thiol to react with glycal 1a giving 2-deoxythiosugar 7c in a 72% yield with a ratio of α/β > 20:1.  [35,36]. After the pronation of the reactive olefin, the oxocarbenium ion B would be generated [1,4,37]. Alkylthio anion (RS -) would attack the anomeric position from the bottom face to yield α-2-deoxythioglycosides because the 3,4-O-carbonate ring would block the upper face.

Conclusions
In conclusion, we have developed an effective strategy to synthesize 2-deoxythioglycosides using 3,4-O-carbonate glycal donors catalyzed by silver triflate in mild conditions. This reaction could tolerate various alkyl thiols and thiophenols, all the target products were obtained in moderate to good yields with excellent α-selectivity. S-Linked disaccharides and late-stage functionalization of natural product thiols were achieved successfully as well. The results of this study suggest that this method may be a promising alternative way to access the 2-deoxythioglycosides applied in natural product synthesis and drug development.

Materials and Methods
General Procedure. The 3,4-O-carbonate glycal donor (0.100 mmol) and thiol reagent (0.110 mmol) were added to anhydrous dichloromethane (2.00 mL) in a Schlenk tube, followed by adding silver triflate (0.01 mmol) under N 2 atmosphere. The reaction mixture was stirred at room temperature and monitored by TLC. Then, aqueous sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, washed by aqueous sodium bicarbonate and dried by sodium sulfate. The organic layer was collected and removed under reduced pressure to afford a crude product which was purified by silica gel flash chromatography with a gradient solvent system (petroleum ether/ethyl acetate as eluent) to yield 2-deoxythioglycosides.    13