Scholarly article on topic 'Cooperative Brønsted Acid-Type Organocatalysis for the Stereoselective Synthesis of Deoxyglycosides'

Cooperative Brønsted Acid-Type Organocatalysis for the Stereoselective Synthesis of Deoxyglycosides Academic research paper on "Chemical sciences"

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Academic research paper on topic "Cooperative Brønsted Acid-Type Organocatalysis for the Stereoselective Synthesis of Deoxyglycosides"

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Cooperative Bronsted Acid-Type Organocatalysis for the Stereoselective Synthesis of Deoxyglycosides

Carlos Palo-Nieto, Abhijit Sau,^ Ryan Williams,^ and M. Carmen Galan*®

School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 ITS, United Kingdom [s) Supporting Information

ABSTRACT: A practical approach for the ^-stereoselective synthesis of deoxyglycosides using cooperative Bronsted acid-type organocatalysis has been developed. The method is tolerant of a wide range of glycoside donors and acceptors, and its versatility is exemplified in the one-pot synthesis of a trisaccharide. Mechanistic studies suggest that thiourea-induced acid amplification of the chiral acid via H-bonding is key for the enhancement in reaction rate and yield, while stereocontrol is dependent on the chirality of the acid.

■ INTRODUCTION

Cooperative catalysis between thioureas and Bronsted acids, whereby the enhanced catalytic activity of the thiourea acts as an acid amplifier, has successfully been applied to asymmetric catalysis,1 and more recently, reports have emerged from the Schmidt group applying this type of synergistic catalysis to glycosylation reactions involving O-glycosyl trichloroacetimi-date donors to yield ^-selective glycosides.2

Deoxy-hexoses are an important class of glycosides that occur widely in many natural products ranging from antibiotics to anticancer agents.3 The stereoselective formation of glycosidic linkages employing 2-deoxyglycosides, where a substituent at C-2 that can direct the coupling reaction is lacking, is a very challenging endeavor and many efforts have been devoted to achieve their stereoselective synthesis.4 Acid-catalyzed direct nucleophilic substitution on a glycal is one of the most widely used and efficient methods for their synthesis, however these reactions often give anomeric mixtures and side products (e.g., Ferrier rearrangement side-products).4e,4r,s As part of our ongoing interest in developing stereoselective glycosylation methods,6 we decided to focus our attention on the synthesis of deoxyglycosides. Recently, our team reported a mild organo-catalytic method for the preparation of 2-deoxygalactosides employing Schreiner's thiourea with excellent yields and a-selectivity.4e,? Although the method worked well with galactals, reactions needed to be refluxed over 24 h to reach completion, and in general, the thiourea catalyst was unable to activate glucal or rhamnal substrates. We postulated that synergistic acid/thiourea activation could provide a more efficient and practical glycosylation strategy for the preparation of deoxyglycosides than current methods that use hydrogen-bonding organocatalysts or acids as the sole promoters (Scheme 1).

Scheme 1. Proposed Cooperative Acid/Thiourea-Catalyzed Synthesis of Deoxyglycosides

To evaluate our hypothesis, thiourea 1 was chosen as the organocatalyst based on previous successful work from our group and others.1a,b,2,7,s Moreover, BINOL-derived phosphoric acids have been shown to be particularly effective in many asymmetric transformations,9 including some success in glycosylations involving trichloroacetimidate glycoside donors.10 More recently, chiral phosphoric acids have also been shown to catalyze the spiroketalization of cyclic enol ethers bearing a pendant alcohol nucleophile in a highly diaster-eoselective syn-selective concerted mechanism whereby the phosphoric acid acts as a bifunctional catalyst activating both the alkene and alcohol nucleophile.11

■ RESULTS AND DISCUSSION

Initial experiments began with the screening of a series of commercial BINOL-derived phosphoric acids for their ability to promote the stereoselective glycosylation of perbenzylated galactal 2a with glucoside acceptor 312 in the absence and presence of 1 in CH2Cl2 at room temperature. As summarized in Table 1, coupling reactions employing 10 mol % of chiral

Received: October 13, 2016

ACS Publications © XXXX American Chemical Society

Table 1. Initial Catalyst Screen in the Glycosylation of Galactal 2a

Acid 4 (10 mol%) CH2CI2, r.t.

entry acid time (h) yield (%)c a:

1 - 24 0 N/A

2 4aa 20 55 9:1

3 4a 3 82 7:1

4 4ba 20 70 >30 :1

5 4b 3 89 >30:1

6 4c 20 82 8:1

7 4d 20 78 12:1

8 pTsOHb 4e 16 76 20:1

9 (O2NC6H4O)2P(O)OHb 4f 6 65 9:1

10 4bd 3 89 >30:1

11 4be 20 79 >30:1

12 4bf 20 74 3:1

13 4b^ 20 75 >30:1

aReactions in the absence of 1. b5 mol %, as reactions at 10 mol % lead to rapid hydrolysis of 2a. cFrom 1H NMR; N/A = not applicable. d20 mol % of 1. eReaction at -40 °C-10 °C. ^Reaction in MeCN. ^Reaction in diethyl ether.

phosphoric acids (S)-4a and (R)-4b (pKa = 2.63 in DMSO)13 proceeded cleanly to give product 5 in 55 and 70% yields, albeit after 20 h (entries 2 and 4) and with different degrees of a: ft stereocontrol 9:1 and >30:1, respectively. When 10 mol % of 1 was added as the cocatalyst (entries 3 and 5), reactions were complete within 3 h, and glycoside 5 was obtained in improved yields of 82% and 89%, respectively, and with an a:ft ratio of 7:1 for the (S)-acid and >30:1 for the (R)-acid catalyst. These results demonstrate the strong influence of thiourea 1, as a cocatalyst, on reaction rate and yield, while the stereochemistry of the acid catalyst has the biggest effect on the a:ft selectivity of the glycosylation reaction. This observation is not completely surprising, as Bennett and co-workers had already reported that the stereo-outcome of acid-catalyzed glycosylation reactions involving trichloroacetimidate donors was dependent on the chirality of the catalyst, the configuration of the leaving group in the glycoside donor, and the nature of the nucleophile acceptor. It is important to note that glycosylation reactions with 10 mol % of thiourea 1 in CH2Cl2 (in the absence of acid) yielded only starting material (entry 1) as previously observed by our team,7 likely due to catalyst inactivation via self-association at high catalyst loading,1c further demonstrating the importance of the synergy between both cocatalysts.

The use of achiral p-toluenesulfonic acid (pTsOH, 5 mol %) 4e or bis(4-nirophenyl)hydrogen phosphate 4f or less acidic phosphoric catalysts 4c and 4d (pKa = 3.86)13 in combination with 1 proved to be detrimental to reaction rate, yield, and stereocontrol, with reactions needing 6-20 h for completion (entries 6-9). Next, we decided to explore the reaction conditions using 4b and 1 as the cocatalyst. Increasing the acid loading to 20 mol % in the presence of 10 mol % of 1 had no effect on the outcome of the model reaction (entry 10), while lowering the reaction temperature significantly slowed product formation (entry 11). Changing the reaction solvent to either MeCN or diethyl ether (Table 1, entries 12 and 13) had a detrimental effect on the rate of the reaction. In the case of MeCN, which is known to participate during the glycosylation reaction involving oxocarbenium ions favoring ft-glycoside products,15 significant erosion of the a-selectivity was observed with 5 being isolated as a 3:1 a:ft mixture (entry 11 vs entry 5).

Having established the optimum reaction conditions, our attention was then turned to exploring the scope of the cooperative catalytic system on coupling reactions between 2a and a range of OH nucleophiles 6a-6j (Table 2). In all cases, reactions proceeded smoothly within 2-6 h and in excellent yields and a-selectivity, as determined by the characteristic anomeric signals in the 1H- and 13C NMR spectra,4,6^7 demonstrating that the catalytic system tolerates the presence of common alcohol and amine protecting groups such as acetals, ethers, esters, and carbamates. Glycosylations with primary alcohols 6a-6d and Boc-protected serine 6h afforded the corresponding glycoside products in 80-86% yield within

2-3 h and with a >30:1 a:ft ratio (entries 1-4 and 8). Reactions with secondary alcohols such as phenols 6e, glycosides 6f and 6g, Boc-protected threonine 6i, or cholesterol 6j prove to be more challenging and required higher reaction temperatures (45 °C) and the use of 20 mol % of 1 in combination with 10 mol % of 4b in CH2Cl2, to drive reactions to completion within 5-6 h. Under these optimized conditions, the desired products were thus isolated with similar high a-selectivity (>30:1 a:ft ratio) and yields of 74-85% (Table 2, entries 5-7, 9, and 10).

Our attention then turned to exploring the scope of the glycal donor. To that end, a series of differentially protected galactals 2b-2f, glucals 8a-8c, and l-rhamnal 9 bearing methyl, acetate, benzyl, allyl, silyl ether, and siloxane protecting groups were prepared and subjected to the reaction conditions with 3 or 6k, which bears a secondary OH, as the acceptor (Table 3). Pleasingly, high yields and excellent selectivities for a-linked glycosides were obtained in most examples (entries 1,

3-5, and 7). Although substrate 2d, which bears an acetate group at C-6, shows that ester groups can be tolerated (entry 3), in the case of acetyl-protected galactal 2c (entry 2), an inseparable mixture of glycosides including Ferrier side-products16 was observed after 20 h under the more forcing conditions (20 mol % of 4b and reflux in CH2Cl2). This lack of reactivity has been previously noted for glycals bearing a deactivating group (e.g., ester) at C-3, which is in close proximity to the reacting double bond.7,17 Encouragingly, the reaction was also amenable to glycosylations with glucal substrates, and both benzyl-derivative 8a and 3,4-O-siloxane protected 8b6b or 8c6b afforded the corresponding glycosides with high a-stereocontrol within 2 h, albeit 11a was isolated in a lower yield (40%) than 11b (81% yield) or 11c (82%). This is not completely unexpected, as 8b has been shown to be a more

Table 2. Acceptor Scope in Glycosylation Reactions with Galactal 2a

aYield of isolated product. ^Reaction performed at 45 °C, 1.5 equiv of donor and thiourea 1 (20 mol %) (5-6 h). cProduct was isolated as the desilylated disaccharide for purification purposes.

optimized conditions. Following disaccharide formation, acceptor 6c was added to the same pot along with NIS and catalytic TMSOTf and trisaccharide 13 was obtained in 58% yield with complete stereoselectivity.

To probe the mechanism of our reaction, a 3:1 a/^-anomeric mixture of 5 was subjected to the reaction conditions and gave no change in the anomeric ratio, indicating that the high a-selectivity is not the result of anomerization. Moreover, reaction with deuterated galactal 14 yielded disaccharide 15 with the newly formed bonds cis to each other, as evidenced by the 1H NMR shifts associated with H-1 (5 4.62 ppm, d, 1H, J = 2.7 Hz) and H-2 (5 2.03-1.99, m, 1H, H-2') of the deuterated 2-deoxygalactoside7 (Scheme 3), which suggest that both the C— H and the C—O bond formation steps are syn-diastereose-lective. 1H NMR spectroscopy studies in CD2Cl2 of mixtures of thiourea 1 and acid 4b showed proton shifts associated with the aromatic signals from both acid and thiourea, indicating that an interaction between both catalysts occurs in solution. Furthermore, NMR mixtures of thiourea 1, acid 4b, and glycoside donor 2a showed additional downfield H-shifts associated with the anomeric protons in 2a (5 6.33 ppm), while shifts for the OH signal from acceptor 3 (from 5 1.84 ppm to 5 2.54 ppm) were detected in mixtures of 1, 4b, and 3 (see Supporting Information for details). Thiourea 1 and chiral phosphoric acid 4b have been shown to individually hydrogen bond with OH nucleophiles.1b,n Thus, as expected, mixtures of 3 and 10 mol % of thiourea 1 or 3 mixed with 10 mol % of acid 4b also showed shifts associated with the OH protons of glycosyl acceptor 3, although the magnitude of those shifts was different to that of mixtures of 3 and both cocatalysts (1 and 4b). These results further demonstrate that the combination of 1 and chiral acid (R)-4b leads to a cooperative catalytic system that can activate both enol ether and OH nucleophiles in a synergistic fashion, leading to an enhancement in reaction rate and a-stereocontrol of the glycosylation reaction. As proposed in Scheme 3, our findings suggest that a hydrogen-bond-mediated complex between thiourea 1 and acid 4b leads to a urea-induced acid amplification, and proton addition from this complex to the less hindered face of the enol ether (I) forms a short-lived oxocarbenium intermediate (II) that is rapidly trapped by the OH nucleophile which is in turn activated by the phosphate intermediate that is generated in situ, to give 15. This might help to explain the effect the chirality of the phosphoric acid has on the stereo outcome of the glycosylation reaction.

effective glycosylation donor than its benzylated counterpart (Table 3, entries 6—8).

2,6-Dideoxyglycosides are also an important class of compounds, and their stereoselective synthesis is further complicated by the lack of oxygen substituents at both C-2 and C-6.18 Excitingly, activation of 3,4-O-siloxane protected l-rhamnal 9 afforded 12 in 74% yield within 3 h and with an 8:1 a:fi ratio (entry 9). It is important to highlight that thiourea 1 alone was not able to activate any of the glucal and rhamnal substrates. These results further emphasize that the synergistic catalytic system works well across a range of reactivity profiles for both glycal donors and nucleophile acceptors.

Having found that thioglycosides are inert under the cooperative organocatalytic glycosylation conditions (Table 2, entry 4), we decided to evaluate the methodology in a three-component, one-pot synthesis of trisaccharide 13 (Scheme 2). Thus, galactal 2a was reacted with thioglycoside 6d under the

■ CONCLUSIONS

In summary, we have described a practical, highly stereo-selective, and efficient direct glycosylation method for glycals using a cooperative Bronsted acid-organocatalytic promoter system. The reaction is widely applicable to a range of glycosyl donors and nucleophile acceptors, proceeds with excellent yields and high selectivity for the a-anomer, and is tolerant of most common protecting groups. We note that the stereoselectivity of the reaction is highly dependent on the chirality of the acid, with (R)-4b leading to the formation of a-glycosides preferentially, while both yield and rate of reaction are greatly enhanced by the synergistic interaction between thiourea and acid. Moreover, we exemplify the generality of the approach in the stereoselective synthesis of a series of disaccharides, glycosyl-amino acids, and other glycoconjugates and also in the one-pot chemo- and stereoselective synthesis of a trisaccharide. Further work from our lab is underway to exploit

Table 3. Reaction of Glycals 2b-2f, 8a, 8b, and 9 with Model Acceptor 3 or 6ka

entry R1 R2 R3 time (h) product yield (%)a a$b

1 2b Me Me Me 2 10b 80 >30:1

2 2c Ac Ac Ac 20c 10c N/A N/A

3 2d Bn Bn Ac 3 10d 86 >20 1

4 2e allyl allyl allyl 3 10e 80 >30 1

5 2f TBS TBS TBS 3 10f 79 >30 1

6 8a Bn Bn Bn 2 11a 40d >30 1

7 8b O[Si(i-Pr)J 2 Bn 3 11b 81 >30 1

8 8c O[Si(i-Pr)J 2 OTIPS 6c 11c 82 only a

9 9 O[Si(i-Pr)J 2 - 3 12a 74 8 1

10 9 O[Si(i-Pr)J 2 - 6c 12b 87 10 1

isolated yield. ^Determined by XH NMR. cReaction performed at 45 °C, 1.5 equiv of donor, and 0.2 equiv of thiourea. dMixture of Ferrier product and disaccharide were produced. N/A: No reaction.

Scheme 2. One-Pot Trisaccharide Synthesis

Scheme 3. Proposed Mechanism

the cooperative catalysis between organocatalysts and chiral acids for the stereoselective synthesis of other important glycosides and chiral acetals.

■ EXPERIMENTAL SECTION

General. Dry DCM was obtained by distillation using standard procedures or by passage through a column of anhydrous alumina. 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 desiccators or under reduced pressure. Liquid reagents, solutions, or solvents were added via syringe through rubber septa. Solid reagents were added via Schlenk-type adapters. 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 ^m)]. Extracts were concentrated in vacuo using both a Buchi 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 bs (broad), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or combinations thereof. Positive ion matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectra were recorded using an HP-MALDI instrument using gentisic acid matrix. Electro-spray ionization (ESI) mass spectra were recorded on a Micromass LCT mass spectrometer or a VG Quattro mass spectrometer.

General Glycosylation Procedure. Monosaccharide donor (1 equiv) and acceptor (0.83 equiv (~0.1 mmol)) were weighed into a microwave vial and placed under vacuum for 1 h, after which time the microwave vial was filled with N2. A mixture of chiral acid (0.1 equiv) and thiourea (0.1 equiv for primary acceptors and 0.2 equiv for secondary acceptors) in anhydrous DCM (1 mL) was stirred for 30 min and then added to the microwave vial containing the donor and acceptor. The reaction mixture was stirred at RT (primary acceptors)

or heated at reflux (secondary acceptors) until the reaction was determined to be complete by either TLC or NMR analysis of the crude material. The reaction mixture was purified by silica gel flash column chromatography.

Methyl 2,3,4-Tri-O-benzyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-a-D-lyxo-hexapyranosyl)-a-D-glucopyranoside (5). Following the general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 3 (46 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 6:1 to 3:1): 5 as a yellow oil (68 mg, 89%). 1H NMR (400 MHz; CDCl3) S 7.39-7.19 (30H, m, Ph), 5.02 (1H, app d, J = 2.4 Hz, H-1'), 4.98 (1H, d, J = 10.8 Hz, OCH HPh), 4.91 (1H, d, J =11.6 Hz, OCH HPh), 4.84 (1H, d, J = 10.9 Hz, OCH HPh), 4.80 (1H, d, J = 10.8 Hz, OCHH Ph), 4.79 (1H, d, J = 12.2 Hz, OCH HPh), 4.68 (1H, d, J = 12.2 Hz, OCHH Ph), 4.60 (1H, d, J = 3.6 Hz, H-1), 4.60 (1H, d, J = 11.6 Hz, OCHH Ph), 4.57 (2H, s, OCH2 Ph), 4.52 (1H, d, J = 10.9 Hz, OCHH Ph), 4.41 (1H, d, J =

12.0 Hz, OCH HPh), 4.34 (1H, d, J = 12.0 Hz, OCHH Ph), 3.98 (1H, t, J = 9.2 Hz, H-3), 3.90-3.84 (3H, m, H-3', H-4', H-5'), 3.81 (1H, dd, J = 11.2,4.6 Hz, H-6a), 3.72 (1H, ddd, J = 10.0,4.5, 1.6 Hz, H-5), 3.61 (1H, dd, J = 11.4, 1.7 Hz, H-6b), 3.54 (1H, dd, J = 9.5, 7.3 Hz, H-6a'), 3.51 (1H, dd, J = 9.5, 3.5 Hz, H-2), 3.50 (1H, dd, J = 9.5, 5.9 Hz, H-6b'), 3.46 (1H, dd, J = 9.9, 9.0 Hz, H-4), 3.31(3H, s, OCH3), 2.20 (1H, td, J = 12.4, 3.7 Hz, H-2a'), 2.01 (1H, app dd, J = 12.7, 4.5 Hz, H-2b'); 13C NMR (126 MHz; CDCl3) S 139.0 (4 °C), 138.9 (4 °C), 138.5 (4 °C), 138.4 (4 °C), 138.30 (4 °C), 138.27 (4 °C), 128.6 (CH), 128.54 (CH), 128.45 (CH), 128.33 (CH), 128.32 (CH), 128.18 (CH), 128.16 (CH), 128.0 (CH), 127.82 (CH), 127.81 (CH),127.78 (CH), 127.7 (CH), 127.6 (CH), 127.5 (CH), 98.4 (C-1'), 98.0 (C-1), 82.3 (C-3), 80.1 (C-2), 78.1 (C-4), 76.0 (C H2 Ph),

75.1 (C H2 Ph), 74.41, 74.35 (C-3', C H2 Ph), 73.5 (C H2 Ph), 73.4 (C H2 Ph), 73.1 (C-4'), 70.4, 70.2 (C-5', CH2Ph), 70.0 (C-5), 69.5 (C-6'), 66.2 (C-6), 55.2 (OCH3), 31.2 (C-2'). Spectroscopic data in agreement with literature.7

Benzyl 2-Deoxy-3,4,6-tri-O-benzyl-a-D-lyxo-hexapyranoside (7a). Following the general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 6a (11 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 10:1 to 8:1): 7a as a colorless oil (42 mg, 80%).1H NMR (500 MHz, CDCl3) S 7.37-7.22 (20H, m, Ph), 5.08 (1H, d, J = 3.5 Hz, H-1), 4.93 (1H, d, J = 11.6 Hz, OCHHPh), 4.67 (1H, d, J = 11.9 Hz, OCHHPh), 4.62 (1H, d, J = 11.7 Hz, OCHHPh), 4.59 (1H, m, OCH2Ph), 4.50 (1H, d, J = 11.8 Hz, OCHHPh), 4.47 (2H, d, J = 11.9 Hz, OCHHPh), 4.43 (1H, d, J =11.8 Hz, OCHHPh), 3.99 (1H, ddd, J = 12.0, 4.6, 2.5 Hz, H-3), 3.96 (1H, t, J = 6.7 Hz, H-5), 3.94 (1H, bs, H-4), 3.61 (1H, dd, J = 9.4, 6.8 Hz, H-6a), 3.56 (1H, dd, J = 9.4, 6.0 Hz, H-6b), 2.25 (1H, td, J = 12.4, 3.8 Hz, H-2a), 2.07-2.01 (1H, m, H-2b); 13C NMR (126 MHz, CDCl3) S 139.1 (4 °C), 138.7 (4 °C), 138.3 (4 °C), 138.0 (4 °C), 128.54 (CH), 128.52 (CH), 128.51 (CH), 128.37 (CH), 128.35 (CH), 128.1 (CH), 127.9 (ch), 127.81 (ch), 127.77 (CH), 127.7 (ch), 127.6 (CH), 127.5 (CH), 97.3 (H-1), 75.0 (C-3), 74.4 (OCH2Ph), 73.6 (OCH2Ph), 73.2 (c-4), 70.7 (OCH2Ph), 70.3 (C-5), 69.7 (C-6), 69.1 (OCH2Ph), 31.3 (C-2). ESI-HRMS for C34H36NaO5+ (MNa+) calcd: 547.2460; found: 547.2459. [a]D = +24 (c = 1, CHCl3). D

Methyl 2,3,4-Tri-O-benzoyl-6-O-(3,4,6-tri-O-benzyl-2-deoxy-a-D-lyxo-hexapyranosyl)-a-D-glucopyranoside (7b). Following the general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 6b (50 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 6:1 to 4:1): 7b as a white solid (79 mg, 86%). Spectroscopic data in agreement with literature.7

6-O-(3,4,6-Tri-O-benzyl-2-deoxy-a-D-lyxo-hexapyranosyl)-1,2,3,4-di-O-isopropylidene-a-D-galactopyranoside (7c). Following the general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 6x (26 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 6:1 to 3:1) 7c as a colorless oil (56 mg, 83%). Spectroscopic data in agreement with literature.7

Phenyl 2,3,4-Tri-O-benzoyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-a-D-lyxo-hexapyranosyl)-a-D-thioglucopyranoside (7d). Following the general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 6d (58 mg, 0.10 mmol) afforded the following purification by

column chromatography (Hexane:EtOAc, 7:1 to 4:1): 7d as a white solid (82 mg 82%). Spectroscopic data in agreement with literature.7

Phenyl 2-Deoxy-3,4,6-tri-O-benzyl-a-D-lyxo-hexapyranosyl (7e). Following the general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 6e (9 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc 20:1 to 12:1): 7e as a colorless oil (43 mg 84%): 1H NMR (400 MHz; CDCl3) S 7.42-6.98 (20H, m, Ph), 5.59 (1H,d, J = 3.4 Hz, H-1), 4.85 (1H, d, J =11.5 Hz, OCHHPh), 4.72 (2H, bs, OCH2Ph), 4.67 (1H, d, J = 11.5 Hz, OCHHPh), 4.28 (1H, d, J = 11.6 Hz, OCHHPh), 4.24 (1H, d, J = 11.6 Hz, OCHHPh), 4.02 (1H,ddd, H-3), 3.93 (1H, t, J = 7.3 Hz, H-5), 3.80 (1H, bs, H-4), 3.53 (1H, dd, J = 9.3, 7.3 Hz, H-6a), 3.40 (1H, dd, J = 9.3, 5.7 Hz, H-6b), 2.28 (1H, td, J = 12.4, 3.6 Hz, H-2a), 2.08 (1H, dd, J = 12.4, 4.4 Hz, H-2b); 13C NMR (101 MHz; CDCl3) S 156.8 (4 °C), 138.8 (4 °C), 138.4 (4 °C), 138.0 (4 °C), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.2 (ch), 128.1 (ch), 128.2 (ch), 127.7 (ch), 127.6 (ch), 127.5 (ch), 127.3 (ch), 121.9 (CH), 116.6 (CH), 96.5 (C-1), 74.5 (CH2Ph), 74.4 (C-3), 73.3 (CH2Ph), 72.8 (C-4), 70.6 (CH2Ph), 70.5 (C-5), 69.1 (C-6), 31.2 (C-2). ESI-HRMS for C33H34NaO5+ (MNa+) calcd: 533.2304; found: 533.2296. [a]D = +36 (3c = 1, CHCl3).

Methyl 2,3-Di-O-benzyl-4-O-(2-deoxy-3,4,6-tri-O-benzyl-a-D-lyxo-hexapyranosyl)-a-D-glucopyranoside (7f). The general glycosylation procedure was followed using donor 2a (50 mg, 0.12 mmol) and acceptor 6f (53 mg, 0.10 mmol). The crude material was then dissolved in a 1 M THF solution of TBAF (0.5 mL, 0.5 mmol) and stirred for 2 h. The solution was then concentrated in vacuo and purified by column chromatography (Hexane:EtOAc, 6:1 to 4:1), affording 7f as a colorless oil (58 mg, 74%). Spectroscopic data in agreement with literature.7

3-O-(2-Deoxy-3,4,6-tri-O-benzyl-a-D-lyxo-hexapyranoside)-1,2:5,6-di-O-isopropylidene-a-D-glucofuranoside (7g). Following the general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 6g (26 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 6:1 to 3:1): 7g as a white solid (53 mg 78%). Spectroscopic data in agreement with literature.19

O-(2-Deoxy-3,4,6-tri-O-benzyl-D-lyxo-hexapyranosyl)-N-(tert-bu-toxycarbonyl) -L-serine Methyl Ester (7h). Following the general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 6h (22 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 10:1 to 4:1): 7h as a pale yellow oil (53 mg 83%). Spectroscopic data in agreement with literature.20

O-(2-Deoxy-3,4,6-tri-O-benzyl-D-lyxo-hexapyranosyl)-N-(tert-bu-toxycarbonyl)-L-threonine Methyl Ester (7i). Following the general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 6i (23 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 10:1 to 4:1): 7i as a pale yellow oil (56 mg 85%). 1H NMR (500 MHz; CDCl3) S 7.37-7.23 (15H, m, Ph), 5.14 (1H, J = 9.8 Hz, NH), 4.94-4.89 (2H, m, H-1, OCHHPh), 4.62-4.53 (3H, m, OCH2Ph, H-6a), 4.51 (1H, d, J = 11.8 Hz, OCHHPh), 4.43 (1H, d, J = 11.8 Hz, OCHHPh), 4.30-4.25 (2H, m, OCHHPh, OCH(CH3)CH(NH)), 3.94-3.89 (2H, m, H-6b, OCH-(CH3)CH(NH)), 3.84- (1H, m, H-3), 3.72 (3H, s, OCH3), 3.60-3.51 (2H, m, 2H-4, H-5), 2.15 (1H, td, J = 12.3, 3.8 Hz, H-2a), 1.86 (1H, dd, J = 12.4, 4.4 Hz, H-2b), 1.48 (9H, s, 3 X CH3), 1.25 (3H, d, J = 6.5 Hz, OCH(CH3)CH(NH)); 13C NMR (126 MHz; CDCl3) S 171.6 (CO), 156.0 (CO), 138.7 (4 °C), 138.3 (4 °C), 138.0 (4 °C), 128.4 (ch), 128.4 (CH), 128.3 (CH), 128.2 (ch), 128.1 (CH), 127.6 (ch), 127.6 (CH), 127.5 (CH), 127.4 (CH), 99.3 (C-1), 80.0 (4 °C), 75.3 (CH2Ph), 74.2 (CH2Ph), 74.2 (C-3), 73.5 (CH2Ph), 72.9 (C-4), 70.3 [OCH(CH3)CH(NH)], 70.3 (C-6), 58.2 [OCH(CH3)CH-(NH)], 52.2 (OCH3), 31.2 (C-2), 28.3 (3 x OCH3), 18.3 [och(ch3)ch(nh)]. ESI-HRMS for C37H47NO9Na+ (MNa+) calcd: 672.3149; found: 672.3144. [a]D = +20 (c = 1, CHCl3).

Cholesteryl (2-Deoxy-3,4,6-triöbenzyl-a-D-lyxo-hexapymnosyl) (7j). Following the general glycosylation procedure, donor 2a (50 mg, 0.12 mmol) and acceptor 6j (39 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 10:1 to 6:1): 7j as a colorless oil (57 mg 74%). Spectroscopic data in agreement with literature.21

Methyl 2,3,6-Tri-O-benzyl-4-O-(2-deoxy-3,4,6-tri-O-methoxy-a-D-lyxo-hexapyranosyl)-a-D-glucopyranoside (10b). Following the general glycosylation procedure, donor 2b (23 mg, 0.12 mmol) and acceptor 3 (47 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 4:1 to 2:1): 5b as a colorless oil (52 mg, 80%): 1H NMR (400 MHz; CDCl3) S 7.41-7.22 (15H, m, Ph), 5.02-4.96 (2H, m, H-1', OCHHPh), 4.92 (1H,d, J = 10.9 Hz, OCHHPh), 4.83-4.77 (2H, m, 2 OCHHPh), 4.68 (1H, d, J = 12.2 Hz, OCHHPh), 4.62 (1H, d, J = 4.6 Hz, OCHHPh), 4.60 (1H, d, J = 2.9 Hz, H-1), 4.01 (1H, t, J = 9.2 Hz, H-3), 3.88-3.79 (2H, m, H-4, 6a'), 3.74 (1H, ddd, J = 9.9, 4.4, 1.8 Hz, H-5), 3.63 (1H, dd, J = 11.4,

2.0 Hz, H-6b'), 3.61-3.56 (2H, m, 3',5'), 3.56-3.51 (5H, m, H-4', OCH3, H-2), 3.51-3.40 (2H, m, H-6a, H-6b), 3.39, 3.37 (6H, 2s, 2 X OCH3), 3.30 (3H, s, OCH3), 2.04-1.90 (2H, m, H-2a',H-2b'). 13C NMR (101 MHz, CDCl3) S 138.6 (4 °C), 138.2 (4 °C), 138.1 (4 °C),

128.5 (CH), 128.4 (CH), 128.4 (CH), 128.1 (ch), 128.1 (ch), 127.9 (CH), 127.7 (CH), 98.2 (C-1'), 97.9 (C-1), 82.1 (C-3), 80.0 (C-2), 77.8 (C-1), 75.9, 75.8, 74.9 (C-3', C-4', C-5'), 74.4 (CH2Ph), 73.3 (CH2Ph), 71.5 (CH2Ph), 69.7 (C-6), 69.7 (C-5), 66.1 (C-4), 60.9 (OCH3), 59.1 (OCH3), 56.1 (OCH3), 55.1 (OCH3), 30.7 (C-2') . ESI-HRMS for C37H48NaO10+ (MNa+) calcd: 675.3145; found: 675.3144. [a]D = +51 (c = 1, CHCl3).

Methyl 2,3,4-Tri-O-benzyl-4-O-6-O-(6-O-acetyl-2-deoxy-3,4-di-O-benzyl-a-D-lyxo-hexapyranosyl)-a-D-glucopyranoside (10d). Following the general glycosylation procedure, donor 2d (50 mg, 0.12 mmol) and acceptor 3 (47 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc 6:1 to 3:1): 10d as a colorless oil (73 mg, 86%): 1H NMR (400 MHz; CDCl3) S 7.41-7.19 (25H, m, Ph), 5.03 (1H, d, J = 3.3 Hz, H-1'), 4.99 (1H, d, J = 10.7 Hz, OCHHPh), 4.94 (1H, d, J = 11.7 Hz, OCHHPh), 4.87 (1H, d, J =11.0 Hz, OCHHPh), 4.83-4.77 (2H, m, OCHHPh), 4.72-4.63 (2H, m, OCHHPh), 4.63-4.55 (3H, m, H-1, OCHHPh), 4.48 (1H, d, J =11.1 Hz, OCHHPh), 4.11-3.95 (3H, m, H-3, H-6a',H-6b'), 3.84 (1H, ddd, J = 11.9, 4.5, 2.3 Hz, H-3'), 3.74 (4H, m, H-4', H-6a, H-2, H-5), 3.60 (1H, d, J = 10.5 Hz, H-6b), 3.51 (1H, dd, J = 9.6, 3.6 Hz, H-2), 3.43 (1H, t, J = 9.3 Hz, H-4), 3.31 (3H, s, OCH3), 2.20 (1H, td, J = 12.3, 3.6 Hz, H-2a'), 2.03 (1H, dd, J = 12.5, 4.4 Hz, H-2b'), 1.85 (3H, s, CH3CO). 13C NMR (101 MHz,CDCl3) S 170.5 (CH3CO) 138.6 (4 °C), 138.4 (4 °C), 138.2 (4 °C), 128.5 (CH), 128.4 (CH), 128.4 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.9 (ch), 127.7 (ch), 127.7 (CH), 127.5 (CH), 127.4 (CH), 98.0 (C-1'), 97.8 (C-1), 82.1 (C-3), 79.9 (C-2), 77.9 (C-4), 75.8 (CH2Ph), 74.9 (CH2Ph), 74.2 (C-3'), 74.0 (CH2Ph), 73.2 (CH2Ph), 72.5 (C-5'), 70.3 (CH2Ph), 69.7 (h-4'), 69.1(H-5), 65.9 (C-6), 64.0 (C-6'), 55.0 (OCH3), 30.7 (C-2'), 20.8 (COCH3). ESI-HRMS for C50H56NaO11+ (MNa+) calcd: 855.3720; found: 855.3711. [a]D = +8 (c = 1, CHCl3).

Methyl 2,3,6-Tri-O-benzyl-4-O-(2-deoxy-3,4,6-tri-O-allyl-a-D-lyxo-hexapyranosyl)-a-D-glucopyranoside (10e). Following the general glycosylation procedure, donor 2e (32 mg, 0.12 mmol) and acceptor 3 (46 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 5:1 to 4:1): 10e as a pale yellow oil (58 mg, 80%): 1H NMR (500 MHz; CDCl3) S 7.41-7.22 (15H, m, Ph), 6.00-5.79 (3H, m, CH=CH2), 5.30 (1H, dt, J = 3.4, 1.6 Hz, CH=CH2), 5.26 (1H, q, J =1.8 Hz, CH=CH2), 5.23 (1H, tt, J = 2.3,

1.1 Hz, CH=CH2), 5.17 (1H, dt, J = 3.4, 1.6 Hz, CH=CH2), 5.155.12 (2H, m, CH=CH2), 5.01 (1H, d, J = 2.6 Hz, H-1'), 4.99 (1H, d, J = 10.8 Hz, OCHHPh), 4.91 (1H, d, J = 10.8 Hz, OCHHPh), 4.82 (1H, d, J = 5.3 Hz, OCHHPh), 4.80 (1H, d, J = 6.6 Hz, OCHHPh), 4.69 (1H, d, J = 12.2 Hz, OCHHPh), 4.62 (1H, d, J = 2.5 Hz, H-1), 4.61 (1H, d, J = 4.8 Hz, OCHHPh), 4.35 (1H, ddt, J = 12.7, 5.6, 1.4 Hz, OCHHCH=CH2), 4.13-4.06 (1H, m, OCHHCH=CH2), 4.05-4.02 (2H, m, OCHHCH=CH2, H-3), 4.01-3.97 (1H, m, OCHHCH=CH2), 3.94-3.91 (2H, OCHHCH=CH2), 3.88-3.81 (2H, m, H-4, H-6a'), 3.78-3.73 (3H, m, H-4', H-3', H-5), 3.64 (1H, dd, J = 11.4, 2.0 Hz, H-6b'), 3.58 (1H, dd, J = 9.3, 7.3 Hz, H-5'), 3.56-3.52 (1H, m, H-2), 3.51-3.46 (2H, m, H-6a, H-6b), 3.37 (3H, s, OCH3), 2.14-2.07 (1H, m, H-2a'), 1.95-1.90 (1H, m, H-2b').13C NMR (126 MHz, CDCl3) S 138.7 (4 °C), 138.2 (4 °C), 138.1 (4 °C),

135.6 (CH=CH2), 134.8 (CH=CH2), 134.6 (CH=CH2), 128.5 (CH), 128.4 (CH), 128.04 (CH), 127.9 (CH), 127.7 (CH), 127.7

(CH), 116.9 (CH=CH2), 116.8 (CH=CH2), 116.6 (CH=CH2), 98.2 (c-1'), 97.9 (C-1), 82.1 (C-3), 80.0 (C-5'), 77.9 (C-2), 75.8 (CH2Ph), 74.9 (CH2Ph), 73.9 (C-4'), 73.5 (OCH2CH), 73.3 (CH2Ph), 72.4 (H-5), 72.2 (OCH2CH), 69.8 (2C, C-4, C-3'), 69.2 (OCH2CH), 69.1 (C-6), 66.0 (C-6'), 55.0 (OCH3), 31.1 (C-2'). ESI-HRMS for C43H54NaO10+ (MNa+) calcd: 753.3615; found: 753.3610. [a]D = +20 (c = 1, CHCl3).

Methyl 2,3,6-Tri-O-benzyl-4-O-(2-deoxy-3,4,6-tri-O-tert-butyldi-methylsilyl-a-D-lyxo-hexapyranosyl)-a-D-glucopyranoside (10f).

Following the general glycosylation procedure, donor 2f (50 mg, 0.10 mmol) and acceptor 3 (39 mg, 0.09 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 5:1 to 4:1): 10f as a colorless oil (64 mg, 79%): 1H NMR (400 MHz, CDCl3) S: 7.38-7.24 (15H, m, Ph), 4.99-4.95 (2H, m, H-1', OCHHPh), 4.87 (1H, d, J = 10.8 Hz, OCHHPh), 4.83 (1H, d, J = 10.7 Hz, OCHHPh), 4.80 (1H, d, J = 12.2 Hz, OCHHPh), 4.67 (1H, d, J = 12.2 Hz, OCHHPh), 4.61 (1H, d, J = 10.8 Hz, OCHHPh), 4.57 (1H, d, J = 3.6 Hz, H-1), 4.05 (1H, m, H-3'), 3.99 (1H, t, J = 9.2 Hz, H-2), 3.80 (1H, bs, H-4'), 3.77-3.73 (2H, m, H-3, H-6'a), 3.70-3.62 (4H, m, H-5', H-6a, H-6b, H-6'b), 3.49 (1H, dd, J = 9.6, 3.6 Hz, H-4), 3.42 (1H, t, J = 9.6 H-5), 3.36 (3H, s, OCH3), 2.08 (1H, td, J = 12.1, 3.5, H-2a'), 1.65 (1H, dd, J = 12.7, 4.5 H-2b'), 0.94-0.86 (27H, m, 3 X SiC(CH3)3), 0.12-0.00 (18H, m, 6 x SiCH3); 13C NMR (126 MHz; CDCl3) 138.7 (4 °C), 138.2 (4 °C), 138.1 (4 °C), 128.4-127.7 (Ph), 97.9 (C-1'),

97.6 (C-1), 82.1 (C-2), 79.9 (C-4), 78.5 (C-5), 75.8 (OCH2Ph), 75.1 (OCH2Ph), 73.3 (OCH2Ph), 72.7 (C-5'), 70.3 (C-4'), 68.3 (C-3'), 65.2 (C-6'), 62.6 (C-6), 54.7 (OCH3), 33.5 (C-2'), 26.2 (SiC(CH3)3),

26.1 (SiC(CH3)3), 25.8 (SiC(CH3)3), 18.6 (SiC(CH3)3), 18.5 (SiC(CH3)3), 18.1 (SiC(CH3)3), -3.9 (SiCH3), -4.4 (SiCH3), -4.8 (SiCH3), -5.0 (SiCH3), -5.3 (SiCH3), -5.4 (SiCH3). ESI-HRMS for C52H84NaSi3O10+ (MNa+) calcd: 975.5270; found: 975.5277. [a]D = +16 (c = 1, CHCl3).

Methyl 2,3,4-Tri-O-benzyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-a/p-D-erythrohexapyranosyl)-a-D-glucopyranoside (11a). Following the general glycosylation procedure, donor 8a (50 mg, 0.10 mmol) and acceptor 3 (50 mg, 0.08 mmol) afforded the following purification by column chromatography (Hexane:EtOAc 5:1 to 4:1): 11a as colorless oil (28 mg, 40%). Spectroscopic data in agreement with literature.6b

Methyl 2,3,6-Tri-O-benzyl-4-O-(2-deoxy-3,4-O-(1,1,3,3-tetraiso-propyldisiloxane-1,3-diyl)-6-O-triisopropylsilyl-a-D-erythro-hexapyr-anosyl)-a-D-glucopyranoside (11b). Following the general glycosylation procedure, donor 8b (50 mg, 0.10 mmol) and acceptor 3 (40 mg, 0.08 mmol) afforded the following purification by column chromatography (Hexane:EtOAc 5:1 to 4:1): 11b as colorless oil (66 mg, 81%). Spectroscopic data in agreement with literature.6b

Methyl 3-O-Benzyl-4,6-O-benzylidene-2-O-(2-deoxy-3,4-O-(1,1,3,3-tetraisopropyldisiloxane- 1,3-diyl)-6-O-triisopropylsilyl-a-D-erythro-hexapyranosyl)-a-D-glucopyranoside (11c). Following the general procedure, donor 8c (50 mg, 0.10 mmol) and acceptor 6k (30 mg, 0.08 mmol) afforded the following purification by column chromatography (Hexane:EtOAc 5:1 to 4:1): 11c as colorless oil (60 mg, 82%): 1H NMR (400 MHz, CDCl3) S: 7.50-7.44 (2H, m, Ph), 7.41-7.31 (5H, m, Ph), 7.25-7.20 (3H, m, Ph), 5.53 (1H, s, PhCHO2), 5.09 (1H, d, J = 3.3 Hz, H-1'), 4.99 (1H, d, J = 3.3 Hz, H-1), 4.88 (1H, d, J = 11.7 Hz, OCHHPh), 4.78 (1H, d, J = 11.7 Hz, OCHHPh), 4.29 (1H, dd, J = 9.9, 4.5 Hz, CHH), 4.13 (1H, ddd, J =

11.3, 8.3, 5.3 Hz, H-3'), 4.07-4.01 (1H, m, CHH), 3.94 (1H, dd, J = 9.4, 3.4 Hz, H-2), 3.92 (1H, dd, J = 9.4, 8.9 Hz, H-3), 3.87-3.75 (3H, m, H-5, H-5', CHH), 3.71 (1H, t, J = 10.1 Hz, CHH), 3.61 (1H, t, J = 9.1 Hz, H-4), 3.51 (1H, dd, J = 9.2, 8.4 Hz, H-4'), 3.43 (3H, s, OCH3), 2.25 (1H, app dd, J = 13.2, 5.1 Hz, H-2a'), 1.73 (1H, ddd, J = 13.5,

11.4, 3.7 Hz, H-2b'), 1.17-0.86 (49H, m, 7 x SiCH(CH3)2); 13C NMR (101 MHz, CDCl3) S: 139.0 (4 °C), 137.6 (4 °C), 129.0 (CH), 128.28 (CH), 128.25 (CH), 127.7 (ch), 127.4 (CH), 126.2 (ch), 101.5 (PhCHO2), 97.4 (C-1), 92.9 (C-1'), 81.5 (H-4), 77.3 (C-3),

75.2 (PhCH2O), 74.7 (C-4'), 73.7 (CH), 73.5 (C-2), 71.9 (C-3'), 69.2, 63.5 (C-6, C-6'), 62.6 (CH), 55.3 (OCH3), 38.0 (C-2'), 18.24 (Si(CH(CH3)2)), 18.20 (Si(CH(CH3)2)), 18.15 (Si(CH(CH3)2)),

17.7 (Si(CH(CH3)2)), 17.6 (Si(CH(CH3)2))0, 17.59 (Si(CH-(CH3X)), 17.53 (Si(CH(CH3)2)), 17.48 (Si(CH(CH3)2)), 17.45

(Si(CH(CH3)2)), 17.4 (Si(CH(CH3)2)), 13.1 (Si(CH(CH3)2)), 12.5 (Si(CH(CH3)2)), 12.4 (Si(CH(CH3)2)), 12.2 (Si(CH(CH3)2)), 12.2 (Si(CH(CH3)2)). MALDI-HRMS for C48H80NaO11Si3+ (MNa+) calcd: 939.48369; found: 939.4896. [a]D2 = -451 (c = 0.0030, CHCl3).

Methyl 2,3,4-Tri-O-benzyl-6-O-(2,6-deoxy-3,4-O-(1,1,3,3-tetraiso-propyldisiloxane-1,3-diyl)-a/ß-L-erythro-hexapyranosyl)-a-D-gluco-pyranoside (12a). Following the general glycosylation procedure, donor 9 (50 mg, 0.13 mmol) and acceptor 3 (52 mg, 0.11 mmol) afforded the following purification by column chromatography (Hexane:EtOAc, 8:1 to 4:1) 12 as a colorless oil (78 mg, 74%, a:ß = 9:1). Spectroscopic data in agreement with literature.7

Methyl 3-O-Benzyl-4,6-O-benzylidene-2-O-(2,6-deoxy-3,4-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-a/ß-L-erythro-hexapyra-nosyl)-a-D-glucopyranoside (12b). Following the general procedure, donor 9 (50 mg, 1.3 mmol) and acceptor 6k (42 mg, 1.1 mmol) afforded the following purification by column chromatography (Hexane:EtOAc 20:1 to 10:1): 12b as colorless oil (72 mg, 87%, a:ß = 10:1): 1H NMR (400 MHz, CDCl3) S: 7.52-7.48 (2H, m, Ph), 7.40-7.25 (8H, m, Ph), 5.58 (1H, s, PhCHO2 a-anomer), 5.56 (1H, s, PhCHO2 ß-anomer), 5.07 (1H, d, J = 3.9 Hz, H-1'), 4.88-4.84 (2H, m, H-1, OCHHPh), 4.78 (1H, d, J = 11.4 Hz, OCHHPh), 4.30 (1H, dd, J = 9.9, 4.5 Hz, H-6a), 4.07 (1H, ddd, J = 11.3, 8.3, 5.3 Hz, H-3'), 3.97 (1H, t, J = 9.3, H-5'), 3.89-3.72 (3H, m, H-4, H-5, H-6b), 3.693.60 (2H, m, H-2, H-3), 3.45 (1H, s, OCH3 ß-anomer), 3.45 (1H, s, OCH3 a-anomer), 3.27 (1H, J = 8.7 Hz, H-4') (2.24 (1H, app dd, J = 13.2, 5.1 Hz, H-2a'), 1.74 (1H, ddd, J = 13.5, 11.4, 3.7 Hz, H-2b'), 1.29 (3H, d, J = 6.3 Hz, CH3) 1.14-1.02 (28H, m, 4 X SiCH(CH3)2); 13C NMR (101 MHz, CDCl3) S: 138.66 (4 °C), 137.42 (4 °c), 128.89 (CH), 128.28 (CH), 128.19 (CH), 127.7 (CH), 127.57 (CH), 126.0 (ch), 101.25 (PhCHO2), 100.6 (c-1'), 100.25 (C-1), 82.0 (C-2), 80.37 (C-3), 79.99 (C-4'), 77.94 (C-5), 75.25 (PhCH2O), 71.22 (C-3'), 69.07 (C-6), 68.3(C-5'), 62.23 (C-4), 55.2 (OCH3), 38.67 (C-2'), 29.7 (CH3), 18.14-12.27 (4 X Si(CH(CH3)2)). ESI-HRMS for C39H60NaO10+ (MNa+) calcd: 767.3623; found: 767.4002. [a]D = +25 (c = 1, CHCl3). [a]D2 = +32 (c = 1, CHCl3).

One-Pot Trisaccharide Synthesis: 6-O-(2,3,4-Tri-O-benzoyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-a-D-lyxo-hexapyranosyl)-a-D-galacto-pyranosyl)-1,2:3,4-di-O-isopropylidene-a-D-galactopyranoside (13). Following general procedure, donor 2a (50 mg, 0.12 mmol), acceptor 6d (58 mg, 0.0998 mmol), and a solution mixture, prepared containing chiral acid (~0.012 mmol) and thiourea (~0.012 mmol) in anhydrous DCM (1 mL), were mixed together. After 2 h, the disaccharide formation was determined to be complete by TLC. The reaction mixture was then cooled to 0 °C, and molecular sieves 4 A were added. Once cooled, a solution of 1,2:3,4-di-O-isopropylidene-a-d-galactopyr-anoside 6c (26 mg, 0.0998 mmol) in anhydrous DCM (0.5 mL) was added followed by addition of NIS (45 mg, 0.2 mmol) and finally the dropwise addition of a solution of TMSOTf (95 ^L, 40 ^L in 20 mL anhydrous DCM, 0.001 mmol). After 1 h, the reaction was determined to be complete and was quenched with Et3N (0.1 mL), diluted with DCM (25 mL), washed with Na2S2O3 (sat. aq.) (25 mL), brine (25 mL), dried over MgSO4, and concentrated in vacuo. Purification by column chromatography (Hexane:EtOAc, 10:1 to 3:1) afforded product 13 as a white solid (59 mg, 51%). Spectroscopic data in agreement with literature.7

Methyl 2,3,4-Tri-O-benzyl-6-O-(2-deoxy-3,4,6-tri-O-benzyl-2-2H-a-D-lyxo-hexapyranosyl)-a-D-glucopyranoside (15). Following the general glycosylation procedure, donor 14 (50 mg, 0.12 mmol) and acceptor 3 (46 mg, 0.10 mmol) afforded the following purification by column chromatography (Hexane:EtOAc 20:1 to 12:1): 15 as a yellow oil (72 mg 83%): 1H NMR (500 MHz; CDCl3) S 7.40-7.21 (m, 30H, Ar-H), 5.04 (1H, d, J = 1.3 Hz, H-1 ' ), 5.00 (1H, d, J = 10.8 Hz, OCHHPh), 4.93 (1H, d, J = 11.6 Hz, OCHHPh), 4.86 (1H, d, J = 10.9 Hz, OCHHPh), 4.83-4.78 (2H, m, OCHHPh), 4.69 (1H, d,J = 12.2 Hz, OCHHPh), 4.62 (1H, d, J = 2.7 Hz, H-1), 4.61 (1H, d, J = 5.4 Hz, OCHHPh), 4.58 (2H, s, OCHHPh), 4.54 (1H, d, J = 10.8 Hz, OCHHPh), 4.42 (1H, d, J = 11.8 Hz, OCHHPh), 4.35 (1H, d, J = 11.8 Hz, OCHHPh), 4.04-3.96 (1H, t, J = 9.3 Hz, H-3), 3.89 (3H, t, J = 3.1 Hz, H-3 ', H-4 ', H-5 ' ), 3.83 (1H, dd, J = 11.4, 4.7 Hz, H-6a), 3.74 (1H, ddd, J = 10.0, 4.6, 1.8 Hz, H-5), 3.63 (1H, dd, J =11.4, 1.9 Hz, H-

6b), 3.58-3.54 (2H, m, H-6a, H-2), 3.54-3.51 (1H, m, H-6b), 3.48 (1H, dd, J = 10.1, 8.9 Hz, H-4), 3.33 (3H, s, OCH3), 2.03-1.99 (1H, m, H-2' ). 13C NMR (126 MHz, CDCl3) 8 138.9 (4 °C), 138.7 (4 °C), 138.4 (4 °C), 138.3 (4 °C), 138.16 (4 °C), 138.1 (4 °C), 128.41 (CH), 128.2 (CH), 127.7 (CH), 98.3 (C-1' ), 97.9 (C-1), 82.1 (C-3), 80.0 (C-2), 77.9 (C-4), 75.8 (CH2Ph), 74.9 (cH2Ph), 74.3 (CH2Ph), 74.16 (C-3 '), 73.3 (CH2Ph), 73.3 (CH2Ph), 72.9 (C-4' ), 70.2 (CH2Ph), 70.1 (CH2Ph), (C-5 ), 69.8 (C-5), 69.4 (C-6 ), 66.0 (C-6), 55.0 (OCH3), 29.7 (C-2' ). ESI-HRMS for C55H59DNaO10+ (MNa+) calcd: 904.4147; found: 904.4142. [a]D = +25 (c = 1, CHCl3). D

■ ASSOCIATED CONTENT Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b02498.

Detail NMR experiments and full characterization data (PDF)

■ AUTHOR INFORMATION Corresponding Author

*E-mail: m.c.galan@bristol.ac.uk. ORCID®

M. Carmen Galan: 0000-0001-7307-2871 Author Contributions ^These authors contributed equally. Notes

The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

This research was supported by EPSRC CAF EP/L001926/1 (MCG), ERC-COG: 648239 (M.C.G., A.S., and R.W.) and RS Newton International fellowship (C.P.-N.).

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