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. Author manuscript; available in PMC: 2011 May 26.
Published in final edited form as: J Org Chem. 2009 Mar 20;74(6):2486–2493. doi: 10.1021/jo900026e

The 4-(tert-Butyldiphenylsiloxy)-3-fluorobenzyl Group: A New Alcohol Protecting Group, Fully Orthogonal with the p-Methoxybenzyl Group and Removable under Desilylation Conditions

David Crich a,b,c,*, Linfeng Li a, Michio Shirai b)
PMCID: PMC3102264  NIHMSID: NIHMS291436  PMID: 19243158

Abstract

A new benzyl ether-type protecting group for alcohols, the 4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl group, is introduced. The protecting group is introduced by means of the readily prepared benzyl bromide and is cleaved with tetrabutylammonium fluoride in dimethylformamide around 90 °C. The fluoride substituent provides stability to oxidizing conditions, such that the new protecting group is fully compatible with the removal of p-methoxybenzyl ethers with DDQ. Applications of the new protecting group in the direct stereocontrolled synthesis of β-mannopyranosides are presented.

Introduction

Benzyl and silyl ethers are some of the most widely used alcohol protecting groups.1 The high degree of mutual orthogonality which they display makes combinations of them attractive protecting systems for complex polyols, whether in the context of total synthesis, combinatorial library synthesis, or oligosaccharide synthesis. In addition to their differing reactivity patterns, the two types of protecting group differ significantly in their steric properties. The appreciably greater bulk of the silyl ethers leads to the much reduced chelating ability of α-siloxycarbonyl systems,2 and contributes to the inverted conformations adopted by some polylsilylated six-membered ring systems.3 In the course of a study targeted at the synthesis of the common core pentasaccharide of the N-linked glycoproteins we uncovered an unanticipated consequence of the steric bulk of silyl ether protecting groups.4 Thus, while 4,6-O-benylidene protected thiomannopyranosides, and their sulfoxides, carrying benzyl ethers at positions 2 and 3 are known to be superb donors in the direct stereocontrolled formation of β-mannopyranoside linkages,5 an analagous system 1 carrying a 3-O-tert-butyldimethylsilyl group in place of a benzyl ether was found to favor the formation of α-mannosides. This result was even more surprising in view of the fact that the regioisomeric 3-O-benzyl-2-O-tert-butyldimethylsilyl system 2 showed adequate β-selectivity. Thus, the more remote 3-O-silyl group in 1 had a greater influence on the stereochemical outcome of the glycosylation than the 2-O-silyl ether adjacent to the reactive site in 2. We rationalized this effect in terms of a buttressing interaction between the 3-O-silyl and 2-O-benzyl ethers in 1, which forces the benzyl closer to the anomeric center leading ultimately to the reduced stereoselectivity.6,7

graphic file with name nihms-291436-f0001.jpg

This interesting reactivity pattern alerted us to the need for a protecting group having the steric characteristics of a benzyl ether but which is removable under typical desilylation conditions. We report here on the design and successful implementation of such a system.8

Results and Discussion

A significant range of substituted benzyl ether protecting groups is reported in the literature,1,9 many of which have been applied in carbohydrate chemistry.10 However, until the description of the p-siletanylbenzyl ether,11 none could be considered to be cleavable under typical desilylation conditions.12 In designing such a protecting group we first considered the obvious simple p-siloxybenzyl type systems, but dismissed them on the grounds that they would be too acid sensitive and subject to cleavage under the same oxidative conditions commonly used for the removal of p-methoxybenzyl1,13 and naphthylmethyl ethers. 14 Rather, we focused on p-siloxybenzyl systems bearing an electron-withdrawing substituent intended to provide enhanced stability under acidic and oxidative conditions, in much the same way that a 3-chloro substituent enhances the stability of the 4-azidobenzyl ethers.15 In view of our requirement for a system with the steric properties of a simple benzyl ether we targeted therefore the 3-fluoro-4-siloxybenzyl groups.

Starting from commercially available 4-carboxy-2-fluorophenol (3), 4-(tert-Butyldiphenylsiloxy)-3-fluorobenzyl bromide (5) was assembled in three convenient steps (Scheme 1).

Scheme 1.

Scheme 1

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Assembly of 4-(tert-Butyldiphenylsiloxy)-3-fluorobenzyl bromide

Before proceeding to applications in oligosaccharide synthesis, the orthogonality of the new protecting group with p-methoxybenzyl ethers was tested. Thus, monoalkylation of 2,2-dibenzyl-1,3-propanediol 6 with p-methoxybenzyl chloride gave 7, which was converted to the fully protected 8 on treatment with sodium hydride in THF in the presence of HMPA, followed by the addition of 5 (Scheme 2). Exposure of 8 to DDQ in wet dichloromethane at room temperature resulted in cleavage of the p-PMB ether in 95% yield. On the other hand, exposure of 8 to tetrabutylammonium fluoride in a variety of solvents, including DMF, at room temperature resulted only in the removal of the silyl ether, giving phenol 10. This result was not totally unexpected in view of similar observations reported in the literature on saponification of p-acetoxybenzyl ethers.9b Fortunately, when desilylation was conducted under microwave irradiation at 90 °C, a satisfactory 85% yield of the desired alcohol 7 was obtained (Scheme 2). The complete orthogonality of the new protecting group with p-methoxybenzyl ethers, for which the system had been designed, was thus established.

Scheme 2.

Scheme 2

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Orthogonality with p-Methoxybenzyl Ethers

Turning to applications in glycosidic bond formation, treatment of Phenyl 4,6-O-benzylidene-1-thio-α-d-mannopyranoside 11 with p-methoxybenzyl chloride under phase transfer conditions16 afforded the 2-O-PMB ether 12. Benzylation with 5 and sodium hydride in DMF then provided the orthogonally protected glycosyl donor 13 (Scheme 3).

Scheme 3.

Scheme 3

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Preparation of Glycosyl Donor 13

With acceptor 13 in hand, the glycosylation of a series of four acceptor alcohols was undertaken. These reactions were carried out in dichloromethane at −60 °C, with prior activation of the thioglycoside with a combination of 1-benzenesulfinyl piperidine (BSP),5c,d,f and trifluoromethanesulfonic anhydride in the presence of the convenient non-nucleophilic base 2,4,6-tri-tert-butylpyrimidine (TTBP),17 before addition of the alcohol. Like the action of trifluoromethanesulfonic anhydride on glycosyl sulfoxides,18 this activation protocol converts the thioglycoside to a covalent α-glycosyl trifluoromethanesulfonate,5c which then undergoes SN2-like reaction with the alcohol with the intermediacy of a transient contact ion pair.19 As is clear from Table 1, all couplings proceeded in high yield and with excellent β-selectivity.20

Table 1.

Glycosylation Reactions with Donor 13

graphic file with name nihms-291436-t0007.jpg

ROH Product Yield β:α ratio
graphic file with name nihms-291436-t0008.jpg 14 85% 11.7:1
graphic file with name nihms-291436-t0009.jpg 15 82% β only
graphic file with name nihms-291436-t0010.jpg 16 79% 8.2:1
graphic file with name nihms-291436-t0011.jpg 17 62% β only
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graphic file with name nihms-291436-f0002.jpg

Glycosides 14-17 were then subjected to partial deprotection by exposure to DDQ at room temperature and by treatment with TBAF in THF at 90 °C with the results set out in Table 2. As in the model experiments (Scheme 2), all attempts at debenzylation with TBAF at lower temperatures resulted only in the cleavage of the silyl group.

Table 2.

Selective Deprotection of Glycosides.a

graphic file with name nihms-291436-t0012.jpg

ROH DDQ Product
(% yield)		 TBAF Product
(% yield)
graphic file with name nihms-291436-t0013.jpg 18 (80) 22 (74)b
22 (77)c
graphic file with name nihms-291436-t0014.jpg 19 (80) 23 (76)
graphic file with name nihms-291436-t0015.jpg 20 (84) 24 (78)
graphic file with name nihms-291436-t0016.jpg 21 (82) 25 (78)
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a)

The deprotections were conducted with the anomerically pure β-anomer.

b)

Heating in a microwave reactor.

c)

Conventional heating in DMF solution.

In a final demonstration of the ability of the new protecting group to support β-mannosylation reactions, donor 13 was coupled to alcohols 18 and 22 to generate the disaccharides 25 and 26, both with excellent β-selectivity (Scheme 4), thereby establishing the viability of this new protecting group for use in the synthesis of mannans containing both the β-(1→2)5g and β-(1→3)16d linkages.

Scheme 4.

Scheme 4

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Disaccharide Synthesis

While the focus of this project has been on the application of the new benzyl protecting group in glycosylation reactions, we anticipate that it will also find use in the broader context of organic synthesis. In particular, we anticipate that the new protecting group will find application in situations requiring chelation control and the subsequent cleavage of the protecting group under desilylation conditions. Finally, we note that while we have concentrated here on benzyl ethers derived from bromide 5 base on the tert-butyldiphenylsilyl ether moiety, we expect that analogous chemistry was displayed by the corresponding 4-(tert-butyldimethylsiloxy)-3-fluorobenzyl and 4-(triisopropylsiloxy)-3-fluorobenzyl systems whose preparation is described in the supporting information.

Experimental Section

4-(tert-Butyldiphenylsiloxy)-3-fluorobenzyl alcohol (4)

To a stirred solution of 3-fluoro-4-hydroxybenzoic acid (2.0 g, 12.8 mmol) and Et3N (10.7 ml, 76.8 mmol) in CH2Cl2 (30 ml) was added TBDPSCl (8.4 ml, 32.0 mmol) dropwise at room temperature. The reaction mixture was stirred at rt overnight and then diluted with CH2Cl2, washed with brine. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was then dissolved in dry THF (30 ml) at 0 °C and LiAlH4 (947 mg, 25.6 mmol) was added portion wise. After 10 min, the cooling bath was removed, the reaction mixture was stirred under refluxed for 4 h. The reaction mixture was cooled to room temperature, and then water was added dropwise until a white solid precipitated. To this mixture was added Na2SO4 and the mixture was filtered through Celite. The filter cake was washed with CH2Cl2 and the filtrate was concentrated and the residue was purified by flash chromatography over silica gel (15% ethyl acetate in hexane) afforded 4 (2.25 g, 46%). Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.79–7.77 (m, 4H), 7.46–7.40 (m, 6H), 7.06–7.04 (dd, J = 2.0, 11.0 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H), 6.65 (t, J = 8.5 Hz, 1H), 4.46 (s, 2H), 2.30 (s, 1H), 1.19 (s, 9H); 13C NMR (125.9 MHz, CDCl3) δ 153.7 (d, J = 246.7 Hz), 142.8 (d, J = 12.9 Hz), 135.5, 134.6 (d, J = 5.0 Hz), 132.6, 130.1, 127.9, 122.5 (d, J = 2.5 Hz), 121.3, 115.2 (d, J = 18.9 Hz), 64.3, 26.6, 19.8; HRESIMS calcd for C23H25O2FSiNa [M + Na]+, 403.1506; found, 403.1496.

4-(tert-Butyldiphenylsiloxy)-3-fluorobenzyl bromide (5)

To a stirred solution of 4 (2.20 g, 5.78 mmol) and PPh3 (2.27g, 8.67 mmol) in CH2Cl2 (10 mL) was added CBr4 portion wise and the resulting solution was stirred for 1h at rt. The reaction mixture was concentrated and the residue was purified by chromatographic purification over silica gel (1% ethyl acetate in hexane) afforded 5 (2.32 g, 92%). Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.76–7.74 (m, 4H), 7.48–7.44 (m, 2H), 7.42–7.38 (m, 4H), 7.12–7.09 (dd, J = 2.0, 11.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.59 (t, J = 8.5 Hz, 1H), 4.37 (s, 2H), 1.16 (s, 9H); 13C NMR (125.9 MHz, CDCl3) δ 153.5 (d, J = 246.7 Hz), 143.7 (d, J = 12.9 Hz), 135.5, 132.3, 131.2 (d, J = 6.3 Hz), 130.2, 127.9, 124.7 (d, J = 2.5 Hz), 121.4, 117.2 (d, J = 18.9 Hz), 33.0, 26.5, 19.7; HRESIMS calcd for C23H24OBrFSiNa [M + Na]+, 465.0662; found, 465.0654.

General procedure for the removal of 4-(tert-butyldiphenylsilyloxy)-3-fluorobenzyl group using microwave reactor (method A)

To a stirred solution of the substrate and 4 Å molecular sieves in THF (0.05 M) was added TBAF (2 equiv, 1.0 M in THF). The reaction mixture was heated to 90 °C in microwave reactor for 2 h and cooled to rt. The reaction mixture was filtered through Celite. Purification by column chromatography on silica gel, eluting with hexane/ethyl acetate mixtures, afforded the corresponding alcohols.

General procedure for the removal of 4-(tert-butyldiphenylsilyloxy)-3-fluorobenzyl group with conventional heating (method B)

To a stirred solution of the substrate and 4 Å molecular sieves in DMF (0.05 M) was added TBAF (2 equiv, 1.0 M in THF). The reaction mixture was heated to 90 °C for 3 h and cooled to rt. The reaction mixture was filtered through Celite filtered and washed with EtOAc. The filtrate was diluted with EtOAc, washed with H2O. The aqueous phase was extracted with EtOAc three times, and the combined organic phase was dried and concentrated. Purification by column chromatography on silica gel, eluting with hexane/ethyl acetate mixtures, afforded the corresponding alcohols.

General procedure for the removal of para-methoxybenzyl group

To a stirred solution of the substrate in CH2Cl2/H2O (9/1, 0.05 M) was added DDQ (2 equiv) in one portion. The reaction mixture was stirred at rt for 2 h and then diluted with CH2Cl2, washed with brine. The organic layer was separated, dried over Na2SO4 and concentrated. Chromatographic purification on silica gel, eluting with hexane/ethyl acetate mixtures, afforded the corresponding alcohols.

2,2-Dibenzyl-3-(4-methoxybenzyloxy)propan-1-ol (7). From 2,2-Dibenzylpropane-1,3-diol 6

To a stirred solution of 2,2-dibenzylpropane-1,3-diol (309 mg, 1.21 mmol) in THF (5 mL) at 0 °C was added sodium hydride (60%, 63 mg, 1.57 mmol). After 10 min, PMBCl (213 μL, 1.57 mmol) was added and the reaction mixture stirred under reflux for 6 h. The reaction mixture was concentrated, dissolved in CH2Cl2, washed with saturated NH4Cl and brine. The organic layer was separated, dried over Na2SO4 and concentrated. Chromatographic purification (7.5 % ethyl acetate in hexane) on silica gel gave 7 (369 mg, 81%). From 8: Prepared by the general procedure for the removal of 4-(tert-butyldiphenylsilyloxy)-3-fluorobenzyl group using microwave reactor (method A) with a yield of 25.4 mg (85%). Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.32–7.20 (m, 12H), 6.94–6.92 (m, 2H), 4.43 (s, 2H), 3.83 (s, 3H), 3.47 (d, J = 5.5 Hz, 2H), 3.25 (s, 2H), 2.82 (d, J = 13.5 Hz, 1H), 2.78 (d, J = 13.5 Hz, 1H), 2.37 (t, J = 5.5 Hz, 1H); 13C NMR (125.9 MHz, CDCl3) δ 159.3, 137.9, 130.7, 130.1, 129.5, 128.1, 126.2, 113.9, 73.7, 73.1, 66.5, 55.4, 43.4, 39.4; HRESIMS calcd for C25H28O3Na [M + Na]+, 399.1931; found, 399.1930.

2,2-Dibenzyl-1-[4-(tert-butyldiphenylsilyloxy)-3-fluorobenzyloxy]-3-(4-methoxybenzyloxy)propane (8)

To a stirred solution of 7 (157 mg, 0.417 mmol) in HMPA (404 μL, 0.417 mmol) and anhydrous THF (4 ml) at 0 °C was added n-BuLi (184 μL, 0.459 mmol). The reaction mixture was stirred at 0 °C for 5 min and then bromide 5 (222 mg, 0.500 mmol) in 1 ml THF was added. The ice bath was removed and the stirring continued for 10 h at rt. The reaction mixture was diluted with CH2Cl2, washed with saturated NaHCO3 and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (2.5% ethyl acetate in hexane) to give 8 (219 mg, 71%). Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.78–7.76 (m, 4H), 7.48–7.35 (m, 8H), 7.26–7.16 (m, 10H), 7.12–7.10 (dd, J = 2.0, 11.0 Hz, 1H), 6.96–6.94 (m, 2H), 6.78 (d, J = 8.5 Hz, 1H), 6.65 (t, J = 8.5 Hz, 1H), 4.42 (s, 2H), 4.32 (s, 2H), 3.85 (s, 3H), 2.93 (s, 2H), 2.89 (s, 2H), 2.853 (s, 2H), 2.849 (s, 2H), 1.18 (s, 9H); 13C NMR (125.9 MHz, CDCl3) δ 159.2, 153.6 (d, J = 245.5 Hz), 142.7 (d, J = 11.3 Hz), 138.4, 135.5, 132.6, 132.2 (d, J = 5.0 Hz), 130.7, 130.6, 130.1, 129.5, 127.8, 126.0, 123.2 (d, J = 2.6 Hz), 121.0, 115.9 (d, J = 17.6 Hz), 113.8, 72.7, 72.2, 70.0, 69.7, 55.4, 43.9, 39.0, 26.6, 19.7; HRESIMS calcd for C48H51O4FSiNa [M + Na]+, 761.3438; found, 761.3400.

2,2-Dibenzyl-3-[4-(tert-butyldiphenylsilyloxy)-3-fluorobenzyloxy]-propan-1-ol (9)

Prepared by the general procedure for the removal of para-methoxybenzyl group from 8 with a yield of 29.6 mg (89%). Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.74–7.72 (m, 4H), 7.46–7.35 (m, 6H), 7.26–7.16 (m, 10H), 7.05–7.02 (dd, J = 2.0, 11.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.60 (t, J = 8.5 Hz, 1H), 4.30 (s, 2H), 3.43 (d, J = 5.5 Hz, 2H), 3.16 (s, 2H), 2.77 (d, J = 13.5 Hz, 1H), 2.73 (d, J = 13.5 Hz, 1H), 2.12 (t, J = 5.5 Hz, 1H), 1.14 (s, 9H); 13C NMR (125.9 MHz, CDCl3) δ 153.4 (d, J = 246.7 Hz), 142.9 (d, J = 11.3 Hz), 137.8, 135.5, 132.6, 131.5 (d, J = 5.0 Hz), 130.6, 130.1, 128.0, 127.8, 126.2, 123.2, 121.1 (d, J = 2.6 Hz), 115.9 (d, J = 18.8 Hz), 73.7, 72.7, 66.2, 43.4, 39.4, 26.5, 19.7; HRESIMS calcd for C40H43O3FSiNa [M + Na]+, 641.2858; found, 641.2854.

2,2-Dibenzyl-1-(4-hydroxy-3-fluorobenzyloxy)-3-(4-methoxybenzyloxy)propane (10)

To a stirred solution of 8 (16.2 mg, 21.9 μmol) in THF (1 ml) was added TBAF (33.0 μl, 1.0 M in THF). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated and chromatographic purification (10% ethyl acetate in hexane) on silica gel afforded 10 (12.5 mg, 92%). Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.34–7.32 (m, 2H), 7.23–7.13 (m, 10H), 7.05–6.97 (m, 2H), 6.94–6.91 (m, 2H), 5.18 (s, 1H), 4.40 (s, 2H), 4.36 (s, 2H), 3.84 (s, 3H), 2.93 (s, 2H), 2.92 (s, 2H), 2.84 (s, 4H); 13C NMR (125.9 MHz, CDCl3) δ 159.2, 150.9 (d, J = 236.6 Hz), 142.9 (d, J = 13.8 Hz), 138.4, 131.6 (d, J = 5.0 Hz), 130.7, 130.6, 129.5, 127.8, 125.9, 124.3 (d, J = 2.6 Hz), 117.0, 115.1 (d, J = 17.6 Hz), 113.8, 72.7, 72.1, 69.6, 55.3, 43.9, 39.0; HRESIMS calcd for C32H33O4FNa [M + Na]+, 523.2255; found, 523.2252.

Phenyl 4,6-O-Benzylidene-2-O-(4-methoxybenzyl)-1-thio-α-D-mannopyranoside (12)

To a mixture of 11 (1.25 g, 3.46 mmol), tetrabutylammonium hydrogensulfate (235 mg, 0.692 mmol) and PMBCl (0.565 mL, 4.16 mmol) in CH2Cl2 (50 mL) was added 1 M aq. NaOH (17 mL). The reaction mixture was stirred under reflux for 24 h, then allowed to cool to room temperature, and diluted with CH2Cl2. The organic layer was separated. The aqueous phase was extracted twice with CH2Cl2. The combined organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4, and concentrated. Chromatographic purification (50% hexane in CH2Cl2) afforded 12 (1.16 g, 70%) as white crystalline solid. M.p. 113 °C. [α]22D : +124.7 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.53–7.25 m, 10H), 6.91–6.88 (m, 2H), 5.57 (s, 1H), 5.53 (s, 1H), 4.68 (d, J = 11.2 Hz, 1H), 4.58 (d, J = 11.2 Hz, 1H), 4.32–4.26 (dt, J = 4.8, 9.6 Hz, 1H), 4.24–4.20 (dd, J = 4.8, 10.4 Hz, 1H), 4.12–4.07 (m, 2H), 3.97 (t, J = 9.6 Hz, 1H), 3.83 (t, J = 10.4 Hz, 1H), 3.80 (s, 3H), 2.47 (d, J = 8.0 Hz, 1H); 13C NMR (100.7 MHz, CDCl3) δ 159.9, 137.5, 133.9, 132.0, 130.0, 129.5, 129.4, 128.5, 128.0, 126.6, 114.3, 102.4, 86.6, 79.9, 79.8, 73.1, 69.2, 68.7, 64.9, 55.5. HRESIMS calcd for C27H28O6SNa [M + Na]+, 503.1504; found, 503.1500.

Phenyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-2-O-(4-methoxybenzyl)-1-thio-α-d-mannopyranoside (13)

To a stirred solution of 12 (700 mg, 1.61 mmol) in DMF (8 mL) at 0 °C was added NaH (60% in mineral oil, 70.8 mg, 1.77 mmol). After 15 min, 5 (857 mg, 1.93 mmol) in DMF (2 ml) was added and the reaction mixture stirred at rt for 10 h. The reaction mixture was diluted with EtOAc, washed with H2O. The aqueous phase was extracted with EtOAc three times, and the combined organic phase was dried and concentrated. Chromatographic purification (7.5 % ethyl acetate in hexane) on silica gel gave 13 (947 mg, 74%). Colorless oil; [α]23D : +51.8 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.75–7.73 (m, 4H), 7.50–7.24 (m, 18H), 7.06–7.03 (dd, J = 2.0, 11.5 Hz, 1H), 6.85 (s, 1H), 6.83 (s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.60 (t, J = 8.5 Hz, 1H), 5.62 (s, 1H), 5.47 (s, 1H), 4.66–4.58 (m, 3H), 4.46 (d, J = 12.0 Hz, 1H), 4.27–4.20 (m, 3H), 3.97–3.96 (dd, J = 1.0, 3.0 Hz, 1H), 3.90–3.85 (m, 2H), 3.78 (s, 3H), 1.15 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 159.7, 153.9 (d, J = 245.6 Hz), 143.0 (d, J = 12.0 Hz), 137.7, 135.7, 134.1, 132.8, 132.2 (d, J = 6.5 Hz), 131.9, 130.3, 130.1, 129.8, 129.4, 129.1, 128.4, 128.0, 127.9, 126.3, 123.3 (d, J = 3.8 Hz), 121.2 (d, J = 1.9 Hz), 116.0 (d, J = 18.6 Hz), 114.1, 101.7, 87.3, 79.2, 77.5, 76.1, 72.7, 72.4, 68.7, 65.7, 55.5, 26.7, 19.9. HRESIMS calcd for C50H51O7FSSiNa [M + Na]+, 865.3007; found, 865.2997.

General glycosylation procedure using the BSP/TTBP/Tf2O system

To a stirred solution of donor (1 equiv.), BSP (1.2 equiv.), TTBP (1.5 equiv.), and 4 Å molecular sieves in CH2Cl2 (0.05 M in donor) at −60 °C, was added Tf2O (1.2 equiv.). After 30 min of stirring at −60 °C, a 0.15 M solution of the glycosyl acceptor (1.5 equiv.) in CH2Cl2 was slowly added. The reaction mixture was stirred for a further 2 h at −60 °C, before saturated NaHCO3 was added to quench the reaction. The reaction mixture was allowed to reach room temperature and then filtered through a pad of Celite and washed with CH2Cl2, after which the filtrate was washed with saturated NaHCO3 and brine. The organic layer was separated, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel, eluting with hexane/ethyl acetate mixtures, afforded the corresponding coupled products.

1-Adamantanyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-2-O-(4-methoxybenzyl)-β-d-mannopyranoside (14β) and 1-Adamantanyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-2-O-(4-methoxybenzyl)-α-d-mannopyranoside (14α)

Prepared by the general glycosylation procedure with a yield of 419 mg (85%, β:α= 11.7:1). 14β: white crystalline solid. M.p. 139 °C. [α]23D : −19.8 (c 2.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.75–7.73 (m, 4H), 7.48–7.27 (m, 13H), 7.00 (d, J = 12.0 Hz, 1H), 6.85 (s, 1H), 6.83 (s, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.56 (t, J = 8.5 Hz, 1H), 5.59 (s, 1H), 4.92 (d, J = 12.5 Hz, 1H), 4.87 (d, J = 12.5 Hz, 1H), 4.76 (s, 1H), 4.48 (d, J = 12.5 Hz, 1H), 4.36 (d, J = 12.0 Hz, 1H), 4.28–4.25 (dd, J = 5.0, 10.5 Hz, 1H), 4.16 (t, J = 9.5 Hz, 1H), 3.93 (t, J = 10.0 Hz, 1H), 3.77 (s, 3H), 3.72 (d, J = 3.0 Hz, 1H), 3.52–3.49 (dd, J = 3.0, 10.0 Hz, 1H), 3.33–3.28 (dt, J = 4.5, 9.5 Hz, 1H), 2.19 (s, 3H), 1.88 (d, J = 11.0 Hz, 3H), 1.78 (d, J = 11.5 Hz, 3H), 1.68 (d, J = 12.5 Hz, 3H), 1.63 (d, J = 12.5 Hz, 3H), 1.15 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 159.4, 153.8 (d, J = 245.6 Hz), 142.9 (d, J = 12.1 Hz), 137.9, 135.7, 132.8, 132.4 (d, J = 6.5 Hz), 130.8, 130.7, 130.3, 129.0, 128.4, 128.0, 126.3, 123.1 (d, J = 2.8 Hz), 121.1 (d, J = 1.9 Hz), 115.9 (d, J = 19.5 Hz), 113.7, 101.6, 95.2 (1JCH = 153.6 Hz), 78.7, 78.5, 76.1, 75.5, 74.2, 71.7, 69.1, 67.5, 55.5, 42.7, 36.5, 30.9, 26.8. HRESIMS calcd for C54H61O8FSiNa [M + Na]+, 907.4017; found, 907.4018. 14α: colorless oil; [α]22D : +37.6 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.74–7.72 (m, 4H), 7.49–7.27 (m, 13H), 7.08–7.05 (dd, J = 2.0, 11.5 Hz, 1H), 6.87 (s, 1H), 6.85 (s, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.58 (t, J = 8.5 Hz, 1H), 5.62 (s, 1H), 5.09 (d, J = 2.0 Hz, 1H), 4.71 (d, J = 12.0 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.21–4.18 (dd, J = 5.0, 10.0 Hz, 1H), 4.15 (t, J = 9.5 Hz, 1H), 3.99–3.93 (dt, J = 5.0, 10.5 Hz, 1H), 3.94–3.91 (dd, J = 3.0, 9.5 Hz, 1H), 3.82 (t, J = 10.0 Hz, 1H), 3.79 (s, 3H), 3.60–3.59 (dd, J = 2.0, 3.0 Hz, 1H), 2.11 (s, 3H), 1.70–1.55 (m, 12H), 1.14 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 159.6, 153.8 (d, J = 244.7 Hz), 142.8 (d, J = 12.3 Hz), 134.0, 135.7, 132.9, 132.7 (d, J = 6.5 Hz), 130.5, 130.2, 130.1, 129.0, 128.4, 128.0, 126.2, 123.1 (d, J = 2.6 Hz), 121.1, 115.8 (d, J = 19.6 Hz), 114.0, 101.5, 92.7 (1JCH = 167.9 Hz), 79.8, 77.3, 76.6, 74.9, 73.1, 72.5, 69.2, 64.0, 55.5, 42.5, 36.4, 30.8, 26.7, 19.9. HRESIMS calcd for C54H61O8FSiNa [M + Na]+, 907.4017; found, 907.4019.

4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-2-O-(4-methoxybenzyl)-β-d-mannopyranosyl-(1→3)-1,2:5,6-di-isopropylidene-α-d-glucofuranose (15)

Prepared by the general glycosylation procedure with a yield of 120.6 mg (82%). Colorless oil; [α]23D : −31.6 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.74–7.72 (m, 4H), 7.48–7.27 (m, 13H), 7.02–6.99 (dd, J = 2.0, 11.5 Hz, 1H), 6.85 (s, 1H), 6.83 (s, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.57 (t, J = 8.5 Hz, 1H), 5.92 (d, J = 3.5 Hz, 1H), 5.59 (s, 1H), 4.78 (d, J = 11.5 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 4.55 (d, J = 11.5 Hz, 1H), 4.54 (s, 1H), 4.45–4.41 (m, 3H), 4.33–4.27 (m, 3H), 4.18–4.13 (m, 2H), 4.09–4.06 (dd, J = 6.0, 8.5 Hz, 1H), 3.91 (t, J = 10.0 Hz, 1H), 3.81 (d, J = 3.0 Hz, 1H), 3.78 (s, 3H), 3.53–3.50 (dd, J = 3.0, 10.0 Hz, 1H), 3.32–3.27 (dt, J = 4.5, 10.0 Hz, 1H), 1.52 (s, 3H), 1.45 (s, 3H), 1.36 (s, 3H), 1.33 (s, 3H), 1.15 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 159.6, 153.9 (d, J = 245.5 Hz), 143.0 (d, J = 12.2 Hz), 137.6, 135.7, 132.8, 132.1 (d, J = 5.5 Hz), 130.4, 130.3, 129.1, 128.5, 128.0, 126.2, 123.3 (d, J = 3.8 Hz), 121.2, 115.9 (d, J = 18.6 Hz), 113.9, 112.2, 108.9, 105.2 (d, J = 183.8 Hz), 101.6, 100.6 (1JCH = 155.7 Hz), 83.1, 81.2, 80.7, 78.7, 78.1, 75.7, 74.6, 73.3, 72.0, 68.7, 68.0, 66.4, 55.5, 27.0, 26.9, 26.7, 26.5, 25.7, 19.9. HRESIMS calcd for C56H65O13FSiNa [M + Na]+, 1015.4076; found, 1015.4038.

Methyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-2-O-(4-methoxybenzyl)-β-d-mannopyranosyl-(1→6)-2,3,4-tri-O-benzyl-α-d-glucopyranoside (16β) and Methyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-2-O-(4-methoxybenzyl)-α-d-mannopyranosyl-(1→6)-2,3,4-tri-O-benzyl-α-d-glucopyranoside (16α)

Prepared by the general glycosylation procedure with a yield of 133.8 mg (79%, β:α= 8.2:1). 16β: colorless oil; [α]23D : −1.1 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.74–7.71 (m, 4H), 7.48–7.17 (m, 28H), 7.02–7.00 (dd, J = 2.0, 11.5 Hz, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.65 (d, J = 8.5 Hz, 1H), 6.57 (t, J = 8.5 Hz, 1H), 5.57 (s, 1H), 5.04 (d, J = 11.0 Hz, 1H), 4.87–4.80 (m, 4H), 4.71 (d, J = 12.0 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.61 (d, J = 4.0 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.51 (d, J = 12.5 Hz, 1H), 4.40 (d, J = 12.5 Hz, 1H), 4.28–4.24 (dd, J = 5.0, 10.5 Hz, 1H), 4.16–4.03 (m, 4H), 3.90 (t, J = 10.0 Hz, 1H), 3.80–3.77 (dd, J = 5.0, 12.0 Hz, 1H), 3.69 (s, 3H), 3.65 (d, J = 3.0 Hz, 1H), 3.55–3.52 (dd, J = 4.0, 10.0 Hz, 1H), 3.50–3.45 (m, 2H), 3.41–3.39 (dd, J = 3.0, 9.5 Hz, 1H), 3.36 (s, 3H), 3.23–3.18 (dt, J = 5.0, 10.0 Hz, 1H), 1.14 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 159.5, 153.9 (d, J = 245.5 Hz), 143.0 (d, J = 12.1 Hz), 139.0, 138.6, 138.2, 137.7, 135.7, 132.8, 132.2 (d, J = 5.5 Hz), 130.5, 130.4, 130.3, 129.1, 128.74, 128.67, 128.6, 128.47, 128.45, 128.4, 128.2, 128.0, 127.9, 126.2, 123.2 (d, J = 1.8 Hz), 121.2, 115.9 (d, J = 18.6 Hz), 113.8, 102.2 (1JCH = 156.7 Hz), 101.6, 98.0 (1JCH = 169.3 Hz),.82.5, 80.1, 78.8, 78.1, 76.1, 75.0, 74.6, 74.1, 73.6, 71.8, 69.9, 68.8, 68.4, 67.7, 55.40, 55.36, 26.7, 19.9. HRESIMS calcd for C72H77O13FSiNa [M + Na]+, 1219.5015; found, 1219.4989. 16α: colorless oil; [α]23D : +25.5 (c 0.4, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.73–7.71 (m, 4H), 7.46–7.23 (m, 28H), 7.06–7.03 (dd, J = 2.0, 12.0 Hz, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.55 (t, J = 8.5 Hz, 1H), 5.59 (s, 1H), 5.00 (d, J = 10.5 Hz, 1H), 4.92 (d, J = 11.0 Hz, 1H), 4.83–4.77 (m, 3H), 4.69–4.56 (m, 6H), 4.43 (d, J = 12.0 Hz, 1H), 4.19–4.15 (m, 2H), 4.00 (t, J = 10.0 Hz, 1H), 3.84–3.62 (m, 10H), 3.50–3.47 (dd, J = 3.5, 10.0 Hz, 1H), 3.40 (t, J = 9.5 Hz, 1H), 3.31 (s, 3H), 1.13 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 159.5, 153.7 (d, J = 245.6 Hz), 142.9 (d, J = 12.2 Hz), 138.8, 138.30, 138.25, 137.9, 135.7, 132.8, 132.6 (d, J = 5.7 Hz), 130.2, 129.9, 129.0, 128.73, 128.71, 128.69, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 126.3, 123.1 (d, J = 1.8 Hz), 121.1, 115.8 (d, J = 19.4 Hz), 114.0, 101.7, 99.7 (1JCH = 171.7 Hz), 98.0 (1JCH = 169.5 Hz),.82.3, 80.3, 79.3, 78.0, 76.6, 76.1, 75.8, 75.2, 73.5, 73.2, 69.9, 66.4, 64.4, 55.5, 55.3, 26.7, 19.9. HRESIMS calcd for C72H77O13FSiNa [M + Na]+, 1219.5015; found, 1219.5043.

Methyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-2-O-(4-methoxybenzyl)-β-d-mannopyranosyl-(1→4)-2-azido-3,6-di-O-benzyl-2-deoxy-α-d-glucopyranoside (17)

Prepared by the general glycosylation procedure with a yield of 126.4 mg (62%). Colorless oil; [α]24D : −7.2 (c 2.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.76–7.74 (m, 4H), 7.47–7.18 (m, 23H), 7.07–7.05 (dd, J = 2.0, 11.0 Hz, 1H), 6.84–6.82 (m, 2H), 6.70 (d, J = 8.0 Hz, 1H), 6.62 (t, J = 8.5 Hz, 1H), 5.49 (s, 1H), 5.21 (d, J = 10.5 Hz, 1H), 4.82–4.67 (m, 5H), 4.40 (d, J = 12.5 Hz, 1H), 4.42–4.37 (m, 3H), 4.07–4.01 (m, 3H), 3.89–3.85 (dd, J = 8.5, 10.0 Hz, 1H), 3.78 (s, 3H), 3.70–3.56 (m, 4H), 3.52–3.48 (m, 1H), 3.49 (s, 3H), 3.41 (t, J = 10.0 Hz, 1H), 3.29–3.26 (dd, J = 3.0, 10.0 Hz, 1H), 3.07–3.02 (dt, J = 5.0, 10.0 Hz, 1H), 1.16 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 159.5, 153.9 (d, J = 245.5 Hz), 143.0 (d, J = 11.7 Hz), 138.9, 137.8, 137.7, 135.7, 132.8, 132.5 (d, J = 5.7 Hz), 130.7, 130.4, 130.3, 129.1, 128.9, 128.5, 128.4, 128.32, 128.30, 128.1, 127.7, 126.3, 122.9 (d, J = 2.8 Hz), 121.2, 115.6 (d, J = 19.6 Hz), 113.8, 101.6, 101.5 (d, J = 161.9 Hz), 98.9 (d, J = 173.1 Hz), 78.9, 78.8, 78.5, 76.4, 75.3, 75.0, 73.9, 71.9, 70.5, 68.6, 68.4, 67.5, 63.2, 55.7, 55.5, 26.8, 19.9. HRESIMS calcd for C65H70N3O12FSiNa [M + Na]+, 1154.4611; found, 1154.4583.

1-Adamantanyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-β-d-mannopyranoside (18)

Prepared by the general procedure for the removal of para-methoxybenzyl group from 14 with a yield of 97.3 mg (80%). Colorless oil; [α]22D : −5.3 (c 1.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.73–7.71 (m, 4H), 7.48–7.34 (m, 11H), 7.10–7.07 (dd, J = 2.0, 11.0 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.57 (t, J = 8.5 Hz, 1H), 5.58 (s, 1H), 4.82 (s, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.5 Hz, 1H), 4.30–4.27 (dd, J = 5.0, 10.5 Hz, 1H), 4.11 (t, J = 9.5 Hz, 1H), 3.92 (d, J = 3.0 Hz, 1H), 3.87 (t, J = 10.5 Hz, 1H), 3.60–3.57 (dd, J = 4.0, 9.5 Hz, 1H), 3.34–3.29 (dt, J = 5.0, 10.0 Hz, 1H), 2.59 (s, 1H), 2.18 (s, 3H), 1.86 (d, J = 11.0 Hz, 3H), 1.78 (d, J = 11.5 Hz, 3H), 1.66 (d, J = 12.5 Hz, 3H), 1.61 (d, J = 12.5 Hz, 3H), 1.12 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 153.9 (d, J = 245.6 Hz), 143.1 (d, J = 12.2 Hz), 137.7, 135.7, 132.8, 132.0 (d, J = 5.6 Hz), 130.3, 129.2, 128.5, 128.0, 126.3, 123.6 (d, J = 2.8 Hz), 121.3, 116.2 (d, J = 19.6 Hz), 101.7, 93.5, 78.4, 77.2, 76.1, 71.78, 71.75, 69.0, 66.9, 42.6, 36.4, 30.9, 26.8, 19.9. HRESIMS calcd for C46H53O7FSiNa [M + Na]+, 787.3442; found, 787.3457.

4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-β-d-mannopyranosyl-(1→3)-1,2:5,6-di-isopropylidene-α-d-glucofuranose (19)

Prepared by the general procedure for the removal of para-methoxybenzyl group from 15 with a yield of 17.7 mg (80%). Colorless oil; [α]23D : −15.2 (c 0.5, CHCl3 ); 1H NMR (500 MHz, CDCl3) δ 7.75–7.73 (m, 4H), 7.50–7.24 (m, 18H), 7.06–7.03 (dd, J = 2.0, 11.5 Hz, 1H), 6.85 (s, 1H), 6.83 (s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.60 (t, J = 8.5 Hz, 1H), 5.62 (s, 1H), 5.47 (s, 1H), 4.66–4.58 (m, 3H), 4.46 (d, J = 12.0 Hz, 1H), 4.27–4.20 (m, 3H), 3.97–3.96 (dd, J = 1.0, 3.0 Hz, 1H), 3.90–3.85 (m, 2H), 3.78 (s, 3H), 2.19–1.78 (br s, 1H), 1.15 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 153.9 (d, J = 245.6 Hz), 143.2 (d, J = 11.2 Hz), 137.5, 135.7, 132.8, 131.7 (d, J = 5.5 Hz), 130.3, 129.2, 128.5, 128.0, 126.2, 123.6 (d, J = 3.8 Hz), 121.3, 116.2 (d, J = 18.6 Hz), 112.3, 109.2, 105.4, 101.7, 98.3, 83.1, 80.8, 79.0, 78.6, 76.4, 73.4, 72.1, 70.0, 68.9, 67.3, 67.0, 27.0, 26.9, 26.7, 26.6, 25.7, 19.9. HRESIMS calcd for C48H57O12FSiNa [M + Na]+, 895.3501; found, 895.3481.

Methyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-β-d-mannopyranosyl-(1→6)-2,3,4-tri-O-benzyl-α-d-glucopyranoside (20)

Prepared by the general procedure for the removal of para-methoxybenzyl group from 16 with a yield of 45.9 mg (84%). Colorless oil; [α]24D : +15.5 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.73–7.70 (m, 4H), 7.47–7.20 (m, 26H), 7.10–7.08 (dd, J = 2.0, 11.0 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.58 (t, J = 8.5 Hz, 1H), 5.55 (s, 1H), 5.02 (d, J = 11.0 Hz, 1H), 4.89 (d, J = 11.0 Hz, 1H), 4.83 (d, J = 11.0 Hz, 1H), 4.80 (d, J = 12.0 Hz, 1H), 4.68–4.57 (m, 5H), 4.29–4.26 (dd, J = 5.0, 10.5 Hz, 1H), 4.18 (s, 1H), 4.09–3.99 (m, 3H), 3.91 (d, J = 3.0 Hz, 1H), 3.84 (t, J = 9.5 Hz, 1H), 3.81–3.77 (ddd, J = 2.0, 5.0, 10.0 Hz, 1H), 3.61–3.58 (dd, J = 5.5, 10.0 Hz, 1H), 3.54–3.51 (dd, J = 3.5, 10.0 Hz, 1H), 3.49–3.46 (dd, J = 3.0, 9.5 Hz, 1H), 3.44 (t, J = 10.0 Hz, 1H), 3.36 (s, 3H), 3.24–3.19 (dt, J = 5.0, 10.0 Hz, 1H), 2.41 (s, 1H), 1.13 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 153.9 (d, J = 246.6 Hz), 143.2 (d, J = 12.1 Hz), 138.9, 138.6, 138.3, 137.6, 135.7, 132.8, 131.8 (d, J = 5.7 Hz), 130.3, 129.2, 128.74, 128.67, 128.5, 128.4, 128.22, 128.17, 128.0, 127.9, 126.2, 123.6 (d, J = 2.8 Hz), 121.2, 116.2 (d, J = 18.6 Hz), 101.8, 100.7, 98.1,.82.4, 80.1, 78.5, 77.7, 76.6, 76.0, 75.0, 73.6, 71.8, 70.0, 69.9, 68.8, 68.6, 67.1, 55.4, 26.7, 19.9.HRESIMS calcd for C64H69O12FSiNa [M + Na]+, 1099.4440; found, 1099.4418.

Methyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-β-d-mannopyranosyl-(1→4)-2-azido-3,6-di-O-benzyl-2-deoxy-α-d-glucopyranoside (21)

Prepared by the general procedure for the removal of para-methoxybenzyl group from 17 with a yield of 24.8 mg (82%). Colorless oil; [α]23D : +24.8 (c 1.0, CHCl3); 7.73–7.71 (m, 4H), 7.47–7.18 (m, 19H), 7.07–7.05 (dd, J = 2.0, 11.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.58 (t, J = 8.5 Hz, 1H), 5.47 (s, 1H), 5.04 (d, J = 11.0 Hz, 1H), 4.81–4.72 (m, 3H), 4.59 (d, J = 12.0 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.46 (s, 1H), 4.40 (d, J = 12.0 Hz, 1H), 4.06–3.64 (m, 8H), 3.48–3.43 (m, 2H), 3.43 (s, 3H), 3.41 (t, J = 10.0 Hz, 1H), 3.29–3.26 (dd, J = 3.0, 10.0 Hz, 1H), 3.07–3.02 (dt, J = 5.0, 10.0 Hz, 1H), 2.46 (s, 1H), 1.14 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 153.9 (d, J = 245.6 Hz), 143.2 (d, J = 11.2 Hz), 138.5, 137.7, 137.6, 135.7, 132.7, 131.8 (d, J = 5.5 Hz), 130.3, 129.2, 128.8, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 126.2, 123.3 (d, J = 2.8 Hz), 121.3, 116.0 (d, J = 19.5 Hz), 101.7, 100.5, 98.9, 78.9, 78.3, 78.5, 75.3, 75.0, 73.9, 71.8, 70.3, 69.8, 68.6, 68.3, 67.0, 63.4, 55.6, 26.7, 19.9. HRESIMS calcd for C57H62N3O11FSiNa [M + Na]+, 1034.4035; found, 1034.4011.

1-Adamantanyl 4,6-O-Benzylidene-2-O-(4-methoxybenzyl)-β-d-mannopyranoside (22)

22 was prepared by the general procedure for the removal of 4-(tert-butyldiphenylsilyloxy)-3-fluorobenzyl group using microwave reactor (method A) from 14 with a yield of 49.5 mg (74%). 22 was also prepared by the general procedure for the removal of 4-(tert-butyldiphenylsilyloxy)-3-fluorobenzyl group with conventional heating (method B) from 14 with a yield of 45.3 mg (77%). Colorless oil; [α]24D : −65.8 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.51–7.31 (m, 7H), 6.91 (s, 1H), 6.89 (s, 1H), 5.53 (s, 1H), 5.08 (d, J = 11.5 Hz, 1H), 4.89 (s, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.29–4.26 (dd, J = 5.0, 10.5 Hz, 1H), 3.87 (t, J = 10.5 Hz, 1H), 3.82 (s, 3H), 3.82–3.73 (m, 3H), 3.36–3.31 (dt, J = 5.0, 9.5 Hz, 1H), 2.39 (d, J = 8.5 Hz, 1H), 2.20 (s, 3H), 1.90 (d, J = 11.0 Hz, 3H), 1.83 (d, J = 11.5 Hz, 3H), 1.69 (d, J = 12.5 Hz, 3H), 1.64 (d, J = 12.0 Hz, 3H); 13C NMR (125.6 MHz, CDCl3) δ 159.7, 153.9 (d, J = 245.6 Hz), 143.0 (d, J = 12.0 Hz), 137.7, 135.7, 134.1, 132.8, 132.2 (d, J = 6.5 Hz), 131.9, 130.3, 130.1, 129.8, 129.4, 129.1, 128.4, 128.0, 127.9, 126.3, 123.3 (d, J = 3.8 Hz), 121.2 (d, J = 1.9 Hz), 116.0 (d, J = 18.6 Hz), 114.1, 101.7, 87.3, 79.2, 77.5, 76.1, 72.7, 72.4, 68.7, 65.7, 55.5, 26.7, 19.9. HRESIMS calcd for C31H38O7Na [M + Na]+, 545.2515; found, 545.2515.

4,6-O-Benzylidene-2-O-(4-methoxybenzyl)-β-d-mannopyranosyl-(1→3)-1,2:5,6-di-isopropylidene-α-d-glucofuranose (23)

Prepared by the general procedure for the removal of 4-(tert-butyldiphenylsilyloxy)-3-fluorobenzyl group using microwave reactor (method A) from 15 with a yield of 19.7 mg (76%). Colorless oil; [α]23D : −53.0 (c 0.4, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.49–7.47 (m, 2H), 7.37–7.27 (m, 5H), 6.92 (s, 1H), 6.90 (s, 1H), 5.94 (d, J = 3.5 Hz, 1H), 5.55 (s, 1H), 4.90 (d, J = 11.5 Hz, 1H), 4.71 (s, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.51 (d, J = 3.5 Hz, 1H), 4.44 (d, J = 11.0 Hz, 1H), 4.42 (d, J = 11.0 Hz, 1H), 4.36 (d, J = 3.5 Hz, 1H), 4.33–4.28 (m, 2H), 4.18–4.15 (dd, J = 6.5, 8.5 Hz, 1H), 4.10–4.10 (dd, J = 5.5, 8.5 Hz, 1H), 3.89–3.79 (m, 3H), 3.82 (s, 3H), 3.38–3.33 (dt, J = 5.0, 10.0 Hz, 1H), 2.52 (s, 1H), 1.53 (s, 3H), 1.46 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13C NMR (125.6 MHz, CDCl3) δ 159.6, 137.4, 130.2, 130.1, 129.4, 128.5, 126.5, 114.3, 112.3, 109.1, 105.2, 102.2, 100.3, 83.0, 81.0, 80.7, 79.5, 77.9, 75.3, 73.2, 70.9, 68.7, 67.4, 66.7, 55.5, 26.98, 26.94, 26.5, 25.8, HRESIMS calcd for C33H42O12Na [M + Na]+, 653.2574; found, 653.2556.

Methyl 4,6-O-Benzylidene-2-O-(4-methoxybenzyl)-β-d-mannopyranosyl-(1→6)-2,3,4-tri-O-benzyl-α-d-glucopyranoside (24)

Prepared by the general procedure for the removal of 4-(tert-butyldiphenylsilyloxy)-3-fluorobenzyl group using microwave reactor (method A) from 16 with a yield of 13.3 mg (78%). Colorless oil; [α]23D : −15.0 (c 0.4, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.47–7.27 (m, 22H), 6.89 (s, 1H), 6.88 (s, 1H), 5.51 (s, 1H), 5.02 (d, J = 11.0 Hz, 1H), 4.96 (d, J = 11.0 Hz, 1H), 4.91 (d, J = 11.0 Hz, 1H), 4.84 (d, J = 11.0 Hz, 1H), 4.81 (d, J = 12.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.59 (s, 1H), 4.52 (d, J = 11.5 Hz, 1H), 4.34 (s, 1H), 4.29–4.26 (dd, J = 5.0, 10.0 Hz, 1H), 4.17–4.15 (dd, J = 2.0, 10.0 Hz, 1H), 4.04 (t, J = 9.5 Hz, 1H), 3.88–3.75 (m, 7H), 3.71–3.66 (dt, J = 3.5, 9.5 Hz, 1H), 3.58–3.54 (dd, J = 5.5, 10.5 Hz, 1H), 3.51–3.49 (dd, J = 3.5, 10.0 Hz, 1H), 3.45 (t, J = 10.0 Hz, 1H), 3.37 (s, 3H), 3.28–3.23 (dt, J = 5.0, 10.0 Hz, 1H), 2.35 (d, J = 9.0 Hz, 1H); 13C NMR (125.6 MHz, CDCl3) δ 159.7, 138.8, 138.5, 138.3, 137.5, 130.4, 130.2, 129.3, 128.72, 128.70, 128.5, 128.43, 128.38, 128.3, 128.2, 128.1, 128.0, 126.4, 114.2, 102.5, 102.2, 98.1, 82.4, 80.2, 79.5, 78.1, 77.9, 76.2, 75.5, 75.1, 73.7, 70.9, 70.0, 68.8, 68.7, 67.3, 55.5, 55.4. HRESIMS calcd for C49H54O12Na [M + Na]+, 857.3513; found, 857.3504.

Methyl 4,6-O-Benzylidene-2-O-(4-methoxybenzyl)-β-d-mannopyranosyl-(1→4)-2-azido-3,6-di-O-benzyl-2-deoxy-α-d-glucopyranoside (25)

Prepared by the general procedure for the removal of 4-(tert-butyldiphenylsilyloxy)-3-fluorobenzyl group using microwave reactor (method A) from 17 with a yield of 21.2 mg (78%). Colorless oil; [α]24D : −9.0 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) 7.49–7.27 (m, 17H), 6.88–6.86 (m, 2H), 5.43 (s, 1H), 5.19 (d, J = 11.0 Hz, 1H), 4.91 (d, J = 11.5 Hz, 1H), 4.81 (d, J = 3.5 Hz, 1H), 4.76 (d, J = 12.0 Hz, 1H), 4.70 (d, J = 11.0 Hz, 1H), 4.57 (d, J = 11.0 Hz, 1H), 4.48 (s, 1H), 4.44 (d, J = 11.5 Hz, 1H), 4.08–4.03 (m, 2H), 3.86 (t, J = 9.5 Hz, 1H), 3.80 (s, 3H), 3.73–3.62 (m, 5H),3.50–3.47 (m, 2H), 3.47 (s, 3H), 3.38 (t, J = 10.0 Hz, 1H), 3.07–3.02 (dt, J = 5.0, 10.0 Hz, 1H); 13C NMR (125.6 MHz, CDCl3) δ 159.7, 138.7, 137.54, 137.48, 130.4, 130.1, 129.4, 129.0, 128.6, 128.5, 128.43, 128.40, 128.3, 128.2, 127.8, 126.5, 126.3, 114.1, 102.2, 101.8, 98.9, 79.3, 78.9, 78.8, 77.9, 75.9, 75.3, 74.0, 71.0, 70.5, 68.6, 68.3, 67.1, 63.2, 55.7, 55.5. HRESIMS calcd for C42H47N3O11Na [M + Na]+, 792.3108; found, 792.3138.

1-Adamantanyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-2-O-(4-methoxybenzyl)-α-d-mannopyranosyl-(1→3)-4,6-O-benzylidene-2-O-(4-methoxybenzyl)-β-d-mannopyranoside (26α) and 1-Adamantanyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-2-O-(4-methoxybenzyl)-β-d-mannopyranosyl-(1→3)-4,6-O-benzylidene-2-O-(4-methoxybenzyl)-β-d-mannopyranoside (26β)

Prepared by the general glycosylation procedure, radical chromatographic purification (5 % ethyl acetate in toluene) on silica gel provided 26 with a yield of 48.2 mg (71%, β:α= 11.4:1). ). 26α: colorless oil;. [α]24D : −12.5 (c 0.2, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.69–7.27 (m, 22H), 7.06–7.03 (dd, J = 2.0, 11.0 Hz, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 6.74 (s, 1H), 6.72 (s, 1H), 6.63–6.62 (m, 3H), 6.51 (t, J = 8.5 Hz, 1H), 5.61 (s, 1H), 5.56 (s, 1H), 5.34 (s, 1H), 4.84 (d, J = 11.5 Hz, 1H), 4.82 (s, 1H), 4.77 (d, J = 12.5 Hz, 1H), 4.49 (d, J = 12.5 Hz, 1H), 4.44 (d, J = 11.5 Hz, 1H), 4.33 (d, J = 12.0 Hz, 1H), 4.28–4.12 (m, 5H), 3.96–3.78 (m, 5H), 3.72 (s, 3H), 3.72–3.66 (m, 2H), 3.48 (s, 3H), 3.40–3.35 (dt, J = 5.0, 10.0 Hz, 1H), 2.18 (s, 3H), 1.86 (d, J = 12.0 Hz, 3H), 1.77 (d, J = 11.5 Hz, 3H), 1.68–1.59 (m, 6H), 1.10 (s, 9H);13C NMR (125.6 MHz, CDCl3) δ 159.39, 159.38, 153.9 (d, J = 245.7 Hz), 142.9 (d, J = 12.2 Hz), 137.9, 137.8, 135.6, 132.8, 132.4 (d, J = 5.0 Hz), 130.3, 130.2, 129.9, 129.7, 129.6, 129.0, 128.6, 128.5, 128.4, 128.0, 126.4, 126.3, 123.0 (d, J = 2.8 Hz), 121.0, 115.8 (d, J = 19.6 Hz), 113.84, 113.80, 102.0, 101.6, 99.8 (1JCH = 169.5 Hz), 95.0 (1JCH = 155.4 Hz), 79.2, 79.1, 78.2, 75.8, 75.7, 75.0, 74.6, 72.3, 72.0, 69.1, 69.0, 67.2, 64.9, 55.4, 55.1, 42.6, 36.4, 30.8, 26.7, 19.9. HRESIMS calcd for C75H83O14FSiNa [M + Na]+,1277.5434; found, 1277.5403. 26β: colorless oil;. [α]24D : −54.2 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.73–7.72 (m, 4H), 7.49–7.17 (m, 21H), 6.70–6.65 (m, 5H), 6.57 (t, J = 8.5 Hz, 1H), 5.61 (s, 1H), 5.49 (s, 1H), 4.93 (d, J = 12.5 Hz, 1H), 4.871 (s, 1H), 4.87 (d, J = 12.0 Hz, 1H), 4.82 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.44 (d, J = 12.5 Hz, 1H), 4.36 (d, J = 12.0 Hz, 1H), 4.32–4.29 (dd, J = 5.0, 10.5 Hz, 1H), 4.18–4.15 (dd, J = 5.0, 10.5 Hz, 1H), 4.10 (t, J = 9.5 Hz, 1H), 4.06–4.03 (dd, J = 3.0, 10.5 Hz, 1H), 4.00 (t, J = 10.0 Hz, 1H), 3.96 (t, J = 10.0 Hz, 1H), 3.88 (s, 1H), 3.83 (t, J = 10.5 Hz, 1H), 3.80 (d, J = 3.0 Hz, 1H), 3.73 (s, 3H), 3.60 (s, 3H), 3.60–3.59 (m, 1H), 3.42–3.38 (dt, J = 5.0, 9.5 Hz, 1H), 3.16–3.13 (dd, J = 3.0, 9.5 Hz, 1H), 2.85–2.80 (dt, J = 4.5, 9.5 Hz, 1H), 2.22 (s, 3H), 1.94 (d, J = 11.0 Hz, 3H), 1.86 (d, J = 11.0 Hz, 3H), 1.70 (d, J = 12.0 Hz, 3H), 1.66 (d, J = 12.5 Hz, 3H), 1.13 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 159.6, 159.2, 153.9 (d, J = 245.7 Hz), 142.9 (d, J = 11.2 Hz), 137.8, 135.7, 132.8, 132.5 (d, J = 5.5 Hz), 131.0, 130.8, 130.4, 130.24, 130.21, 129.1, 129.0, 128.41, 128.37, 128.0, 126.5, 126.2, 122.8 (d, J = 3.7 Hz), 121.1, 115.7 (d, J = 19.6 Hz), 113.9, 113.7, 102.0, 101.5, 97.4 (1JCH = 156.5 Hz), 95.8 (1JCH = 154.0 Hz), 78.4, 77.8, 77.2, 75.9, 75.0, 74.3, 73.76, 73.74, 73.6, 71.2, 69.1, 68.7, 67.9, 67.7, 55.45, 55.42, 42.8, 36.4, 30.9, 26.8, 19.0. HRESIMS calcd for C75H83O14FSiNa [M + Na]+,1277.5434; found, 1277.5483.

1-Adamantanyl 4,6-O-Benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-2-O-(4-methoxybenzyl)-β-d-mannopyranosyl-(1→2)-4,6-O-benzylidene-3-O-[4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl]-β-d-mannopyranoside (27)

Prepared by the general glycosylation procedure with a yield of 98.4 mg (62%). 27: colorless oil;. [α]23D : −29.7 (c 2.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.75–7.71 (m, 8H), 7.48–7.34 (m, 22H), 7.26–7.22 (dd, J = 2.0, 12.0 Hz, 1H), 6.91–6.89 (dd, J = 1.5, 12.0 Hz, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.76 (t, J = 8.0 Hz, 1H), 6.58–6.51 (m, 3H), 5.59 (s, 1H), 5.47 (s, 1H), 4.97 (d, J = 12.0 Hz, 1H), 4.93 (d, J = 12.0 Hz, 1H), 4.87 (s, 1H), 4.80 (s, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1H), 4.31–4.22 (m, 5H), 4.15 (t, J = 9.5 Hz, 1H), 4.04 (t, J = 9.5 Hz, 1H), 4.01 (d, J = 3.5 Hz, 1H), 3.90 (t, J = 10.0 Hz, 1H), 3.76 (t, J = 9.5 Hz, 1H), 3.74 (s, 3H), 3.60–3.58 (dd, J = 3.0, 10.0 Hz, 1H), 3.43–3.41 (dd, J = 3.0, 10.0 Hz, 1H), 3.37–3.32 (dt, J = 5.0, 9.5 Hz, 1H), 3.29–3.25 (dt, J = 5.0, 10.0 Hz, 1H), 2.18 (s, 3H), 1.76 (d, J = 10.0 Hz, 3H), 1.70 (d, J = 11.0 Hz, 3H), 1.67 (d, J = 11.5 Hz, 3H), 1.60 (d, J = 12.0 Hz, 3H), 1.14 (s, 9H); 13C NMR (125.6 MHz, CDCl3) δ 159.3, 153.88 (d, J = 245.0 Hz), 153.85 (d, J = 246.1 Hz), 142.83 (d, J = 12.1 Hz), 142.79 (d, J = 12.1 Hz), 137.9, 137.7, 135.7, 132.91, 132.88, 132.87, 132.7 (d, J = 5.7 Hz), 132.3 (d, J = 6.0 Hz), 131.2, 131.0, 130.2, 129.1, 129.0, 128.5, 128.4, 128.0, 126.30, 126.26, 123.1 (d, J = 2.8 Hz), 121.0, 120.9, 116.0 (d, J = 18.5 Hz), 115.7 (d, J = 19.6 Hz), 113.7, 104.4 (1JCH = 154.0 Hz), 101.8, 101.5, 94.6 (1JCH = 154.0 Hz), 79.1, 78.5, 78.3, 76.6, 75.7, 74.0, 73.9, 70.7, 70.6, 69.2, 68.9, 68.0, 67.5, 55.4, 42.8, 36.4, 30.8, 26.8. HRESIMS calcd for C90H98O14F2Si2Na [M + Na]+,1519.6361; found, 1519.6327.

Supplementary Material

Supporting Information

Acknowledgment

We thank the NIH (GM57335 and GM62160) for financial support.

Footnotes

Supporting Information Available. Complete experimental details and copies of 1H and 13C-NMR spectra of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.or

References

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