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Article

α-Selective Glycosidation of the Rare Sugar d-Tagatofuranose and the Synthesis of α-d-Tagatofuranosylceramide

by
Yui Makura
1,
Akihiro Iyoshi
1,
Makito Horiuchi
2,
Yiming Hu
1,
Masakazu Tanaka
1 and
Atsushi Ueda
1,*
1
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
2
School of Pharmaceutical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(17), 8459; https://doi.org/10.3390/ijms26178459
Submission received: 31 July 2025 / Revised: 22 August 2025 / Accepted: 29 August 2025 / Published: 30 August 2025
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis, Design, and Biological Activity)
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Abstract

d-Tagatose is a rare sugar that exhibits intriguing biological properties, such as its role as a low-calorie sweetener and its ability to reduce the glycemic response. Consequently, the synthesis of d-tagatose derivatives is a crucial endeavor for the advancement of their functionalities, as well as elucidation of their biological properties. In this study, we present the α-selective glycosidation of a 1,3,4,6-tetra-O-benzoylated d-tagatofuranosyl donor with various glycosyl acceptors. In contrast to d-allulose, which is the C3,C4-epimer of d-tagatose and does not exhibit the neighboring group effect, the current d-tagatofuranosyl donor demonstrated significant neighboring group participation, achieving high α-selectivity ratios up to α:β = 99:1. This method was also applicable to the synthesis of α-d-tagatofuranosylceramide, which has potential as a novel functional molecule. Meanwhile, the glycosylation of sterically congested glycosyl acceptors, such as 2-hydroxycumene, resulted in poor α-selectivity, which may be attributed to the interaction with the C1-benzoyloxy group of d-tagatofuranosyl donors in the transition state.

1. Introduction

Rare sugars are naturally occurring sugars present in minimal amounts in nature [1]. d-Allulose (d-psicose) and d-tagatose are representatives of rare sugars and have been reported to exhibit significant physiological effects [2,3,4]. For instance, d-allulose has garnered attention because of its biological activities as an antioxidant [5], its role as an inhibitor of N-acetylglycosyltransferase [6,7] and α-glucosidase [8,9], its antitumor activity [10], and its GLP-1 releasing activity [11]. d-Tagatose is also an important rare sugar, as it can be used as a low-calorie sweetener and food additive, and has received a Generally Recognized As Safe (GRAS) status certified by the U.S. Food and Drug Administration [12]. In addition, d-Tagatose has remarkable properties [13,14,15], including its ability to significantly lower serum glucose levels following oral glucose intake [16,17,18], and its potential in treating plant diseases [19,20]. Consequently, derivatives of rare sugars are promising compounds for enhancing the functional properties and broadening the diversity of biological properties. On the other hand, glycosylceramides (cerebroside), which are composed of sugar and ceramide moieties, are essential constituents of the human body. Numerous glycosylceramides have been synthesized because of their notable biological activities. For instance, α-galactosylceramide (KRN7000), a ceramide with an α-O-glycosidic linkage, is recognized for its ability to activate natural killer T (NKT) cells and stimulate the production of substantial quantities of cytokines [21,22,23]. Recently, several derivatives of KRN7000 have been developed for use as adjuvants in COVID-19 subunit vaccines, immunostimulating agents, and Toll-like receptor 4 (TLR4) agonists [24,25,26]. These examples predominantly involve pyranose as the sugar component, whereas furanosylceramides have rarely been reported. Therefore, d-tagatofuranosylceramides could be promising candidates, although they highlight the necessity for developing stereoselective glycosidation methods. In particular, because d-tagatose is known to exist predominantly in the pyranose form, it is crucial to control these conformers during synthesis [27,28,29].
We previously reported that the presence of an isopropylidene group at the C3,4-diol position of d-allulofuranosides and d-tagatofuranosides significantly influenced α-selectivity in their glycosidation reactions [30,31,32,33,34,35]. Notably, the N- and S-glycosidation reactions of a 3,4-O-(3-pentylidene)-protected d-allulofuranosyl donor exhibited higher β-selectivities compared to those involving a 3,4-O-isopropylidene-protected d-allulofuranosyl donor [36]. Given this context, we initially attempted the glycosidation reaction of the d-tagatofuranosyl donor 1 [34] with ceramide 2 [37], which led to the formation of protected d-tagatofuranosylceramide 3 with a 38% yield and α-selectivity (Scheme 1a). However, attempts to deprotect the acetonide group were unsuccessful due to the concomitant cleavage of the glycosidic bond under acidic conditions. These conditions included the use of aqueous trifluoroacetic acid in CH2Cl2, p-toluenesulfonic acid in MeOH/CH2Cl2. Consequently, we shifted our focus to a strategy using neighboring acyl group participation, a commonly employed method for stereoselective 1,2-trans-glycosylation. Unlike pyranoses, such as d-glucose, this strategy is not consistently effective for 2-ketohexofuranoses. For instance, glycosidation reactions of a d-fructofuranosyl donor with a 3-O-benzoyl neighboring group yielded α-glycosides stereoselectively (Scheme 1b) [35,38,39,40]. In contrast, glycosidation of the d-allulofuranosyl donor, the C3-stereoisomer of d-fructofuranose, protected with a 3-O-benzoyl group, yielded a mixture of α- and β-glycosides. This outcome is attributed to the C2–C3 eclipsed conformation, which inhibits the participation of the C3-neighboring group effect [39,41]. In this study, we explored the stereoselectivities in the glycosidation of a d-tagatofuranosyl donor, the C4-stereoisomer of d-fructofuranose, protected with 1,3,4,6-tetra-O-benzoyl groups, and applied this to the synthesis of α-d-tagatofuranosylceramide using the neighboring group participating strategy (Scheme 1c).

2. Results and Discussion

We synthesized d-tagatofuranosyl donor 8 through a six-step process starting from commercially available d-tagatose (4; Scheme 2). First, primary alcohols at the C1/C6 positions of d-tagatose were protected using tert-butyldiphenylsilyl (TBDPS) groups [42,43,44,45]. Thioglycosidation at the anomeric position was then performed with 1-dodecanethiol and BF3·OEt2 as the promoter, yielding diol 5 in 90% yield over two steps. Subsequently, the TBDPS groups were removed using tetrabutylammonium fluoride (TBAF), followed by protection with benzoyl chloride in the presence of triethylamine and 4-dimethylaminopyridine (DMAP), resulting in tetrabenzoate 6 in 71% yield over two steps. The thioglycosidic bond in 6 was hydrolyzed by treatment with N-bromosuccinimide (NBS) in aqueous acetone, producing hemiacetal 7 in 89% yield. Finally, the anomeric hydroxy group of 7 was esterified with benzyl hydrogen phthalate [46] using N,N′-dicyclohexylcarbodiimide (DCC) and DMAP, yielding d-tagatofuranosyl donor 8 in 53% yield.
We also attempted to synthesize glycosyl donor precursor 7 through the direct benzoylation of d-tagatose (Scheme 3). Yamanoi et al. reported that the reaction of d-allulose, the C3, C4-stereoisomer of d-tagatose, with benzoyl chloride preferentially yielded benzoylated furanose in 54% yield along with benzoylated pyranose as a minor byproduct (12%) [39]. However, when applying the same benzoylation conditions as those reported by Yamanoi et al., direct benzoylation of d-tagatose did not result in the formation of furanose 7. Instead, tetrabenzoylated pyranose 7′ and perbenzoylated products were predominantly formed [47]. Owing to the anomeric effect, d-tagatose as well as its glycoside predominantly adopt the α-d-tagatopyranose form with a 5C2 conformation, as corroborated by the NOESY correlation and X-ray crystallographic analysis [47,48]. When benzoyl chloride was gradually added to the reaction solution at 50 °C, a small amount of tetrabenzoylated d-tagatofuranose 7 (17%, purity: >90%) was isolated after iterative chromatographic separations, along with several byproducts, including pyranose 7′ (40%). Although the process involves many reaction steps, proper protection of d-tagatose followed by thioglycosidation before benzoylation is a necessary step for the synthesis of the benzoylated donor.
Using the prepared d-tagatofuranosyl donor 8, we investigated its glycosidation reaction with various alcohols. The glycosidation reaction was conducted using 1.5 equivalents of glycosyl acceptors and 1.0 equivalents of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as a promoter in dichloromethane at −20 °C (Table 1). When glycosidation of 8 was performed with primary alcohols such as phenethyl alcohol and 1-dodecanol, the corresponding α-d-tagatofuranosides 9a and 9b were stereoselectively obtained in yields of 80% and 72%, respectively (entries 1 and 3). The glycosidation of 8 with phenethyl alcohol at room temperature resulted in a decrease in both the yield and α-selectivity (entry 2). The reaction with 4-nitrobenzyl alcohol yielded 9c in 81% yield, with an α/β-ratio of 92:8 (entry 4). Glycosidation with secondary alcohols, such as cyclohexanol and isopropanol, resulted in 9d and 9e with yields of 78% and 81% and α-selectivities of α/β = 94:6 and 93:7, respectively (entries 5 and 6). However, the use of p-methoxyphenol as the glycosyl acceptor led to a lower yield (56% of 9f) and selectivity (α/β = 89:11, entry 7). The glycosidation reaction with more sterically hindered 2-hydroxycumene further reduced the reaction efficiency, producing only a 15% yield of glycoside 9g with poor α-selectivity (α/β = 71:29, entry 8). Glycosidation with glycosyl acceptors derived from α-amino acids and sugars were also successful. For instance, the glycosidation of 8 with Fmoc-L-Ser-OMe yielded glycoside 9h in 76% yield with an α/β ratio of 97:3 (entry 9), and the reactions with methyl 2,3-O-isopropylidene-β-d-ribofuranoside and methyl 2,3,4-tri-O-benzyl-α-d-glucopyranoside proceeded with high α-selectivity to produce the desired disaccharides 9i in 82% yield (α/β = 88:12, entry 10) and 9j in 78% yield (α/β = 96:4, entry 11), respectively. Although the efficiency and α-selectivity of glycosidation depend on the steric hindrance of the acceptor, 3-O-benzoylated d-tagatofuranosyl donor 8 proved to be a suitable α-selective glycosyl donor.
Scheme 4 illustrates a plausible mechanism for the glycosidation reaction of d-tagatofuranosyl donor 8 with alcohols. TMSOTf facilitated the activation of the leaving group (LG = benzyl phthalate) in compound 8, leading to the formation of oxocarbenium ion intermediates. Owing to the presence of the oxocarbenium ion moiety, these intermediates adopt an envelope-type conformation, either I (4E type) or I′ (E4 type) [41,49,50,51]. In the case of conformer I′, a 1,3-diaxial interaction occurred between the C3-benzoyloxy group and the C5-benzoyloxymethyl group. Consequently, the conformer I is the more favorable intermediate for forming cyclic oxocarbenium intermediate II, facilitated by the neighboring group effect of the adjacent C3-benzoyloxy group. As the β-side of the anomeric position in II is obstructed by the neighboring group, less sterically hindered alcohols, such as primary alcohols, attack from the α-face of II, resulting in the formation of α-anomer α-9 with high stereoselectivities. Conversely, the approach of more sterically hindered alcohols, such as phenols, may be interrupted by the C1-benzoyloxy group of II, which slows down the glycosidation reaction with intermediate II and leads to the formation of an alternative cyclic oxocarbenium intermediate III. Ultimately, more sterically hindered alcohols partially undergo glycosidation with III, yielding undesired β-9 and resulting in lower α-selectivity in the glycosidation reaction.
As depicted in Scheme 5, we successfully synthesized d-tagatofuranosylceramide 11 using glycosyl donor 8. The glycosidation reaction between d-tagatofuranosyl donor 8 and ceramide 2 [37] was proceeded α-selectively, yielding the glycoside 10 in 91% yield. In this method, benzoyl protecting groups of 10 were easily removed by a treatment with sodium methoxide in methanol and chloroform and the desired product 11 was obtained in 76% yield. The N-methylated d-tagatofuranosylceramide 14 can also be synthesized starting from glycosyl donor 8 and glycosyl acceptor 12. The glycosidation and saponification of benzoyl groups occurred as similar as 11 to produce N-methyl-d-tagatofuranosylceramide 14 in 87% yield in 2 steps.

3. Materials and Methods

3.1. General Methods

Melting points (Mps) were determined using an AS ONE apparatus ATM-01 and reported without correction (AS ONE Corporation, Osaka, Japan). Optical rotations were measured in CHCl3 using a JASCO polarimeter DIP-370 (JASCO Corporation, Tokyo, Japan). IR spectra were measured on an IRAffinity-1 FT-IR spectrophotometer of Shimadzu (Shimadzu Corporation, Kyoto, Japan). 1H NMR and 13C NMR spectra were measured on Varian NMR System 500PS SN (500 MHz and 126 MHz, Agilent Inc., Santa Clara, CA, USA) or JEOL JNM-ECZ400R (400 MHz and 100 MHz, JEOL Ltd., Tokyo, Japan) spectrometers with chemical shifts (δ) in parts per million (ppm). Tetramethylsilane served as the internal reference (0.00 ppm in CDCl3) for the 1H NMR spectra, and the central solvent peak was used as the reference (77.0 ppm in CDCl3) for the 13C NMR spectra. For clarification purposes, the protons of the aldose ring of disaccharides are denoted as 1′, 2′, and so forth. High-resolution mass spectra (HRMS) were collected using a JEOL JMS-T100TD instrument with electrospray ionization (ESI) in time of flight (TOF) mode (JEOL Ltd., Tokyo, Japan). Analytical TLC was conducted using Merck Millipore pre-coated TLC plates, silica gel 60 F254 with a layer thickness of 0.25 mm (MilliporeSigma, Burlington, VT, USA). All the moisture sensitive reactions were performed under a nitrogen or an argon atmosphere.

3.2. 3-O-Benzoyl-1-O-(1,6-Di-O-benzoyl-3,4-O-isopropylidene-α-d-tagatofuranosyl)-N-stearoyl-d-erythro-sphingosine (3)

A mixture of d-tagatofuranosyl donor 1 (72.0 mg, 0.108 mmol) and ceramide 2 (36.1 mg, 0.0539 mmol) was subjected to azeotropic drying through coevaporation with toluene three times, followed by further drying in vacuo. Activated molecular sieves 4 Å (100 mg) and CH2Cl2 (2 mL) were introduced to this mixture, and the solution was cooled to –20 °C. Subsequently, TMSOTf (9.8 μL, 0.054 mmol) was added to the mixture, and the mixture was stirred at −20 °C for 30 min. After the addition of Et3N (0.2 mL), the solvent was removed by evaporation, and the resulting residue was purified by flash column chromatography on silica gel (15% EtOAc in n-hexane), yielding product 3 (22.4 mg, 38%) as a white solid. Rf = 0.69 (40% EtOAc in n-hexane). Mp 67–69 °C. [α]30D: +13.6 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 8.06–7.95 (6H, m, ArH), 7.58–7.47 (3H, m, ArH), 7.47–7.34 (6H, m, ArH), 5.81 (1H, dt, J4′,5′ = 15.4, J5′,6′ = 6.8 Hz, H-5′), 5.65 (1H, d, J2′,NH = 8.7 Hz, NH), 5.53 (1H, dd, J3′,4′ = 7.2, J2′,3′ = 5.2 Hz, H-3′), 5.43 (1H, dd, J4′,5′ = 15.4, J3′,4′ = 7.2 Hz, H-4′), 4.98 (1H, d, J1a,1b = 11.9 Hz, H-1a), 4.90 (1H, dd, J3,4 = 5.9, J4,5 = 3.8 Hz, H-4), 4.67 (1H, dd, J6a,6b = 11.9, J5,6a = 4.2 Hz, H-6a), 4.62 (1H, d, J3,4 = 5.9 Hz, H-3), 4.48 (1H, dd, J6a,6b = 11.9, J5,6b = 7.4 Hz, H-6b), 4.43 (1H, dddd, J2′,NH = 8.7, J1′a,2′ = 7.4, J2′,3′ = 5.2, J1′b,2′ = 3.8 Hz, H-2′), 4.28 (1H, d, J1a,1b = 11.9 Hz, H-1b), 4.27 (1H, ddd, J5,6b = 7.4, J5,6a = 4.2, J4,5 = 3.8, H-5), 3.84 (1H, dd, J1′a,1′b = 10.0, J1′a,2′ = 7.4 Hz, H-1′a), 3.75 (1H, dd, J1′a,1′b = 10.0, J1′b,2′ = 3.8 Hz, H-1′b), 1.92 (2H, td, J6′,7′ = 7.2, J5′,6′ = 6.8 Hz, H-6′), 1.89–1.78 (2H, m, CH2), 1.51 (3H, s, accetonide-CH3), 1.47–1.35 (2H, m, CH2), 1.34 (3H, s, accetonide-CH3), 1.32–1.03 (50H, m, CH2), 0.88 (6H, t, J = 7.0, CH3). 13C{1H} NMR (126 MHz, CDCl3) δ: 173.0, 166.43, 166.39, 165.6, 137.1, 133.4, 133.2, 133.1, 130.2, 129.9 (2C), 129.83 (2C), 129.81, 129.76 (2C), 128.6 (2C), 128.53 (2C), 128.50 (3C), 124.6, 113.5, 107.5, 85.0, 80.1, 78.5, 75.1, 63.0, 59.9, 59.4, 51.5, 36.8, 32.4, 32.1 (2C), 29.9 (5C), 29.83 (5C), 29.81 (2C), 29.76, 29.7, 29.6, 29.52, 29.51 (2C), 29.3 (2C), 29.1, 26.2, 25.8, 24.9, 22.8 (2C), 14.3 (2C). IR (KBr): 2913, 2851, 1721, 1643, 1558 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C66H97NO11Na, 1102.6959; found, 1102.6961.

3.3. (1-Dodecyl) 1,6-Di-O-(tert-butyldiphenylsilyl)-2-thio-d-tagatofuranoside (5)

In a solution of d-tagatose (2.00 g, 11.1 mmol) dissolved in pyridine (74 mL), TBDPSCl (8.66 mL, 33.3 mmol) and DMAP (269 mg, 2.22 mmol) were introduced at ambient temperature. The reaction mixture was stirred for three days at the same temperature prior to quenching with 1 M HCl. The aqueous layer was extracted with EtOAc three times, which was washed with sat. NaHCO3 aq (twice) and with brine (twice). After drying over anhydrous MgSO4 and concentrating under vacuum, the residue was purified using a short pad of silica gel (n-hexane, followed by 20% EtOAc in n-hexane) to yield crude 1,6-di-O-(tert-butyldiphenylsilyl)-d-tagatofuranose, which was utilized in the next step without further purification. The above crude product, 1-dodecanethiol (5.32 mL, 22.2 mmol) and activated powdered molecular sieves 4 Å (7.00 g) in CH2Cl2 (56 mL) were stirred at room temperature for 20 min. Subsequently, BF3·OEt2 (2.74 mL, 22.2 mmol) was introduced to the mixture at −40 °C, and the mixture was stirred for an additional 15 min at the same temperature. The reaction mixture was quenched by adding Et3N (7.0 mL), and the resulting suspension was filtered through a Celite pad. After concentration under vacuum, the residue was purified by flash column chromatography on silica gel (20% EtOAc in n-hexane) to afford desired product 5 (8.36 g, 90% in two steps) as colorless oil. Rf = 0.67 (40% EtOAc in n-hexane). 1H NMR (400 MHz, CDCl3) δ for the major isomer: 7.77–7.65 (8H, m, ArH), 7.49–7.28 (12H, m, ArH), 4.30 (1H, ddd, J4,4-OH = 10.4, J3,4 = 4.5, J4,5 = 3.6 Hz, H-4), 4.23 (1H, dd, J3,3-OH = 9.7, J3,4 = 4.5 Hz, H-3), 4.22 (1H, ddd, J5,6b = 5.8, J5,6a = 5.4, J4,5 = 3.6 Hz, H-5), 4.03 (1H, dd, J6a,6b = 10.7, J5,6a = 5.4 Hz, H-6a), 3.93 (1H, dd, J6a,6b = 10.7, J5,6b = 5.8 Hz, H-6b), 3.89 (1H, d, J1a,1b = 10.8 Hz, H-1a), 3.84 (1H, d, J1a,1b = 10.8 Hz, H-1b), 3.46 (1H, d, J4,4-OH = 10.4 Hz, 4-OH), 3.46 (1H, d, J3,3-OH = 9.7 Hz, 3-OH), 1.44–1.13 (23H, m), 1.11–0.97 (17H, m), 0.92–0.83 (3H, m). 13C{1H} NMR (100 MHz, CDCl3) δ for the major isomer: 135.7 (2C), 135.6 (2C), 135.5 (2C), 133.2, 133.0, 132.1, 131.8, 130.1, 129.9, 129.7 (2C), 127.9 (2C), 127.8 (2C), 127.73 (3C), 127.71 (3C), 93.2, 80.6, 79.2, 72.2, 65.1, 61.8, 31.9, 30.3, 29.62 (2C), 29.56, 29.50, 29.3, 29.1, 29.0, 28.9, 26.7 (3C), 26.6 (3C), 22.7, 19.2, 19.0, 14.1. IR (KBr): 3393, 3073, 2957, 2928, 2857 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C50H72O5SSi2Na, 863.4537; found, 863.4544.

3.4. (1-Dodecyl) 1,3,4,6-Tetra-O-benzoyl-2-thio-d-tagatofuranoside (6)

To a solution of 5 (7.31 g, 8.96 mmol) in THF (87 mL) was added tetra-n-butylammonium fluoride (TBAF; 1 M in THF, 34.8 mL, 34.8 mmol) solution at room temperature. After stirring at room temperature for 1 d, the ice-cold reaction mixture was quenched by adding Dowex 50W × 8 (21.4 g), CaCO3 (7.14 g), and MeOH (51 mL) [52], which was further stirred for 10 min at 0 °C and for 30 min at room temperature. The reaction mixture was filtered through a Celite pad and the filter cake was washed with MeOH. After concentration in vacuo, the residue was passed through a short plug of silica gel (2 cm, CHCl3, then 10% MeOH in n-hexane) to give crude (1-dodecyl) 2-thio-d-tagatofuranoside (S2) as a colorless oil [Rf = 0.37 (EtOAc)]. To a solution of the above tetraol S2, Et3N (24.3 mL, 174 mmol), and DMAP (531 mg, 4.35 mmol) in CH2Cl2 (87 mL) was added benzoyl chloride (BzCl; 10.1 mL, 86.9 mmol) dropwise at 0 °C and then the mixture was stirred at room temperature for 1 d. The reaction mixture was quenched by adding MeOH (10 mL) at 0 °C and stirred for a further 40 min at room temperature. After removal of MeOH by evaporation, the residue was partitioned into 1 M HCl aq (30 mL) and EtOAc (30 mL) layers. The aqueous residue extracted with EtOAc (40 mL) three times, and the combined organic layers were washed with water, sat. NaHCO3 aq, and brine (20 mL each), dried over anhydrous MgSO4 and concentrated under vacuum. The crude material was purified by flash column chromatography on silica gel (5% then 20% EtOAc in n-hexane) to afford tetrabenzoate 6 (4.84 g, 71% in two steps, α:β = 17:1) as a pale-yellow oil. Rf = 0.54 (30% EtOAc in n-hexane). Rf = 0.51 (30% EtOAc in n-hexane). 1H NMR (400 MHz, CDCl3) δ for the major isomer: 7.99–7.94 (2H, m, ArH), 7.94–7.89 (2H, m, ArH), 7.87–7.81 (4H, m, ArH), 7.56–7.42 (4H, m, ArH), 7.41–7.35 (2H, m, ArH), 7.34–7.28 (2H, m, ArH), 7.28–7.20 (4H, m, ArH), 6.24 (1H, dd, J4,5 = 6.0, J3,4 = 5.5 Hz, H-4), 5.89 (1H, d, J3,4 = 5.5 Hz, H-3), 4.96 (1H, ddd, J5,6a = 6.6, J4,5 = 6.0, J5,6b = 5.6 Hz, H-5), 4.85 (1H, d, J1a,1b = 11.9 Hz, H-1a), 4.73 (1H, dd, J6a,6b = 11.6, J5,6a = 6.6 Hz, H-6a), 4.68 (1H, d, J1a,1b = 11.9 Hz, H-1b), 4.68 (1H, dd, J6a,6b = 11.6, J5,6b = 5.6 Hz, H-6b), 2.75 (2H, t, J = 7.3 Hz, SCH2), 1.70–1.56 (2H, m, SCH2CH2), 1.43–1.32 (2H, m, SCH2CH2CH2), 1.32–1.19 (16H, m), 0.88 (3H, t, J = 7.0 Hz, CH3). 13C{1H} NMR (100 MHz, CDCl3) δ for the major isomer: 166.1, 165.8, 165.1, 164.7, 133.4 (2C), 133.1, 133.0, 129.70 (3C), 129.67 (2C), 129.65 (3C), 129.5 (2C), 128.7, 128.6, 128.4 (4C), 128.3 (2C), 128.2 (2C), 92.5, 77.0, 76.0, 72.6, 62.9, 62.5, 31.9, 29.7, 29.62, 29.59, 29.54, 29.49, 29.3, 29.1, 29.0, 28.6, 22.7, 14.1. IR (KBr): 3065, 2955, 2924, 2853, 1726, 1603 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C46H52O9SNa, 803.3230; found, 803.3233.

3.5. 1,3,4,6-Tetra-O-benzoyl-d-tagatofuranose (7)

Synthesis from 6: To a solution of 6 (4.78 g, 6.13 mmol) in a mixture of acetone (55 mL) and H2O (6 mL) was added N-bromosuccinimide (2.18 g, 12.2 mmol) at 0 °C and the reaction was stirred at 0 °C for 15 min. An additional N-bromosuccinimide (1.09 g, 6.13 mmol) was added to the reaction, which was further stirred at 0 °C for 15 min. After quenching the reaction by adding sat. NaHCO3 aq, the solvent was removed under reduced pressure. The reaction mixture was extracted with EtOAc three times and dried over anhydrous MgSO4. The crude material obtained after evaporation was purified by flash column chromatography on silica gel (10% then 30% EtOAc in n-hexane) to afford the desired product 7 (3.23 g, 89%, α:β = 1.1:1). Synthesis from 4: To a solution of d-tagatose (901 mg, 5.00 mmol) in pyridine (15 mL), benzoyl chloride (2.90 mL, 25.0 mmol) was added at 50 °C over 15 min using a syringe pump, and the mixture was stirred for an additional 25 min. The reaction was quenched by the addition of MeOH (3 mL) and stirring at room temperature for 10 min. After evaporating pyridine, the residue was dissolved in 50% EtOAc in n-hexane and washed with 1 M HCl aq and water. The organic phase was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (30% EtOAc in n-hexane, iterative), yielding compound 7 (495 mg, 17%) along with 7′ [28] (1.18 g, 40%). Colorless oil. Rf = 0.23 (30% EtOAc in n-hexane). 1H NMR (400 MHz, CDCl3) δ: 8.08–7.82 (8H, m, ArH), 7.62–7.45 (4H, m, ArH), 7.45–7.26 (8H, m, ArH), 6.21 (0.5H, dd, J4,5 = 5.9, J3,4 = 5.1 Hz, α-H-4), 6.17 (0.5H, dd, J3,4 = 5.3, J4,5 = 5.0 Hz, β-H-4), 5.93 (0.5H, d, J3,4 = 5.1 Hz, α-H-3), 5.85 (0.5H, d, J3,4 = 5.3 Hz, β-H-3), 5.01 (0.5H, ddd, J5,6a = 6.9, J4,5 = 5.9, J5,6b = 5.6 Hz, α-H-5), 4.89 (0.5H, dd, J6a,6b = 11.3, J5,6a = 7.1 Hz, β-H-6a), 4.86 (0.5H, d, J1a,1b = 11.8 Hz, H-1), 4.81 (0.5H, dt, J5,6a = 7.1, J4,5 = J5,6b = 5.0 Hz, β-H-5), 4.70 (0.5H, dd, J6a,6b = 11.6, J5,6a = 6.9 Hz, α-H-6a), 4.65–4.56 (2H, m, H-1a, 1b, α-H-6b, β-H-6b), 4.54 (0.5H, d, J1a,1b = 11.7 Hz, H-1), 4.00 (1H, br s, OH). 13C{1H} NMR (100 MHz, CDCl3) δ: 166.8 (0.5C), 166.4 (0.5C), 166.1 (0.5C), 165.9 (0.5C), 165.1 (0.5C), 165.0 (0.5C), 164.9 (0.5C), 164.8 (0.5C), 133.7 (0.5C), 133.6 (0.5C), 133.57 (0.5C), 133.55 (0.5C), 133.3 (0.5C), 133.2, 133.1 (0.5C), 129.8–129.7 (8C), 129.5 (0.5C), 129.4 (0.5C), 129.3 (0.5C), 129.1 (0.5C), 128.7–128.2 (10C), 103.7 (0.5C), 101.7 (0.5C), 76.5 (0.5C), 76.2 (0.5C), 75.9 (0.5C), 72.3 (0.5C), 72.1 (0.5C), 71.5 (0.5C), 66.1 (0.5C), 65.2 (0.5C), 63.2 (0.5C), 63.1 (0.5C). IR (KBr): 3437, 3065, 3032, 2965, 1732 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C34H28O10Na, 619.1580; found, 619.1579.

3.6. 1,3,4,6-Tetra-O-benzoy-d-tagatofuranosyl phthalate (8)

DCC (158 mg, 0.758 mmol) and DMAP (31.3 mg, 0.256 mmol) were added to a mixed solution of 7 (153 mg, 0.256 mmol) and monobenzyl phthalate (230 mg, 0.898 mmol) in CH2Cl2 (3 mL) at 0 °C. The reaction mixture was subsequently allowed to gradually reach room temperature over 3 h. The reaction mixture was filtered through a pad of Celite and the filter cake was rinsed by CH2Cl2. The filtrate was washed sequentially with 5% Na2CO3 aqueous solution, water, and brine. The organic phase was dried over MgSO4 and concentrated under vacuum to give a residue, which was purified by flash column chromatography on silica gel eluted with 5% EtOAc in n-hexane to yield compound 8 (114 mg, 53%). Colorless oil. Rf = 0.57 (5% Et2O in CHCl3). [α]23D: +39.8 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ for the major isomer: 7.98–7.84 (8H, m, ArH), 7.84–7.80 (1H, m, ArH), 7.73–7.68 (1H, m, ArH), 7.56–7.45 (6H, m, ArH), 7.43–7.39 (2H, m, ArH), 7.39–7.26 (11H, m, ArH), 6.53 (1H, d, J = 5.3 Hz, H-3), 6.20 (1H, dd, J3,4 = 5.3, J4,5 = 4.7 Hz, H-4), 5.37 (1H, d, J = 12.3 Hz, -CH2Ph), 5.32 (1H, d, J = 12.3 Hz, -CH2Ph), 5.25 (1H, d, J1a,1b = 12.0 Hz, H-1a), 5.20 (1H, ddd, J5,6a = 6.4, J5,6b = 5.7, J4,5 = 4.7 Hz, H-5), 4.94 (1H, d, J1a,1b = 12.0 Hz, H-1b), 4.70 (1H, dd, J6a,6b = 11.7, J5,6a = 6.4 Hz, H-6a), 4.64 (1H, dd, J6a,6b = 11.7, J5,6b = 5.7 Hz, H-6b). 13C{1H} NMR (100 MHz, CDCl3) δ for the major isomer: 166.7, 166.1, 166.0, 165.7, 165.1, 164.4, 135.5, 133.6, 133.5, 133.1, 133.1, 132.5, 131.6, 131.2, 131.0, 129.7 (9C), 129.41, 129.38, 129.3, 129.0, 128.6, 128.5 (4C), 128.4 (4C), 128.29 (2C), 128.3 (2C), 109.3, 78.5, 75.5, 72.3, 67.5, 63.2, 62.4. IR (KBr): 3065, 3032, 2961, 1724, 1601 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C49H38O13Na, 857.2210; found, 857.2219.

3.7. General Procedure for the Glycosidation Described in Table 1

Azeotropic drying with toluene in vacuo was performed on the glycosyl acceptor (0.150 mmol) and glycosyl donor 8 (83.5 mg, 0.100 mmol), resulting in a mixture, which was subsequently dissolved in CH2Cl2 (2.0 mL) and TMSOTf (18.1 μL, 0.100 mmol) was added at −20 °C (at 0 °C for entry 3). Upon completion of the reaction under the conditions specified in Table 1, Et3N (0.1 mL) was added to the reaction mixture, which was stirred at ambient temperature for an additional 5 min. After removing the solvent in vacuo, the residue was purified by flash column chromatography on silica gel (EtOAc/n-hexane, and CHCl3 if necessary) to yield the corresponding product.

3.7.1. (2-Phenethyl) 1,3,4,6-Tetra-O-benzoyl-α-d-tagatofuranoside (9a)

According to the general procedure for the glycosidation reaction, compound 9a (56.3 mg) was obtained from the glycosyl donor 8 (83.5 mg, 0.100 mmol) and phenethyl alcohol (0.0180 mL, 0.150 mmol) in 80% yield as a 99:1 mixture of α- and β-anomers. Colorless oil. Eluent for column: 10% EtOAc in n-hexane for the first column and CHCl3 for second column. [α]23D: +92.7 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.96–7.87 (6H, m, ArH), 7.81–7.73 (2H, m, ArH), 7.57–7.47 (3H, m, ArH), 7.47–7.42 (1H, m, ArH), 7.40–7.30 (6H, m, ArH), 7.28–7.26 (3H, m, ArH), 7.26–7.19 (3H, m, ArH), 7.19–7.13 (1H, m, ArH), 5.97 (1H, dd, J4,5 = 6.6, J3,4 = 5.2 Hz, H-4), 5.89 (1H, d, J3,4 = 5.2 Hz, H-3), 4.89 (1H, d, J1a,1b = 12.2 Hz, H-1a), 4.57 (1H, dd, J6a,6b = 11.5, J5,6a = 6.8 Hz, H-6a), 4.44 (1H, dd, J6a,6b = 11.5, J5,6b = 5.8 Hz, H-6b), 4.44 (1H, d, J1a,1b = 12.2 Hz, H-1b), 4.13 (1H, ddd, J5,6a = 6.8, J4,5 = 6.6, J5,6b = 5.8 Hz, -5H), 3.99–3.83 (2H, m, OCH2CH2Ph), 2.94–2.83 (2H, m, CH2Ph). 13C{1H} NMR (126 MHz, CDCl3) δ: 166.0, 165.7, 165.0, 164.7, 139.0, 133.4, 133.3, 133.1, 133.0, 129.7 (2C), 129.62 (6C), 129.57, 129.3, 129.0 (2C), 128.9, 128.7, 128.5 (2C), 128.4 (2C), 128.3 (4C), 128.2 (2C), 126.3, 106.0, 75.7, 75.4, 72.0, 63.0, 62.9, 59.7, 36.2. IR (KBr): 3063, 2957, 1724 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C42H36O10Na, 723.2206; found, 723.2209.

3.7.2. (1-Dodecyl) 1,3,4,6-Tetra-O-benzoyl-α-d-tagatofuranoside (9b)

According to the general procedure for the glycosidation reaction, compound 9b (55.1 mg) was obtained from the glycosyl donor 8 (83.5 mg, 0.100 mmol) and 1-dodecanol (27.9 mg, 0.150 mmol) in 72% yield as a 99:1 mixture of α- and β-anomers. Colorless oil. Eluent for column: 5% EtOAc in n-hexane for the first column and CHCl3 for second column. [α]23D: +79.5 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.99–7.90 (6H, m, ArH), 7.83–7.77 (2H, m, ArH), 7.55–7.48 (3H, m, ArH), 7.48–7.42 (1H, m, ArH), 7.40–7.31 (6H, m, ArH), 7.28–7.21 (2H, m, ArH), 6.18 (1H, dd, J4,5 = 6.6, J3,4 = 5.2 Hz, H-4), 5.94 (1H, d, J3,4 = 5.2 Hz, H-3), 4.93 (1H, d, J1a,1b = 12.3 Hz, H-1a), 4.84 (1H, ddd, J5,6a = 6.7, J4,5 = 6.6, J5,6b = 5.6 Hz, H-5), 4.71 (1H, dd, J6a,6b = 11.5, J5,6a = 6.7 Hz, H-6a), 4.58 (1H, dd, J6a,6b = 11.5, J5,6b = 5.6 Hz, H-6b), 4.48 (1H, d, J1a,1b = 12.3 Hz, H-1b), 3.71 (1H, dt, J = 9.0, 6.5 Hz, OCHHCH2-), 3.61 (1H, dt, J = 9.0, 6.4 Hz, OCHHCH2-), 1.62–1.54 (2H, m, OCH2CH2-), 1.39–1.31 (2H, m, OCH2CH2CH2-), 1.30–1.19 (16H, m, CH2), 0.88 (3H, t, J = 6.9 Hz, CH3). 13C{1H} NMR (126 MHz, CDCl3) δ: 166.1, 165.7, 165.2, 164.7, 133.40, 133.36, 133.1, 133.0, 129.71 (2C), 129.67 (2C), 129.6 (4C), 129.5, 129.4, 128.9, 128.7, 128.5 (2C), 128.31 (2C), 128.29 (2C), 128.25 (2C), 106.2, 75.9, 75.5, 72.2, 63.3, 62.0, 59.6, 31.9, 29.7, 29.6, 29.6, 29.6, 29.6, 29.4, 29.3, 26.2, 22.7, 14.1. IR (KBr): 3063, 2926 1728 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C46H52O10Na, 787.3458; found, 787.3454.

3.7.3. (4-Nitrobenzyl) 1,3,4,6-Tetra-O-benzoyl-α-d-tagatofuranoside (9c)

According to the general procedure for the glycosidation reaction, compound 9c (59.4 mg) was obtained from the glycosyl donor 8 (83.5 mg, 0.100 mmol) and 4-nitrobenzyl alcohol (23.0 mg, 0.150 mmol) in 81% yield as a 92:8 mixture of α- and β-anomers. Colorless oil. Eluent for column: 10% EtOAc in n-hexane for the first column and CHCl3 for second column. [α]23D: +71.7 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 8.16–8.09 (2H, m, ArH), 7.99–7.92 (4H, m, ArH), 7.89–7.80 (4H, m, ArH), 7.56–7.47 (6H, m, ArH), 7.41–7.32 (6H, m, ArH), 7.30–7.26 (2H, m, ArH), 6.18 (1H, dd, J4,5 = 6.3, J3,4 =5.3 Hz, H-4), 6.08 (1H, d, J3,4 = 5.3 Hz, H-3), 5.07 (1H, d, J1a,1b = 12.5 Hz, H-1a), 4.89 (1H, d, J = 13.0 Hz, OCHHAr), 4.86 (1H, d, J = 13.0 Hz, OCHHAr), 4.83 (1H, ddd, J5,6a = 6.8, J4,5 = 6.3, J5,6b = 5.3 Hz, H-5), 4.76 (1H, dd, J6a,6b = 11.5, J5,6a = 6.8 Hz, H-6a), 4.60 (1H, dd, J6a,6b = 11.5, J5,6b = 5.3 Hz, H-6b), 4.53 (1H, d, J1a,1b = 12.5 Hz, H-1b). 13C{1H} NMR (126 MHz, CDCl3) δ: 166.0, 165.6, 165.1, 164.6, 147.3, 145.0, 133.6, 133.5, 133.3, 133.2, 129.7 (4C), 129.6 (4C), 129.4, 129.0, 128.7, 128.6 (2C), 128.5, 128.43 (2C), 128.36 (2C), 128.32 (2C), 127.7 (2C), 123.6 (2C), 106.9, 76.6, 75.6, 72.0, 63.2, 63.0, 59.6. IR (KBr): 3065, 2963, 1732 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C41H33NO12Na, 754.1900; found, 754.1902.

3.7.4. Cyclohexyl 1,3,4,6-Tetra-O-benzoyl-α-d-tagatofuranoside (9d)

According to the general procedure for the glycosidation reaction, compound 9d (53.2 mg) was obtained from the glycosyl donor 8 (83.5 mg, 0.100 mmol) and cyclohexanol (0.0158 mL, 0.150 mmol) in 78% yield as a 94:6 mixture of α- and β-anomers. Colorless oil. Eluent for column: 10% EtOAc in n-hexane for the first column and CHCl3 for second column. [α]23D: +70.1 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.96–7.86 (6H, m, ArH), 7.83–7.77 (2H, m, ArH), 7.55–7.43 (4H, m, ArH), 7.39–7.28 (6H, m, ArH), 7.27–7.21 (2H, m, ArH), 6.19 (1H, dd, J4,5 = 6.5, J3,4 = 5.2 Hz, H-4), 5.94 (1H, d, J3,4 = 5.2 Hz, H-3), 4.90 (1H, ddd, J5,6a = 6.9, J4,5 = 6.5, J5,6b =5.2 Hz, H-5), 4.77 (1H, d, J1a,1b = 12.3 Hz, H-1a), 4.70 (1H, dd, J6a,6b = 11.4, J5,6a = 6.9 Hz, H-6a), 4.59 (1H, dd, J6a,6b = 11.4, J5,6b =5.2 Hz, H-6b), 4.57 (1H, d, J1a,1b = 12.3 Hz, H-1b), 3.99–3.89 (1H, m, OCH of cHex), 1.98–1.85 (1H, m, CH2 of cHex), 1.78–1.67 (3H, m, CH2 of cHex), 1.55–1.44 (2H, m, CH2 of cHex), 1.42–1.32 (2H, m, CH2 of cHex), 1.29–1.17 (2H, m, CH2 of cHex). 13C{1H} NMR (126 MHz, CDCl3) δ: 166.1, 165.8, 165.2, 164.7, 133.3 (2C), 133.1, 133.0, 129.7 (2C), 129.63 (2C), 129.61 (2C), 129.59 (2C), 129.52, 129.3, 128.9, 128.7, 128.4 (2C), 128.33 (2C), 128.29 (2C), 128.23 (2C), 106.5, 76.3, 76.1, 72.2, 71.0, 63.3, 60.8, 34.4, 33.7, 25.4, 24.2 (2C). IR (KBr): 3063, 2936, 1728 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C40H38O10Na, 701.2363; found, 701.2360.

3.7.5. Isopropyl 1,3,4,6-Tetra-O-benzoyl-α-d-tagatofuranoside (9e)

According to the general procedure of the glycosidation reaction, compound 9e (48.4 mg) was obtained from the glycosyl donor 8 (83.5 mg, 0.100 mmol) and isopropanol (11.5 μL, 0.150 mmol) in 76% yield as a 93:7 mixture of α- and β-anomers. Colorless oil. Eluent for column: 20% EtOAc in n-hexane. Rf = 0.55 (30% EtOAc in n-hexane). [α]23D = +79.0 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.95–7.89 (6H, m, ArH), 7.83–7.78 (2H, m, ArH), 7.54–7.44 (4H, m, ArH), 7.38–7.29 (6H, m, ArH), 7.27–7.23 (2H, m, ArH), 6.18 (1H, dd, J4,5 = 6.5, J3,4 = 5.1 Hz, H-4), 5.92 (1H, d, J3,4 = 5.1 Hz, H-3), 4.90 (1H, ddd, J5,6a = 6.8, J4,5 = 6.5, J5,6b = 5.5 Hz, H-5), 4.81 (1H, d, J1a,1b = 12.4 Hz, H-1a), 4.70 (1H, dd, J6a,6b = 11.5, J5,6a = 6.8 Hz, H-6a), 4.58 (1H, dd, J6a,6b = 11.5, J5,6b = 5.5 Hz, H-6b), 4.55 (1H, d, J1a,1b = 12.4 Hz, H-1b), 4.27 (1H, qq, J = 6.1, 6.1 Hz, OCH(CH3)2), 1.29 (3H, d, J = 6.1 Hz, OCH(CH3)2), 1.16 (3H, d, J = 6.1 Hz, OCH(CH3)2). 13C{1H} NMR (126 MHz, CDCl3) δ: 166.1, 165.8, 165.2, 164.7, 133.4 (2C), 133.1, 133.0, 129.7 (2C), 129.64 (2C), 129.62 (2C), 129.61 (2C), 129.5, 129.3, 128.9, 128.7, 128.5 (2C), 128.4 (2C), 128.31 (2C), 128.25 (2C), 106.6, 76.2, 76.1, 72.2, 65.6, 63.4, 60.6, 24.3, 23.8. IR (film): 3063, 2980, 2932, 1744, 1730, 1603 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C37H34O10Na, 661.2050; found, 661.2054.

3.7.6. (4-Methoxyphenyl) 1,3,4,6-Tetra-O-benzoyl-α-d-tagatofuranoside (9f)

According to the general procedure of the glycosidation reaction, compound 9f (39.1 mg) was obtained from the glycosyl donor (83.5 mg, 0.100 mmol) and 4-methoxyphenol (18.6 mg, 0.150 mmol) in 56% yield as an 89:11 mixture of α- and β-anomers. White solid. Eluent for column: 10% EtOAc in n-hexane. Rf = 0.38 (30% EtOAc in n-hexane). Mp 43–45 °C. [α]19D = +25.9 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.99–7.96 (2H, m, ArH), 7.93–7.89 (2H, m, ArH), 7.87–7.82 (4H, m, ArH), 7.58–7.42 (2H, m, ArH), 7.50–7.44 (2H, m, ArH), 7.43–7.33 (2H, m, ArH), 7.38–7.33 (2H, m, ArH), 7.31–7.24 (4H, m, ArH), 7.14–7.08 (2H, m, ArH), 6.81–6.75 (2H, m, ArH), 6.26 (1H, dd, J3,4 = 5.3, J4,5 = 5.3 Hz, H-4), 6.24 (1H, d, J3,4 = 5.3 Hz, H-3), 5.08 (1H, ddd, J5,6a = 7.0, J5,6b = 5.5, J4,5 = 5.3 Hz, H-5), 4.75 (1H, dd, J6a,6b = 11.6, J5,6a = 7.0 Hz, H-6a), 4.67 (1H, dd, J6a,6b = 11.6, J5,6b = 5.5 Hz, H-6b), 4.63 (1H, d, J1a,1b = 12.3 Hz, H-1a), 4.61 (1H, d, J1a,1b = 12.3 Hz, H-1b), 3.75 (3H, s, OCH3). 13C{1H} NMR (126 MHz, CDCl3) δ: 166.0, 165.5, 165.2, 164.6, 156.5, 145.8, 133.5, 133.4, 133.2, 133.1, 129.72 (2C), 129.66 (2C), 129.63 (4C), 129.5, 129.2, 128.62, 128.58, 128.44 (2C), 128.42 (2C), 128.33 (2C), 128.32 (2C), 123.6 (2C), 114.4 (2C), 108.3, 76.6, 76.2, 72.1, 62.9, 61.0, 55.5. IR (KBr): 3073, 2959, 2928, 2841, 1732, 1603 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C41H34O11Na, 725.1999; found, 725.1984.

3.7.7. (2-Isopropylphenyl) 1,3,4,6-Tetra-O-benzoyl-α-d-tagatofuranoside (9g)

According to the general procedure for the glycosidation reaction, compounds 9gα (10.5 mg) and 9gβ (4.3 mg) were obtained from the glycosyl donor 8 (83.5 mg, 0.100 mmol) and 2-isopropylphenol (20.4 μL, 0.150 mmol) in 15% and 6% yields, respectively.
9gα: Colorless oil. Eluent for column: 8% EtOAc in n-hexane. Rf = 0.44 (30% EtOAc in n-hexane). 1H NMR (500 MHz, CDCl3) δ: 8.00–7.95 (2H, m, ArH), 7.91–7.87 (2H, m, ArH), 7.86–7.80 (4H, m, ArH), 7.57–7.51 (2H, m, ArH), 7.51–7.45 (3H, m, ArH), 7.42–7.36 (2H, m, ArH), 7.33–7.27 (6H, m, ArH), 7.19 (1H, dd, J = 7.6, 1.9 Hz, ArH), 7.13 (1H, td, J = 7.8, 1.9 Hz, ArH), 7.06 (1H, td, J = 7.4, 1.3 Hz, ArH), 6.26 (1H, d, J3,4 = 5.3 Hz, H-3), 6.25 (1H, dd, J3,4 = 5.3, J4,5 = 4.5 Hz, H-4), 5.08 (1H, ddd, J5,6a = 7.0, J5,6b = 5.4, J4,5 = 4.5 Hz, H-5), 4.95 (1H, d, J1a,1b = 12.3 Hz, H-1a), 4.79 (1H, dd, J6a,6b = 11.6, J5,6a = 7.0 Hz, H-6a), 4.68 (1H, d, J1a,1b = 12.3 Hz, H-1b), 4.66 (1H, dd, J6a,6b = 11.6, J5,6b = 5.4 Hz, H-6b), 3.39 (1H, qq, J = 7.0, 6.8 Hz, -CHMe2), 1.18 (3H, d, J = 6.8 Hz, -CH3), 0.96 (3H, d, J = 7.0 Hz, -CH3). HRMS (ESI) m/z: [M + Na]+ calcd for C43H38O10Na, 737.2363; found, 737.2365. 9gβ: Colorless oil. Eluent for column: 12% EtOAc in n-hexane. Rf = 0.39 (30% EtOAc in n-hexane). 1H NMR (500 MHz, CDCl3) δ: 8.02–7.96 (4H, m, ArH), 7.96–7.92 (2H, m, ArH), 7.87–7.82 (2H, m, ArH), 7.75–7.71 (1H, m, ArH), 7.57–7.49 (3H, m, ArH), 7.47–7.37 (3H, m, ArH), 7.35–7.28 (4H, m, ArH), 7.23–7.17 (3H, m, ArH), 7.12 (1H, ddd, J = 8.3, 7.3, 2.0 Hz, ArH), 7.05 (1H, td, J = 7.5, 1.3 Hz, ArH), 6.28 (1H, dd, J3,4 = 6.0, J4,5 = 5.6 Hz, H-4), 6.01 (1H, d, J3,4 = 6.0 Hz, H-3), 5.04 (1H, dt, J5,6a =7.2, J4,5 = J5,6b = 5.6 Hz, H-5), 4.82 (1H, dd, J6a,6b = 11.7, J5,6a = 7.2 Hz, H-6a), 4.77 (1H, dd, J6a,6b = 11.7, J5,6b = 5.6 Hz, H-6b), 4.73 (1H, d, J1a,1b = 12.1 Hz, H-1a), 4.61 (1H, d, J1a,1b = 12.1 Hz, H-1b), 3.45 (1H, qq, J = 7.1, 6.8 Hz, -CHMe2), 1.04 (3H, d, J = 6.8 Hz, -CH3), 0.90 (3H, d, J = 7.1 Hz, -CH3). HRMS (ESI) m/z: [M + Na]+ calcd for C43H38O10Na, 737.2363; found, 737.2371.

3.7.8. (Fmoc-L-Ser-OMe) 1,3,4,6-Tetra-O-benzoyl-α-d-tagatofuranoside (9h)

According to the general procedure of the glycosidation reaction, compound 9h (74.4 mg) was obtained from the glycosyl donor 8 (83.5 mg, 0.100 mmol) and Fmoc-L-Ser-OMe (51.2 mg, 0.150 mmol) in 81% yield as a 97:3 mixture of α- and β-anomers. White solid. Eluent for column: 30% EtOAc in n-hexane. Rf = 0.22 (30% EtOAc in n-hexane). Mp 64–66 °C. [α]23D = +58.6 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.95–7.87 (6H, m, ArH), 7.85–7.80 (2H, m, ArH), 7.72 (2H, d, J = 7.5 Hz, ArH), 7.61 (2H, d, J = 7.5 Hz, ArH), 7.53–7.45 (4H, m, ArH), 7.37–7.25 (12H, m, ArH), 6.13 (1H, dd, J4,5 = 6.5, J3,4 = 5.3 Hz, H-4), 5.97 (1H, d, J3,4 = 5.3 Hz, H-3), 5.82 (1H, d, J = 7.9 Hz, NH), 4.92 (1H, d, J1a,1b =12.5 Hz, H-1a), 4.87 (1H, ddd, J5,6a = 7.2, J4,5 = 6.5, J5,6b = 5.2 Hz, H-5), 4.70 (1H, dd, J6a,6b = 11.6, J5,6a = 7.2 Hz, H-6a), 4.62 (1H, dt, J = 7.9, 3.6 Hz, NHCH), 4.50 (1H, dd, J6a,6b = 11.6, J5,6b = 5.3 Hz, H-6b), 4.48 (1H, d, J1a,1b = 12.5 Hz, H-1b), 4.38 (1H, dd, J = 10.5, 7.2 Hz, ArCHCHH), 4.33 (1H, dd, J = 10.5, 7.2 Hz, ArCHCHH), 4.22 (1H, t, J = 7.2 Hz, ArCH), 4.13 (1H, dd, J = 9.8, 3.6 Hz, NHCH2CHH), 4.09 (1H, dd, J = 9.8, 3.6 Hz, NHCH2CHH), 3.57 (3H, s). 13C{1H} NMR (126 MHz, CDCl3) δ: 170.2, 166.0, 165.6, 165.0, 164.5, 155.8, 143.8, 143.7, 141.18, 141.16, 133.52, 133.47, 133.23, 133.01, 129.69 (2C), 129.66 (2C), 129.63 (2C), 129.59 (2C), 129.3, 129.1, 128.7 (2C), 128.5 (2C), 128.4 (2C), 128.3 (2C), 128.2 (2C), 127.6 (2C), 127.04, 127.00, 125.2, 125.1, 119.9, 106.4, 76.6, 75.3, 71.9, 67.4, 63.1 62.3, 59.7, 54.0, 52.6 (2C), 47.0. IR (KBr): 3067, 2959, 1724, 1601 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C53H45NO14Na, 942.2738; found, 942.2735.

3.7.9. Methyl 5-O-(1,3,4,6-tetra-O-benzoyl-α-d-tagatofuranosyl)-2,3-O-isopropylidene-β-d-ribofuranoside (9i)

According to the general procedure of the glycosidation reaction, compound 9i (64.6 mg) was obtained from the glycosyl donor 8 (83.5 mg, 0.100 mmol) and methyl 2,3-O-isopropylidene-β-d-ribofuranoside (26.2 μL, 0.150 mmol) in 82% yield as an 88:12 mixture of α- and β-anomers. White solid. Eluent for column: 15% EtOAc in n-hexane. Rf = 0.29 (30% EtOAc in n-hexane). Mp 45–47 °C. [α]21D = +36.2 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.98–7.92 (6H, m, ArH), 7.84–7.77 (2H, m, ArH), 7.56–7.49 (3H, m, ArH), 7.48–7.44 (1H, m, ArH), 7.39–7.32 (6H, m, ArH), 7.28–7.22 (2H, m, ArH), 6.18 (1H, dd, J4,5 = 6.5, J3,4 = 5.3 Hz, H-4), 5.98 (1H, d, J3,4 = 5.3 Hz, H-3), 4.95 (1H, s, H-1′), 4.93 (1H, d, J1a,1b = 12.4 Hz, H-1a), 4.92 (1H, ddd, J5,6a = 6.8, J4,5 = 6.5, J5,6b = 5.4 Hz, H-5), 4.73 (1H, dd, J6a,6b = 11.6, J5,6a = 6.8 Hz, H-6a), 4.64 (1H, dd, J2′,3′ = 6.0, J3′,4′ = 1.0 Hz, H-3′), 4.57 (1H, dd, J6a,6b = 11.6, J5,6a = 5.4 Hz, H-6b), 4.51 (1H, d, J1a,1b = 12.4 Hz, H-1b), 4.49 (1H, d, J2′,3′ = 6.0 Hz, H-2′), 4.34 (1H, ddd, J4′,5b′ = 9.3, J4′,5a′ = 5.7, J3′,4′ = 1.0 Hz, H-4′), 3.79 (1H, dd, J5a′,5b′ = 9.3, J4′,5a′ = 5.7 Hz, H-5a′), 3.61 (1H, t, J5a′,5b′ = 9.3, J4′,5a′ = 9.3 Hz, H-5b), 3.33 (3H, s, OCH3), 1.46 (3H, s, CCH3), 1.18 (3H, s, CCH3). 13C{1H} NMR (126 MHz, CDCl3) δ: 166.0, 165.6, 165.1, 164.6, 133.5, 133.4, 133.2, 133.1, 129.69 (2C), 129.66 (2C), 129.64 (2C), 129.63 (2C), 129.5, 129.2, 128.8, 128.60, 128.5 (2C), 128.37 (2C), 128.35 (2C), 128.26 (2C), 112.3, 109.4, 106.4, 85.0, 84.9, 82.0, 76.4, 75.5, 72.0, 63.1, 62.7, 59.5, 55.0, 26.3, 24.6. IR (KBr): 3065, 3032, 2988, 2940, 1736, 1719, 1601 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C43H42O14Na, 805.2472; found, 805.2470.

3.7.10. Methyl 6-O-(1,3,4,6-tetra-O-benzoyl-α-d-togatofuranosyl)-2,3,4-tri-O-benzyl-α-d-glucopyranoside (9j)

According to the general procedure of the glycosidation reaction, compound 9j (81.7 mg) was obtained from the glycosyl donor 8 (83.5 mg, 0.100 mmol) and methyl 2,3,4-tri-O-benzyl-α-d-glucopyranoside (69.6 mg, 0.150 mmol) in 78% yield as a 96:4 mixture of α- and β-anomers. Colorless oil. Eluent for column: 15% EtOAc in n-hexane. Rf = 0.31 (30% EtOAc in n-hexane). [α]22D = +65.5 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.98–7.93 (4H, m), 7.93–7.89 (2H, m), 7.82–7.74 (2H, m), 7.55–7.42 (4H, m), 7.38–7.20 (23H, m), 6.15 (1H, dd, J4,5 = 6.7, J3,4 = 5.3 Hz, H-4), 5.92 (1H, d, J3,4 = 5.3 Hz, H-3), 4.96 (1H, d, J = 10.9 Hz), 4.91 (1H, d, J = 11.0 Hz), 4.85 (1H, d, J = 12.0 Hz), 4.82 (1H, ddd, J5,6a = 6.8, J4,5 = 6.7, J5,6b = 6.0 Hz, H-5), 4.80 (1H, d, J = 10.9 Hz), 4.66 (1H, dd, J6a,6b = 11.6, J5,6a = 6.8 Hz, H-6a), 4.64 (1H, d, J = 11.0 Hz), 4.61 (1H, d, J = 12.0 Hz), 4.54 (1H, dd, J6a,6b = 11.6, J5,6b = 6.0 Hz, H-6b), 4.54 (1H, d, J = 12.0 Hz), 4.49 (1H, d, J1′,2′ = 3.7 Hz, H-1′), 4.47 (1H, d, J = 12.0 Hz), 3.97 (1H, t, J2′,3′ = 9.2, J3′,4′ = 9.2 Hz, H-3′), 3.90–3.84 (1H, m, H-6a), 3.81–3.74 (2H, m, H-5, 6b), 3.44 (1H, t, J3′,4′ = 9.2, J4′,5′ = 9.2 Hz, H-4′), 3.37 (1H, dd, J2′,3′ = 9.2, J1′,2′ = 3.7 Hz, H-2′), 3.37 (3H, s). 13C{1H} NMR (126 MHz, CDCl3) δ: 166.0, 165.6, 165.1, 164.7, 138.7, 138.1, 138.0, 133.4, 133.3, 133.04, 133.01, 129.7 (2C), 129.63 (2C), 129.61 (2C), 129.59 (2C), 129.5, 129.4, 128.9, 128.6, 128.5 (2C), 128.39 (2C), 128.36 (2C), 128.31 (4C), 128.29 (2C), 128.2 (2C), 127.91 (2C), 127.87 (4C), 127.7 (2C), 127.5, 106.2, 97.5, 82.0, 80.1, 78.0, 75.9, 75.6, 75.4, 75.0, 73.1, 72.0, 69.4, 63.1, 61.4, 60.0, 55.1. IR (film): 3065, 3032, 2936, 1736, 1601 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C62H58O15Na, 1065.3673; found, 1065.3670.

3.8. 3-O-Benzoyl-1-O-(1,3,4,6-tetra-O-benzoyl-α-d-tagatofuranosyl)-N-stearoyl-d-erythro-sphingosine (10)

According to the general procedure for the glycosidation reaction in the presence of activated molecular sieves 4 Å (100 mg), compound 10 (114 mg) was obtained from the glycosyl donor 8 (100 mg, 0.12 mmol) and ceramide 2 (67.0 mg, 0.100 mmol) in 91% yield as a white solid. Eluent for column: 17% EtOAc in n-hexane. Rf = 0.62 (40% EtOAc in n-hexane). Mp 76–78 °C. 1H NMR (500 MHz, CDCl3) δ: 8.01–7.90 (6H, m, ArH), 7.85–7.78 (4H, m, ArH), 7.56–7.43 (5H, m, ArH), 7.43–7.33 (6H, m, ArH), 7.31–7.23 (4H, m, ArH), 6.12 (1H, dd, J4,5 = 6.5, J3,4 = 5.2 Hz, H-4), 5.96 (1H, d, J3,4 = 5.2 Hz, H-3), 5.86 (1H, dt, J4′,5′ = 15.2, J5′,6′ = 7.1 Hz, H-5′), 5.80 (1H, d, J2′,NH = 8.9 Hz, NH), 5.58 (1H, dd, J2′,3′ = 7.2, J3′,4′ = 7.2 Hz, H-3′), 5.49 (1H, ddt, J4′,5′ = 15.2, J3′,4′ = 7.2, J4′,6′ = 1.4 Hz, H-4′), 4.99 (1H, d, J1a,1b = 12.4 Hz, H-1a), 4.85 (1H, ddd, J5,6a = 6.8, J4,5 = 6.5, J5,6b = 5.4 Hz, H-5), 4.70 (1H, dd, J6a,6b = 11.6, J5,6a = 6.8 Hz, H-6a), 4.54 (1H, dd, J6a,6b = 11.6, J5,6b = 5.4 Hz, H-6b), 4.58–4.51 (1H, m, H-2′), 4.42 (1H, d, J1a,1b = 12.4 Hz, H-1b), 3.93 (2H, m, H-1′), 2.06 (2H, t, J = 7.7 Hz, CH2), 2.02–1.96 (2H, m, CH2), 1.61–1.47 (2H, m, CH2), 1.35–1.15 (50H, m, CH2), 0.88 (3H, t, J = 7.0, CH3), 0.87 (3H, t, J = 7.0, CH3). 13C{1H} NMR (126 MHz, CDCl3) δ: 173.0, 166.2, 166.1, 165.5, 165.2, 164.8, 137.4, 133.7, 133.6, 133.4, 133.3, 133.1, 130.2, 129.88 (2C), 129.86 (3C), 129.82 (2C), 129.80, 129.78 (2C), 129.6, 129.2, 128.9, 128.74 (2C), 128.72, 128.6 (2C), 128.53 (2C), 128.47 (2C), 128.4 (2C), 124.7, 106.8, 76.8, 75.4, 74.9, 72.1, 63.2, 60.7, 59.9, 51.3, 36.9, 32.5, 32.1 (2C), 29.9 (4C), 29.84 (3C), 29.81 (3C), 29.77 (2C), 29.7, 29.6, 29.54, 29.51 (3C), 29.44, 29.39, 29.0, 25.9, 22.8 (2C), 14.3 (2C). IR (KBr): 3385, 2920, 2851, 1719, 1655 cm−1.

3.9. 1-O-(α-d-Tagatofuranosyl)-N-stearoyl-d-erythro-sphingosine (11)

To a solution of glycoside 10 (80.0 mg, 64.1 μmol) in a 1:1 mixture of MeOH/CHCl3 (2 mL), a solution of 5 M NaOMe in MeOH (0.032 mL, 0.16 mmol) was added at room temperature. After 5 h, an excess of ion exchange resin (Amberlite FPC3500) was introduced into the reaction mixture, and the resulting suspension was filtered through a Celite pad. After removal of the solvent, the residue was purified by column chromatography on silica gel (7%MeOH in CHCl3), yielding the desired cerebroside 11 (35.3 mg) in 76% yield as a white solid. Rf = 0.31 (10% MeOH in CHCl3). Mp 118–120 °C. 1H NMR (500 MHz, CDCl3/CD3OD = 1:1) δ: 5.72 (1H, dt, J4′,5′ = 15.3, J5′,6′ = 6.8 Hz, H-5′), 5.45 (1H, dd, J4′,5′ = 15.3, J3′,4′ = 7.2 Hz, H-4′), 4.54 (1H, t, J = 5.8 Hz), 4.13–4.11 (1H, m), 4.08 (1H, t, J = 7.1 Hz), 4.02 (1H, d, J = 5.1 Hz), 3.96–3.93 (1H, m), 3.81–3.68 (5H, m), 3.60 (1H, dd, J = 10.1, 3.5 Hz), 2.19 (2H, t, J = 7.6 Hz, CH2), 2.06–2.00 (2H, m, CH2), 1.64–1.56 (2H, m, CH2), 1.43–1.18 (50H, m, CH2), 0.89 (6H, t, J = 6.9 Hz, CH3). 13C{1H} NMR (126 MHz, CDCl3/CD3OD = 1:1) δ: 175.4, 134.7, 129.7, 108.6, 80.6, 78.3, 75.2, 72.6, 72.1, 61.2, 60.8, 58.9, 54.3, 36.9, 32.9, 32.5 (2C), 30.25, 30.22 (8C), 30.19 (2C), 30.17, 30.1 (2C), 30.0, 29.88, 29.87 (2C), 29.85, 29.8, 26.5, 23.2 (2C), 14.3 (2C). IR (KBr): 3294 (br), 2918, 2851, 1638 cm−1.

3.10. 3-O-Benzoyl-1-O-(1,3,4,6-tetra-O-benzoyl-α-d-tagatofuranosyl)-N-methyl-N-stearoyl-d-erythro-sphingosine (13)

According to the general procedure for the glycosidation reaction (4.6), compound 13 (114 mg) was obtained from the glycosyl donor 8 (100 mg, 0.12 mmol) and N-methylceramide 12 (67.0 mg, 0.0979 mmol) in 92% yield as a colorless syrup. 1H NMR (500 MHz, CDCl3, 4:1 mixture of rotamers) δ: 8.06–7.77 (10H, m, ArH), 7.56–7.38 (5H, m, ArH), 7.38–7.22 (10H, m, ArH), 6.10 (0.8H, dd, J4,5 = 6.4, J3,4 = 5.1 Hz, major-H-4), 6.10–6.06 (0.2H, m, minor-H-4), 5.92 (1H, d, J3,4 = 5.1 Hz, H-3), 5.91–5.86 (1H, m, H-5′), 5.67–5.57 (1H, m, H-3′), 5.46 (1H, dd, J4′,5′ =15.4, J3′,4′ = 7.5 Hz, H-4′), 5.16 (0.8H, br s, major-H-2′), 4.95 (0.8H, ddd, J5,6a = 7.1, J4,5 = 6.4, J5,6b = 5.2 Hz, major-H-5), 4.87 (1H, d, J1a,1b = 12.3 Hz, H-1a), 4.84–4.78 (0.2H, m, minor-H-5), 4.70 (0.8H, dd, J6a,6b = 11.6, J5,6a = 7.1 Hz, major-H-6a), 4.67–4.61 (0.2H, m, minor-H-6a), 4.55 (1H, dd, J6a,6b = 11.6, J5,6b = 5.2 Hz, H-6b), 4.53–4.46 (1H, m, H-6b), 4.49 (0.2H, d, J1a,1b = 12.3 Hz, minor-H-1b), 4.42 (0.8H, d, J1a,1b = 12.3 Hz, major-H-1b), 4.35–4.28 (0.2H, m, minor-H-2′), 4.06 (0.8H, dd, J1′a,1′b = 10.6, J1′a,2′ = 3.8 Hz, major-H-1′a), 3.99 (0.2H, d, J1′a,1′b = 9.8, J1′a, 2′ = 4.1 Hz, minor-H-1′a), 3.96–3.85 (1H, m, H-1′b), 2.89 (2.4H, s, major-N-CH3), 2.79 (0.6H, s, minor-N-CH3), 2.46–2.38 (0.4H, m, minor-CH2), 2.33–2.19 (1.6H, m, major-CH2), 2.06–1.91 (2H, m, CH2), 1.68–1.55 (2H, m, CH2), 1.37–1.16 (50H, m, CH2), 0.88 (6H, t, J = 6.8, CH3). 13C{1H} NMR (126 MHz, CDCl3) δ: 174.5, 166.2, 165.7, 165.5, 165.1, 164.7, 137.9, 133.6, 133.5, 133.4, 133.2, 133.1, 130.2, 129.82 (2C), 129.80 (2C), 129.76 (5C), 129.7 (2C), 129.3, 128.9, 128.8, 128.7, 128.6 (2C), 128.53 (2C), 128.49 (2C), 128.41 (2C), 128.39 (2C), 125.4, 106.6, 76.7, 75.8, 74.1, 72.2, 63.3, 60.3, 59.5, 34.1, 32.3, 32.0 (2C), 29.84 (5C), 29.81 (3C), 29.78 (3C), 29.76, 29.73 (2C), 29.68, 29.66, 29.6, 29.5 (3C), 29.3, 29.0 25.2, 22.8 (2C), 14.2 (2C). IR (KBr): 2924, 2853, 1728, 1651, 1603 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C78H103NO13Na, 1284.7327; found, 1284.7324.

3.11. 1-O-(α-d-Tagatofuranosyl)-N-methyl-N-stearoyl-d-erythro-sphingosine (14)

Cerebroside 14 (51.7 mg) was obtained from glycoside 13 (93.0 mg, 0.0737 mmol) in a manner similar to that described for the synthesis of cerebroside 11 in 95% yield as a white solid. Eluent for column: 5% MeOH in CHCl3. Rf = 0.31 (10% MeOH in CHCl3). Mp 58–60 °C. 1H NMR (400 MHz, CDCl3/CD3OD = 1:1, 2:1 mixture of rotamers) δ: 5.81–5.63 (1H, m, H-5′), 5.40 (1H, ddd, J = 15.4, 7.9, 3.3 Hz, H-4′), 4.48 (2/3H, t, J = 5.7 Hz), 4.44 (1/3H, t, J = 5.7 Hz), 4.27–4.10 (2H, m), 4.03 (1/3H, d, J = 5.1 Hz), 4.00 (2/3H, d, J = 5.1 Hz), 3.93–3.61 (7H, m), 2.96 (2H, s, N-CH3), 2.82 (1H, s, N-CH3), 2.46–2.23 (2H, m), 2.14–1.91 (2H, m), 1.67–1.51 (2H, m), 1.49–1.15 (50H, m), 0.89 (6H, t, J = 6.7 Hz, CH3). 13C{1H} NMR (100 MHz, CDCl3/CD3OD = 1:1) δ: 175.8, 135.0, 130.4, 108.7, 80.7, 78.4, 75.6, 72.2, 71.4, 60.9, 60.3, 58.9, 34.6, 32.9, 32.5 (2C), 30.3 (13C), 30.23 (2C), 30.18 (2C), 30.1, 29.94 (2C), 29.88, 29.7, 25.8, 23.2 (2C), 14.4 (2C). IR (KBr): 3363 (br), 2913, 2849, 1616 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C43H83NO8Na, 764.6016; found, 764.6020.

4. Conclusions

In conclusion, we demonstrated the utility of a benzoyl-protected d-tagatofuranosyl donor. This donor predominantly yielded α-glycosides in d-tagatofuranosidation with various glycosyl acceptors, similar to the 3,4-O-isopropylidene-protected tagatofuranosyl donor. The synthesis of α-d-tagatofuranosylceramide has been challenging because of the deprotection issue associated with the 3,4-O-isopropylidene-protected tagatofuranosyl donor. However, in this method, the benzoyl protecting groups can be easily removed after the glycosidation reaction. We successfully synthesized α-d-tagatofuranosylceramide for the first time in this study. This strategy may serve as a valuable method for the synthesis of new d-tagatose derivatives.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms26178459/s1.

Author Contributions

Conceptualization, A.U.; methodology, A.U.; validation, Y.M., A.I., M.H., Y.H. and A.U.; formal analysis, Y.M., A.I., M.H., Y.H., M.T. and A.U.; investigation, Y.M., A.I., M.H., Y.H. and A.U.; writing—original draft preparation, A.U.; writing—review and editing, Y.M., A.I., M.H., Y.H., M.T. and A.U.; visualization, Y.M. and A.U.; supervision, A.U.; project administration, A.U.; funding acquisition, A.U. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partially funded by JSPS KAKENHI Grant Number JP23K06050 (A.U.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding author.

Acknowledgments

This work was the result of using research equipment shared in the MEXT Project for promoting the public utilization of advanced research infrastructure (program for supporting the introduction of the new sharing system), Grant Number JPMXS0422500320.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
BzBenzoyl
DMAPBenzyl
TBAFTetrabutylammonium fluoride
TBDPStert-Butyldiphenylsilyl
NBSN-Bromosuccinimide
BnBenzyl
DCCN,N’-Dicyclohexylcarbodiimide
Fmoc9-Fluorenylmethyloxycarbonyl
TMSOTfTrimethylsilyl trifluoromethanesulfonate

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Ijms 26 08459 sch001
Scheme 1. Glycosidation reaction of 2-ketohexofuranoses in previous reports and this work.
Scheme 1. Glycosidation reaction of 2-ketohexofuranoses in previous reports and this work.
Ijms 26 08459 sch001
Ijms 26 08459 sch002
Scheme 2. Synthesis of d-tagatofuranosyl donor 8.
Scheme 2. Synthesis of d-tagatofuranosyl donor 8.
Ijms 26 08459 sch002
Ijms 26 08459 sch003
Scheme 3. Direct synthesis of tetrabenzoylated d-tagatofuranose 7 along with known pyranose 7′ [47] from d-tagatose.
Scheme 3. Direct synthesis of tetrabenzoylated d-tagatofuranose 7 along with known pyranose 7′ [47] from d-tagatose.
Ijms 26 08459 sch003
Ijms 26 08459 sch004
Scheme 4. A plausible mechanism for glycosidation of d-tagatofuranosyl donor 8.
Scheme 4. A plausible mechanism for glycosidation of d-tagatofuranosyl donor 8.
Ijms 26 08459 sch004
Ijms 26 08459 sch005
Scheme 5. Synthesis of α-d-tagatofuranosylceramide.
Scheme 5. Synthesis of α-d-tagatofuranosylceramide.
Ijms 26 08459 sch005
Table 1. Glycosidation of d-tagatofuranosyl donor 8.
Table 1. Glycosidation of d-tagatofuranosyl donor 8.
Ijms 26 08459 i001
EntryR9Temp (°C)Time (min)Yield (%)α/β a
1Ijms 26 08459 i0029a−20308099:1
2Ijms 26 08459 i0039art306985:15
3Ijms 26 08459 i0049b0307299:1
4Ijms 26 08459 i0059c−20 to −10608192:8
5Ijms 26 08459 i0069d−20 to −10607894:6
6Ijms 26 08459 i0079e−20 to −10607693:7
7 bIjms 26 08459 i0089f−20 to 0605689:11
8 bIjms 26 08459 i0099g−20 to 06015 (α) + 6 (β)71:29 c
9Ijms 26 08459 i0109h−20308197:3
10Ijms 26 08459 i0119i−20308288:12
11Ijms 26 08459 i0129j−20307896:4
a The ratio was determined by 1H NMR except for entry 8. b An additional TMSOTf (1 equiv.) was added after 20 min. c Based on isolated yields.
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Makura, Y.; Iyoshi, A.; Horiuchi, M.; Hu, Y.; Tanaka, M.; Ueda, A. α-Selective Glycosidation of the Rare Sugar d-Tagatofuranose and the Synthesis of α-d-Tagatofuranosylceramide. Int. J. Mol. Sci. 2025, 26, 8459. https://doi.org/10.3390/ijms26178459

AMA Style

Makura Y, Iyoshi A, Horiuchi M, Hu Y, Tanaka M, Ueda A. α-Selective Glycosidation of the Rare Sugar d-Tagatofuranose and the Synthesis of α-d-Tagatofuranosylceramide. International Journal of Molecular Sciences. 2025; 26(17):8459. https://doi.org/10.3390/ijms26178459

Chicago/Turabian Style

Makura, Yui, Akihiro Iyoshi, Makito Horiuchi, Yiming Hu, Masakazu Tanaka, and Atsushi Ueda. 2025. "α-Selective Glycosidation of the Rare Sugar d-Tagatofuranose and the Synthesis of α-d-Tagatofuranosylceramide" International Journal of Molecular Sciences 26, no. 17: 8459. https://doi.org/10.3390/ijms26178459

APA Style

Makura, Y., Iyoshi, A., Horiuchi, M., Hu, Y., Tanaka, M., & Ueda, A. (2025). α-Selective Glycosidation of the Rare Sugar d-Tagatofuranose and the Synthesis of α-d-Tagatofuranosylceramide. International Journal of Molecular Sciences, 26(17), 8459. https://doi.org/10.3390/ijms26178459

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