Substrate-Controlled Direct α-Stereoselective Synthesis of Deoxyglycosides from Glycals Using B(C₆F₅)₃ as Catalyst

Abstract

B(C₆F₅)₃ enables the metal-free unprecedented substrate-controlled direct α-stereoselective synthesis of deoxyglycosides from glycals. 2,3-Unsaturated α-O-glycoside products are obtained with deactivated glycals at 75 °C in the presence of the catalyst, while 2-deoxyglycosides are formed using activated glycals that bear no leaving group at C-3 at lower temperatures. The reaction proceeds in good to excellent yields via concomitant borane activation of glycal donor and nucleophile acceptor. The method is exemplified with the synthesis of a series of rare and biologically relevant glycoside analogues.

Introduction

Deoxyglycosides are an important class of carbohydrates commonly found in nature as part of biologically active glycoconjugates.¹ These compounds are characterized by the lack of substitution at one or several positions around the carbohydrate ring, often at C-2, which makes them more challenging to synthesized than their fully oxygenated counterparts. The absence of directing groups adjacent to the anomeric center to bias the nucleophile approach during the glycosylation reaction, often leads to mixtures of anomers and/or Ferrier-type products.² Owing to their relevance in drug discovery, research efforts have focused in achieving their stereoselective synthesis.³

Coupling reactions involving glycals are one of the most atom-efficient routes to access deoxyglycosides.⁴ Traditional methods to yield the corresponding 2-deoxyglycoside rely on acid catalyzed direct addition of an alcohol to the glycal, which often leads to either moderate to low yields and/or variable selectivities which are dependent on the nature of the OH nucleophile (e.g., primary vs secondary, axial vs equatorial) with 2,3-unsaturated glycosides and hydrolyzed starting material as common side products.^2a,3a,3q However, most acid-catalyzed processes to access 2,3-unsaturated glycosides directly, which are also versatile synthons in organic chemistry,⁵ tend to use harsh promoters, required specific protected building blocks, and often lead to moderate overall yields and diastereocontrol, which has limited their utility.^3a Given the range of glycoside donor and OH nucleophile reactivity profiles, there is currently no universal Lewis acid glycosylation promoter that can be used for the activation of glycals.³ Thus, there is a need to find improved and more general catalysts to access these high value glycosides.

Our group has been interested over the past few years in the development of practical, selective and catalytic methods for the direct activation of glycals using thiourea-based organocatalysts,^4b−4d as well as palladium and gold catalytic activators.⁹ Encouraged by our previous work, we undertook synthetic studies toward the development of a metal-free and improved organocatalytic method for the activation of glycals.

Trivalent boron reagents are often employed as Lewis acids because of their ubiquitous electrophilic nature and ability to reversibly form bonds with oxygen and thus are attractive catalysts in glycosylation chemistry including examples in regioselective glycosylations.^3a,3p,6 Among the boron-based Lewis acids available, B(C₆F₅)₃ (BCF) has demonstrated extensive versatility in a wide variety of reactions including borylation, hydrogenation, hydrosilylation, frustrated Lewis pair (FLP) chemistry, and Lewis acid catalysis.⁷ In the context of glycosylation chemistry, the utility of BCF has only been shown in the activation of fully substituted trichloroacetimidate glycosyl donors in good to excellent yields and moderate to good diastereoselectivity,⁸ with no examples reported in the synthesis of deoxyglycosides.

Herein we describe the metal-free, atom-economic, and versatile substrate-controlled borane-catalyzed highly α-stereoselective synthesis of deoxyglycosides directly from glycals (Scheme 1).

Scheme 1. BCF-Catalysed Synthesis of 2,3-Unsaturated Glycosides from “Disarmed” Glycals (Pathway A) and 2-α-Deoxyglycosides from “armed” Glycals (Pathway B).

Results and Discussion

Initial studies began by screening BCF for its ability to promote the stereoselective glycosylation of peracetylated galactal 1a with glucoside acceptor 2a in the presence of different catalyst loadings, solvents, and temperatures. It was found that 5 mol % BCF in toluene at 75 °C was the optimum condition to yield the corresponding 2,3-unsaturated glycoside 3a after 2 h (88%, α:β 30:1, entry 1 in Table 1). Reactions were less efficient at lower catalyst loadings or at lower temperatures; changing the solvent to CH₂Cl₂ or CH₃CN was also detrimental to the reaction (see Table S1 in the Supporting Information (SI) for solvent and temperature screen details). Having established the optimal reaction conditions, our attention then turned to exploring the substrate scope of the reaction between 1a and a range of OH nucleophiles 2b–2k (Table 1). In all cases, reactions proceeded smoothly within 1.5–4 h and in good to excellent yields and a clear preference for the α-products, demonstrating the reaction is tolerant of primary, secondary, and phenolic OH nucleophiles, as well as common alcohol protecting groups (e.g., acetals, ethers, and esters).

Table 1. Glycosylation Reactions with Galactal 1a^c.

^aIsolated yield.

^bDetermined by ¹H-NMR.

^cReaction did not proceed in the absence of catalyst.

^dActivation with BF₃.OEt₂ afforded 3a in 19% as a 6:1 mixture of anomers.

Glycosylations with primary alcohols 2b–2e afforded the corresponding 2,3-unsaturated glycosides in 72–86% yield within 2 h and with a 30:1 α:β ratio (entries 2–5). Reactions with secondary alcohols such as 4-methoxyphenol 2i, cholesterol 2j, or N-hydroxysuccinimide 2k (entries 9–11) proceeded smoothly giving the desired products in similar high α-selectivity (>30:1 to >20:1, α/β ratio) and yields of 77–82%. Reactions with glycosides 2g, 2h, and propargyl alcohol 2f (entries 6–8) prove to be more challenging and afforded the products in lower yields and stereoselectivity, albeit in favor of the α-products (67–86%, 6:1–7:1 α:β ratio). The ability to effectively activate galactals is noteworthy, as generally glycal substrates that favor a bigger shift toward ⁵H₄ conformations (e.g., glucals) undergo rearrangement more readily than their C-4 epimer galactals where the equilibria is shifted toward the ⁴H₅ form and as a result galactals often give mixtures of products, as well as lower overall yields.¹⁰

The scope of the reaction was further investigated with regards to glycal donor. To this end, a series of peracetylated glycals: d-glucal 1b, l-fucal 1c, d-xylal 1d and l-rhamnal 1e were subjected to the reaction conditions with 2e as the model OH nucleophile (Scheme 2). In general, moderate to good yields (65–86%) and α-selectivities were obtained in all cases leading to the formation of 2-deoxy and 2,6-dideoxy Ferrier-type products. Best diastereoselectivities were observed for 2,6-dideoxyglycals (15:1–30:1 α:β, 1c-1e), while glucal 1b yielded 4b in 86% yield and a 3:1 α:β ratio.

Scheme 2. Reaction of Glycals 1a–1e, with Glycosyide Acceptors 2e.

The synthetic utility of our strategy was further exemplified on the preparation of rare glycoside analogues 6–8, which are often difficult to access by traditional methods¹¹ bearing a Boc-protected amino propyl linker that could be used for array conjugation (Scheme 3). Glycosylation of 3-(Boc-amino)-1-propanol with 1c, followed by ester deprotection gave 2,3-unsaturated fucoside 5 in 83% yield (2 steps) and a 10:1 α/β ratio. Alkene reduction of 5 with Rh–Al₂O₃ afforded α-l-Rhodinose 6 in 76% yield. Alternatively, subjecting 5 to reduction followed by treatment with Dess-Martin periodinane gave α-l-cinerulose 7 (55%), while direct alcohol oxidation of 5 yields α-l-aculose 8 (79%).

Scheme 3. Synthesis of Rare Glycosides 6–8.

Next, we explored whether “armed” glycosides lacking a leaving group at C-3 could undergo BCF-activation and give substitution products selectively. To probe this, reactions between perbenzylated galactal 9a, acceptor 2a and BCF were screened at different catalyst loadings, solvents and temperatures as before. Best results were found when 5 mol % B(C₆F₅)₃ was used in toluene at 50 °C to give 2-deoxyglycoside 10a after 2 h (88%, α/β > 30:1, entry 1, Table 2). As before, reactions were less efficient at lower catalyst loadings or temperatures below 50 °C and changing the solvent to CH₂Cl₂, CH₃CN or CF₃Ph was also detrimental (SI Table S2 for full details).

Table 2. Reaction of Glycals 9a–d and 11a–c with Model Glycosyide Acceptors 2a, 2e, or 2g.

entry		R1	R2	R3	product	time (h)	yield (%)a	α/βb
1	9a	Bn	Bn	Bn	10a	1	88d,e	21:1
2	9a	Bn	Bn	Bn	10c	1	94	26:1
3	9a	Bn	Bn	Bn	10e	2	84	30:1
4	9a	Bn	Bn	Bn	10g	7	62	25:1
5	9a	Bn	Bn	Bn	10h	7	68	20:1
6	9b	TBS	TBS	TBS	11b	1	92	30:1
7	9c	MOM	MOM	MOM	11c	1	71	20:1
8	9d	Si(tBu)2		MOM	11d	1	82	20:1
9	11a	Bn	Bn	Bn	12ac	17	54	30:1
10	11b	O[Si(i-Pr)2]2		Bn	12b	17	78	30:1
11	11c	O[Si(i-Pr)2]2		TIPS	12c	17	75	30:1
12	11c	O[Si(i-Pr)2]2		TIPS	13	17	86	30:1
13	11c	O[Si(i-Pr)2]2		TIPS	14	17	64	20:1

^aIsolated yield.

^bDetermined by ¹H NMR.

^c10% Ferrier product 12a′ also isolated.

^dReaction did not proceed in the absence of catalyst.

^eReaction with BF₃.OEt₂ afforded 10a (<35%) and a mixture of products and starting material.

To explore the substrate scope of the glycosylation, galactals 9b–d and glucals 11a–c were reacted with a range of primary and secondary OH nucleophiles 2a, 2e, or 2g under the optimized reaction conditions. In all cases, reactions proceeded smoothly in yields of 62–94% and high α-selectivity (20:1–30:1 α:β), with secondary OHs requiring longer reaction times (entries 4 and 5 vs 1–3). Subsequently, a series of differentially protected galactals 9b–d and glucals 11a–c bearing benzyl, methoxymethyl acetal, silyl ethers and acetals, and siloxane protecting groups were prepared and subjected to the reaction conditions to investigate the effect of glycal donor on the reaction. Pleasingly, reactions involving all galactals were complete within 1–7 h, in good yields (71–82%) and high α-selectivities (20:1 to 30:1 α/β) (entries 6–8). The reaction was also amenable to glycosylations with glucal substrates, albeit required longer reaction times (17 h) and afforded the glycoside products in moderate to good yields (54–86%) with similarly high α-stereocontrol. Siloxane protected donors 11b and 11c gave better yields that perbenzylated glucal 11a (entries 9–13) as expected.^4c These results further highlight that the catalytic system works well across a range of reactivity profiles in both the glycal moiety and nucleophile acceptor.

To probe the mechanism of this versatile reaction, deuterated perbenzylated galactal 15 was reacted with 2a to yield α-glycoside 16a and 16b (90% yield) as a 2:1 mixture of cis/trans products, with a preference for syn addition of both H and O-nucleophile across the double bond (Scheme 4A). Addition of K₂CO₃ to the reaction between either 1a or 9a with 2a inhibited the reaction, which supports an acid catalyzed process. Monitoring the reaction between 1a or 9a and hexafluoroisopropanol 17 (Scheme 4B) by ¹H NMR over 60 min at 45 °C or 90 min at RT, respectively, only showed anomeric signals corresponding to the starting material and product, without any observable changes in the anomeric ratio of the product throughout the time scales of the reaction (SI Figures S1 and S3).¹³ Moreover, subjecting a 4:1 α/β-anomeric mixture of 10a to the reaction conditions in the presence of acceptor 2a gave no change in the anomeric ratio (see SI for details). These results suggest the reaction proceeds via short-lived intermediates and that the high α-selectivity is not likely the result of anomerization. ¹⁹F-NMR of the reactions (SI Figures S2 and S4) showed the appearance of fluorinated signals assigned to products 18 and 19, respectively, and also shifts associated with the formation of other BCF species, suggesting the presence of BCF-adducts. Moreover, ¹H NMR spectroscopy studies in Toluene-d⁸ of a 1:1 mixture of BCF with galactal donor 1a or 9a, also showed H-shifts associated with the enol ether alkene protons, in each case (SI Figures S5 and S7). ¹⁹F-NMR of the same mixtures showed additional signals associated with several distinct BCF-species (SI Figures S6 and S8), suggesting activation of the glycal enol ethers by BCF can take place and formation of adducts. Interestingly, ¹H NMR equimolar mixtures of B(C₆F₅)₃ and OH nucleophile 2a at room temperature showed proton shifts associated with 2a (Figure S9). This effect was more evident in the ¹⁹F-NMR spectra of the same mixtures (SI Figure S10) which showed the shift of the fluorine signals from the catalysts and appearance of different fluorinated species, further supporting the formation of an adduct between the catalyst and the OH nucleophile. This is in agreement to previous reports of glycosyl acceptor activation with boron-based catalysts such as BCF and PhBF₂ in the acid–base activation of trichloroacetimidate glycosyl donors.^8b,12

Scheme 4. Model Glycosylations of 2a or 17 with Glycal Donors 15, 1a, or 9a.

As our preliminary findings suggest, BCF could act as a Lewis acid to promote the effective allylic rearrangement¹³ (A) of deactivated glycals such as 1a to form transient oxocarbenium ion (B) that can undergo nucleophilic substitution by the BCF-activated nucleophile adduct (H—BCF—OR) in a stereoselective manner to give 2,3-unsaturated glycosides. In the presence of more reactive glycals, which lack a leaving group at C-3 (e.g., 9a), enol ether direct activation to form oxacarbenium ion (D) might take place, which after nucleophilic substitution by the BCF-activated nucleophile and concomitant protonolysis leads to deoxyglycoside products. In both instances, there is a clear preference for an α-face nucleophilic approach, likely due to sterics and a favorable anomeric effect¹⁴ (Scheme 5, top). However, in the presence of Lewis basic oxygen atoms, BCF coordination to the pyran oxygen in the donor is also possible. Therefore, an acid–base catalyzed mechanism whereby the boron ate adduct promotes both oxocarbenium ion formation and nucleophile activation can not be discarded and it is likely to occur in parallel (Scheme 5, bottom). Further investigations are ongoing to better understand the mechanism of this reaction.

Scheme 5. Proposed Mechanism.

Conclusions

In summary, we have described the unprecedented BCF-catalyzed substrate-controlled stereoselective synthesis of α-deoxyglycosides directly from glycals. We show that 2,3-unsaturated α-O-glycoside products are obtained with deactivated glycals at 75 °C, while 2-α-deoxyglycosides are formed with activated glycals lacking a leaving group at C-3 at slightly lower temperatures. This metal-free and versatile reaction is applicable to a range of glycal donors and nucleophile acceptors, and is tolerant of most common protecting groups. The reaction proceeds with good to excellent yields and high selectivity for the α-anomer. We exemplify the robustness and utility of the approach in the stereoselective synthesis of a series of oligosaccharides, glycosyl-amino acids, and other glyco-conjugates including rare glycosides analogues of α-l-Rhodinose α-l-cinerulose and α-l-aculose. Work from our lab is currently underway to exploit this chemistry for the stereoselective synthesis of other important glycosides.

Experimental Section

General Experimental Procedures

Chemicals were purchased and used without further purification. Glycal donors 1a–1e, 9a, and 11a were purchased from Carbosynth and OH acceptors 2b, 2e, 2f, 2h, 2i, 2j, and 2k were obtained from Sigma-Aldrich. Galactal donors 9b and 9c and glycosyl acceptors 2a, 2c, and 2d were prepared following literature procedures,^4d while glucal 11b and 11c and glycosyl acceptor 2g were synthesized by Balmond et al. reported methods.^4c Dry solvents were obtained by distillation using standard procedures or by passage through a column of anhydrous alumina using equipment from Anhydrous Engineering (University of Bristol) based on the Grubbs’ design. Reactions requiring anhydrous conditions were performed under nitrogen; glassware and needles were either flame-dried immediately prior to use or placed in an oven (150 °C) for at least 2 h and allowed to cool either in a desiccator or under reduced pressure; liquid reagents, solutions, or solvents were added via syringe through rubber septa; solid reagents were added via Schlenk type adapters. Teflon rings were used between the joints of the condensers and round-bottom flasks. Reactions were monitored by TLC on Kieselgel 60 F254 (Merck). Detection was by examination under UV light (254 nm) and by charring with 10% sulfuric acid in ethanol. Flash column chromatography was performed using silica gel [Merck, 230–400 mesh (40–63 μm)]. Extracts were concentrated in vacuo using both a Büchi rotary evaporator (bath temperatures up to 40 °C) at a pressure of either 15 mmHg (diaphragm pump) or 0.1 mmHg (oil pump), as appropriate, and a high vacuum line at room temperature. ¹H NMR and ¹³C NMR spectra were measured in the solvent stated at 400 or 500 MHz. Chemical shifts are quoted in parts per million from residual solvent peak (CDCl₃: ¹H–7.26 ppm and 13C–77.16 ppm) and coupling constants (J) given in Hertz. Multiplicities are abbreviated as b (broad), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or combinations thereof. Mass spectra were determined by the University of Bristol mass spectrometry service by electrospray ionization (SI) modes. The units of the specific rotation, (deg·mL)/(g·dm), are implicit and are not included with the reported value. Concentration c is given in g/100 mL.

General Glycosylation Procedure

Glycal donor (1.0 equiv), OH nucleophile acceptor (0.75 equiv), and B(C₆F₅)₃ (5 mol %) were weighed into an oven-dried microwave vial, sealed and placed under vacuum for 1 h. Then the vial was filled with N₂ followed by the addition of ∼1.0 mL of anhydrous toluene. The solutions were stirred and heated at 75 °C for Ferrier glycosylation and 50 °C for 2-deoxy glycosylation until the reaction was determined to be complete by either TLC or NMR analysis of the crude material (times are given in Tables S1 and S2 and Tables 1 and 2 of the main manuscript). The reaction mixture was concentrated in vacuo and the dried residue was purified by silica gel column chromatography.

Methyl-6-O-(4,6-di-O-acetyl-2,3-dideoxy-α-d-threo-hex-2-enopyranosyl)-2,3,4-tri-O-benzyl-α-d-glucopyranoside 3a)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol), and acceptor 2a (64 mg, 0.14 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 6:1 to 3:1) 3a as a colorless oil (82 mg, 88%). Spectroscopic data in agreement with literature.¹⁵

Benzyl-4,6-di-O-acetyl-2,3-dideoxy-α-d-threo-hex-2-enopyranoside (3b)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol) and acceptor 2b (15 mg, 0.14 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 12:1 to 8:1) 3b as a colorless oil (37 mg, 84%). Spectroscopic data in agreement with literature.¹⁵

Methyl-6-O-(4,6-di-O-acetyl-2,3-dideoxy-α-d-threo-hex-2-enopyranosyl)-2,3,4-tri-O-benzoyl-α-d-glucopyranoside (3c)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol) and acceptor 2c (70 mg, 0.14 mmol) to afford following purification by silica gel column chromatography (Hexane: EtOAc, 5:1 to 2:1) 3c as a colorless oil (72 mg, 72%). ¹H NMR (500 MHz, CDCl₃) δ 7 δ 7.98 (dd, J = 18.7, 7.7 Hz, 5H, Ar–H), 7.87 (d, J = 7.8 Hz, 2H, Ar–H), 7.55–7.52 (m, 2H, Ar–H), 7.39 (t, J = 7.7 Hz, 4H, Ar–H), 7.32–7.28 (m, 2H, Ar–H), 6.20–6.09 (m, 2H, H-2, H-2’), 6.04 (dd, J = 10.0, 3.0 Hz, 1H, H-3′), 5.72 (t, J = 9.8 Hz, 1H, H-4), 5.30–5.26 (m, 2H, H-1, H-3), 5.13 (d, J = 2.9 Hz, 1H, H-1’), 5.04 (dd, J = 5.5, 2.5 Hz, 1H, H-4’), 4.39 (ddd, J = 7.8, 5.4, 2.4 Hz, 1H, H-5′), 4.26 (dt, J = 10.4, 3.7 Hz, 1H, H-5), 4.16–3.99 (m, 3H, H-6a, H-6a’, H-6b’), 3.74 (dd, J = 11.1, 3.0 Hz, 1H, H-6b), 3.50 (s, 3H, OCH₃), 2.07 (s, 3H, COCH₃), 1.86 (s, 3H, COCH₃).¹³C NMR (126 MHz, CDCl₃) δ 170.5 (COCH₃), 170.3 (COCH₃), 165.8 (COPh), 165.8 (COPh), 165.2 (COPh), 133.5 (Ar–C), 133.4 (Ar–C), 133.1 (Ar–C) 130.1 (Ar–C), 129.9 (Ar–C), 129.8 (Ar–C), 129.2 (C-2’), 129.1 (Ar–C), 128.5 (Ar–C), 128.4 (Ar–C), 128.3 (Ar–C), 125.3, (C-3′) 97.1 (C-1), 93.9 (C-1′), 72.1(C-3), 70.6 (C-2), 69.4 (C-4), 68.3 (C-5), 66.6 (C-5′), 66.1 (C-6), 62.6 (2C- 4′, 6′), 55.7 (OCH₃), 20.8 (COCH₃), 20.5 (COCH₃); ESI-HRMS for C₃₈H₃₈O₁₄Na⁺ (MNa⁺) calculated: 741.2159; found: 741.2161

Thiophenyl-6-O-(4,6-di-O-acetyl-2,3-dideoxy-α-d-threo-hex-2-enopyranosyl)-2,3,4-tri-O-benzoyl-α-d-glucopyranoside (3d)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol) and acceptor 2d (80 mg, 0.14 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 5:1 to 1:1) 3d as a colorless oil (85 mg, 72%). ¹H NMR (500 MHz, CDCl₃) δ 8.00–7.96 (m, 2H, Ar–H), 7.96–7.91 (m, 2H, Ar–H), 7.82–7.78 (m, 2H, Ar–H), 7.57–7.50 (m, 4H, Ar–H), 7.41 (m, 5H, Ar–H), 7.35–7.25 (m, 5H, Ar–H), 6.10 (ddd, J = 10.1, 5.5, 1.0 Hz, 1H, H-2’), 5.96 (dd, J = 10.0, 3.1 Hz, 1H, H-3′), 5.91 (t, J = 9.5 Hz, 1H, H-3), 5.63 (t, J = 9.7 Hz, 1H, H-4), 5.49 (t, J = 9.7 Hz, 1H, H-2), 5.12 (d, J = 3.1 Hz, 1H, H-1’), 5.08 (d, J = 10.0 Hz, 1H, H-1), 4.97 (dd, J = 5.5, 2.5 Hz, 1H, H-4’), 4.32 (ddd, J = 7.8, 5.4, 2.5 Hz, 1H, H-5′), 4.16–4.08 (m, 2H, H-6a′. H-6b′), 4.07–4.00 (m, 2H, H-5, H-6a), 3.83–3.77 (m, 1H, H-6b), 2.08 (s, 3H, COCH₃), 1.93 (s, 3H, COCH₃). ¹³C NMR (126 MHz, CDCl₃) δ 170.5 (COCH₃), 170.3 (COCH₃), 165.8 (COPh), 165.1 (COPh), 165.0 (COPh), 133.5 (Ar–C), 133.2 (Ar–C), 132.6 (Ar–C), 132.1 (Ar–C), 130.1 (C-3′), 129.9 (Ar–C), 129.8 (Ar–C), 129.7 (Ar–C), 129.2 (Ar–C), 128.9 (Ar–C), 128.9 (Ar–C), 128.8 (Ar–C), 128.5 (Ar–C), 128.4 (Ar–C), 128.3 (Ar–C), 128.2 (Ar–C), 125.3 (C-2’), 93.8 (C-1′), 85.9 (C-1), 77.2 (C-5), 74.3 (C-3), 70.5 (C-2), 69.5 (C-4) 66.7 (C-5′) 66.5 (C-6), 62.7 (C-6′), 62.6 (C-4′), 20.8 (COCH₃), 20.6 (COCH₃). ESI-HRMS for C₄₃H₄₀O₁₃SNa⁺ (MNa⁺) calculated: 819.2087; found: 819.2103.

6-O-(4,6-di-O-acetyl-2,3-dideoxy-α-d-threo-hex-2-enopyranosyl)-1,2:4,5-di-O-isopropylidene-α-d-galacopyranoside (3e)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol), and acceptor 2e (36 mg, 0.14 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 7:1 to 4:1) 3e as a colorless oil (49 mg, 75%). Spectroscopic data in agreement with literature.¹⁵

2′-Propyn-1′-yl-4,6-di-O-acetyl-2,3-dideoxy-α/β-d-threo-hex-2-enopyranoside (3f)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol) and acceptor 2f (7.73 mg, 0.14 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 8:1 to 4:1) 3f as a colorless oil (32 mg, 86%). Spectroscopic data in agreement with literature.¹⁵

Methyl 3-O-(4,6-di-O-acetyl-2,3-dideoxy-α-d-threo-hex-2-enopyranosyl)-4,6-O-benzylidene 2-O-benzyl-α-d-glucopyranoside (3g)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol) and acceptor 2g (51 mg, 0.14 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 5:1 to 3:1) 3g as a colorless oil (55 mg, 68%)¹H NMR (500 MHz, CDCl₃) δ 7.42 (dd, J = 6.7, 2.8 Hz, 2H, Ar–H), 7.37–7.32 (m, 7H, Ar–H), 7.32–7.29 (m, 1H, Ar–H), 6.07 (dd, J = 3.2, 1.8 Hz, 2H, H-2′, H-3′), 5.54 (d, J = 2.0 Hz, 1H, H-1), 5.51 (s, 1H, H-PhCH), 5.00 (dd, J = 4.3, 2.7 Hz, 1H, H-4’), 4.81–4.69 (m, 1H, PhCHH), 4.57 (d, J = 12.2 Hz, 1H, PhCHH), 4.54 (d, J = 3.7 Hz, 1H, H-1), 4.51–4.46 (m, 1H, H-5′), 4.41 (t, J = 9.4 Hz, 1H, H-3), 4.25 (ddt, J = 13.2, 7.3, 3.3 Hz, 2H, H-6a′, H-6a), 4.05 (dd, J = 11.2, 7.2 Hz, 1H, H-6b’), 3.82 (td, J = 9.9, 4.8 Hz, 1H, H-5), 3.69 (t, J = 10.3 Hz, 1H, H-6b), 3.56 (t, J = 9.5 Hz, 1H, H-4), 3.46 (ddd, J = 13.1, 9.4, 3.6 Hz, 1H, H-2), 3.35 (s, 3H, OCH₃), 2.06 (d, J = 6.1 Hz, 6H, 2 COCH₃). ¹³C NMR (126 MHz, CDCl₃) δ 170.8 (COCH₃), 170.4 (COCH₃), 138.2 (Ar–C), 137.2 (Ar–C), 130.8 (C-3′), 129.0 (Ar–C), 128.4 (Ar–C), 128.3 (Ar–C), 128.1 (Ar–C), 127.9 (Ar–C), 126.0 (Ar–C), 124.9 (C-2′), 101.4 (C-PhCH), 99.1 (C-1), 93.6 (C-1′), 82.8 (C-4), 78.1 (C-2), 73.4 (C-PhCH₂), 73.1 (C-3), 69.1 (C-6), 66.4 (C-5′), 62.7 (C-4′), 62.2 (C-6′), 62.0 (C-5), 55.2 (OCH₃), 20.8 (COCH₃), 20.70 (COCH₃). ESI-HRMS for C₃₁H₃₆O₁₁Na⁺ (MNa⁺) calculated: 607.2155; found: 607.2155.

3-O-(4,6-di-O-acetyl-2,3-dideoxy-α-d-threo-hex-2- enopyranosyl)-l,2:5,6-di-O-isopropylidene-α-d-glucofuranose (3h)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol), and acceptor 2h (36 mg, 0.14 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 7:1 to 3:1) 3h as a colorless oil (44 mg, 67%). ¹H NMR (500 MHz, CDCl₃) δ 6.16 (ddd, J = 10.0, 5.5, 1.1 Hz, 1H, H-2’), 6.09–5.99 (m, 1H, H-3′), 5.90 (d, J = 3.6 Hz, 1H, H-1), 5.39–5.34 (m, 1H, H-1′), 5.04 (dt, J = 5.5, 2.8 Hz, 1H, H-4′), 4.63 (d, J = 3.6 Hz, 1H, H-2), 4.41–4.28 (m, 3H, H-5′, H-3, H-6a′), 4.25–4.18 (m, 2H, H-4, H-6b′), 4.16–4.08 (m, 2H, H-5, H-6a), 3.99 (dd, J = 8.6, 5.1 Hz, 1H, H-6b), 2.13 (s, 3H), 2.10 (s, 3H), 1.52 (s, 3H), 1.42 (s, 3H), 1.33 (d, J = 4.1 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 170.8 (COCH₃), 170.3 (COCH₃), 130.0 (C-3′), 125.4 (C-2′), 112.0 (4°C), 109.17(4°C), 105.4 (C-1), 94.9 (C-1′), 84.3 (C-2), 81.3 (C-4), 80.77 (C-3), 72.7 (C-5), 67.8 (C-6), 67.2 (C-5′), 63.1 (C-6’), 62.8 (C-4′), 27.0 (CCH₃), 26.9 (CCH₃), 26.5 (CCH₃), 25.4 (CCH₃), 20.8 (COCH₃), 20.7 (COCH₃). ESI-HRMS for C₂₂H₃₂O₁₁Na⁺ (MNa⁺) calculated: 495.1842; found: 495.1832.

4-Methoxyphenyl,4,6-di-O-acetyl-2,3-dideoxy-α-d-threo-hex-2-enopyranoside (3i)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol) and acceptor 2i (17 mg, 0.14 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 9:1 to 3:1) 3i as a colorless oil (36 mg, 82%)¹H NMR (500 MHz, CDCl₃) δ 7.10–7.05 (m, 4H, Ar–H), 6.88–6.83 (m, 2H, Ar–H), 6.27 (ddd, J = 9.9, 5.4, 1.0 Hz, 1H, H-2), 6.21 (dd, J = 10.0, 3.0 Hz, 1H, H-3), 5.64 (dt, J = 3.0, 0.6 Hz, 1H, H-1), 5.13 (dd, J = 5.4, 2.5 Hz, 1H, H-4), 4.54 (ddd, J = 7.7, 5.3, 2.5 Hz, 1H, H-5), 4.29–4.23 (m, 2H, H-6a, H-6b), 3.80 (s, 3H, OCH₃), 2.12 (s, COCH₃), 1.98 (s, 3H, COCH₃). ¹³C NMR (126 MHz, CDCl₃) δ 170.6 (COCH₃), 170.4 (COCH₃), 155.2 (Ar–C), 151.0 (Ar–C), 129.9 (C-3), 125.9 (C-2), 118.8 (Ar–C), 114.5 (Ar–C), 93.7 (C-1), 67.5 (C-5), 62.6 (C-4), 62.5 (C-6), 55.7 (OCH₃), 20.8 (COCH₃), 20.7 (COCH₃). ESI-HRMS for C₁₇H₂₀O₇Na⁺ (MNa⁺) calculated: 359.1107; found: 359.1117.

Cholesteryl-4,6-diacetyl-2,3-dideoxy-α-d-threo-2-enopyranoside (3j)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol) and acceptor 2j (53 mg, 0.14 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 4:1 to 2:1) 3j as a colorless oil (65 mg, 79%) ¹H NMR (500 MHz, Chloroform-d) δ 6.12 (dd, J = 10.0, 5.3 Hz, 1H, H-3), 6.03 (dd, J = 10.0, 3.0 Hz, 1H, H-2), 5.38 (dd, J = 4.9, 2.4 Hz, 1H, C = CH), 5.23 (d, J = 3.1 Hz, 1H, H-1), 5.04 (dd, J = 5.4, 2.5 Hz, 1H, H-4), 4.43 (ddd, J = 7.7, 5.6, 2.5 Hz, 1H, H-5), 4.27–4.20 (m, 2H, H-6a, H-6b), 3.59 (m, 1H), 2.44 (ddd, J = 13.4, 5.2, 2.1 Hz, 1H), 2.39–2.24 (m, 1H), 2.09 (d, J = 5.2 Hz, 6H, 2 COCH₃), 2.05–1.95 (m, 3H), 1.93–1.79 (m, 3H), 1.63–1.05 (m, 16H), 1.02 (s, 5H), 0.93 (d, J = 6.5 Hz, 4H), 0.88 (dd, J = 6.6, 2.2 Hz, 8H), 0.69 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 170.7 (COCH₃), 170.4 (COCH₃), 140.8 (C = CH), 131.2 (C-2), 125.0 (C-3), 121.8 (C = CH), 92.4 (C-1), 78.0, 66.7 (C-5), 63.0 (2C-6, 4)), 56.8 (CH), 56.2 (CH), 50.2 (CH), 42.3 (4 °C), 40.4 (CH₂), 39.8 (CH₂), 39.5 (CH₂), 37.2 (4 °C), 36.7 (CH₂), 36.2 (CH), 35.8, 31.9, 31.9, 28.2, 28.0, 24.3, 23.8, 22.8, 22.6, 21.1 (COCH₃), 20.8 (COCH₃), 19.3 (CH₃), 18.7 (CH₃), 11.9 (CH₃). ESI-HRMS for C₃₇H₅₈O₆Na⁺ (MNa⁺) calculated: 621.4131; found: 621.4126.

N-Succinimido-4,6-diacetyl-2,3-dideoxy-α-d-threo-2-enopyranoside (3k)

Following the general glycosylation procedure, donor 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol) and acceptor 2k (16 mg, 0.14 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 3:1 to 1:1) 3k as a colorless oil (41 mg, 91%). ¹H NMR (500 MHz, CDCl₃) δ 6.36 (ddd, J = 10.0, 5.6, 1.2 Hz, 1H, H-3), 6.20 (ddd, J = 10.0, 3.1, 0.6 Hz, 1H, H-2), 5.64 (ddd, J = 3.2, 1.2, 0.6 Hz, 1H, H-1), 5.15 (ddd, J = 5.6, 2.7, 0.6 Hz, 1H, H-4), 4.81 (td, J = 6.3, 2.7 Hz, 1H, H-5), 4.33 (dd, J = 11.3, 6.2 Hz, 1H, H-6a), 4.07 (dd, J = 11.3, 6.5 Hz, 1H, H-6b), 2.75 (s, 4H, 2CH₂), 2.08 (s, 3H, COCH₃), 2.07 (s, 3H, COCH₃). ¹³C NMR (126 MHz, CDCl₃) δ 171.0 (2 NHS CO), 170.6 (COCH₃), 170.1 (COCH₃), 128.8 (C-3), 125.9 (C-2), 97.5 (C-1), 68.3 (C-5), 61.9 (C-4), 61.8 (C-6), 25.5 (2 CH₂), 20.8 (COCH₃), 20.7 (COCH₃). ESI-HRMS for C₁₄H₁₇NO₈Na⁺ (MNa⁺) calculated: 350.0852; found: 350.0862.

6-O-(4,6-di-O-acetyl-2,3-dideoxy-α-d-erythro-hex-2-enopyranosyl)-1,2:4,5-di-O-isopropylidene-α-d-galacopyranoside (4b)

Following the general glycosylation procedure, donor 1b (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.01 mmol) and acceptor 2e (36 mg, 0.14 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 8:1 to 4:1) 4b as a yellow oil (56 mg, 86%). Spectroscopic data in agreement with literature.^9b

4-O-(acetyl)-2,3,6-trideoxy-α-l-hex-2-enopyranosyl-(1 → 6)-1,2;3,4-di-O-isopropylidene-α-d-galactopyranoside (4c)

Following the general glycosylation procedure, donor 1c (50 mg, 0.12 mmol), B(C₆F₅)₃ (6 mg 0.011 mmol), and acceptor 2e (46 mg, 0.10 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 8:1 to 5:1) 4c as a yellow oil (52 mg, 71%). ¹H NMR (500 MHz, CDCl₃) δ 6.14–5.95 (m, 2H, H-2′, H-3′), 5.53 (d, J = 5.0 Hz, 1H, H-1), 5.10 (d, J = 1.8 Hz, 1H, H–I′), 4.92 (dd, J = 4.4, 2.5 Hz, 1H, H-4’), 4.60 (dd, J = 7.9, 2.4 Hz, 1H, H-3), 4.31 (dd, J = 5.1, 2.4 Hz, 1H, H-2), 4.28–4.21 (m, 2H, H-5′, H-4), 3.99–3.91 (m, 2H, H-5, H-6a), 3.72–3.64 (m, 1H, H-6b), 2.10 (s, 3H, COCH₃), 1.53 (s, 3H, CCH₃), 1.45 (s, 3H, CCH₃), 1.33 (s, 5H, CCH₃), 1.22 (d, J = 6.6 Hz, 3H, CCH₃). ¹³C NMR (126 MHz, CDCl₃) δ 170.7 (COCH₃), 130.5 (C-3′), 125.8 (C-2′), 109.2 (CCH₃), 108.5 (CCH₃), 96.3 (C-1), 94.0 (C-1′), 71.1 (C-5′), 70.6 (C-3), 70.5 (C-2), 67.0 (C-5), 66.1 (C-6), 65.1 (C4′), 64.6 (C-4), 26.1 (CCH₃), 26.0 (CCH₃), 24.9 (CCH₃), 24.5 (CCH₃), 20.9 (COCH₃), 15.9 (CCH₃). ESI-HRMS for C₂₀H₃₀O₉Na⁺ (MNa⁺) calculated: 437.1788; found: 437.1788.

6-O-(R-2,3-dihydro-2H-pyran-4-yl acetate)-1,2:4,5-di-O-isopropylidene-α-d-galacopyranoside (4d)

Following the general glycosylation procedure, donor 1d (50 mg, 0.18 mmol), B(C₆F₅)₃ (6 mg 0.011 mmol) and acceptor 2e (36 mg, 0.14 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 10:1 to 6:1) 4d as a colorless oil (56 mg, 75%). ¹H NMR (400 MHz, CDCl₃) δ 6.09–5.99 (m, 2H, H-2′, H-3′), 5.54 (d, J = 5.1 Hz, 1H, H-1), 5.09 (d, J = 2.3 Hz, 1H, H-1′), 4.95–4.91 (m, 1H, H-4′)), 4.59 (dd, J = 7.9, 2.4 Hz, 1H, H-3), 4.30 (dd, J = 5.1, 2.4 Hz, 1H, H-2), 4.23–4.15 (m, 2H, H-4, H-6a), 3.99 (ddd, J = 7.1, 4.8, 1.9 Hz, 1H, H-5), 3.90–3.72 (m, 3H, H-6b, H-5a′, H-5b′), 2.08 (s, 3H, COCH₃), 1.52 (s, 3H, CCH₃), 1.43 (s, 3H CCH₃), 1.32 (s, 6H, 2 CCH₃). ¹³C NMR (101 MHz, CDCl₃) δ 170.6 (COCH₃), 130.9 (C-3′), 124.7 C-2′), 109.3 (CCH₃), 108.5 (CCH₃), 96.3 (C-1), 93.5 (C-1′), 71.2 (C-4′), 70.7 (C-3), 70.4 (C-2), 67.4 (C-5), 67.3 (C-5′), 63.4 (C-4), 61.4 (C-6), 26.0 (CCH₃), 26.0 (CCH₃), 24.9 (CCH₃), 24.5 (CCH₃), 21.1 (COCH₃).). ESI-HRMS for C₁₉H₂₈O₉Na⁺ (MNa⁺) calculated: 423.1631; found: 423.1623.

4-O-(acetyl)-2,3,6-trideoxy-α-l-hex-2-enopyranosyl-(1 → 6)-1,2;3,4-di-O-isopropylidene-α-d-galactopyranoside (4e)

Following the general glycosylation procedure, donor 1e (50 mg, 0.12 mmol), B(C₆F₅)₃ (6 mg 0.011 mmol) and acceptor 2e (46 mg, 0.10 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 15:1 to 8:1) 4e as a yellow oil (48 mg, 65%). Spectroscopic data in agreement with literature.^9b

3-N-Boc-propyl acetyl-2,3,6-trideoxy-α-l-hex-2-enopyranosyl (4f)

Following the general glycosylation procedure, donor 1e (50 mg, 0.12 mmol), B(C₆F₅)₃ (6 mg 0.011 mmol), and acceptor 2l (31 mg, 0.10 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 5:1 to 3:1) 4f as a yellow oil (50 mg, 85%). ¹H NMR (500 MHz, CDCl₃) δ 1.24 (d, J = 6.6 Hz, 3H, CCH₃), 1.45 (s, 9H, OC(CH₃)₃), 1.80 (dt, J = 11.6, 5.9 Hz, 2H, CH₂), 2.12 (s, 3H, COCH₃), 3.18–3.29 (m, 2H, NHCH₂), 3.56 (dt, J = 9.9, 6.0 Hz, 1H, OCHH), 3.82–3.87 (m, 1H. OCHH), 4.23 (qd, J = 6.7, 2.3 Hz, 1H, H-5), 4.70 (s, 1H, NH), 4.93 (dd, J = 5.4, 2.5 Hz, 1H, H-4), 5.02 (d, J = 2.9 Hz, 1H, H-1), 6.02 (ddt, J = 9.9, 3.1, 0.7 Hz, 1H, H-2), 6.09 (ddd, J = 10.0, 5.4, 1.0 Hz, 1H, H-3). ¹³C NMR (126 MHz, CDCl₃) δ 170.7 (COCH₃), 155.9 (NHCO), 130.3 (C-2), 125.9 (C-3), 94.3 (C-1), 69.5 (OC(CH₃)₃) 66.3 (OCH₂), 65.0 (C-4), 64.7 (C-5), 38.2 (NHCH₂), 29.9 (CH₂), 28.4 (OC(CH₃)₃), 20.9(COCH₃), 16.1. ESI-HRMS for C₁₆H₂₇NO₆Na⁺ (MNa⁺) calculated: 352.1736; found: 352.1748

(3-N-Boc-propyl)-acetyl-2,3,6-trideoxy-α-l-hex-2-enopyranosyl (5)

To a stirring solution of glycoside 4f (200 mg, 0.18 mmol) in 5 mL of methanol, 20 mol % K₂CO₃ (36 mg, 0.14 mmol) was added. The solution was stirred at RT until the reaction was determined to be complete by TLC. The reaction mixture was concentrated in vacuo and the dried residue diluted in CHCl₃ (20 mL) and washed with water (20 mL), brine (20 mL), and dried over anhydrous MgSO₄. The organic phase was concentrated in vacuo and purified by silica gel column chromatography (Hexane:EtOAc, 3:1 to 1:1) to afford 5 as a colorless oil (170 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ 1.30 (dd, J = 6.7, 2.3 Hz, 3H, CCH₃), 1.44 (s, 9H, OC(CH₃)₃), 1.79 (p, J = 6.9 Hz, 2H, CH₂), 3.24 (s, 2H, NHCH₂), 3.51–3.63 (m, 2H, OCHH, H-4), 3.84 (dddd, J = 10.4, 9.3, 5.6, 2.8 Hz, 1H, OCHH), 4.11 (qd, J = 6.7, 3.2 Hz, 1H, H-5), 4.72 (s, 1H, NH), 4.95 (s, 1H, H-1), 5.84–5.92 (m, 1H, H-2), 6.15–6.22 (m, 1H, H-3). ¹³C NMR (126 MHz, CDCl₃) δ 155.9 (NHCO), 130.3 (C-3), 128.1 (C-2), 94.6 (C-1), 79.1 (OC(CH₃)₃), 66.4 (C-5), 66.2 (OCH₂), 63.9 (C-4), 38.2 (NHCH₂), 29.9 (CH₂), 28.4 (OC(CH₃)₃), 16.1 (CCH₃). ESI-HRMS for C₁₄H₂₅NO₅Na⁺ (MNa⁺) calculated: 310.1630; found: 310.1629.

(3-N-Boc-propyl)-α-l-Rhodinoside (6)

To a stirring solution of glycoside 5 (100 mg 0.348 mmol) in 2 mL of a 1:6 mixture of ethyl acetate;toluene at RT, 5 mol % of Rh–Al₂O₃ (25 mg) was added. The reaction mixture was placed under a H₂ atmosphere (balloon) and was stirred at RT for 5h. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum. The dry residue was purified by silica gel column chromatography (Hexane:EtOAc, 5:1 to 2:1) 6 as a colorless oil (77 mg, 76%). ¹H NMR (500 MHz, CDCl₃) δ 4.87 (s, 1H, NH), 4.73–4.77 (m, 1H, H-1), 3.90 (q, J = 6.7, 6.0 Hz, 1H, H-5), 3.70 (ddd, J = 9.9, 7.2, 5.1 Hz, 1H, OCHH), 3.55 (s, 1H, H-4), 3.39–3.48 (m, 1H, OCHH), 3.19 (dd, J = 26.9, 5.8 Hz, 2H, NHCH₂), 2.08 (s, 1H, OH), 1.89–2.02 (m, 2H, H-2a, H-3a), 1.67–1.81 (m, 3H, H-3b, CH₂), 1.48–1.55 (m, 1H, H-2b), 1.41 (s, 9H, OC(CH₃)₃), 1.15 (d, J = 6.6 Hz, 3H, CCH₃),¹³C NMR (126 MHz, CDCl₃) δ 155.9 (NHCO), 97.2 (C-1), 73.9 (OC(CH₃)₃), 67.2 (C-5), 66.2 (C-4), 65.4 (OCH₂), 38.7 (NHCH₂), 29.5 (CH₂), 28.4 (OC(CH₃)₃), 25.7 (C-3), 23.4 (C-2), 17.1 (CCH₃). ESI-HRMS for C₁₄H₂₇NO₅Na⁺ (MNa⁺) calculated: 312.1787; found: 312.1781.

(3-N-Boc-propyl)-α-l-Cineruloside (7)

To a stirring solution of 5 (100 mg 0.348 mmol) in 2 mL of a 1:6 mixture of ethyl acetate;toluene at RT, 5% Rh–Al₂O₃ (25 mg) was added. The reaction mixture was placed under a H₂ atmosphere (balloon) and was stirred at room temperature for 5 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. To the dried residue, Dess-Martin periodinane (221 mg 0.52 mmol) in 5 mL CH₂Cl₂ solvent were added and the reaction left to stir for another 5h at RT. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The dry residue was purified by silica gel column chromatography (Hexane:EtOAc, 4:1 to 2:1) 7 as a colorless oil (77 mg, 76%). ¹H NMR (500 MHz, CDCl₃) δ 4.97 (t, J = 4.7 Hz, 1H, H-1), 4.73 (s, 1H, NH), 4.24 (q, J = 6.7 Hz, 1H, H-5), 3.83 (ddd, J = 10.0, 6.8, 5.5 Hz, 1H, OCHH), 3.55 (ddd, J = 10.0, 6.5, 5.4 Hz, 1H, OCHH), 3.25 (q, J = 6.0 Hz, 2H, NHCH₂), 2.53 (ddd, J = 16.1, 8.0, 5.7 Hz, 1H, H-3b), 2.44 (ddd, J = 16.1, 8.7, 5.8 Hz, 1H, H-3a), 2.25–2.32 (m, 1H, H-2a), 2.01 (dddd, J = 14.1, 8.3, 5.7, 4.3 Hz, 1H, H-2b), 1.75–1.85 (m, 2H, CH₂), 1.44 (s, 9H, OC(CH₃)₃), 1.29 (d, J = 6.7 Hz, 3H, CCH₃).¹³C NMR (126 MHz, CDCl₃) δ 210.3 (C-4, C₂CO), 155.9 (NHCO), 96.8 (C-1), 79.2 (OC(CH₃)₃), 71.0 (C-5), 65.8 (OCH₂), 38.3 (NHCH₂), 33.6 (C-3), 29.8 (CH₂), 29.0 (CH₂), 28.4 (OC(CH₃)₃), 14.9 (CCH₃). ESI-HRMS for C₁₄H₂₅NO₅Na⁺ (MNa⁺) calculated: 310.1630; found: 310.1630.

(3-N-Boc-propyl)-α-l-Aculoside (8)

To a flask loaded with 5 (100 mg 0.18 mmol), Dess-Martin periodinane (221 mg 0.52 mmol) in 5 mL CH₂Cl₂ solvent was added and the reaction left to stir for 6 h at RT. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The dry residue was purified by silica gel column chromatography (Hexane:EtOAc, 5:1 to 3:1) 8 as a colorless oil (84 mg 86% yield). ¹H NMR (500 MHz, CDCl₃) δ 6.84 (dd, J = 10.2, 3.5 Hz, 1H, H-2), 6.09 (d, J = 10.4 Hz, 1H, H-3), 5.18 (d, J = 3.5 Hz, 1H, H-1), 4.67 (s, 1H, NH), 4.55 (q, J = 6.8 Hz, 1H, H-5), 3.92 (dt, J = 9.9, 6.0 Hz, 1H, OCHH), 3.64 (dt, J = 9.9, 6.0 Hz, 1H, OCHH), 3.21–3.31 (m, 2H, NHCH₂), 1.83 (p, J = 6.6 Hz, 2H, CH₂), 1.45 (s, 9H, OC(CH₃)₃), 1.40 (d, J = 6.8 Hz, 3H, CCH₃),¹³C NMR (126 MHz, CDCl₃) δ 196.9 (C-4 CO), 155.9 (NHCO), 143.3 (C-2), 127.3 (C-3), 93.3 (C-1), 70.4 (OC(CH₃)₃), 67.2 (C-5), 38.0 (CH₂), 30.0 (CH₂), 29.7 (CH₂), 28.0, (OC(CH₃)₃), 15.3 (CCH₃). ESI-HRMS for C₁₄H₂₃NO₅Na⁺ (MNa⁺) calculated: 308.1474; found: 308.1461.

Methyl-2,3,4-tri-O-benzyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-α-d-lyxo-hexapyranosyl)-α-d-glucopyranoside (10a)

Following the general glycosylation procedure. Donor 9a (50 mg, 0.10 mmol), B(C₆F₅)₃ (3 mg 0.006 mmol), and acceptor 2a (42 mg, 0.09 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 6:1 to 3:1) 10a as a colorless oil (82 mg, 88%). Spectroscopic data in agreement with literature.^9a

Benzyl 2-deoxy-3,4,6-tri-O-benzyl-α-d-lyxo-hexapyranoside (10b)

Following the general glycosylation procedure. Donor 9a (50 mg, 0.10 mmol), B(C₆F₅)₃ (3 mg 0.006 mmol) and acceptor 2b (10 mg, 0.09 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 20:1 to 10:1) 10b as a colorless oil (46 mg, 94%). Spectroscopic data in agreement with literature.^9a

6-O-(3,4,6-tri-O-benzyl-α-d-lyxo-hexapyranosyl)-1,2,3,4-di-O-isopropylidene-α-d-galactopyranoside (10e)

Following the general glycosylation procedure. Donor 9a (50 mg, 0.10 mmol), B(C₆F₅)₃ (3 mg 0.006 mmol), and acceptor 2e (23 mg, 0.09 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 6:1 to 4:1) 10e as a colorless oil (50 mg, 84%). Spectroscopic data in agreement with literature.⁴

Methyl 3-O-benzyl-2-O-(2-deoxy-3,4,6-tri-O-benzyl-α-d-lyxo-hexapyranosyl)-4,6-O-benzylidene-α-d-glucopyranoside (10g)

Following the general glycosylation procedure. Donor 9a (50 mg, 0.10 mmol), B(C₆F₅)₃ (3 mg 0.006 mmol), and acceptor 2e (34 mg, 0.09 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 6:1 to 4:1) 10g as a colorless oil (45 mg, 62%). Spectroscopic data in agreement with literature.^9a

3-O-(2-deoxy-3,4,6-Tri-O-benzyl-α-d-lyxo-hexapyranoside)-1,2:5,6-di-O-isopropylidene-α-d-glucofuranoside (10h)

Following the general glycosylation procedure. Donor 9a (50 mg, 0.10 mmol), B(C₆F₅)₃ (3 mg 0.006 mmol) and acceptor 2h (23 mg, 0.09 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 6:1 to 3:1) 10h as a colorless oil (41 mg, 68%). Spectroscopic data in agreement with literature.^9d

Methyl-2,3,4-tri-O-benzyl-6-O-(2-deoxy-3,4,6-Tri-O-tert-butyldimethylsilyl-α-d-lyxo-hexapyranosyl)-α-d-glucopyranoside (11b)

Following the general glycosylation procedure. Donor 9b (50 mg, 0.10 mmol), B(C₆F₅)₃ (3 mg 0.006 mmol) and acceptor 2a (36 mg, 0.08 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 10:1 to 8:1) 11b as a colorless oil (68 mg, 92%). Spectroscopic data in agreement with literature.^9a

Methyl-2,3,4-tri-O-benzyl-6-O-(2-deoxy-3,4,6-tri-O-methoxymethyl ether-α-d-lyxo-hexapyranosyl)-α-d-glucopyranoside (11c)

Following the general glycosylation procedure, donor 9c (50 mg, 0.10 mmol), B(C₆F₅)₃ (5 mg 0.009 mmol) and acceptor 2a (63 mg, 0.11 mmol) to afford following purification by silkica gel column chromatography (Hexane:EtOAc, 7:1 to 5:1) 11c as a colorless oil (71 mg, 71%). Spectroscopic data in agreement with literature.^9a

Methyl-2,3,4-tri-O-benzyl-6-O-(2-deoxy-4,6-O-[Bis(tert-butyl)silylene]-3-O-methoxymethyl ether-α-d-lyxo-hexapyranosyl)-α-d-glucopyranoside (11d)

Following the general glycosylation procedure, donor 9d (50 mg, 0.10 mmol), B(C₆F₅)₃ (4 mg 0.008 mmol) and acceptor 2a (53 mg, 0.11 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 10:1 to 7:1) 11d as a colorless oil (74 mg, 82%). 1H NMR (400 MHz, CDCl₃) δ 7.31 (dddd, J = 20.0, 16.0, 8.5, 5.8 Hz, 15H, Ar–H), 5.02–4.93 (m, 3H, H-1′, PhCHH), 4.83–4.77 (m, 3H, PhCHH, OCH-H), 4.74–4.65 (m, 2H, PhCHH, OCH-H), 4.61 (d, J = 3.5 Hz, 1H, H-1), 4.55 (d, J = 11.4 Hz, 1H, PhCHH), 4.38 (d, J = 2.0 Hz, 1H, H-4′), 4.05–3.96 (m, 3H, H-3, H-6a′, H-6b′), 3.88 (ddd, J = 12.2, 4.4, 2.7 Hz, 1H, H-3′), 3.78 (m, 2H, H-5, H-6a), 3.63 (d, J = 9.6 Hz, 1H, H-6b), 3.54 (dd, J = 9.7, 3.6 Hz, 1H, H-2), 3.51–3.45 (m, 1H, H-4), 3.42 (d, J = 3.1 Hz, 4H, H-5′, CH₂OCH₃), 3.38 (s, 3H, OCH₃), 2.18 (td, J = 12.4, 3.6 Hz, 1H, H-2a′), 1.82 (dd, J = 12.5, 4.7 Hz, 1H, H-2b′), 1.04 (s, 18H, 2C(CH₃)₃). ¹³C NMR (101 MHz, CDCl₃) δ 138.6 (Ar–C), 138.3 (Ar–C), 138.1 (Ar–C), 128.5 (Ar–C), 128.4 (Ar–C), 127.9 (Ar–C), 127.7 (Ar–C), 127.2 (Ar–C), 98.2 (C-1′), 97.9 (C-1), 95.0 (OCH₂–CH₃), 82.2 (C-3), 80.1 (C-2), 78.1 (C-4), 75.8 (PhCH₂), 74.8 (PhCH₂), 73.3 (PhCH₂), 72.1 (C-3′), 70.4 (C-4′), 69.7 (C-5), 67.56 (2C, C-6′, C-5′), 65.9 (C-6), 55.7 (OCH₂CH₃), 55.1 (OCH₃), 30.1 (C-2′), 27.6 (C(CH₃)₃), 27.4 (C(CH₃)₃), 23.4 (C(CH₃)₃), 20.8 (C(CH₃)₃). ESI-HRMS for C₄₄H₆₂O₁₁SiNa⁺ (MNa⁺) calculated: 817.3959; found: 817.3965.

Methyl-2,3,4-tri-O-benzyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-α-d-lyxo-hexapyranosyl)-α-d-glucopyranoside (12a) and Methyl-6-O-(4,6-di-O-acetyl-2,3-dideoxy-α-d-erythreo-hex-2-enopyranosyl)-2,3,4-tri-O-benzyl-α-d-glucopyranoside(12a′)

Following the general glycosylation procedure. Donor 11a (50 mg, 0.10 mmol), B(C₆F₅)₃ (3 mg 0.006 mmol) and acceptor 2a (42 mg, 0.09 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 6:1 to 3:1) 12a as a colorless oil (44 mg, 54%) and 12a′ as a colorless oil (7 mg, 10%). Spectroscopic data in agreement with literature.^4c

Methyl-2,3,4-tri-O-benzyl-6-O-(2-deoxy-3,4-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-6-O-benzyl-α-d-erythro-hexapyranosyl)-α-d-glucopyranoside (12b)

Following the general glycosylation procedure, donor 11b (50 mg, 0.10 mmol), B(C₆F₅)₃ (3 mg 0.006 mmol), and acceptor 2a (36 mg, 0.08 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 12:1 to 8:1) 12b as a colorless oil (56 mg, 78%). Spectroscopic data in agreement with literature.^9a

Methyl-2,3,4-tri-O-benzyl-6-O-(2-deoxy-3,4-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-6-O-triisopropylsilyl-α-d-erythro-hexapyranosyl)-α-d-glucopyranoside (12c)

Following the general glycosylation procedure, donor 11c (50 mg, 0.10 mmol), B(C₆F₅)₃ (2 mg 0.005 mmol) and acceptor 2a (32 mg, 0.07 mmol) to afford following purification by silica gel column chromatography (Hexane:EtOAc, 12:1 to 8:1) 12c as a colorless oil (51 mg, 73%). Spectroscopic data in agreement with literature.^9a

6-O-(2-deoxy-3,4-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-6-O-triisopropylsilyl-α-d-erythro-hexapyranosyl)-1,2,3,4-di-O-isopropylidene-α-d-galactopyranoside (13)

Following the general glycosylation procedure, donor 11c (50 mg, 0.10 mmol), B(C₆F₅)₃ (2 mg 0.005 mmol), and acceptor 2e (18 mg, 0.07 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 16:1 to 10:1) 13 as a colorless oil (48 mg, 86%). ¹H NMR (400 MHz, CDCl₃) δ 0.83–1.18 (m, 49H, 7× SiCH(CH₃)₂), 1.32 (s, 6H, 2 O₂CCH₃), 1.43 (s, 3H, O₂CCH₃), 1.51 (s, 3H, O₂CCH₃), 1.66 (ddd, J = 13.3, 11.4, 3.7 Hz, 1H, H-2a′), 2.10 (dd, J = 12.9, 5.3 Hz, 1H, H-2b′), 3.49 (dd, J = 9.4, 8.3 Hz, 1H, H-4′), 3.54–3.61 (m, 1H, H-5′), 3.65 (dd, J = 10.7, 6.2 Hz, 1H, H-6b′), 3.79 (ddd, J = 17.8, 10.7, 6.4 Hz, 2H, H-6b, H-6a′), 3.97 (td, J = 6.5, 1.6 Hz, 1H, H-5), 4.00–4.08 (m, 2H, H-6a, H-3′), 4.20 (dd, J = 7.9, 1.8 Hz, 1H, H-4), 4.30 (dd, J = 5.0, 2.4 Hz, 1H, H-2), 4.60 (dd, J = 7.9, 2.3 Hz, 1H, H-3), 4.95 (d, J = 3.1 Hz, 1H, H-1′), 5.51 (d, J = 5.0 Hz, 1H, H-1). ¹³C NMR (101 MHz, CDCl₃) δ 109.2 (O₂CCH₃), 108.4 (O₂CCH₃), 96.3 (C-1), 96.0 (C-1′), 74.6 (C-4′), 73.4 (C-5′), 71.6 (C-3′), 71.1 (C-4), 70.7 (2C, C-2, C-3), 65.5 (C-5), 64.5 (C-6′), 63.3 (C-6), 38.0 (C-2′), 26.0 (O₂CCH₃), 25.9 (O₂CCH₃), 24.9 (O₂CCH₃), 24.4 (O₂CCH₃), 18.0, 17.9, 17.6, 17.4, 17.37, 17.3, 17.2 (Si(CH(CH₃)₂)), 13.0, 12.8, 12.4, 12.3, 12.0 (Si(CH(CH₃)₂)). ESI-HRMS for C₃₉H₇₆O₁₁Si₃Na⁺ (MNa⁺) calculated: 827.4593; found: 827.4586

Methyl-3-O-benzyl-2-O-(2-deoxy-3,4-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-6-O-triisopropylsilyl-α-d-erythro-hexapyranosyl)-4,6-O-benzylidene-α-d-glucopyranoside (14)

Following the general glycosylation procedure, donor 11c (50 mg, 0.10 mmol), B(C₆F₅)₃ (2 mg 0.005 mmol), and acceptor 2g (26 mg, 0.07 mmol) to afford following purification by column chromatography (Hexane:EtOAc, 10:1 to 5:1) 14 as a colorless oil (41 mg, 64%). Spectroscopic data in agreement with literature.^9a

Methyl-2,3,4-tri-O-benzyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-(axial/equatorial)2-²H-α-d-lyxo-hexapyranosyl)-α-d-glucopyranoside (16a/16b)

Following the General Glycosylation Procedure, galactal 9 (50 mg, 0.120 mmol), B(C₆F₅)₃ (3 mg 0.006 mmol), and acceptor 2a (42 mg, 0.090 mmol). Following purification by silica gel column chromatography (8:1 to 4:1, Hexane:EtOAc) to afford glycoside 16a/16b as an oil (70 mg, 88%).^9a

Hexafluoroisopropayl-4,6-di-O-acetyl-2,3-dideoxy-α-d-threo-hex-2-enopyranoside (18)

Following the General Glycosylation Procedure, galactal 1a (50 mg, 0.18 mmol), B(C₆F₅)₃ (5 mg 0.009 mmol) acceptor 17 (42 mg, 0.090 mmol) at 45°C. Following purification by silica gel column chromatography (6:1 to 4:1, Hexane:EtOAc) product 18 was obtained as an oil (45 mg, 87%). ¹H NMR (500 MHz, CDCl₃) δ 6.29 (ddd, J = 10.0, 5.7, 1.2 Hz, 1H, H-3), 6.09 (dd, J = 10.0, 3.0 Hz, 1H, H-2), 5.34 (d, J = 2.6 Hz, 1H, H-1), 5.08 (dd, J = 5.7, 2.5 Hz, 1H, H-4), 4.63 (hept, J = 5.4 Hz, 1H, HC(CF₃)₂), 4.35 (ddd, J = 7.3, 4.6, 2.4 Hz, 1H, H-5), 4.30 (dd, J = 11.6, 4.6 Hz, 1H, H-6a), 4.18 (dd, J = 11.6, 7.5 Hz, 1H, H-6b), 2.09 (s, 3H, COCH₃), 2.07 (s, 3H, COCH₃). ¹³C NMR (126 MHz, CDCl₃) δ 170.5 (COCH₃), 170.1 (COCH₃), 127.9(C-2), 126.9 (C-3), 122.9 (CF₃), 122.2 (CF₃), 94.8 (C-1), 71.6–71.1 (C(CF₃)₂), 68.1 (C-5), 62.4 (C-6), 62.1 (C-4), 20.7 (COCH₃), 20.5 (COCH₃). ¹⁹F NMR (470 MHz, CDCl₃) δ −73.52 (m, CF₃), −73.61 (m, CF₃). ESI-HRMS for C₁₃H₁₄F₆O₆Na⁺ (MNa⁺) calculated: 403.0592; found: 403.0600.

Hexafluoroisopropayl-2-deoxy-3,4,6-tri-O-benzyl-α-D-lyxo-hexapyranoside (19)

Following the General Glycosylation Procedure, galactal 9a (50 mg, 0.120 mmol), B(C₆F₅)₃ (3 mg 0.006 mmol) acceptor 17 (42 mg, 0.090 mmol) at RT. Following purification by silica gel column chromatography (12:1 to 8:1, Hexane:EtOAc) product 19 was obtained as an oil (48 mg, 92%). ¹H NMR (500 MHz, CDCl₃) δ 7.46–7.23 (m, 15H, Ar–H), 5.28 (d, J = 3.6 Hz, 1H, H-1), 4.97 (d, J = 11.5 Hz, 1H, PhCHH), 4.67–4.61 (m, 3H, PhCHH. PhCHH), 4.50 (q, J = 11.9 Hz, 3H, PhCHH, HC(CF₃)₂), 4.06–3.99 (m, 2H, H-4, H-5), 3.95 (ddd, J = 12.1, 4.6, 2.3 Hz, 1H, H-3), 3.63 (dd, J = 9.3, 7.0 Hz, 1H, H-6a), 3.58 (dd, J = 9.3, 5.9 Hz, 1H, H-6b), 2.37 (td, J = 12.7, 3.9 Hz, 1H, H-2a), 2.19 (dd, J = 13.2, 4.6 Hz, 1H, H-2b). ¹³C NMR (126 MHz, CDCl₃) δ 138.6 (Ar–C), 138.1 (Ar–C), 138.0 (Ar–C), 128.5 (Ar–C), 128.4 (Ar–C), 128.3 (Ar–C), 128.2 (Ar–C), 127.7 (Ar–C), 127.7 (Ar–C), 127.6 (Ar–C), 127.6 (Ar–C), 127.4 (Ar–C), 122.4 (CF₃). 120.2 (CF₃), 100.0 (C-1), 74.4 (PhCH₂), 73.8 (C-3), 73.4 (PhCH₂), 72.5 (C-4), 71.5 (C(CF₃)₂) 71.4 (C-5), 70.7 (PhCH₂), 68.8 (C-6), 30.2 (C-2). ¹⁹F NMR (470 MHz, CDCl₃) −73.24 (m, CF₃), −73.40 (m, CF₃). ESI-HRMS for C₃₀H₃₀F₆O₅Na⁺ (MNa⁺) calculated: 607.1895; found:607.1903.

Synthesis of Methyl-2,3,4-tri-O-benzyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-α/b-d-lyxohexapyranosyl)-α-d-glucopyranoside (10a)

The glycosyl donor 9a (1 equiv) and acceptor 2a (0.83 equiv) were weighed into a microwave vial and placed under vacuum for 1 h, after which time the microwave vial was filled with N2. A solution mixture containing (R)-3,3′-Bis[3,5-bis(trifluoromethyl)phenyl]-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (0.1 equiv) and thiourea (0.1 equiv) in anhydrous CH₃CN (1 mL) was stirred for 30 min, before adding it to the microwave vial containing 1a and 2a.The reaction mixture was stirred at RT for 4 h and then was purified by silica gel column chromatography (Hexane:EtOAc, 7:1 to 4:1) affording disaccharide 3a as a colorless oil (66 mg 70%, 4:1 α:β). The spectroscopic data was in agreement with previously reported data.¹⁵

In Situ Anomerization Test of 10a in the Presence of 2a

Disaccharide 10a (4:1 α:β, 1 equiv), acceptor monosaccharide 2a (1 equiv), and B(C₆F₅)₃ (5 mol %) were weighed into an oven-dried microwave vial, sealed and placed under vacuum for 1 h. Then the vial was filled with N2 followed by the addition of ∼1.0 mL of anhydrous toluene. The solutions were stirred and heated at 50 °C for 2 h without observing any change in the anomeric ratio (4:1 α/β) as monitored by NMR of the crude mixture.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02613.

• Reaction optimization tables and NMR reaction studies and NMR spectra for all compounds (PDF)

The authors declare no competing financial interest.