Practical Glucosylations and Mannosylations Using Anomeric Benzoyloxy as a Leaving Group Activated by Sulfonium Ion.

One obstacle for practical glycosylations is the high cost of promoters and low-temperature equipment. This problem has been at least partially solved by using MeSCH2Cl/KI as a low-cost promoter system. MeSCH2Cl has an estimated cost of <$1/mol compared with $1741/mol for AgOTf and $633/mol for TMSOTf. This new promoter system is capable of activating various leaving groups including anomeric Cl, F, trichloroacetimidate, and acyloxy groups. Stable and easy-to-prepare anomeric benzoloxy carbohydrate donors were investigated in the glycosylations of carbohydrates, aliphatic alcohols, amino acids, steroids, and nucleoside acceptors. Most of these glycosylations were operationally simple with fast reaction rates and moderate yields of 35-79%. In addition, direct glycosylations of nucleosides using less than 2 equiv of anomeric benzoloxy donors and high stereoselective mannosylation have been achieved. From an economic point of view, this glycosylation method should be highly applicable to industrial processes.

Introduction

Carbohydrates play an important role in life science[1,2] and related fields such as medicinal chemistry and pharmaceuticals[3] because carbohydrate-derived drugs are used clinically and glycosylations are an important tool in drug discovery.[4] Thus, glycosylations are one of the most important research topics in carbohydrate chemistry.[5] As a result, a myriad of chemical glycosylation methods have been developed.[6−12] These methods are adapted for various glycosylation purposes by using different pairs of catalysts or promoters with an appropriate anomeric leaving group. Some well-known pairs include BF3/trichloroacetimidate,[13] NIS-TMSOTf or AgOTf/alkyl- or arylthio,[14,15] IDCP/pentenyl,[16,17] and AgOTf/halides.[18] The wide variety of leaving groups and catalyst or promoter pairs has made it possible to carry out chemoselective glycosylations as well as multistep glycosylations to obtain complex oligosaccharides[19−21] and one-pot synthesis of tris- or tetrasaccharides.[22−24] However, it continues to be important to further broaden the scope of leaving groups and catalyst or promoter pairs.

Classically, when these reactions are promoted by strong Lewis acids such as BF3[25] or SnCl4,[16] the acceptors used are more than 4 equiv. However, HClO4-catalyzed glycosylations have been reported to require only 1.2 equiv of donors.[26] Most of the other research have focused on employing functionalized acyloxy leaving groups including glycosyl phthalates,[27,28] glycosyl o-methoxybenzoates,[29] and glycosyl alkynylbenzoates,[30,31] catalyzed by SnCl3ClO4,[28] Ph3PAuOTf,[30,31] PhCCH/AuCl3,[32] and TMSOTf.[27,29,33−36] In most of these cases, the glycoside yields are excellent, but catalysts such as TMSOTf or AgOTf are very expensive and moisture-sensitive, or they contaminate the products with metals. In addition, low-temperature conditions are often required to conduct these reactions, and this is not cost-effective in terms of energy and equipment. These have somewhat restricted the use of these methods, especially in the pharmaceutical industry. Our research is aimed at the development of economic glycosylations using anomeric acyloxy carbohydrates as donors with an inexpensive promoter. To this end, we have developed a promoter system consisting of MeSCH2Cl/KI, which is capable of activating the anomeric benzoloxy of a carbohydrate donor for glycosylations. The results are reported herein.

Results and Discussion

Crystalline β-glycosyl benzoate 1a, which can be prepared quantitatively according to our recently published method,[37] was selected as the carbohydrate donor, and lauryl alcohol (2a) was selected as the acceptor (Table ). Cyanuric chloride-activated dimethyl sulfoxide (DMSO) has been investigated as a precatalyst in several synthetic methods,[38−41] and it has been shown to have Lewis acid properties. Therefore, cyanuric chloride and DMSO were used to promote the glycosylation between 1a and 2a in acetonitrile (MeCN) at 80 °C. The reaction gave glycoside 3a in 10% yield. A nuclear magnetic resonance (NMR) analysis of the reaction product of cyanuric chloride and DMSO showed the presence of MeSCH2Cl. This compound was also reported by Knorr in the reaction between acyl chloride and DMSO.[42] On the basis of this, a mixture of 1a and 2a (1.0 equiv each) was treated with MeSCH2Cl (2.5 equiv) and KI (0.7 equiv) in MeCN (2 mL) at room temperature and at 45 °C, but no glycosylations occurred (Table , entries 1 and 2). However, to our delight, elevating the temperature to 80 °C produced 3a in 35% yield (Table , entry 3), and increasing the amount of glycosyl ester to 1.9 equiv raised the yield to 46% (Table , entry 4). Using KI, NaI, or tetrabutyl ammonium iodide (TBAI) determined that KI is the optimal source of I– (Table , entries 4–6). Various solvents including MeCN, dichloroethane (DCE), tetrahydrofuran (THF), toluene, chloroform, ethyl acetate, and DMSO were screened, and the results indicated that toluene is the optimal solvent (Table , entries 7–12). A 73% yield was obtained with toluene (Table , entry 12). Changing the amount of toluene from 1 to 4 mL did not affect the results (Table , entries 13 and 14). In summary, the optimized conditions were 1.9 equiv of β-glycosyl benzoate 1a and 1.0 equiv of lauryl alcohol (2a) promoted by 2.5 equiv of MeSCH2Cl and 0.7 equiv of KI, with 4 Å molecular sieves (MS) in toluene (2 mL) at 80 °C under N2.

Table 1

Optimization of Glucosylation Conditionsa

entry	1a (equiv)	I–	solvent	temperature (°C)	yield (%)b	α/β
1	1.0	KI	MeCN (2 mL)	r.t.	NRc
2	1.0	KI	MeCN (2 mL)	45	NRc
3	1.0	KI	MeCN (2 mL)	80	35	3:2
4	1.9	KI	MeCN (2 mL)	80	46	3:2
5	1.9	NaI	MeCN (2 mL)	80	40	6:5
6	1.9	TBAI	MeCN (2 mL)	80	NRc
7	1.9	KI	DCE (2 mL)	80	38	6:5
8	1.9	KI	THF (2 mL)	80	25	8:3
9	1.9	KI	DMSO (2 mL)	80	NRc
10	1.9	KI	CHCl3 (2 mL)	80	71	13:5
11	1.9	KI	EA (2 mL)	80	70	14:5
12	1.9	KI	toluene (2 mL)	80	73	4:1
13	1.9	KI	toluene (1 mL)	80	73	4:1
14	1.9	KI	toluene (4 mL)	80	73	4:1

Reaction conditions: β-glucosyl ester 1a, lauryl alcohol (2a, 1.0 equiv), MeSCH2Cl: 2.5 equiv, KI: 0.7 equiv, and 4 Å MS under N2 at 80 °C.

Isolated yield.

NR, no reaction.

Under the optimized condition, 11 glucosylations were performed, among which 3 products were disaccharides (Scheme , 3f, 3g, and 3e). The carbohydrate acceptor with a primary hydroxyl group gave a better yield than the acceptor with a secondary one (3f vs 3h). The yields were lower for the nitrogen-containing (3c) and tertiary alcohol (3e) acceptors. The best yield was achieved for 3j (79%), starting from a steroid acceptor with a secondary hydroxyl group.

Scheme 1

Expanding the Substrate Scope for Glucosylations Using 1.9 equiv of Donor 1a and Promoted by MeSCH2Cl/KI

Reaction conditions: β-glucosyl ester 1a (1.9 equiv), acceptor 2 (1.0 equiv), MeSCH2Cl: 2.5 equiv, KI: 0.7 equiv, and 4 Å MS under N2 at 80 °C.

These results demonstrate that when glucosylations are promoted by MeSCH2Cl/KI, a benzoloxy group at the anomeric center can function as a good leaving group. The advantages of this leaving group are its easy preparation and long-shelf life. In the glycosylations using anomeric acyloxy as the leaving group activated by a strong Lewis acid such as SnCl4,[16] an excess amount of a strong acid can activate the glycosidic bond of the product, causing a substitution of the acceptor by the acetoxy group. This can be avoided by using an excess amount of acceptor to drive the glycosylation to completion. The high-cost problems of catalysts for new anomeric esters developed from functionalized acids[30−35] can be solved using cheap promoters/catalysts such as MeSCH2Cl/KI. MeSCH2Cl is readily prepared from the cheap bulk chemicals cyanuric chloride and DMSO,[43] a liquid with a slight garlic odor, bp 105–108 °C. The preparation cost of MeSCH2Cl is estimated to be <$1/mol compared with $1741/mol for AgOTf and $633/mol for TMSOTf. Therefore, this method has obvious cost advantages.

Another advantage of the MeSCH2Cl/KI promoter system is that it does not activate the glycosidic bond, and as a result, less than 2 equiv of carbohydrate donor is enough to drive the reaction to completion.

Next, the applicability of this promoter to other leaving groups was explored. As shown in Scheme , anomeric fluoro donor 1b gave glucosylated 2f in 33% yield. Anomeric chloro donor 1c gave a 42% yield of disaccharide 3f. Schmidt donor 1e proved to be almost as effective (61%) as anomeric benzoloxy donor 1a. Mannosyl donor β-1f with an anomeric benzoloxy group was activated to yield 3l stereoselectively (38%, only α-anomer). All reactions were fast (1–4.5 h). When the leaving group was Br (1d), EtS (1g), TBDMSO (1h), or OH (1i), no glycosylations occurred. In addition, with disarmed donors, glycosylations with 2f all ended in failure. This suggests that armed and disarmed donors can be employed orthogonally[5] in oligosaccharide synthesis when promoted by MeSCH2Cl/KI along with other catalyst/promoter systems.

Scheme 2

Expanding the Carbohydrate Donor Scope for Glycosylations Using 1.9 equiv of Donor 1 and Promoted by MeSCH2Cl/KI

Reaction conditions: β-glycosyl donor 1 (1.9 equiv), acceptor 2f (1.0 equiv), MeSCH2Cl: 2.5 equiv, KI: 0.7 equiv, and 4 Å MS under N2 at 80 °C.

The MeSCH2Cl/KI-promoted glycosylation with the reactive leaving group was further explored for other acceptors, and better results were obtained using steroid 2j as the acceptor (Scheme ). Both glucosyl donors 1c and 1e and mannosyl donors α-1f, β-1f, and 1o were subjected to the conditions, and most of the yields were around 56–69%. In the case of α-1f and β-1f, similar yields were obtained (68 and 69%). For all three cases that started from mannosyl donors (α-1f, β-1f, and 1o), α-mannoside was stereoselectively obtained. Other methods have been reported for the diastereoselective synthesis of α-mannosylations,[7,8] but most of them are more expensive than this procedure. Glucosylations of tigogenin (2k) using 1c and 1e as the glucosyl donors delivered glucoside 3k with even better yields (74 and 79%, respectively).

Scheme 3

Further Expanding the Carbohydrate Donor Scope for Glycosylations Using 2j or 2k as Acceptors Promoted by MeSCH2Cl/KI

Reaction conditions: β-glycosyl ester 1 (1.9 equiv), acceptor 2j or 2k (1.0 equiv), MeSCH2Cl: 2.5 equiv, KI: 0.7 equiv, and 4 Å MS under N2 at 80 °C.

Finally, the glycosylation acceptor scope was expanded to include nucleosides (Scheme ). Six glycosylated nucleosides were synthesized, including three glucosylations and three mannosylations. Although the yields for the nucleoside glycosylations are not high (34–47%), this represents a practical procedure with a benzoloxy leaving group that uses less than 2 equiv of donors. It is well-known that direct glycosylations of nucleosides are difficult and excessive amounts of glycosyl donors are necessary. Only one direct glycosylation of nucleosides has previously been reported,[44] which used 1.2 equiv of the donors and was promoted by 1.5 equiv of In(OTf)3 to give fair-to-excellent yields of nucleoside disaccharides. However, our method has advantage in terms of cost efficiency because the cost of In(OTf)3 is about $3855/mol compared with <$1/mol for MeSCH2Cl. In addition, our method avoids the use of toxic heavy metals.

Scheme 4

Direct Glycosylations of Nucleosides Promoted by MeSCH2Cl/KI

Reaction conditions: β-glycosyl ester 1 (1.9 equiv), nucleosides 2n–2p (1.0 equiv), MeSCH2Cl: 2.5 equiv, KI: 0.7 equiv, and 4 Å MS under N2 at 80 °C.

Among the six glycosylated nucleosides, two products started from zidovudine (AZT, a nucleoside), the first clinical drug used to treat HIV.[45] For the first time, AZT was successfully glucosylated (3r) and mannosylated (3s). Bioassays of these two products will be conducted.

A proposed mechanism for glycosylation is shown in Scheme . Chloromethyl methyl sulfide is in equilibrium or in resonance with sulfonium ion A, which is capable of associating with the sp2 oxygen atom of ester 1a, but cannot effectively associate with sp3 oxygen atoms. Intermediate B forms from the activation of 1a by A, and then, B decomposes to D and glycosyl cation C. Trapping glycosyl cation C with the carbohydrate acceptor ROH leads to glycoside 3. The reason that more than 2 equiv of chloromethyl methyl sulfide is required is probably because more BzOCH2SMe (E) is formed from D than from A, and/or the formation of E is irreversible. Therefore, only some of the chloromethyl methyl sulfide functions as the catalyst, and the majority acts as a promoter.

Scheme 5

Proposed Mechanism for the Glycosylation Promoted by MeSCH2Cl/KI

To support the SN1-like mechanism involving C (Scheme ),[46] a set of reactions between lauryl alcohol and glycosyl ester α/β-1a (α/β = 1:2.1) and α/β-1p (α/β = 1:2.3) were conducted (Scheme ). The two glycosylations resulted in similar α/β ratios (3:1 vs 2.7:1) in diasteroeselectivity, reaction yields (70 vs 72%), and reaction times (4 vs 3 h). This indicates that anomeric benzoloxy and acetoxy function as leaving groups in similar ways. The faster reaction rate of α/β-1p (compared with α/β-1a) suggests that sulfonium ion A is a weak Lewis acid (Scheme ) that activates the stronger Lewis base α/β-1p more efficiently. To our knowledge, a sulfonium ion has never been reported as a Lewis acid, although Lewis acid phosphonium and siliconium ions are known.[47] It was reported that the formation of the side product thioacetal from the alcohol oxidation by activated DMSO is attributed to the addition of alcohol to sulfonium ion A.[48]

Scheme 6

Glucosylations of α/β Donor Mixtures Promoted by MeSCH2Cl/KI

Reaction conditions: β-glucosyl ester 1 (1.9 equiv), lauryl alcohol (2a, 1.0 equiv), MeSCH2Cl: 2.5 equiv, KI: 0.7 equiv, and 4 Å MS under N2 at 80 °C.

Similar results for pure β-1a (Scheme ) and α/β-1a (Scheme ) indicate that mixed acyloxy anomers can be used as carbohydrate donors without the need for separation. This is also supported by the similar performance of mannosyl donors α-1f and β-1f with acceptor 2f (Scheme ). This means that α/β glycosyl ester donor mixtures, which are much easier to prepare than their single anomer counterparts, are applicable to this procedure.

In summary, cost-effective glycosylation reactions with a broad spectrum of anomeric leaving groups have been achieved using a new promoter. This organo-promoter system can replace many expensive catalysts, some of which contain toxic heavy metals. This promoter is capable of facilitating glycosylations with anomeric benzoloxy donors on various acceptors. A notable result is the first direct glycosylation of a nucleoside using a benzoloxy leaving group in a cost-effective and heavy metal-free way. This practical method is attractive to industries for reducing the costs of expensive catalysts and low-temperature equipment. The mechanism of glycosylation has been discussed.

Experimental Section

General Information

Commercially available reagents were used without further purification. The starting materials 1a,[37]1c–1o,[49−57]2c,[58]2f,[59]2g,[54]2h,[60]2n–2o,[54] and MeSCH2Cl[43] were prepared according to the literature. 1H NMR and 13C NMR spectra were recorded with a 400 or 600 MHz spectrometer using tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are reported relative to TMS (1H) or CDCl3 (13C). High-resolution mass spectra (HRMS) were recorded on a quadrupole time-of-flight (QTOF) mass analyzer using electrospray ionization (ESI).

Procedure for the Synthesis of 1a

A mixture of 2,3,4,6-tetra-O-benzyl-α-d-glucopyranosyl chloride (300 mg), benzoic acid (1.05 equiv, 69 mg), Cs2CO3 (0.51 equiv, 89 mg), tetrabutyl ammonium bromide (TBAB, 0.05 equiv, 9 mg), and granular polytetrafluoroethylene (PTFE) sand (5 g) was mechanically stirred (400 rpm) at 80 °C for 2 min, followed by the addition of water (10 equiv, 97 mg). Initially, the reaction media appeared as thick milk, and it gradually turned to a semisolid that adhered to the glass. After thin-layer chromatography (TLC) indicated completion of the reaction, ethyl acetate (2 × 10 mL) was added to extract the crude product, which was washed with 5% aqueous Na2CO3 (1 × 10 mL) and water (1 × 10 mL) and dried over Na2SO4. Concentration under reduced pressure gave 2,3,4,6-tetra-O-benzyl-β-d-glucopyranosyl benzoate 1a (351 mg, >99%).

General Procedure for Glycosylation Using the Glycosylation of 2a as an Example

To a solution of 2a (0.5 mmol, 93 mg) in dry toluene (2 mL) were added 1a (0.95 mmol, 612 mg), MeSCH2Cl (2.5 mmol, 120 mg), KI (0.35 mmol, 58 mg), and 4 Å MS. The mixture was stirred at 80 °C under N2 (monitored by TLC). After completion, the reaction mixture was quenched with 5% aqueous Na2CO3 (10 mL) and extracted with dichloromethane (DCM) (2 × 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and evaporated under vacuum. The residue was purified by chromatography to yield 3a (89 mg, 73%).

n-Dodecyl 2,3,4,6-Tetra-O-benzyl-α/β-glucopyranoside (3a)[61]

Method A: starting from β-glucosyl ester 1a (Scheme ). β-Glucosyl ester 1a (0.95 mmol, 612 mg) and alcohol 2a (0.5 mmol, 93 mg) were reacted according to the general procedure. After chromatography, glucoside 3a was isolated as a syrup (258 mg, 73% yield, α/β = 4/1); 1H NMR (400 MHz, CDCl3): δ 7.42–7.09 (m, 25H), 4.99 (d, J = 10.8 Hz, 1H), 4.93 (d, J = 10.8 Hz, 0.5H), 4.89–4.73 (m, 4H), 4.72 (d, J = 11.0 Hz, 0.5H), 4.62 (dd, J = 24.6, 11.3 Hz, 2.5H), 4.46 (dd, J = 11.2, 2.8 Hz, 2H), 4.39 (d, J = 7.5 Hz, 0.5H), 3.99 (t, J = 9.3 Hz, 1.25H), 3.77 (d, J = 10.4 Hz, 1H), 3.73 (dd, J = 10.4, 3.2 Hz, 1H), 3.69–3.59 (m, 3.25H), 3.55 (dd, J = 9.6, 3.6 Hz, 1.5H), 3.48–3.37 (m, 1.5H), 1.71–1.58 (m, 2.5H), 1.26 (s, 22.5H), 0.88 (t, J = 6.6 Hz, 3.75H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.4, 138.3, 138.0, 128.4, 128.2, 128.1, 128.0, 127.98, 127.88, 127.82, 127.75, 127.6, 96.9, 82.2, 80.1, 77.8, 75.8, 75.2, 74.9, 73.5, 73.2, 70.1, 68.5, 68.3, 29.7, 29.5, 26.3, 22.8, 14.2.

Method B: starting from α/β-glucosyl ester 1a (α/β = 1/2.1) (Scheme ). α/β-Glucosyl ester 1a (0.95 mmol, 612 mg) and alcohol 2a (0.5 mmol, 93 mg) were reacted according to the general procedure. After chromatography, glucoside 3a was isolated as a syrup (248 mg, 70% yield, α/β = 3/1); 1H NMR (400 MHz, CDCl3): δ 7.42–7.09 (m, 26H), 4.99–3.37 (m, 22H), 1.71–1.58 (m, 2.6H), 1.26 (s, 23H), 0.88 (t, J = 6.6 Hz, 3.9H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.4, 138.3, 138.0, 128.4, 128.2, 128.1, 128.0, 127.98, 127.88, 127.82, 127.75, 127.6, 96.9, 82.2, 80.1, 77.8, 75.8, 75.2, 74.9, 73.5, 73.2, 70.1, 68.5, 68.3, 29.7, 29.5, 26.3, 22.8, 14.2.

Method C: starting from α/β-glucosyl ester 1p (α/β = 1/2.3) (Scheme ). α/β-Glucosyl ester 1p (0.95 mmol, 553 mg) and alcohol 2a (0.5 mmol, 93 mg) were reacted according to the general procedure. After chromatography, glucoside 3a was isolated as a syrup (248 mg, 72% yield, α/β = 2.7/1); 1H NMR (400 MHz, CDCl3): δ 7.42–7.09 (m, 27H), 4.99–3.37 (m, 23H), 1.71–1.58 (m, 2.7H), 1.26 (s, 24H), 0.88 (t, J = 6.6 Hz, 4H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.4, 138.3, 138.0, 128.4, 128.2, 128.1, 128.0, 127.98, 127.88, 127.82, 127.75, 127.6, 96.9, 82.2, 80.1, 77.8, 75.8, 75.2, 74.9, 73.5, 73.2, 70.1, 68.5, 68.3, 29.7, 29.5, 26.3, 22.8, 14.2.

n-Cyclohexyl 2,3,4,6-Tetra-O-benzyl-α/β-glucopyranoside (3b)[62,63]

Glucosyl ester 1a (0.95 mmol, 612 mg) and alcohol 2b (0.5 mmol, 50 mg) were reacted according to the general procedure. After chromatography, glucoside 3b was isolated as a syrup (168 mg, 54% yield, α/β = 3.5/1); 1H NMR (400 MHz, CDCl3): δ 7.41–7.09 (m, 26H), 5.00 (d, J = 10.8 Hz, 1.3H), 4.97–4.89 (m, 1.3H), 4.86–4.77 (m, 2.6H), 4.77–4.56 (m, 4H), 4.56–4.49 (m, 0.6H), 4.49–4.43 (m, 2H), 4.00 (t, J = 9.3 Hz, 1H), 3.88 (d, J = 9.0 Hz, 1H), 3.74 (dd, J = 10.6, 3.8 Hz, 1.6H), 3.69–3.60 (m, 2.6H), 3.60–3.49 (m, 2.3H), 3.45 (dd, J = 13.8, 5.9 Hz, 0.6H), 2.07–1.80 (m, 2.6H), 1.80–1.69 (m, 2.6H), 1.51–1.13 (m, 6.9H); 13C NMR (101 MHz, CDCl3): δ 139.1, 138.4, 138.3, 138.1, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.96, 127.88, 127.79, 127.75, 127.72, 127.6, 102.0, 94.7, 84.9, 82.2, 80.0, 78.1, 77.9, 75.7, 75.3, 75.2, 75.1, 74.92, 74.87, 73.5, 73.0, 70.1, 68.6, 33.9, 33.4, 32.1, 31.5, 25.7, 24.6, 24.3.

(4S)-[(2′,3′,4′,6′-Tetra-O-benzyl-β-d-glucopyranosyl)oxy]-1-[(4-methylphenyl)sulfonyl]-l-proline (3c)

Glucosyl ester 1a (0.95 mmol, 612 mg) and amino acid 2c (0.5 mmol, 143 mg) were reacted according to the general procedure. After chromatography, glucoside 3c was isolated as a syrup (117 mg, 29% yield, α/β = 5/1); 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1.2H), 7.79 (d, J = 7.9 Hz, 2H), 7.45–7.10 (m, 26H), 4.93 (d, J = 10.8 Hz, 1.2H), 4.89–4.70 (m, 4H), 4.68 (d, J = 5.7 Hz, 0.2H), 4.60 (t, J = 11.2 Hz, 2.2H), 4.50–4.41 (m, 2H), 4.40 (d, J = 5.8 Hz, 0.2H), 4.36–4.28 (m, 1H), 4.20 (t, J = 7.1 Hz, 1H), 3.85 (dd, J = 10.3, 5.2 Hz, 1H), 3.76–3.53 (m, 4.4H), 3.49 (dd, J = 8.9, 3.2 Hz, 1H), 3.44 (d, J = 9.1 Hz, 1H), 3.39 (dd, J = 10.4, 2.9 Hz, 1H), 2.40–2.35 (m, 0.4H), 2.30 (d, J = 7.1 Hz, 2H), 2.23 (s, 2.2H), 2.10 (s, 1.4H); 13C NMR (101 MHz, CDCl3): δ 177.0, 143.9, 138.8, 138.2, 138.1, 137.9, 129.9, 128.6, 128.5, 128.4, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 97.5, 81.7, 79.8, 75.6, 75.2, 73.5, 73.2, 70.9, 68.1, 60.5, 53.9, 37.1, 21.5; HRMS (ESI) m/z: [M + Na]+ calcd for C46H49NO10SNa+ 830.2969; found 830.2969.

l-Menthyl 2,3,4,6-Tetra-O-benzyl-α/β-glucopyranoside (3d)[64,65]

Glucosyl ester 1a (0.95 mmol, 612 mg) and alcohol 2d (0.5 mmol, 78 mg) were reacted according to the general procedure. After chromatography, glucoside 3d was isolated as a syrup (234 mg, 69% yield, α/β = 5/1); 1H NMR (400 MHz, CDCl3): δ 7.39–7.05 (m, 22H), 5.06–4.95 (m, 2H), 4.93 (d, J = 10.8 Hz, 0.4H), 4.83 (dd, J = 10.8, 5.1 Hz, 2.4H), 4.75–4.62 (dt, J = 24.0, 12.0 Hz, 3.2H), 4.56 (dd, J = 16.2, 11.9 Hz, 0.6H), 4.46 (dd, J = 11.4, 7.9 Hz, 2.2H), 4.00 (dd, J = 20.8, 11.0 Hz, 2H), 3.75 (dd, J = 10.4, 3.3 Hz, 1H), 3.69 (d, J = 2.4 Hz, 0.4H), 3.67–3.58 (m, 2.4H), 3.55 (dd, J = 9.8, 3.3 Hz, 1H), 3.51–3.40 (m, 0.6H), 3.35 (td, J = 10.6, 4.1 Hz, 1H), 2.48–2.36 (m, 1.2H), 2.12 (d, J = 11.8 Hz, 1.2H), 1.71–1.55 (m, 2.8H), 1.44–1.20 (m, 3.4H), 1.10–0.74 (m, 12H), 0.70 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.5, 138.4, 138.1, 128.44, 128.43, 128.36, 128.2, 128.0, 127.9, 127.7, 127.6, 98.7, 85.0, 82.1, 81.0, 80.6, 78.1, 75.6, 75.2, 73.5, 73.2, 70.4, 68.7, 48.8, 43.1, 34.3, 31.8, 24.6, 23.0, 22.4, 21.2, 16.2.

1′-Adamantyl 2,3,4,6-Tetra-O-benzyl-α/β-glucopyranoside (3e)[66]

Glucosyl ester 1a (0.95 mmol, 612 mg) and alcohol 2e (0.5 mmol, 76 mg) were reacted according to the general procedure. After chromatography, glucoside 3e was isolated as a syrup (138 mg, 41% yield, α/β = 1.5/1); 1H NMR (400 MHz, CDCl3): δ 7.43–7.05 (m, 33H), 5.28 (d, J = 3.6 Hz, 1H), 5.05–4.95 (m, 1.67H), 4.91 (d, J = 10.9 Hz, 0.67H), 4.86–4.77 (m, 2.67H), 4.74 (d, J = 12.3 Hz, 0.67H), 4.71–4.61 (m, 3H), 4.61–4.50 (m, 2H) (β), 4.47 (d, J = 5.0 Hz, 1H), 4.44 (d, J = 6.5 Hz, 1H), 4.18–3.95 (m, 2H), 3.81–3.70 (m, 1.67H), 3.69–3.58 (m, 3.34H), 3.53 (dd, J = 9.6, 3.7 Hz, 1H), 3.49 (d, J = 8.4 Hz, 0.67H), 3.44 (dd, J = 16.1, 7.9 Hz, 0.67H), 2.14 (s, 5H), 2.04–1.76 (m, 10H), 1.69–1.55 (m, 10H); 13C NMR (101 MHz, CDCl3): δ 139.2, 138.8, 138.7, 138.5, 138.44, 138.40, 138.3, 138.2, 128.50, 128.49, 128.43, 128.40, 128.37, 128.29, 128.11, 128.09, 128.02, 127.98, 127.89, 127.85, 127.81, 127.73, 127.69, 127.61, 127.59, 96.4, 90.0, 85.2, 82.4, 82.2, 80.2, 78.3, 78.2, 75.9, 75.7, 75.4, 75.2, 75.1, 74.7, 73.6, 73.5, 73.0, 69.8, 69.6, 68.8, 42.9, 42.6, 36.4, 30.8, 30.7.

6-O-(2′,3′,4′,6′-Tetra-O-benzyl-α/β-glucopyranosyl)-(1-6)-1,2:3,4-di-O-isopropylidene-α-d-galactopyranose (3f)[64]

Method A: starting from β-glucosyl ester 1a (Scheme ). Glucosyl ester 1a (0.95 mmol, 612 mg) and galactose 2f (0.5 mmol, 130 mg) were reacted according to the general procedure. After chromatography, glucoside 3f was isolated as a syrup (242 mg, 62% yield, α/β = 3.3/1); 1H NMR (400 MHz, CDCl3): δ 7.46–7.10 (m, 26H), 5.57 (d, J = 5.0 Hz, 0.3H), 5.52 (d, J = 5.0 Hz, 1H), 5.05 (d, J = 11.1 Hz, 0.3H), 5.02–4.89 (m, 2H), 4.81 (dd, J = 10.8, 8.2 Hz, 2.6H), 4.72 (q, J = 11.8 Hz, 2.6H), 4.66–4.51 (m, 3.2H), 4.47 (dd, J = 11.4, 6.1 Hz, 2.3H), 4.35 (dd, J = 7.9, 1.7 Hz, 1H), 4.31 (dd, J = 4.9, 2.3 Hz, 1.3H), 4.24 (dd, J = 7.9, 1.7 Hz, 0.3H), 4.16 (dd, J = 10.6, 3.6 Hz, 0.3H), 4.09 (d, J = 7.5 Hz, 0.3H), 4.03 (t, J = 6.9 Hz, 1H), 3.98 (t, J = 9.3 Hz, 1H), 3.85–3.55 (m, 8.5H), 3.46 (s, 0.6H), 1.53 (s, 3H), 1.50 (s, 0.9H), 1.45 (s, 3.9H), 1.32 (d, J = 4.9 Hz, 7.8H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.7, 138.4, 138.0, 128.8, 128.5, 128.3, 128.03, 127.97, 127.91, 127.81, 127.76, 127.6, 127.5, 109.4, 109.3, 108.7, 104.5, 97.1, 96.5, 96.4, 84.6, 82.0, 81.7, 79.8, 77.7, 77.5, 75.7, 75.1, 74.8, 74.4, 73.5, 72.4, 71.5, 70.9, 70.7, 70.3, 69.8, 68.3, 67.4, 66.2, 65.7, 26.3, 26.2, 26.11, 26.08, 25.1, 25.0, 24.7, 24.5.

Method B: starting from α-glucosyl fluoride 1b (Scheme ). α-Glucosyl fluoride 1b (0.95 mmol, 515 mg) and galactose 2f (0.5 mmol, 130 mg) were reacted according to the general procedure. After chromatography, glucoside 3f was isolated as a syrup (129 mg, 33% yield, α/β = 3.3/1); 1H NMR (400 MHz, CDCl3): δ 7.51–6.95 (m, 26H), 5.57 (d, J = 4.9 Hz, 0.3H), 5.52 (d, J = 4.9 Hz, 1H), 5.09–3.41 (m, 28H), 1.53 (s, 3H), 1.50 (s, 1H), 1.45 (s, 3.9H), 1.31 (s, 7.8H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.7, 138.4, 138.0, 128.8, 128.5, 128.3, 128.03, 127.97, 127.91, 127.81, 127.76, 127.6, 127.5, 109.4, 109.3, 108.7, 104.5, 97.1, 96.5, 96.4, 84.6, 82.0, 81.7, 79.8, 77.7, 77.5, 75.7, 75.1, 74.8, 74.4, 73.5, 72.4, 71.5, 70.9, 70.7, 70.3, 69.8, 68.3, 67.4, 66.2, 65.7, 26.3, 26.2, 26.11, 26.08, 25.1, 25.0, 24.7, 24.5.

Method C: starting from α-glucosyl chloride 1c (Scheme ). α-Glucosyl chloride 1c (0.95 mmol, 530 mg) and galactose 2f (0.5 mmol, 130 mg) were reacted according to the general procedure. After chromatography, glucoside 3f was isolated as a syrup (164 mg, 42% yield, α/β = 2.7/1); 1H NMR (400 MHz, CDCl3): δ 7.51–6.95 (m, 28H), 5.57 (d, J = 4.9 Hz, 0.37H), 5.52 (d, J = 4.9 Hz, 1H), 5.09–3.41 (m, 30H), 1.53 (s, 3H), 1.50 (s, 1.11H), 1.45 (s, 4.11H), 1.31 (s, 8.22H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.7, 138.4, 138.0, 128.8, 128.5, 128.3, 128.03, 127.97, 127.91, 127.81, 127.76, 127.6, 127.5, 109.4, 109.3, 108.7, 104.5, 97.1, 96.5, 96.4, 84.6, 82.0, 81.7, 79.8, 77.7, 77.5, 75.7, 75.1, 74.8, 74.4, 73.5, 72.4, 71.5, 70.9, 70.7, 70.3, 69.8, 68.3, 67.4, 66.2, 65.7, 26.3, 26.2, 26.11, 26.08, 25.1, 25.0, 24.7, 24.5.

Method D: starting from α-glucosyl imidate 1e (Scheme ). α-Glucosyl imidate 1e (0.95 mmol, 649 mg) and galactose 2f (0.5 mmol, 130 mg) were reacted according to the general procedure. After chromatography, glucoside 3f was isolated as a syrup (238 mg, 61% yield, α/β = 2.2/1); 1H NMR (400 MHz, CDCl3): δ 7.51–6.95 (m, 29H), 5.57 (d, J = 4.9 Hz, 0.46H), 5.52 (d, J = 4.9 Hz, 1H), 5.09–3.41 (m, 31H), 1.53 (s, 3H), 1.50 (s, 1.38H), 1.45 (s, 4.38H), 1.31 (s, 8.76H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.7, 138.4, 138.0, 128.8, 128.5, 128.3, 128.03, 127.97, 127.91, 127.81, 127.76, 127.6, 127.5, 109.4, 109.3, 108.7, 104.5, 97.1, 96.5, 96.4, 84.6, 82.0, 81.7, 79.8, 77.7, 77.5, 75.7, 75.1, 74.8, 74.4, 73.5, 72.4, 71.5, 70.9, 70.7, 70.3, 69.8, 68.3, 67.4, 66.2, 65.7, 26.3, 26.2, 26.11, 26.08, 25.1, 25.0, 24.7, 24.5.

Methyl 2,3,4-Tri-O-acetyl-6-O-(2′,3′,4′,6′-tetra-O-benzyl-α/β-d-glucopyranosyl)-(1-6)-α-d-glucopyranoside (3g)[67]

Glucosyl ester 1a (0.95 mmol, 612 mg) and glucoside 2g (0.5 mmol, 160 mg) were reacted according to the general procedure. After chromatography, glucoside 3g was isolated as a syrup (206 mg, 49% yield, α/β = 7/1); 1H NMR (400 MHz, CDCl3): δ 7.39–7.10 (m, 22.8H), 5.52–5.40 (m, 1H), 5.06–4.96 (m, 1H), 4.94 (d, J = 10.9 Hz, 1.14H), 4.90 (d, J = 3.6 Hz, 1.14H), 4.85–4.72 (m, 5H), 4.62 (dd, J = 30.6, 12.1 Hz, 1H), 4.46 (dd, J = 11.6, 6.7 Hz, 1H), 4.05–3.99 (m, 2H), 3.99–3.90 (m, 2H), 3.82 (d, J = 9.2 Hz, 1H), 3.76–3.71 (m, 1H), 3.67 (dd, J = 11.4, 7.8 Hz, 2H), 3.63–3.58 (m, 2H), 3.55 (dd, J = 9.7, 3.5 Hz, 1H), 3.53–3.47 (m, 1H), 3.36 (s, 3H), 3.30 (s, 0.42H), 2.06 (s, 3.42H), 1.99 (m, 6.84H); 13C NMR (101 MHz, CDCl3): δ 170.23, 170.17, 169.8, 138.8, 138.5, 138.4, 137.9, 128.5, 128.4, 128.3, 128.0, 127.97, 127.96, 127.82, 127.75, 127.71, 127.6, 97.2, 96.4, 81.8, 79.8, 77.6, 75.6, 74.9, 73.5, 73.1, 71.1, 70.4, 70.3, 69.5, 68.4, 68.1, 66.5, 55.4, 20.81, 20.80.

Methyl 3-O-Benzyl-2-O-(2′,3′,4′,6′-tetra-O-benzyl-α-glucopyranosyl)-(1-2)-4,6-O-methylene-α-d-glucopyranoside (3h)

Glucosyl ester 1a (0.95 mmol, 612 mg) and glucoside 2h (0.5 mmol, 148 mg) were reacted according to the general procedure. After chromatography, glucoside 3h was isolated as a syrup (135 mg, 33%, α-only); 1H NMR (400 MHz, CDCl3): δ 7.44–6.97 (m, 25H), 5.09 (d, J = 6.2 Hz, 1H), 5.00 (d, J = 10.8 Hz, 1H), 4.90 (d, J = 3.5 Hz, 1H), 4.88–4.77 (m, 5H), 4.75–4.65 (dd, J = 14.1, 11.4 Hz, 2H), 4.61 (d, J = 6.3 Hz, 1H), 4.51 (d, J = 12.1 Hz, 1H), 4.43 (d, J = 10.9 Hz, 1H), 4.26 (d, J = 12.1 Hz, 1H), 4.22–4.07 (m, 3H), 4.03 (t, J = 9.4 Hz, 1H), 3.80 (dd, J = 9.5, 3.6 Hz, 1H), 3.77–3.70 (m, 1H), 3.69–3.63 (m, 1H), 3.57 (dd, J = 9.7, 3.6 Hz, 1H), 3.53–3.40 (m, 5H), 3.40–3.25 (m, 2H); 13C NMR (101 MHz, CDCl3): δ 138.9, 138.7, 138.4, 138.0, 137.9, 128.7, 128.4, 128.3, 128.3, 128.2, 128.1, 128.03, 128.00, 127.9, 127.8, 127.6, 127.5, 97.1, 94.4, 93.8, 82.4, 82.2, 79.1, 77.7, 77.0, 75.7, 75.0, 74.2, 73.2, 73.1, 70.0, 68.8, 68.0, 62.4, 55.1; HRMS (ESI) m/z: [M + Na]+ calcd for C49H54O11Na+ 841.3558; found 841.3563.

(3β)-Cholest-5-en-3-yl 2,3,4,6-Tetra-O-benzyl-α/β-glucopyranoside (3i)[62,68]

Glucosyl ester 1a (0.95 mmol, 612 mg) and steroid 2i (0.5 mmol, 193 mg) were reacted according to the general procedure. After chromatography, glucoside 3i was isolated as a syrup (205 mg, 45% yield, α/β = 4/1); 1H NMR (400 MHz, CDCl3): δ 7.50–7.02 (m, 25H), 5.38 (s, 0.25H), 5.31 (d, J = 4.8 Hz, 1H), 5.04 (d, J = 10.8 Hz, 1H), 5.00–4.95 (m, 1.25H), 4.85 (dd, J = 10.8, 6.4 Hz, 2.25H), 4.80 (dd, J = 11.5, 4.6 Hz, 1.25H), 4.75 (d, J = 10.9 Hz, 0.5H), 4.66 (dd, J = 16.8, 12.1 Hz, 2.25H), 4.58 (d, J = 4.6 Hz, 0.25H), 4.55 (d, J = 4.5 Hz, 0.25H), 4.52–4.44 (m, 2.25H), 4.03 (t, J = 9.3 Hz, 1H), 3.91 (d, J = 9.2 Hz, 1H), 3.77 (dd, J = 10.7, 3.6 Hz, 1.25H), 3.72–3.63 (m, 2.75H), 3.58 (dd, J = 9.6, 3.5 Hz, 1.25H), 3.49 (dd, J = 10.4, 6.2 Hz, 1H), 2.45 (t, J = 11.3 Hz, 1.25H), 2.31 (dd, J = 13.7, 3.9 Hz, 1.25H), 2.04 (d, J = 12.5 Hz, 1.5H), 2.00–1.84 (m, 3.75H), 1.85–1.70 (m, 1.25H), 1.67–1.06 (m, 26H), 1.04 (s, 4H), 0.95 (d, J = 6.4 Hz, 4H), 0.90 (dd, J = 6.6, 1.5 Hz, 8H), 0.71 (s, 4H); 13C NMR (101 MHz, CDCl3): δ 140.9, 139.0, 138.3, 138.0, 128.49, 128.46, 128.40, 128.2, 128.1, 128.0, 127.9, 127.79, 127.75, 127.72, 127.6, 121.8, 94.6, 84.9, 82.2, 79.9, 77.9, 76.5, 75.8, 75.2, 73.5, 73.2, 70.1, 68.6, 56.8, 56.2, 50.2, 42.4, 39.9, 39.8, 39.6, 37.2, 36.8, 36.3, 35.9, 32.0, 31.9, 28.3, 28.1, 27.5, 24.4, 23.9, 22.9, 22.6, 21.1, 19.5, 18.8, 11.9.

(3β,5α)-3-[(2,3,4,6-Tetra-O-benzyl-α/β-glucopyranosyl)oxy]androstan-17-one (3j)[69]

Method A: starting from β-glucosyl ester 1a (Scheme ). Glucosyl ester 1a (0.95 mmol, 612 mg) and steroid 2j (0.5 mmol, 145 mg) were reacted according to the general procedure. After chromatography, glucoside 3j was isolated as a syrup (321 mg, 79% yield, α/β = 2/1); 1H NMR (400 MHz, CDCl3): δ 7.40–7.11 (m, 30H), 5.00 (d, J = 10.7 Hz, 1H), 4.92 (d, J = 3.6 Hz, 1.5H), 4.87–4.44 (m, 9H), 3.99 (t, J = 9.2 Hz, 1H), 3.87 (d, J = 9.9 Hz, 1H), 3.77–3.40 (m, 7H), 2.44 (dd, J = 19.3, 8.7 Hz, 1.5H), 2.12–0.88 (m, 30H), 0.86 (s, 4.5H), 0.83 (s, 4.5H), 0.68 (d, J = 7.2 Hz, 1.5H); 13C NMR (101 MHz, CDCl3): δ 221.5, 139.0, 138.3, 138.1, 128.51, 128.48, 128.42, 128.32, 128.26, 128.10, 128.07, 128.01, 127.99, 127.95, 127.81, 127.77, 127.74, 127.6, 102.0, 94.8, 82.2, 80.0, 78.9, 77.9, 76.0, 75.8, 75.2, 73.5, 73.1, 70.1, 68.7, 54.5, 51.5, 47.9, 45.2, 44.8, 36.9, 35.9, 35.8, 35.1, 31.6, 31.0, 28.5, 27.4, 21.9, 20.6, 13.9, 12.4.

Method B: starting from α-glucosyl chloride 1c (Scheme ). α-Glucosyl chloride 1c (0.95 mmol, 530 mg) and steroid 2j (0.5 mmol, 145 mg) were reacted according to the general procedure. After chromatography, glucoside 3j was isolated as a syrup (227 mg, 56% yield, α/β = 2/1); 1H NMR (400 MHz, CDCl3): δ 7.40–7.11 (m, 30H), 5.00 (d, J = 10.7 Hz, 1H), 4.92 (d, J = 3.6 Hz, 1.5H), 4.87–4.69 (m, 4H), 4.68–4.56 (m, 2.5H), 4.57–4.49 (m, 1H), 4.46 (dd, J = 11.4, 4.2 Hz, 1.5H), 3.99 (t, J = 9.2 Hz, 1H), 3.87 (d, J = 9.9 Hz, 1H), 3.77–3.70 (m, 1.5H), 3.67–3.59 (m, 2.5H), 3.59–3.50 (m, 2H), 3.48–3.33 (m, 1H), 2.44 (dd, J = 19.3, 8.7 Hz, 1.5H), 2.12–0.88 (m, 30H), 0.86 (s, 4.5H), 0.83 (s, 4.5H), 0.68 (d, J = 7.2 Hz, 1.5H); 13C NMR (101 MHz, CDCl3): δ 221.5, 139.0, 138.3, 138.1, 128.51, 128.48, 128.42, 128.32, 128.26, 128.10, 128.07, 128.01, 127.99, 127.95, 127.81, 127.77, 127.74, 127.6, 102.0, 94.8, 82.2, 80.0, 78.9, 77.9, 76.0, 75.8, 75.2, 73.5, 73.1, 70.1, 68.7, 54.5, 51.5, 47.9, 45.2, 44.8, 36.9, 35.9, 35.8, 35.1, 31.6, 31.0, 28.5, 27.4, 21.9, 20.6, 13.9, 12.4.

Method C: starting from α-glucosyl imidate 1e (Scheme ). α-Glucosyl imidate 1e (0.95 mmol, 649 mg) and steroid 2j (0.5 mmol, 145 mg) were reacted according to the general procedure. After chromatography, glucoside 3j was isolated as a syrup (240 mg, 59% yield, α/β = 3.3/1); 1H NMR (400 MHz, CDCl3): δ 7.40–7.11 (m, 26H), 5.00 (d, J = 10.7 Hz, 1H), 4.92 (d, J = 3.6 Hz, 1.3H), 4.87–4.44 (m, 8.2H), 3.99 (t, J = 9.2 Hz, 1H), 3.87 (d, J = 9.9 Hz, 1H), 3.77–3.40 (m, 6.2H), 2.44 (dd, J = 19.3, 8.7 Hz, 1.3H), 2.12–0.88 (m, 26H), 0.86 (s, 3.9H), 0.83 (s, 3.9H), 0.68 (d, J = 7.2 Hz, 1.3H); 13C NMR (101 MHz, CDCl3): δ 221.5, 139.0, 138.3, 138.1, 128.51, 128.48, 128.42, 128.32, 128.26, 128.10, 128.07, 128.01, 127.99, 127.95, 127.81, 127.77, 127.74, 127.6, 102.0, 94.8, 82.2, 80.0, 78.9, 77.9, 76.0, 75.8, 75.2, 73.5, 73.1, 70.1, 68.7, 54.5, 51.5, 47.9, 45.2, 44.8, 36.9, 35.9, 35.8, 35.1, 31.6, 31.0, 28.5, 27.4, 21.9, 20.6, 13.9, 12.4.

(3β,5α,25S)-Spirostan-3-yl 2,3,4,6-Tetra-O-benzyl-α/β-glucopyranoside (3k)[69,70]

Method A: starting from β-glucosyl ester 1a (Scheme ). Glucosyl ester 1a (0.95 mmol, 612 mg) and steroid 2k (0.5 mmol, 208 mg) were reacted according to the general procedure. After chromatography, glucoside 3k was isolated as a syrup (281 mg, 60% yield, α/β = 3.3:1); 1H NMR (400 MHz, CDCl3): δ 7.40–7.10 (m, 26H), 5.00 (d, J = 10.8 Hz, 1H), 4.93 (d, J = 3.4 Hz, 1.3H), 4.87–4.71 (m, 3.6H), 4.62 (dd, J = 19.0, 12.0 Hz, 2.3H), 4.57–4.50 (m, 0.6H), 4.46 (d, J = 11.5 Hz, 2H), 4.39 (dd, J = 15.0, 7.4 Hz, 1H), 3.99 (t, J = 9.3 Hz, 1H), 3.88 (d, J = 9.3 Hz, 1H), 3.72 (dd, J = 10.5, 3.8 Hz, 1.3H), 3.67–3.60 (m, 2.3H), 3.54 (dd, J = 9.7, 3.5 Hz, 2H), 3.47 (dd, J = 11.7, 3.9 Hz, 1.6H), 3.39 (q, J = 10.7 Hz, 1.3H), 2.03–1.91 (m, 1.3H), 1.91–1.00 (m, 30H), 0.96 (d, J = 7.0 Hz, 3.9H), 0.92–0.82 (m, 4H), 0.82 (s, 3.9H), 0.79 (d, J = 6.3 Hz, 3.9H), 0.76 (s, 3.9H), 0.64 (d, J = 7.7 Hz, 1.3H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.32, 138.31, 138.0, 128.5, 128.41, 128.38, 128.2, 128.1, 128.0, 127.90, 127.87, 127.80, 127.72, 127.69, 127.57, 109.3, 94.8, 82.2, 80.9, 78.0, 77.9, 76.2, 75.7, 75.1, 73.5, 73.1, 70.0, 68.7, 66.9, 62.2, 56.3, 54.3, 45.1, 41.6, 40.6, 40.1, 36.9, 35.8, 35.1, 32.3, 31.8, 31.4, 30.3, 28.8, 28.6, 27.4, 21.1, 17.2, 16.5, 14.6, 12.4.

Method B: starting from α-glucosyl chloride 1c (Scheme ). α-Glucosyl chloride 1c (0.95 mmol, 530 mg) and steroid 2k (0.5 mmol, 208 mg) were reacted according to the general procedure. After chromatography, glucoside 3k was isolated as a syrup (347 mg, 74% yield, α/β = 2:1); 1H NMR (400 MHz, CDCl3): δ 7.40–7.10 (m, 30H), 5.00 (d, J = 10.8 Hz, 1H), 4.93 (d, J = 3.4 Hz, 1.5H), 4.87–4.50 (m, 7.5H), 4.46 (d, J = 11.5 Hz, 2H), 4.39 (dd, J = 15.0, 7.4 Hz, 1H), 3.99 (t, J = 9.3 Hz, 1H), 3.88 (d, J = 9.3 Hz, 1H), 3.76–3.34 (m, 9.5H), 2.03–1.91 (m, 1.5H), 1.91–0.82 (m, 42H), 0.82 (s, 4.5H), 0.79 (d, J = 6.3 Hz, 4.5H), 0.76 (s, 4.5H), 0.64 (d, J = 7.7 Hz, 1.5H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.32, 138.31, 138.0, 128.5, 128.41, 128.38, 128.2, 128.1, 128.0, 127.90, 127.87, 127.80, 127.72, 127.69, 127.57, 109.3, 94.8, 82.2, 80.9, 78.0, 77.9, 76.2, 75.7, 75.1, 73.5, 73.1, 70.0, 68.7, 66.9, 62.2, 56.3, 54.3, 45.1, 41.6, 40.6, 40.1, 36.9, 35.8, 35.1, 32.3, 31.8, 31.4, 30.3, 28.8, 28.6, 27.4, 21.1, 17.2, 16.5, 14.6, 12.4.

Method C: starting from α-glucosyl imidate 1e (Scheme ). α-Glucosyl imidate 1e (0.95 mmol, 649 mg) and steroid 2k (0.5 mmol, 208 mg) were reacted according to the general procedure. After chromatography, glucoside 3k was isolated as a syrup (370 mg, 79% yield, α/β = 2.2:1); 1H NMR (400 MHz, CDCl3): δ 7.40–7.10 (m, 29H), 5.00 (d, J = 10.8 Hz, 1H), 4.93 (d, J = 3.4 Hz, 1.45H), 4.87–4.50 (m, 7.25H), 4.46 (d, J = 11.5 Hz, 2H), 4.39 (dd, J = 15.0, 7.4 Hz, 1H), 3.99 (t, J = 9.3 Hz, 1H), 3.88 (d, J = 9.3 Hz, 1H), 3.76–3.34 (m, 9.25H), 2.03–1.91 (m, 1.45H), 1.91–0.82 (m, 40.6H), 0.82 (s, 4.35H), 0.79 (d, J = 6.3 Hz, 4.35H), 0.76 (s, 4.35H), 0.64 (d, J = 7.7 Hz, 1.45H); 13C NMR (101 MHz, CDCl3): δ 139.0, 138.32, 138.31, 138.0, 128.5, 128.41, 128.38, 128.2, 128.1, 128.0, 127.90, 127.87, 127.80, 127.72, 127.69, 127.57, 109.3, 94.8, 82.2, 80.9, 78.0, 77.9, 76.2, 75.7, 75.1, 73.5, 73.1, 70.0, 68.7, 66.9, 62.2, 56.3, 54.3, 45.1, 41.6, 40.6, 40.1, 36.9, 35.8, 35.1, 32.3, 31.8, 31.4, 30.3, 28.8, 28.6, 27.4, 21.1, 17.2, 16.5, 14.6, 12.4.

6-O-(2′,3′,4′,6′-Tetra-O-benzyl-α-mannopyranosyl)-(1-6)-1,2:3,4-di-O-isopropylidene-α-d-galactopyranose (3l)[71]

Mannosyl ester 1a (0.95 mmol, 612 mg) and galactose 2f (0.5 mmol, 130 mg) were reacted according to the general procedure. After chromatography, glucoside 3l was isolated as a syrup (149 mg, 38% yield); 1H NMR (400 MHz, CDCl3): δ 7.41–7.10 (m, 20H), 5.52 (d, J = 5.0 Hz, 1H), 5.02 (d, J = 1.6 Hz, 1H), 4.86 (d, J = 10.8 Hz, 1H), 4.75–4.65 (m, 3H), 4.63–4.57 (m, 3H), 4.55–4.46 (m, 2H), 4.31 (dd, J = 5.0, 2.4 Hz, 1H), 4.15 (dd, J = 7.9, 1.8 Hz, 1H), 4.02 (t, J = 9.1 Hz, 1H), 3.96 (td, J = 6.6, 1.5 Hz, 1H), 3.91 (dd, J = 9.4, 3.1 Hz, 1H), 3.83 (dd, J = 2.9, 2.0 Hz, 1H), 3.81–3.74 (m, 3H), 3.74–3.67 (m, 2H), 1.50 (s, 3H), 1.43 (s, 3H), 1.32 (s, 3H), 1.32 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 138.6, 138.50, 138.45, 138.4, 128.3, 128.1, 127.8, 127.64, 127.60, 127.56, 127.50, 127.46, 109.4, 108.6, 97.2, 96.4, 80.1, 75.1, 74.9, 74.5, 73.3, 72.3, 72.1, 70.9, 70.7, 70.6, 69.1, 65.3, 65.2, 26.2, 26.0, 24.9, 24.6.

(3β,5α)-3-[(2,3,4,6-Tetra-O-benzyl-α-mannopyranosyl)oxy]androstan-17-one (3m)

Method A: starting from α-mannosyl ester 1f (Scheme ). α-Mannosyl ester 1f (0.95 mmol, 612 mg) and steroid 2j (0.5 mmol, 145 mg) were reacted according to the general procedure. After chromatography, glucoside 3m was isolated as a syrup (280 mg, 69% yield); 1H NMR (400 MHz, CDCl3): δ 7.41–7.12 (m, 20H), 5.01 (s, 1H), 4.88 (d, J = 10.7 Hz, 1H), 4.73 (dd, J = 23.3, 12.5 Hz, 2H), 4.68–4.60 (m, 3H), 4.52 (dd, J = 14.8, 11.4 Hz, 2H), 3.97–3.89 (m, 2H), 3.89–3.84 (m, 1H), 3.82–3.70 (m, 3H), 3.60–3.45 (m, 1H), 2.43 (dd, J = 19.2, 8.6 Hz, 1H), 2.05 (dd, J = 19.0, 9.3 Hz, 1H), 1.96–1.87 (m, 1H), 1.83–1.65 (m, 4H), 1.59–1.45 (m, 2H), 1.36–1.18 (m, 8H), 1.07 (d, J = 12.1 Hz, 1H), 1.01–0.87 (m, 3H), 0.85 (s, 3H), 0.79 (s, 3H), 0.70–0.62 (m, 1H); 13C NMR (101 MHz, CDCl3): δ 221.5, 138.7, 138.54, 138.49, 128.38, 128.36, 128.29, 128.1, 127.9, 127.73, 127.66, 127.6, 127.54, 127.47, 95.9, 80.4, 76.0, 75.23, 75.21, 75.16, 73.3, 72.6, 72.1, 71.8, 69.5, 54.4, 51.4, 47.8, 44.9, 36.8, 35.9, 35.8, 35.1, 31.6, 30.9, 28.4, 27.5, 21.8, 20.5, 13.9, 12.3; HRMS (ESI) m/z: [M + Na]+ calcd for C53H64O7Na+ 835.4544; found 835.4537.

Method B: starting from β-mannosyl ester 1f (Scheme ). β-Mannosyl ester 1f (0.95 mmol, 612 mg) and steroid 2j (0.5 mmol, 145 mg) were reacted according to the general procedure. After chromatography, glucoside 3m was isolated as a syrup (276 mg, 68% yield).

Method C: starting from α-glucosyl chloride 1o (Scheme ). α-Glucosyl chloride 1o (0.95 mmol, 530 mg) and steroid 2j (0.5 mmol, 145 mg) were reacted according to the general procedure. After chromatography, glucoside 3m was isolated as a syrup (179 mg, 44% yield).

5-Methyl-2′,3′-di-O-acetate-5′-O-(2,3,4,6-tetra-O-benzyl-α/β-glucopyranosyl)uridine (3n)

Glucosyl ester 1a (0.95 mmol, 612 mg) and nucleoside 2n (0.5 mmol, 171 mg) were reacted according to the general procedure. After chromatography, glucoside 3n was isolated as a syrup (203 mg, 47% yield, α/β = 5/1); 1H NMR (400 MHz, CDCl3): δ 9.41 (s, 1H), 9.08 (s, 0.2H), 7.64 (s, 0.2H), 7.37–7.15 (m, 24H), 7.12 (s, 1H), 6.42 (d, J = 8.0 Hz, 0.2H), 6.14 (d, J = 6.2 Hz, 1H), 5.58 (t, J = 12.5 Hz, 0.2H), 5.43–5.34 (m, 0.4H), 5.34–5.22 (m, 2.2H), 5.00 (d, J = 1.1 Hz, 0H), 4.94–4.42 (m, 12H), 4.33–4.17 (m, 1.6H), 4.08–3.94 (m, 2.6H), 3.91 (dd, J = 9.1, 2.6 Hz, 1.2H), 3.84–3.71 (m, 5H), 3.69–3.63 (m, 1H), 3.59 (dd, J = 9.3, 2.3 Hz, 0.2H), 2.17 (s, 0.6H), 2.11 (s, 3.6H), 2.08 (d, J = 5.6 Hz, 3H), 1.69 (s, 3.6H); 13C NMR (101 MHz, CDCl3): δ 169.8, 169.6, 163.6, 150.6, 138.4, 138.3, 138.3, 138.1, 134.7, 128.6, 128.52, 128.47, 128.38, 128.36, 128.0, 127.9, 127.8, 127.72, 127.69, 127.6, 111.9, 98.4, 86.0, 81.2, 80.4, 75.3, 74.9, 74.7, 73.4, 72.9, 72.8, 72.7, 72.3, 71.3, 69.0, 66.6, 20.7, 20.5, 12.7; HRMS (ESI) m/z: [M + Na]+ calcd for C48H52N2O13Na+ 887.3362; found 887.3367.

5-Methyl-2′,3′-di-O-acetate-5′-O-(2,3,4,6-tetra-O-benzyl-α/β-mannopyranosyl)uridine (3o)

Mannosyl ester 1a (0.95 mmol, 612 mg) and nucleoside 2n (0.5 mmol, 171 mg) were reacted according to the general procedure. After chromatography, glucoside 3o was isolated as a syrup (186 mg, 42% yield, α/β = 4/1); 1H NMR (400 MHz, CDCl3): δ 8.20 (s, 1H), 8.17 (s, 0.26H), 7.59 (s, 0.26H), 7.49 (s, 1H), 7.36–7.13 (m, 25.2H), 6.26 (d, J = 7.1 Hz, 1.26H), 5.47 (dd, J = 5.4, 1.7 Hz, 0.26H), 5.43–5.37 (m, 1H), 5.33 (dd, J = 5.6, 2.6 Hz, 1H), 4.95–4.77 (m, 5H), 4.73 (d, J = 3.6 Hz, 1H), 4.65–4.39 (m, 5H), 4.28 (d, J = 2.4 Hz, 1.26H), 4.02–3.89 (m, 2H), 3.84–3.53 (m, 7H), 2.13 (s, 0.82H), 2.12 (s, 3H), 2.08 (s, 3.82H), 1.84 (s, 0.82H), 1.80 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 167.0, 169.6, 163.9, 151.1, 138.7, 138.4, 138.1, 137.9, 135.2, 128.6, 128.5, 128.43, 128.35, 128.2, 128.02, 127.98, 127.91, 127.8, 127.7, 127.6, 112.4, 97.7, 85.16, 82.19, 81.3, 79.8, 75.8, 74.8, 73.6, 73.5, 73.2, 72.1, 71.5, 71.1, 68.2, 67.5, 20.8, 20.6, 12.3; HRMS (ESI) m/z: [M + Na]+ calcd for C48H52N2O13Na+ 887.3362; found 887.3363.

3′-O-Acetate-5′-O-(2,3,4,6-tetra-O-benzyl-α/β-glucopyranosyl)thymidine (3p)

Glucosyl ester 1a (0.95 mmol, 612 mg) and nucleoside 2o (0.5 mmol, 142 mg) were reacted according to the general procedure. After chromatography, glucoside 3p was isolated as a syrup (193 mg, 48% yield, α/β = 3.3/1); 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H), 7.64 (s, 0.3H), 7.55 (s, 1H), 7.41–7.06 (m, 26H), 6.39 (td, J = 9.2, 5.4 Hz, 1.3H), 5.29 (d, J = 5.9 Hz, 0.3H), 5.19 (d, J = 6.1 Hz, 1H), 4.84 (dt, J = 26.1, 14.0 Hz, 5H), 4.72 (d, J = 3.6 Hz, 1H), 4.61 (dd, J = 12.2, 5.6 Hz, 3H), 4.46 (dd, J = 11.3, 4.1 Hz, 2.3H), 4.32–4.21 (m, 0.6H), 4.17 (s, 1H), 3.98 (dd, J = 10.6, 2.5 Hz, 1H), 3.87–3.44 (m, 9H), 3.42–3.34 (m, 0.3H), 2.35 (dd, J = 13.7, 5.1 Hz, 1.3H), 2.16–2.03 (m, 4.9H), 1.84 (s, 0.9H), 1.80 (s, 2.7H). 13C NMR (101 MHz, CDCl3): δ 170.6, 163.8, 150.8, 138.5, 138.02, 137.98, 137.8, 135.0, 128.6, 128.50, 128.45, 128.2, 128.1, 128.0, 127.9, 127.82, 127.79, 127.73, 112.1, 97.5, 84.2, 83.3, 82.1, 79.8, 75.7, 75.3, 75.1, 73.6, 73.5, 71.0, 68.2, 68.0, 37.5, 21.0, 12.2. HRMS (ESI) m/z: [M + Na]+ calcd for C46H50N2O11Na+ 829.3307; found 829.3296.

3′-O-Acetate-5′-O-(2,3,4,6-tetra-O-benzyl-α/β-mannopyranosyl)thymidine (3q)

Mannosyl ester 1a (0.95 mmol, 612 mg) and nucleoside 2o (0.5 mmol, 142 mg) were reacted according to the general procedure. After chromatography, glucoside 3q was isolated as a syrup (153 mg, 38% yield, α/β = 5/1); 1H NMR (400 MHz, CDCl3): δ 9.25 (s, 1H), 8.84 (s, 0.2H), 7.60 (s, 0.2H), 7.42–7.13 (m, 24H), 7.10 (s, 1H), 6.43 (dd, J = 9.4, 5.4 Hz, 0.2H), 6.28 (dd, J = 9.1, 5.3 Hz, 1H), 5.36 (d, J = 5.4 Hz, 0.2H), 5.09 (d, J = 5.9 Hz, 1H), 4.96 (s, 1.2H), 4.88 (d, J = 10.7 Hz, 1.2H), 4.79 (d, J = 3.4 Hz, 2H), 4.72–4.38 (m, 7H), 4.20–4.13 (m, 1.2H), 4.08 (t, J = 9.5 Hz, 1H), 4.00 (dd, J = 10.8, 2.7 Hz, 1H), 3.84–3.65 (m, 6H), 3.59 (d, J = 9.4 Hz, 1.2H), 3.45 (dt, J = 13.4, 6.9 Hz, 0.4H), 2.25 (dd, J = 14.0, 5.1 Hz, 1.2H), 2.14–2.03 (m, 4H), 1.67 (s, 3.6H). 13C NMR (101 MHz, CDCl3): δ 170.5, 163.8, 150.5, 138.3, 138.10, 138.07, 138.01, 134.6, 128.6, 128.51, 128.47, 128.38, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 111.3, 98.1, 84.7, 83.4, 79.1, 75.3, 75.2, 74.9, 73.4, 72.7, 72.6, 72.4, 68.8, 67.3, 37.5, 21.0, 12.8. HRMS (ESI) m/z: [M + Na]+ calcd for C46H50N2O11Na+ 829.3307; found 829.3310.

5′-O-(2,3,4,6-Tetra-O-benzyl-α/β-glucopyranosyl)zidovudine (3r)

Glucosyl ester 1a (0.95 mmol, 612 mg) and nucleoside 2p (0.5 mmol, 134 mg) were reacted according to the general procedure. After chromatography, glucoside 3r was isolated as a syrup (134 mg, 34% yield, α/β = 3/1); 1H NMR (400 MHz, CDCl3): δ 9.02 (s, 1H), 7.51 (s, 0.34H), 7.44 (s, 1H), 7.38–7.06 (m, 27H), 6.23 (t, J = 6.3 Hz, 1H), 6.16 (t, J = 6.3 Hz, 0.34H), 4.96–4.69 (m, 7H), 4.62–4.38 (m, 5H), 4.27–4.18 (m, 1.34H), 4.12–3.99 (m, 2H), 3.86 (dd, J = 11.2, 3.4 Hz, 2H), 3.75–3.56 (m, 7H), 3.54–3.47 (m, 0.34H), 3.41 (t, J = 8.4 Hz, 0.34H), 2.44–2.35 (m, 1.34H), 2.22 (dt, J = 22.0, 7.5 Hz, 1.34H), 1.87 (s, 0.9H), 1.82 (s, 1H); 13C NMR (101 MHz, CDCl3): δ 163.9, 150.4, 138.5, 138.0, 137.9, 137.7, 135.3, 128.6, 128.52, 128.49, 128.2, 128.14, 128.1, 128.0, 127.9, 127.8, 127.6, 111.7, 97.6, 84.5, 82.5, 82.1, 79.9, 75.7, 75.3, 75.1, 73.6, 73.5, 71.0, 68.3, 67.3, 60.2, 37.7, 12.3; HRMS (ESI) m/z: [M + Na]+ calcd for C44H47N5O9Na+ 812.3266; found 812.3264.

5′-O-(2,3,4,6-Tetra-O-benzyl-α/β-mannopyranosyl)zidovudine (3s)

Mannosyl ester 1a (96 mg, 0.50 mmol) and nucleoside 2p (0.5 mmol, 134 mg) were reacted according to the general procedure. After chromatography, glucoside 3s was isolated as a syrup (162 mg, 41% yield, α/β = 2.1/1); 1H NMR (400 MHz, CDCl3): δ 9.26 (d, J = 35.8 Hz, 1H), 8.92 (d, J = 32.9 Hz, 0.3H), 7.50 (s, 0.3H), 7.43–7.13 (m, 26H), 7.10 (s, 1H), 6.28 (s, 0.3H), 6.10 (t, J = 6.5 Hz, 1H), 4.95 (s, 1H), 4.92–4.71 (m, 4H), 4.67–4.41 (m, 8H), 4.29–4.24 (m, 0.3H), 4.18 (d, J = 10.2 Hz, 0.3H), 4.14–3.93 (m, 4H), 3.90 (dd, J = 10.9, 2.7 Hz, 1.3H), 3.81–3.57 (m, 8H), 3.54–3.42 (m, 0.6H), 2.32–2.24 (m, 1.3H), 1.96 (dt, J = 13.8, 7.1 Hz, 1.3H), 1.72 (s, 3H), 1.62 (s, 1H); 13C NMR (101 MHz, CDCl3): δ 163.8, 150.2, 138.14, 138.09, 138.00, 135.2, 128.6, 128.50, 128.48, 128.46, 128.42, 128.38, 128.21, 127.8, 127.7, 127.6, 111.0, 98.3, 85.2, 82.6, 79.4, 75.3, 75.2, 74.9, 73.5, 72.7, 72.4, 69.1, 67.1, 61.31, 37.6, 12.8; HRMS (ESI) m/z: [M + Na]+ calcd for C44H47N5O9Na+ 812.3266; found 812.3274.