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. Author manuscript; available in PMC: 2008 Sep 3.
Published in final edited form as: Carbohydr Res. 2007 Jun 2;342(12-13):1668–1679. doi: 10.1016/j.carres.2007.05.031

Synthesis of a C-linked hyaluronic acid disaccharide mimetic

Zhong-Xu Ren 1, Qiang Yang 1, Kenneth N Price 1, Tianniu Chen 1, Cara Nygren 1, John F C Turner 1, David C Baker 1,*
PMCID: PMC1989762  NIHMSID: NIHMS28226  PMID: 17572398

Abstract

The synthesis of a C-disaccharide that is designed as a mimetic for the repeating unit disaccharide of hyaluronic acid is described. The target compound was obtained via the SmI2-promoted coupling reaction of the sulfone, 2-acetamido-4,6-O-benzylidene-3-O-tert-butyldimethylsilyl-1,2-dideoxy-1-pyridinylsulfonyl-β-D-glucopyranose (6), and the aldehyde, p-methoxyphenyl 2,3-di-O-benzyl-4-deoxy-4-C-formyl-6-O-p-methoxybenzyl-β-D-glucopyranoside (14).

Keywords: C-glycosyl compounds, C-glycosides, C-disaccharide, Hyaluronic acid mimetic, Samarium diiodide

1. Introduction

Hyaluronic acid (hyaluronan, HA, Figure 1) is a polysaccharide of high molecular weight (Mr >106) that is composed of a repeating disaccharide unit in which D-glucuronic acid is linked to the 3-position of 2-acetamido-2-deoxy-D-glucose (N-acetyl-D-glucosamine) i.e., [→3)-β-D-GlcNAc-(1→4)-β-D-GlcA-(1→)]n. HA, which is synthesized in the plasma membrane and is associated with the complement of glycosaminoglycans (GAGs) located in the extracellular matrix, has a variety of functions in the human body. For example, it serves as the gelling agent of the virtreous body of the eye, is a component in the lubricants associated with the synovial fluid in joints, and is found in significant quantities in the placenta.1,2 A process that has come to the forefront in recent years concerns the role that HA plays in the metastasis of cancer: the binding of a migrating cancer cell’s CD44 receptor to HA performs a critical role in the metastasis of certain cancers, especially the migration of melanoma cells to the lung.3 Several lines of evidence further implicate that this CD44–HA interaction facilitates cell movement in cancer cells during metastasis.4–6

Figure 1.

Figure 1

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Hyaluronic acid (hyaluronan, HA).

As a part of an ongoing project, a goal was to synthesize a “C-disaccharide” that would be a mimetic for the repeating unit of HA and would be totally resistant, due to the interresidue C–C–C linkages, to enzymes that degrade the natural polymer. Further objectives are to study its conformation and incorporate it into a synthetic oligosaccharide in such a way that the oligomer would be resistant to enzymes that degrade HA. Herein is presented a total synthesis of the target C-disaccharide as its p-methoxyphenyl glycoside.

2. Results and discussion

2.1 Synthetic approaches

Approaches to C-linked disaccharides (C-glycosylic compounds, often referred to as “C-glycosides”) are varied;7,8 however, the success in any C-glycosylic coupling depends on the peculiar reactivities of the sugar units (i.e., whether primary or secondary carbon atoms are targeted in the glycosyl acceptor), as well as the stabilities of the protecting groups involved and their influence on the reactivity of both the glycosyl donor and acceptor. For our purposes, several processes were attempted in this laboratory,9–11 among them the Henry coupling advocated by Martin and co-workers,12,13 the olefin metathesis method of Postema and coworkers,14,15 as well as the dianion approach advocated by Kessler and co-workers.16,17 Of these, only the latter method, which had been developed for simple C-glycosyl–alkyl conjugates, gave good results with our specific compounds that have multiple functionality present; however, this rather harsh organometallic reaction limited the type of OH protection that could be employed, which limited future possibilities in construction of more complex C-glycosylic compounds. Another approach that involves the use of samarium diiodide-mediated coupling of a glycosyl sulfone (donor) with a C-formyl sugar (an aldehyde, the acceptor), as developed by Beau and co-workers for glucosamine derivatives18–22 and by Linhardt23, 24 and co-workers for the synthesis of sialic acid mimetics, was carried out and gave the most promising results. Using this SmI2 strategy, the synthesis, which makes use of the glycosyl donor 6 and the acceptor 14, was carried out as described in the following sections.

2.2 Synthesis of protected sulfone 6

The synthesis of sulfone 6 was carried out as shown in Scheme 1. Thus, the reaction of glycosyl chloride 1 with K2CO3 and 2-mercaptopyridine in dry acetone at 50 °C gave the desired pyridinyl thioglycoside 2.25 In order to manipulate the protective groups, 2 was treated with NaOMe in 1:5 CH2Cl2–MeOH to afford the free-hydroxy compound 3 that was directly reacted with benzaldehyde and ZnCl2 at room temperature for 16 h to give the 4,6-O-benzylidenated 4.26,27 Treatment of 4 with tert-butylchlorodimethylsilane (TBDMSCl) in the presence of imidazole in DMF at room temperature overnight28 gave compound 5, which was readily converted to the corresponding protected sulfone 6 in 79% yield via treatment with m-chloroperoxybenzoic acid (m-CPBA) in CH2Cl2 at 0 °C.19 The β configuration for 6 was clearly indicated by the doublet for H-1 at δ 5.81 (J1,2 = 10.3 Hz.); furthermore, there was no resonance indicative of any α anomer.

Scheme 1.

Scheme 1

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Synthesis of the C-glycosyl donor, protected sulfone 6.

2.3 Synthesis of protected aldehyde 14

The synthesis of aldehyde 14 proceeded from known compound 729 as shown in Scheme 2. Deacetylation of 7 with NaOMe in 1:5 CH2Cl2 and MeOH gave the corresponding tetraol 8 in nearly quantitative yield. Regioselective bis-protection of the 4-OH and 6-OH positions with a p-methoxybenzylidene group was accomplished via treatment of 8 with anisaldehyde dimethyl acetal (ADMA) in the presence of a catalytic amount of p-TsOH in dry CH3CN to afford diol 9 as a precipitate in 84% yield.30 The resulting diol 9 was then treated with NaH at 0 °C for 10 min, followed by addition of benzyl bromide in DMF, to give O-dibenzylated 10 in 95% yield. Regioselective reductive cleavage of the benzylidene ring of compound 10 was achieved via treatment with NaBH3CN and CF3CO2H in the presence of 4A MS in DMF at room temperature for 10 h to render the 4-OH isomer 11 in 74% yield as the major product, along with the 6-OH isomer as a byproduct (21%, data not provided).31 Treatment of compound 11 with (CF3SO)2O in pyridine at 0 °C overnight gave the corresponding triflate 12 in nearly quantitative yield. Reaction of triflate 12 with Bu4NCN in THF afforded the SN2 product 13 in 63% yield. The major byproduct was the E2 elimination product, which is slightly less polar than the substitution product on TLC (data not provided). Reduction of compound 13 with DIBALH in THF at −78 °C, followed by treatment with 1.0 N H3PO4 at 0 °C, afforded aldehyde 14 in 71% yield.32,33 Aldehyde 14 was definitively shown to be the equatorial isomer (D-gluco configuration) by the appearance of H-4 at δ 3.01 as a broad doublet of doublets (pseudo triplet) with J3,4 ≈ J4,5 = 10.2 Hz.

Scheme 2.

Scheme 2

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Synthesis of C-glycosyl acceptor, aldehyde 14.

2.4 Synthesis of the C-disaccharides

With sulfone 6 and aldehyde 14 in hand, the stage was set for the synthesis of C-disaccharides as shown in Scheme 3. Thus, treatment of sulfone 6 and aldehyde 14 with samarium diiodide (SmI2) in THF at room temperature, following the general protocols of Beau and co-workers,20,21 gave three disaccharides, 15a, 15b and 15c as shown in Scheme 3. The β anomers 15a and 15b appeared as the high- and low-running zones on TLC, with the α anomer 15c situated between them. All three of the disaccharides were easily identified by positive-ion ESI mass spectroscopy, which gave inter alia [M + H], [M + Na] and [M + K] ions as expected (see Experimental section). The NMR spectra of the pure anomeric compounds were complex, even at 600 MHz, and did not lend themselves to complete assignments of all resonances. However, H-1II for 15a showed J1,2 8.4 Hz, which is indicative of the β anomer. Further corroboration of the β linkage for 15a was provided by single-crystal X-ray diffraction analysis that showed the β-(1→4)-C-linkage and the configuration of the linking CHOH group, as shown in Figure 2. Thus 15a is the β-(4aR)-isomer. Disaccharide 15b, which showed J1,2 9.6 Hz, was also assigned the β linkage. Furthermore 15b, after deoxygenation at the 4a position, gave the same disaccharide as that derived from 15a (as described in the section which follows). Both 15a and 15b gave large, negative optical rotations (−41.2 and −97.1, respectively). Disaccharide 15c was assigned as the α anomer, as the deoxygenated derivative of 15c is different from that derived from either 15a or 15b. From the appearance of the H-1I and H-1II signals and other resonances in the 1H NMR spectrum of 15c, a single epimer at H-4a was indicated; however, little support for firm epimeric and anomeric assignments was otherwise afforded by either the NMR spectra or optical rotations (see data in Experimental section). The structural relationship of 15c to the β anomers 15a and 15b was established chemically as described in the following section.

Scheme 3.

Scheme 3

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SmI2-promoted coupling reaction.

Figure 2.

Figure 2

Figure 2

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ORTEP depiction of compound 15a.

Conversion of the presumed α isomer 15c to the β isomers (15a and 15b) was achieved via a series of reactions as shown in Scheme 4. Compound 15c was oxidized to the corresponding α ketone 16 (H-1II, J1,2 6.0 Hz) with pyridinium chlorochromate (PCC) in CH2Cl2, and subsequent isomerization of the resulting α ketone to the β ketone 17 (H-1II, J1,2 10.8 Hz) was cleanly effected with NaOMe in MeOH. The yield of the β anomer was 36%, with 50% recovery of starting material 16. No side products from elimination reactions or epimerization at the C-4 carbon were observed. Reduction of the β ketone 17 to a ~1:3 mixture of 15a and 15b was carried out with NaBH4 in EtOH, which served to increase the amounts of these compounds that were required for synthesis of the targeted disaccharide.

Scheme 4.

Scheme 4

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Conversion of 15c to 15a and 15b.

Deoxygenation at the 4a-position was achieved according to the procedure of Barton and McCombie,34 as modified by Dietrich and Schmidt (Scheme 5).35 Thus treatment of 15a or 15b with NaH in the presence of imidazole in THF at room temperature, followed by addition of CS2 and then MeI after 40 min, afforded thionocarbonate 18a or 18b in 54% or 50% yield, respectively. The modest yields of these compounds are most likely due to their limited stability to column chromatography. Treatment of 18a or 18b with Bu3SnH and azoisobutyronitrile (AIBN) in refluxing toluene afforded the desired C-linked disaccharide 19 in 91% yield, which after removal of the tert-butyldimethylsilyl (TBDMS) group with Bu4NF (TBAF) in THF,28 gave disaccharide 20 in 93% yield. The disaccharide showed the expected [M + H], [M + NH4], [M + Na] and [M + K] peaks in the positive-ion ESIMS. The NMR spectra, in general, supported the assigned structure; however, while the 1H NMR spectrum showed a distinct signal for H-1I, H-1II was hopelessly buried in an envelope of signals at δ 3.47–3.34, which prevented firm confirmation of the β linkage, although the β assignment is not in doubt, beginning with the series of reactions from 15a. Disaccharide 20 will also serve as an acceptor in the synthesis of C-/O-linked HA tetrasaccharide mimetics (details to be published).

Scheme 5.

Scheme 5

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Synthesis of the C-disaccharide.

Following removal of the p-methoxybenzyl (PMB) group on 20 with DDQ,36 the resulting primary hydroxyl group was selectively oxidized to the corresponding carboxylic (uronic) acid with 5% aq NaClO in the presence of a catalytic amount of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO).37 Debenzylation with Pearlman’s catalyst (1 atm) afforded the target C-disaccharide 21. The structure of 21 was supported by the negative-ion HRESIMS that showed the expected ion for [M – H]. In the 1H NMR spectrum H-1II appeared as a complex multiplet at δ 3.26–3.21, and resonances for H-6, 6aI of 20 disappeared and were replaced by a 13C resonance at δ 174.3, which is indicative of a carboxylic acid.37 The other resonances were supportive of the structure.

2.5 Conclusions

The target C-linked disaccharide that constitutes the repeat unit of HA was synthesized as its p-methoxyphenyl glycoside using SmI2-mediated coupling of the sugar units. Extension of this methodology to higher oligosaccharides that incorporate the C/O linked sugars, as well as extensive biological studies of these synthetic HA mimetics, are underway.

3. Experimental Section

3.1 General methods

1H (250 MHz, 300 MHz, and 600 MHz) and 13C (62.5 MHz, 75 MHz, and 150 MHz) NMR spectra were recorded at 25 °C as designated. Chemical shifts are expressed in δ units (ppm) and were measured relative to an internal standard of TMS for 1H, and relative to the signal for CDCl3 (δ 77.0) or DMSO-d6 (δ 39.5) for 13C, unless otherwise stated. Apparent, first-order multiplicities are indicated by s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet, and m, multiplet. All assignments were confirmed with the aid of two-dimensional experiments (gCOSY, HSQC, HMBC and TOCSY as needed) at 600 MHz. Sugar units are numbered analogously to O-glycosides using the Whelan system (Rule 2-Carb-37.2)38 where “I” designates the reducing end unit, “II” the next unit, etc.; NMR resonances are indicated by the appropriate superscript. Nomenclature follows the use of the “carba” designation for C replacement of O in sugar units (Rule 2-Carb-37.5).38 Electrospray-ionization mass spectrometry (ESIMS) was carried out at low resolution using a Micromass Quattro-II triple quadrupole instrument operating in the positive-ion mode; the HRESIMS measurement (negative-ion) was made on an Applied Biosystems QSTAR XL quadrupole instrument. Column chromatography was performed on 60 Å (63–200 mm, termed “coarse”) silica gel (Sorbent Technologies, Atlanta, Ga), and fractions were monitored by TLC on Silica Gel UV254 [0.2-mm aluminum-backed plates (Sorbent Technologies)] by detection with 254-nm UV light and then spray–heat development using a p-anisaldehyde–sulfuric acid reagent.39 Melting points were measured with a capillary melting point apparatus, and optical rotations were carried out at the sodium D line in a 1-dm cell at 20 °C; units are (degrees·mL)/(g·dm). Microanalyses were carried out by Atlantic Microlabs, Inc., Atlanta, GA.

3.2 2-Pyridinyl 2-acetamido-4,6-O-benzylidene-2-deoxy-1-thio-β-D-glucopyranoside (4)

To a solution of compound 225 (20.0 g, 45.5 mmol) in MeOH (150 mL) and CH2Cl2 (30 mL) was added NaOMe (25% in MeOH, 1.0 mL). The reaction was stirred at room temperature for 1 h, after which time 1 mL of satd NH4Cl solution was added, and the solvent was evaporated to afford compound 3 (13.6 g, 43.2 mmol, 95%) as a white amorphous solid that was used directly in the next step; mp 154–156 °C; [α]D +9.5 (c 1.0, DMSO). Compound 3 (16.0 g, 51.0 mmol) was stirred with dry ZnCl2 (14 g, 0.10 mol) in benzaldehyde (100 mL) at room temperature for 16 h, after which time the reaction was quenched with water (250 mL). The suspension was filtered, and the solid was sequentially washed with EtOAc and MeOH to afford compound 4 as a white amorphous solid (16.3 g, 40.5 mmol, 80%). TLC (10:1 CHCl3–MeOH): Rf 0.4; mp 164–166 °C; [α]D +4.6 (c 0.5, DMSO); 1H NMR (250 MHz, DMSO-d6): δ 8.43–7.12 (m, 4 H, ArH), 7.47–7.32 (m, 5 H, ArH), 5.62 (s, 1 H, PhCH), 5.54 (d, 1 H, H-1, J1, 2 = 10.5 Hz), 5.46 (d, 1 H, NH), 4.19–4.17 (m, 1 H, H-6), 3.85 (dd, 1 H, H-2), 3.74–3.63 (m, 2 H, H-3, H-4), 3.59–3.48 (m, 2 H, H-6, H-5), 3.16 (d, 1 H, OH), 1.80 (s, 3 H, CH3CO); 13C NMR (62.5 MHz, DMSO-d6): δ 169.2, 157.2, 149.4, 137.7, 137.2, 128.9, 128.0, 126.4, 122.0, 120.5, 100.7, 83.3, 81.0, 71.7, 70.2, 67.6, 54.0, 23.0; ESIMS (positive-ion): m/z 403.1 [M + H], 425.1 [M + Na], 441.1 [M + K]. Anal. Calcd for C20H22N2O5S·0.16CH2Cl2 (416.06): C, 58.20; H, 5.41; N, 6.73. Found: C, 58.19; H, 5.56; N, 6.50. CH2Cl2 complexed with 4 was confirmed by NMR spectroscopy.

3.3 2-Pyridinyl 2-acetamido-4,6-O-benzylidene-3-O-tert-butyldimethylsilyl-2-deoxy-1-thio-β-D-glucopyranoside (5)

To a solution of compound 4 (16.30 g, 40.54 mmol) and imidazole (6.25 g, 96.0 mmol) in dry DMF was added tert-butylchlorodimethylsilane (10.4 g, 69.0 mmol) at 0 °C. The reaction was allowed to stir and warm to room temperature over 15 h, after which time it was quenched with water, washed with satd NaHCO3 and extracted with CH2Cl2. The organic phase was dried with anhyd Na2SO4 and then evaporated to dryness. The residue was submitted to silica gel column chromatography (2.5:1 to 1:1 hexanes–EtOAc) to yield compound 5 as a pale-yellow solid (16.3 g, 31.6 mmol, 78%). TLC (1:2 hexanes–EtOAc): Rf 0.5; mp 210–212 °C; [α]D +4.3 (c 1.0, CH2Cl2); 1H NMR (250 MHz, CDCl3): δ 8.44–7.03 (m, 4 H, ArH), 7.55–7.34 (m, 5 H, ArH), 5.98 (d, 1 H, NH), 5.85 (d, 1 H, H-1, J1, 2 = 10.6 Hz), 5.51 (s, 1 H, PhCH), 4.31 (dd, 1 H, H-6), 4.20–3.96 (m, 2 H, H-2, H-3), 3.82–3.48 (m, 3 H, H-6, H-5, H-4), 1.91 (s, 3 H, CH3CO), 0.82 (s, 9 H, C(CH3)3), 0.05 (s, 3 H, SiCH3), −0.02 (s, 3 H, SiCH3); 13C NMR (62.5 MHz, CDCl3): δ 170.1, 156.6, 149.4, 137.2, 136.6, 129.0, 128.1, 126.3, 123.5, 120.6, 101.8, 83.2, 82.1, 74.0, 70.8, 68.7, 56.2, 25.6, 23.5, 18.1, −4.1, −5.0; ESIMS (positive-ion): m/z 517.2 [M + H], 539.2 [M + Na], 555.2 [M + K]. Anal. Calcd for C26H36N2O5SSi (516.74): C, 60.43; H, 7.02; N, 5.42. Found: C, 60.41; H, 6.83; N, 5.36.

3.4 2-Acetamido-4,6-O-benzylidene-3-O-tert-butyldimethylsilyl-1,2-dideoxy-1-pyridinylsulfonyl-β-D-glucopyranose (6)

To a stirred solution of compound 5 (16.3 g, 31.6 mmol) in CH2Cl2 (200 mL) was added m-CPBA (50–60%, 33.0 g) at 0 °C. The reaction was allowed to stir and warm to room temperature over 1.5 h, after which time the reaction mixture was diluted with CH2Cl2, washed consecutively with satd Na2S2O3, satd Na2CO3 and brine, and extracted with CH2Cl2. The organic phase was dried with anhyd Na2SO4 and then concentrated to dryness. The residue was submitted to silica gel column chromatography (1:1 hexanes–EtOAc) to give compound 6 as a white amorphous solid (13.9 g, 25.4 mmol, 79%). TLC (1:2 hexanes–EtOAc): Rf 0.4; mp 162–164 °C; [α]D −34.8 (c 1.0, CH2Cl2); 1H NMR (250 MHz, CDCl3): δ 8.85 (d, 1 H, ArH), 8.16 (d, 1 H, ArH), 8.02 (t, 1 H, ArH), 7.62 (t, 1 H, ArH), 7.50–7.39 (m, 5 H, ArH), 6.84 (d, 1 H, NH), 5.81 (d, 1 H, H-1, J1, 2 = 10.3 Hz), 4.72–4.61 (m, 1 H, H-6), 4.12–4.02 (m, 2 H, H-2, H-3), 3.69–3.48 (m, 3 H, H-6, H-5, H-4), 2.06 (s, 3 H, CH3CO), 0.09 (s, 9 H, C(CH3)3), 0.06 (s, 3 H, SiCH3), −0.01 (s, 3 H, SiCH3); 13C NMR (62.5 MHz, CDCl3): δ 171.0, 155.1, 150.2, 137.8, 136.8, 128.9, 127.9, 127.6, 126.1, 124.2, 101.7, 86.1, 81.6, 71.0, 70.1, 67.9, 53.5, 25.6, 23.5, 17.9, −4.4, −5.1; ESIMS (positive-ion): m/z 549.0 [M + H], 571.0 [M + Na], 587.0 [M + K]. Anal. Calcd for C26H36N2O7SSi (548.74): C, 56.91; H, 6.61; N, 5.11. Found: C, 56.72; H, 6.60; N, 4.96.

3.5 p-Methoxyphenyl 4,6-O-p-methoxybenzylidene-β-D-galactopyranoside (9)

To a solution of compound 740 (20.5 g, 45.4 mmol) in dry CH2Cl2 (50 mL) and dry MeOH (250 mL) was added NaOMe (25% in MeOH, 0.25 mL). The reaction was stirred at room temperature for 1 h, after which time the reaction was quenched with Dowex 50 × 2–100 (H+ form). The suspension was filtered and evaporated to afford 8 as a white amorphous solid (12.7 g, 44.0 mmol, 97%), which was used in the next step without characterization. TLC (9:1 CH2Cl2–MeOH): Rf 0.1; mp 158–160 °C; [α]D −35.7 (c 1.1, H2O). To a suspension of 8 (11.0 g, 38.5 mmol) in dry CH3CN (250 mL) were added anisaldehyde dimethyl acetal (ADMA, 69.0 mL, 0.40 mol) and p-toluenesulfonic acid (0.75 g, 3.9 mmol, 0.1 equiv). The solution was stirred at room temperature for about 4 h. After this time the reaction was quenched with Et3N. The suspension was filtered, and the solid was sequentially washed with EtOAc and hexanes to afford compound 9 as a white amorphous solid (13.1 g, 32.2 mmol, 84%). TLC (9:1 CH2Cl2–MeOH): Rf 0.5; mp 224–226 °C; [α]D −74.9 (c 1.0, DMSO); 1H NMR (250 MHz, DMSO-d6): δ 7.37 (d, 2 H, ArH), 7.01 (d, 2 H, ArH), 6.91 (d, 2 H, ArH), 6.86 (d, 2 H, ArH), 5.51 (s, 1 H, CH3OPhCH), 5.26 (d, 1 H, H-2), 5.02 (d, 1 H, H-3), 4.83 (d, 1 H, H-1, J1, 2 = 6.5 Hz), 4.10 (s, 1 H, H-4), 4.02 (s, 2 H, H-6), 3.74 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 3.67 (s, 1 H, H-5), 3.58 (m, 1 H, OH); 13C NMR (62.5 MHz, DMSO-d6): δ 159.4, 154.3, 151.3, 131.0, 127.5, 117.6, 114.4, 113.2, 101.5, 99.7, 75.8, 71.7, 69.7, 68.4, 66.0, 55.3, 55.1; ESIMS (positive-ion): m/z 404.7 [M + H], 426.7 [M + Na], 442.6 [M + K]. Anal. Calcd for C21H24O8 (404.72): C, 62.37; H, 5.98. Found: C, 62.30; H, 5.99.

3.6 p-Methoxyphenyl 2,3-di-O-benzyl-4,6-O-p-methoxybenzylidene-β-D-galactopyranoside (10)

To a solution of diol 9 (7.35 g, 18.1 mmol) in dry DMF (40 mL) was added NaH (60% in mineral oil, 2.17 g, 54.3 mmol) at 0 °C. The reaction was stirred at 0 ºC for 10 min, and then BnBr (8.49 mL, 72.4 mmol) was added dropwise. The reaction was allowed to stir and warm to room temperature over 10 h, after which time it was quenched with water and extracted with CH2Cl2. The organic phase was dried with anhyd Na2SO4 and then concentrated to dryness. The residue was submitted to silica gel column chromatography (3:1 to 2:1 hexanes–EtOAc) to give compound 10 as a white amorphous solid (10.0 g, 17.1 mmol, 95%). TLC (1:1 hexanes–EtOAc): Rf 0.5; mp 167–169 °C; [α]D −6.3 (c 1.0, CHCl3); 1H NMR (250 MHz, CDCl3): δ 7.49 (d, 2 H, ArH), 7.40–7.25 (m, 10 H, ArH), 7.06 (d, 2 H, ArH), 6.90 (d, 2 H, ArH), 6.80 (d, 2 H, ArH), 5.47 (s, 1 H, MeOPhCH), 5.00 (d, 1 H, H-1, J1, 2 = 10.7 Hz), 4.86 (m, 2 H, H-2, H-3), 4.78 (s, 2 H, ArCH2O), 4.31 (d, 1 H, ArCH2O), 4.15–3.99 (m, 3 H, H-6, H-4, ArCH2O), 3.81 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.61 (dd, 1 H, H-5), 3.39 (s, 1 H, H-6); 13C NMR (62.5 MHz, CDCl3): δ 160.0, 155.2, 151.6, 138.6, 138.3, 130.4, 128.3, 128.2, 128.0, 127.8, 127.7, 127.5, 118.9, 114.4, 113.4, 103.1, 101.2, 79.1, 78.1, 75.4, 73.6, 71.9, 69.0, 66.4, 55.6, 55.2; ESIMS (positive-ion): m/z 585.2 [M + H], 607.2 [M + Na], 623.2 [M + K]. Anal. Calcd for C35H36O8 (584.67): C, 71.90; H, 6.21. Found: C, 71.84; H, 6.30.

3.7 p-Methoxyphenyl 2,3-di-O-benzyl-6-O-p-methoxybenzyl-β-D-galactopyranoside (11)

A suspension of compound 10 (0.900 g, 1.54 mmol), NaBH3CN (0.390 g, 6.16 mmol) and 4 Å MS (0.41 g) in dry DMF (20 mL) was stirred at 0 °C for 15 min, and then a solution of CF3CO2H (0.95 mL, 12.3 mmol) in dry DMF (3 mL) was added dropwise. The reaction was allowed to stir and warm to room temperature over 10 h, after which time the mixture was filtered through a bed of Celite, washed with satd NaHCO3, and extracted with CH2Cl2. The organic phase was dried with anhyd Na2SO4 and then concentrated to dryness. The residue was submitted to silica gel column chromatography (4:1 to 3.5:1 hexanes–EtOAc) to give compound 11 as colorless crystals (0.670 g, 1.14 mmol, 74%). TLC (2:1 hexanes–EtOAc): Rf 0.5; mp 93–95 °C; [α]D −6.2 (c 1.0, CHCl3); 1H NMR (250 MHz, CDCl3): δ 7.38–7.22 (m, 12 H, ArH), 7.03 (d, 2 H, ArH), 6.85 (d, 2 H, ArH), 6.80 (d, 2 H, ArH), 5.01 (d, 1 H, ArCH2O), 4.84 (d, 1 H, H-1, J1, 2 = 7.5 Hz), 4.81 (d, 1 H, ArCH2O), 4.74 (s, 2 H, ArCH2O), 4.50 (s, 2 H, ArCH2O), 4.05 (d, 1 H, H-6), 3.91 (dd, 1 H, H-2), 3.80 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), ~3.7 (m, 1 H, H-6a), 3.63 (dd, 1 H, H-3), 3.56 (m, 1 H, H-5), 2.56 (s, 1 H, OH); 13C NMR (62.5 MHz, CDCl3): δ 159.3, 155.2, 151.5, 138.4, 137.8, 130.1, 129.4, 128.5, 128.3, 128.1, 127.9, 127.8, 127.7, 118.6, 114.5, 113.8, 102.9, 80.6, 78.7, 75.3, 73.5, 73.4, 72.5, 68.9, 66.8, 55.6, 55.2; ESIMS (positive-ion): m/z 609.3 [M + Na], 625.2 [M + K]. Anal. Calcd for C35H38O8 (586.69): C, 71.65; H, 6.53. Found: C, 71.54; H, 6.60.

3.8 p-Methoxyphenyl 2,3-di-O-benzyl-4-C-cyano-4-deoxy-6-O-p-methoxybenzyl-β-D-glucopyranoside (13)

To a solution of compound 11 (10.0 g, 17.06 mmol) in dry CH2Cl2 (80 mL) and pyridine (3.5 mL, 43.3 mmol) was added trifluoromethanesulfonic anhydride (3.5 mL, 21.3 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 10 h, after which time it was concentrated and passed through a short plug of silica gel (3:1 hexanes–EtOAc) to give triflate 12 as an unstable, pale-yellow syrup that was used in the nest step without characterization. TLC (2:1 hexanes–EtOAc): Rf 0.72. To a solution of triflate 12 (12.26 g, 17.06 mmol) in dry THF (40 mL) was added Bu4NCN (50 mL, 0.44 M in THF, 1.2 equiv) dropwise at −45 °C. The solution was allowed to stir and warm to room temperature over 4 h, at which time TLC (3:1 hexanes–EtOAc) showed complete consumption of starting material and formation of two main spots. The reaction was concentrated to dryness, and the residue was subjected to silica gel column chromatography (7:1 to 5.5:1 hexanes–EtOAc) to afford compound 13 as a yellow syrup (6.40 g, 10.75 mmol, 63%). TLC (3:1 hexanes–EtOAc): Rf 0.4; [α]D −19.1 (c 1.0, CHCl3); 1H NMR (250 MHz, CDCl3): δ 7.34–7.20 (m, 12 H, ArH), 6.99 (d, 2 H, ArH), 6.83 (d, 2 H, ArH), 6.79 (d, 2 H, ArH), 5.01 (d, 1 H, ArCH2O), 4.87 (s, 2 H, ArCH2O), 4.85 (d, 1 H, H-1, J1, 2 = 7.5 Hz), 4.78 (d, 1 H, ArCH2O), 4.47 (dd, 2 H, ArCH2O), 3.71 (s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 3.78–3.64 (m, 4 H, H-2, H-5, H-6), 3.55 (t, 1 H, H-3), 2.98 (t, 1 H, H-4); 13C NMR (62.5 MHz, CDCl3): δ 158.4, 154.6, 150.2, 136.9, 136.4, 128.7, 128.4, 127.5, 127.4, 127.2, 127.1, 127.0, 117.6, 116.6, 113.7, 112.9, 101.9, 80.5, 78.4, 74.9, 74.2, 72.5, 71.4, 68.2, 54.6, 54.3, 35.0; ESIMS (positive-ion): m/z 618.2 [M + Na], 634.2 [M + K]. Anal. Calcd for C36H37NO7 (595.70): C, 72.59; H, 6.26; N, 2.35. Found: C, 72.59; H, 6.45; N, 2.24.

3.9 p-Methoxyphenyl 2,3-di-O-benzyl-4-deoxy-4-C-formyl-6-O-p-methoxybenzyl-β-D-glucopyranoside (14)

To a solution of compound 13 (1.06 g, 1.78 mmol) in dry THF (25 mL) was added Bu2AlH [DIBALH (Aldrich), 7.11 mL, 1.5 M in toluene, 6 equiv] at −78 °C. The reaction was allowed to stir and warm to room temperature over 10 h, after which time it was quenched with EtOAc, and the solution was stirred with 1.0 N H3PO4 (10 mL) for another 30 min at 0 °C. The mixture was then neutralized with satd NaHCO3, filtered though a bed of Celite and extracted with CH2Cl2. The organic phase was dried with anhyd Na2SO4 and then concentrated to dryness. The residue was adsorbed onto a short plug of silica gel and eluted (3.5:1 hexanes–EtOAc) to give compound 14 as a pale-yellow syrup (0.76 g, 1.26 mmol, 71%). TLC (3:1 hexanes–EtOAc): Rf 0.3; [α]D −31.7 (c 0.5, CH2Cl2); 1H NMR (250 MHz, CDCl3): δ 9.65 (d, 1 H, CHO), 7.33–7.16 (m, 12 H, ArH), 6.99 (d, 2 H, ArH), 6.83 (d, 2 H, ArH), 6.80 (d, 2 H, ArH), 5.05 (d, 1 H, ArCH2O), 4.84 (m, 3 H, ArCH2O, H-1, J1, 2 = 10.0 Hz), 4.56 (d, 1 H, ArCH2O), 4.40 (dd, 2 H, ArCH2O), 4.00 (dd, 1 H, H-3), 3.74 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.81–3.67 (m, 2 H, H-5, H-3), 3.58 (m, 2 H, H-6), 3.01 (dd, 1 H, J = 10.2 Hz, H-4); 13C NMR (62.5 MHz, CDCl3): δ 200.1, 159.4, 155.5, 151.4, 138.3, 138.0, 129.8, 129.5, 128.5, 128.5, 128.3, 128.1, 127.9, 118.5, 114.7, 113.9, 102.8, 82.6, 78.8, 75.2, 75.1, 73.2, 72.1, 70.3, 57.3, 55.7, 55.3; ESIMS (positive-ion): m/z 621.1 [M + Na], 637.2 [M + K]. Anal. Calcd for C36H38O8 (598.70): C, 72.22; H, 6.40. Found: C, 72.44; H, 6.28.

3.10 Samarium diiodide-promoted coupling reaction: Synthesis of 15a–c

To a stirred solution of sulfone 6 (2.90 g, 5.3 mmol) and aldehyde 14 (2.50 g, 4.2 mmol) in THF (50 mL) was added a solution of SmI2 (Aldrich) in dry THF (0.1 M, 150 mL, 15 mmol) under N2. The reaction was stirred at room temperature for 1 h, after which time it was quenched with satd NH4Cl and extracted with CH2Cl2. The organic phase was dried with anhyd Na2SO4, and then evaporated to dryness. The residue was submitted to silica gel column chromatography (3:1 to 1:1 hexanes–EtOAc) to afford 15a (845 mg, 0.84 mmol, 20%), 15b (630 mg, 0.63 mmol, 15%) and 15c (1.25 g, 1.24 mmol, 30%) as white amorphous solids. Physicochemical data for 15a–c are provided in the paragraphs that follow.

3.10.1 p-Methoxyphenyl C-(2-acetamido-4,6-O-benzylidene-3-O-tert-butyldi-methylsilyl-2-deoxy-β-D-glucopyranosyl)-(1→4a)-(4aR)-2,3-di-O-benzyl-4a-hydroxy-6-O-p-methoxybenzyl-4a-carba-β-D-glucopyranoside (15a)

TLC (2:1 hexanes–EtOAc): Rf 0.5; mp 176–178 °C; [α]D −41.2 (c 0.5, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 7.51–7.19 (m, 17 H, ArH), 7.07 (d, 2 H, ArH), 6.84 (d, 2 H, ArH), 6.75 (d, 2 H, ArH), 5.44 (s, 1 H, PhCH), 5.07 (d, 1 H, ArCH2O), 4.99 (d, 1 H, ArCH2O), 4.99 (d, 1 H, NH), 4.91 (d, 1 H, H-1I, J1, 2 = 7.2 Hz), 4.80 (d, 1 H, ArCH2O), 4.59 (d, 1 H, ArCH2O), 4.45 (dd, 2 H, ArCH2O), 4.21 (dd, 1 H, H-6II), 4.02 (s, 1 H, CH-OH), 3.97 (dd, 1 H, H-6I), 3.91–3.83 (m, 2 H, H-5I, H-2II), 3.80–3.76 (m, 3 H, H-2I, H-3I, CH-OH), 3.78 (s, 3 H, CH3O), 3.76 (s, 3 H, CH3O), 3.62–3.57 (m, 2 H, H-6I, H-6II), 3.43–3.36 (m, 2 H, H-4II, H-1II, J1, 2 = 8.4 Hz), 3.29–3.21 (m, 2 H, H-3II, H-5II), 2.32–2.26 (m, 1 H, H-4I), 1.76 (s, 3 H, CH3CO), 0.77 (s, 9 H, C(CH3)3), −0.05 (s, 3 H, SiCH3), −0.08 (s, 3 H, SiCH3); 13C NMR (62.5 MHz, CDCl3): δ 171.2, 158.9, 155.0, 151.5, 138.8, 138.1, 137.1, 130.8, 129.8, 129.0, 128.6, 128.4, 128.1, 127.8, 127.7, 126.2, 118.2, 114.5, 113.6, 102.7, 101.8, 83.1, 82.0, 78.5, 78.4, 74.6, 74.2, 73.7, 73.5, 72.8, 71.4, 70.5, 68.6, 67.3, 55.5, 55.1, 53.5, 46.0, 25.6, 23.2, 18.0, −4.0, −4.9; ESIMS (positive-ion): m/z 1028.4 [M + Na], 1044.5 [M + K]. Anal. Calcd for C57H71NO13Si (1006.28): C, 68.04; H, 7.11; N, 1.39. Found: C, 67.76; H, 7.22; N, 1.34.

3.10.2 p-Methoxyphenyl C-(2-acetamido-4,6-O-benzylidene-3-O-tert-butyldi-methylsilyl-2-deoxy-β-D-glucopyranosyl)-(1→4a)-(4aS)-2,3-di-O-benzyl-4a-hydroxy-6-O-p-methoxybenzyl-4a-carba-β-D-glucopyranoside (15b)

TLC (1:2 hexanes–EtOAc): Rf 0.2; mp 90–92 °C; [α]D −97.1 (c 0.5, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 7.47–7.24 (m, 17 H, ArH), 7.04 (d, 2 H, ArH), 6.87 (d, 2 H, ArH), 6.79 (d, 2 H, ArH), 5.40 (s, 1 H, PhCH), 5.09 (d, 1 H, ArCH2O), 5.03 (d, 1 H, ArCH2O), 4.99 (d, 1 H, NH), 4.94 (d, 1 H, H-1I, J1, 2 = 6.6 Hz), 4.77 (d, 1 H, ArCH2O), 4.65 (d, 1 H, ArCH2O), 4.50 (d, 1 H, ArCH2O), 4.43 (d, 1 H, ArCH2O), 4.17 (dd, 1 H, H-6II), 3.88–3.74 (m, 5 H, H-5I, H-3II, H-2I, CH-OH, H-3I), 3.78 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 3.72 (dd, 1 H, H-6I), 3.61 (dd, 1 H, H-6I), 3.58–3.52 (m, 2 H, H-6II, H-1II, J1, 2 = 9.6 Hz), 3.48 (dd, 1 H, H-2II), 3.28 (t, 1 H, H-4II), 3.26–3.21 (m, 1 H, H-5II), 2.25–2.08 (m, 1 H, H-4I), 1.89 (s, 3 H, CH3CO), 0.08 (s, 9 H, C(CH3)3), −0.03 (s, 3 H, SiCH3), −0.07 (s, 3 H, SiCH3); 13C NMR (62.5 MHz, CDCl3): δ 170.8, 159.3, 155.1, 151.4, 138.5, 138.0, 137.2, 130.0, 129.7, 129.0, 128.7, 128.4, 128.1, 128.1, 127.8, 127.7, 126.3, 126.2, 114.5, 113.8, 102.8, 101.7, 83.2, 82.2, 79.5, 78.7, 74.4, 73.1, 72.9, 71.5, 71.5, 69.6, 68.6, 56.9, 55.6, 55.2, 45.3, 25.7, 23.5, 18.1, −4.1, −5.0; ESIMS (positive-ion): m/z 1006.4 [M + H], 1028.5 [M + Na], 1044.6 [M + K]. Anal. Calcd for C57H71NO13Si (1006.28): C, 68.04; H, 7.11; N, 1.39. Found: C, 67.74; H, 6.95; N, 1.38.

3.10.3 p-Methoxyphenyl C-(2-acetamido-4,6-O-benzylidene-3-O-tert-butyldi-methylsilyl-2-deoxy-α-D-glucopyranosyl)-(1→4a)-2,3-di-O-benzyl-4a-hydroxy-6-O-p-methoxybenzyl-4a-carba-β-D-glucopyranoside (15c)

TLC (2:1 hexanes–EtOAc): Rf 0.4; mp 96–98 °C; [α]D −2.9 (c 0.1, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 7.47–7.26 (m, 15 H, ArH), 7.21 (d, 2 H, ArH), 7.00 (d, 2 H, ArH), 6.84 (d, 2 H, ArH), 6.81 (d, 2 H, ArH), 6.10 (d, 1 H, NH), 5.44 (s, 1 H, PhCH), 5.11 (d, 1 H, ArCH2O), 5.05 (d, 1 H, ArCH2O), 4.93 (d, 1 H, H-1I, J1, 2 = 7.2 Hz), 4.75 (d, 1 H, ArCH2O), 4.74 (d, 1 H, ArCH2O), 4.46 (d, 1 H, ArCH2O), 4.35 (d, 1 H, ArCH2O), 4.27 (m, 1 H, H-2II) 4.12 (dd, 1 H, H-6II), 4.02 (m, 1 H, H-4II), 3.95 (m, 2 H, H-3I, H-3II), 3.84–3.71 (m, 4 H, H-6I, H-5I, H-1II, CH-OH), 3.78 (s, 3 H, CH3O), 3.78 (s, 3 H, CH3O), 3.68 (t, 1 H, H-2I), 3.65–3.61 (m, 1 H, H-6I), 3.56 (t, 1 H, H-6II), 3.50–3.40 (m, 1 H, H-5II), 2.05–1.98 (m, 1 H, H-4I), 1.86 (s, 3 H, CH3CO), 0.75 (s, 9 H, C(CH3)3), −0.08 (s, 3 H, SiCH3), −0.13 (s, 3 H, SiCH3); 13C NMR (62.5 MHz, CDCl3): δ 169.7, 159.1, 155.1, 150.9, 137.5, 137.3, 137.1, 129.6, 129.0, 128.8, 128.6, 128.3, 128.1, 128.1, 128.0, 127.7, 127.7, 126.1, 118.2, 114.4, 113.5, 102.5, 101.6, 83.0, 82.7, 80.0, 75.2, 74.3, 73.5, 73.2, 71.9, 71.4, 71.3, 69.1, 67.6, 65.4, 55.6, 55.2, 54.5, 48.3, 25.7, 23.4, 18.0, −4.0, −4.9; ESIMS (positive-ion): m/z 1006.2 [M + H], 1023.2 [M + NH4], 1028.2 [M + Na], 1044.2 [M + K]. Anal. Calcd for C57H71NO13Si (1006.28): C, 68.04; H, 7.11; N, 1.39. Found: C, 67.79; H, 7.03; N, 1.47.

3.11 p-Methoxyphenyl C-(2-acetamido-4,6-O-benzylidene-3-O-tert-butyldimethyl-silyl-2-deoxy-α-D-glucopyranosyl)-(1→4a)-2,3-di-O-benzyl-4a-oxo-6-O-p-methoxybenzyl-4a-carba-β-D-glucopyranoside (16)

To a solution of compound 15c (640 mg, 0.636 mmol) in dry CH2Cl2 (15 mL) was added PCC (1.35 g, 6.26 mmol, ~10 equiv). The reaction was stirred for 12 h, after which time it was concentrated to dryness, and the residue was submitted to silica gel column chromatography (3:1 to 2:1 hexanes–EtOAc) to yield 16 as a white solid (420 mg, 0.418 mmol, 66%). TLC (2:1 hexanes–EtOAc): Rf 0.5; mp 68–69 °C; [α]D −10.6 (c 0.5, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 7.46–7.43 (m, 2 H, ArH), 7.36–7.26 (m, 11 H, ArH), 7.21 (d, 2 H, ArH), 7.16 (d, 2 H, ArH), 7.00 (d, 2 H, ArH), 6.82 (d, 2 H, ArH), 6.80 (d, 2 H, ArH), 6.05 (d, 1 H, NH), 5.46 (s, 1 H, PhCH), 5.07 (d, 1 H, ArCH2O), 4.95 (d, 1 H, ArCH2O), 4.92 (d, 1 H, H-1I, J1, 2 = 7.2 Hz), 4.75 (d, 1 H, ArCH2O), 4.61 (d, 1 H, H-1II, J1, 2 = 6.0 Hz), 4.52–4.45 (m, 3 H, ArCH2O, H-2II), 4.20 (dd, 1 H, H-6II), 3.89–3.84 (m, 2 H, ArCH2O, H-3I), 3.82–3.71 (m, 3 H, H-3II, H-5I, H-2I), 3.78 (s, 3 H, CH3O), 3.76 (s, 3 H, CH3O), 3.68–3.65 (m, 1 H, H-5I), 3.62–3.50 (m, 4 H, H-6II, H-6I, H-6I, H-4I), 3.45 (t, 1 H, H-4II), 1.79 (s, 3 H, COCH3), 0.77 (s, 9 H, C(CH3)3), −0.06 (s, 3 H, CH3Si), −0.08 (s, 3 H, CH3Si); 13C NMR (62.5 MHz, CDCl3): δ 211.9, 169.1, 159.0, 155.3, 151.0, 137.6, 137.0, 136.8, 129.4, 129.1, 128.8, 128.5, 128.3, 128.0, 127.8, 127.7, 127.5, 126.1, 118.4, 114.4, 113.6, 102.7, 101.6, 82.6, 82.5, 81.2, 80.2, 75.2, 74.6, 73.0, 72.9, 70.7, 69.1, 68.6, 67.8, 55.4, 54.9, 52.5, 51.6, 25.4, 23.2, 17.8, −4.2, −5.1; ESIMS: m/z 1026.6 [M + Na], 1042.5 [M + K]. Anal. Calcd for C57H69NO13Si: C, 68.17; H, 6.93; N, 1.39. Found: C, 68.16; H, 6.89; N, 1.44.

3.12 p-Methoxyphenyl C-(2-acetamido-4,6-O-benzylidene-3-O-tert-butyldimethyl-silyl-2-deoxy-β-D-glucopyranosyl)-(1→4a)-2,3-di-O-benzyl-4a-oxo-6-O-p-methoxybenzyl-4a-carba-β-D-glucopyranoside (17)

To a solution of compound 16 (250 mg, 0.244 mmol) in MeOH (5 mL) was added NaOMe (0.75 mmol, 3 equiv). The reaction was stirred at room temperature for 2 h, after which time it was neutralized with Dowex 50W × 2 (H+) and concentrated to dryness. The residue was submitted to silica gel column chromatography (3:1 to 2:1 hexanes–EtOAc) to give starting material 16 (125 mg, 50%) and product 17 as a white solid (89 mg, 36%). TLC (2:1 hexanes–EtOAc): Rf 0.4; mp 94–95 °C; [α]D +0.2 (c 0.5, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 7.45–7.43 (m, 2 H, ArH), 7.38–7.25 (m, 13 H, ArH), 7.17 (d, 2 H, ArH), 7.02 (d, 2 H, ArH), 6.85 (d, 2 H, ArH), 6.81 (d, 2 H, ArH), 5.44 (s, 1 H, PhCH), 5.09 (d, 1 H, ArCH2O), 5.05 (d, 1 H, ArCH2O), 4.95 (d, 1 H, H-1I, J1, 2 = 7.2 Hz), 4.81 (d, 1 H, ArCH2O), 4.65–4.62 (m, 2 H, H-1II, J1,2 = 10.8 Hz, NH), 4.56 (t, 1 H, H-3II), 4.47 (d, 1 H, ArCH2O), 4.38 (dd, 2 H, ArCH2O), 4.15 (dd, 1 H, H-6II), 4.06 (dd, 1 H, H-3I), 3.78 (s, 3 H, CH3O), 3.78 (s, 3 H, CH3O), 3.76–3.70 (m, 2 H, H-5I, H-2I), 3.63 (t, 1 H, H-6II), 3.49–3.41 (m, 4 H, H-4I, H-5II, H-6I,), 3.29 (t, 1 H, H-4II), 2.81–2.76 (m, 1 H, H-2II), 1.64 (s, 3 H, COCH3), 0.76 (s, 9 H, C(CH3)3), −0.12 (s, 3 H, SiCH3), -0.16 (s, 3 H, SiCH3); 13C NMR (62.5 MHz, CDCl3): δ 204.8, 170.3, 159.2, 155.3, 151.2, 138.4, 137.8, 137.1, 129.6, 129.2, 129.0, 128.8, 128.4, 128.2, 128.0, 128.0, 127.8, 126.7, 126.3, 118.2, 114.5, 113.8, 102.9, 101.9, 82.7, 82.5, 80.6, 79.4, 75.2, 74.6, 74.1, 72.9, 70.5, 70.1, 69.3, 68.4, 55.6, 55.5, 55.2, 51.5, 25.8, 23.6, 18.1, −4.5, −5.0; ESIMS: m/z 1026.6 [M + Na], 1042.5 [M + K]. Anal. Calcd for C57H69NO13Si: C, 68.17; H, 6.93; N, 1.39. Found: C, 68.09; H, 6.90; N, 1.45.

3.13 Reduction of 17 to 15a and 15b

To a solution of 17 (120 mg, 0.117 mmol) in abs EtOH (10 mL) was added NaBH4 (15 mg). The reaction was stirred for 4 h, after which time 1 M HCl was added, and the mixture was diluted with wet CH2Cl2 (20 mL), poured into water (50 mL), and extracted with CH2Cl2. The organic phase was dried with anhyd Na2SO4 and evaporated to dryness. The residue was submitted to silica gel column chromatography to yield 15a (25.0 mg, 0.024 mmol, 21%) and 15b (75.0 mg, 0.075 mmol, 62%) as white solids. The physicochemical and spectral data for these compounds matched those of 15a and 15b synthesized using SmI2 as the promoter.

3.14 p-Methoxyphenyl C-(2-acetamido-4,6-O-benzylidene-3-O-tert-butyldimethyl-silyl-2-deoxy-β-D-glucopyranosyl)-(1→4a)-(4aR)-2,3-di-O-benzyl-4a-O-methylthiothiocarbonyl-6-O-p-methoxybenzyl-4a-carba-β-D-glucopyranoside (18a)

To a solution of compound 15a (1.90 g, 1.68 mmol) and imidazole (10 mg, 0.15 mmol) in dry THF (15 mL) was added NaH (60% in mineral oil, 135 mg, 3.38 mmol). The reaction was stirred for 30 min, after which time CS2 (1.74 mL, 3.78 mmol) was added. MeI (0.42 mL, 6.72 mmol) was then added after another 40 min. The mixture was stirred for 40 min, after which time it was quenched with wet CH2Cl2 (20 mL), poured into water (50 mL), and extracted with CH2Cl2. The organic phase was dried with anhyd Na2SO4 and then evaporated to dryness. The residue was submitted to silica gel column chromatography (3:1 to 2:1 hexanes–EtOAc) to yield compound 18a as a white amorphous solid (1.01 g, 0.91 mmol, 54%). TLC (2:1 hexanes–EtOAc): Rf 0.5; mp 85–87 °C; [α]D −4.3 (c 0.1, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 7.46–7.23 (m, 17 H, ArH), 7.06 (d, 2 H, ArH), 6.85 (d, 2 H, ArH), 6.74 (d, 2 H, ArH), 6.33 (m, 1 H, CHOC=S), 5.44 (s, 1 H, PhCH), 5.09 (d, 1 H, ArCH2O), 5.08 (d, 1 H, ArCH2O), 4.86 (d, 1 H, H-1I, J1, 2 = 7.8 Hz), 4.75 (d, 1 H, ArCH2O), 4.67 (d, 1 H, ArCH2O), 4.51 (d, 1 H, ArCH2O), 4.42 (d, 1 H, ArCH2O), 4.23 (dd, 1 H, H-6II) 4.00–3.95 (m, 2 H, H-6I, H-5I), 3.80–3.74 (m, 1 H, H-2I), 3.77 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 3.66–3.32 (m, 8 H, H-3I, H-6II, H-6I, H-3II, H-2II, H-1II, H-5II, H-4II), 2.72–2.52 (m, 1 H, H-4I), 2.55 (s, 3 H, SCH3), 1.49 (s, 3 H, CH3CO), 0.77 (s, 9 H, C(CH3)3), −0.08 (s, 3 H, SiCH3), −0.09 (s, 3 H, SiCH3); 13C NMR (62.5 MHz, CDCl3): δ 216.3, 169.7, 158.9, 155.1, 151.5, 139.0, 138.0, 137.1, 130.8, 129.0, 128.3, 128.0, 127.7, 127.4, 127.3, 126.3, 118.3, 114.4, 113.5, 102.9, 101.9, 83.4, 82.3, 78.9, 75.5, 74.5, 74.3, 73.4, 72.9, 71.8, 71.0, 70.6, 68.5, 55.5, 55.1, 54.5, 44.9, 25.6, 23.3, 19.4, 18.0, −4.2, −5.1; ESIMS (positive-ion): m/z 1096.4 [M + H], 1118.5 [M + Na], 1134.6 [M + K]. Anal. Calcd for C59H73NO13S2Si (1096.45): C, 64.63; H, 6.71; N, 1.28. Found: C, 64.58; H, 6.71; N, 1.26.

3.15 p-Methoxyphenyl C-(2-acetamido-4,6-O-benzylidene-3-O-tert-butyldimethyl-silyl-2-deoxy-β-D-glucopyranosyl)-(1→4a)-(4aS)-2,3-di-O-benzyl-4a-O-methylthiothiocarbonyl-6-O-p-methoxybenzyl-4a-carba-β-D-glucopyranoside (18b)

Compound 18b was synthesized from 15b using the same procedure as that for 18a. (50% yield). TLC (2:1 hexanes–EtOAc): Rf 0.45; mp 80–82 °C; [α]D −9.0 (c 0.5, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 7.46–7.23 (m, 17 H, ArH), 7.11 (d, 2 H, ArH), 6.85 (d, 2 H, ArH), 6.75 (d, 2 H, ArH), 6.42 (m, 1 H, CHOC=S), 5.37 (s, 1 H, PhCH), 5.32 (d, 1 H, ArCH2O), 5.05 (d, 1 H, ArCH2O), 5.00 (d, 1 H, NH), 4.93 (d, 1 H, H-1I, J1, 2 = 7.2 Hz), 4.78 (dd, 2 H, ArCH2O), 4.58 (t, 1 H, H-4II), 4.48 (dd, 2 H, ArCH2O), 4.43 (d, 1 H, H-1II, J1, 2 = 10.8 Hz), 4.14 (d, 1 H, H-6II), 4.02 (d, 1 H, H-6I), 3.77 (s, 3 H, CH3O), 3.76 (s, 3 H, CH3O), 3.79–3.73 (m, 3 H, H-3II, H-2I, H-3I), 3.49–3.43 (m, 4 H, H-5I, H-1II, H-6II, H-6I), 3.19 (t, 1 H, H-5II), 2.73 (m, 1 H, H-2II), 2.55 (s, 3 H, SCH3), 2.21 (t, 1 H, H-4I), 1.33 (s, 3 H, CH3CO), 0.79 (s, 9 H, C(CH3)3), −0.11 (s, 3 H, SiCH3), −0.14 (s, 3 H, SiCH3); 13C NMR (62.5 MHz, CDCl3): δ 216.7, 170.2, 159.1, 155.0, 151.5, 138.8, 137.8, 137.2, 130.6, 129.2, 129.1, 128.9, 128.3, 128.2, 128.0, 127.8, 126.3, 126.2, 118.0, 114.5, 113.7, 102.7, 101.8, 83.1, 82.5, 80.4, 79.1, 76.8, 75.0, 74.3, 73.9, 73.0, 72.3, 69.7, 68.9, 68.3, 56.9, 55.5, 55.1, 42.2, 25.6, 23.4, 19.0, 18.1, −4.3, −5.1; ESIMS (positive-ion): m/z 1118.1 [M + Na], 1134.1 [M + K]. Anal. Calcd for C59H73NO13S2Si (1096.45): C, 64.63; H, 6.71; N, 1.28. Found: C, 64.39; H, 6.86; N, 1.22.

3.16 p-Methoxyphenyl C-(2-acetamido-4,6-O-benzylidene-3-O-tert-butyldimethyl-silyl-2-deoxy-β-D-glucopyranosyl)-(1→4a)-2,3-di-O-benzyl-6-O-p-methoxybenzyl-4a-carba-β-D-glucopyranoside (19)

To a refluxing solution of Bu3SnH (1.33 mL, 5.0 mmol) in dry toluene (10 mL) was added dropwise a solution of compound 18a or 18b (1.00 g, 0.91 mmol) and AIBN (11 mg) in dry toluene (10 mL). The reaction was stirred for 30 min, and then the reaction mixture was extracted with CH2Cl2. The organic phase was dried with anhyd Na2SO4 and concentrated to dryness. The residue was submitted to silica gel column chromatography (2:1 hexanes–EtOAc) to yield compound 19 as a white amorphous solid (820 mg, 0.83 mmol, 91%). TLC (2:1 hexanes–EtOAc): Rf 0.3; mp 67–69 °C; [α]D −21.3 (c 0.5, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 7.47–7.25 (m, 20 H, ArH), 7.04 (d, 2 H, ArH), 6.89 (d, 2 H, ArH), 6.80 (d, 2 H, ArH), 5.44 (s, 1 H, PhCH), 5.08 (d, 1 H, ArCH2O), 5.02 (d, 1 H, ArCH2O), 4.84 (d, 1 H, H-1I, J1,2 = 7.8 Hz), 4.79 (d, 1 H, ArCH2O), 4.60 (d, 1 H, ArCH2O), 4.57 (d, 1 H, NH), 4.51 (d, 1 H, ArCH2O), 4.44 (d, 1 H, ArCH2O), 4.19 (dd, 1 H, H-6II), 3.79 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.74–3.68 (m, 3 H, H-6I, H-2I, H-3II), 3.60–3.50 (m, 4 H, H-6I, H-6II, H-2II, H-3I), 3.50–3.44 (m, 2 H, H-5I, H-4II), 3.34–3.28 (m, 1 H, H-1II, J1, 2 = 8.4 Hz), 3.25–3.20 (m, 1 H, H-5II), 2.12–2.05 (m, 1 H, H-4I), 1.73 (m, 1 H, CH2), 1.67 (s, 3 H, CH3CO), 1.61 (dd, 1 H, CH2), 0.77 (s, 9 H, C(CH3)3), −0.03 (s, 3 H, SiCH3), −0.08 (s, 3 H, SiCH3); 13C NMR (62.5 MHz, CDCl3): δ169.5, 159.1, 155.1, 151.5, 139.1, 138.1, 137.1, 130.2, 129.5, 128.9, 128.4, 128.3, 128.1, 128.0, 127.5, 126.2, 118.3, 114.4, 113.7, 103.0, 101.7, 83.2, 82.4, 80.7, 75.8, 74.5, 73.8, 73.3, 73.0, 70.0, 68.7, 57.0, 55.4, 55.1, 39.8, 28.8, 25.5, 23.3, 17.9, −4.1, −5.1; ESIMS (positive-ion): m/z 1012.4 [M + Na], 1028.5 [M + K]. Anal. Calcd for C57H71NO12Si (990.28): C, 69.13; H, 7.23; N, 1.41. Found: C, 68.57; H, 7.28; N, 1.34.

3.17 p-Methoxyphenyl C-(2-acetamido-4,6-O-benzylidene-2-deoxy-β-D-gluco- pyranosyl)-(1→4a)-2,3-di-O-benzyl-6-O-p-methoxybenzyl-4a-carba-β-D-glucopyranoside (20)

To a solution of compound 19 (1.22 g, 1.23 mmol) in dry THF (20 mL) was added Bu4NF (1.35 mL, 1.0 M in THF, 1.1 equiv). The reaction was stirred at room temperature for 1.5 h, after which time it was quenched with water, and the mixture was extracted with CH2Cl2. The organic phase was dried with anhyd Na2SO4 and evaporated to dryness. The residue was submitted to silica gel column chromatography (50:1 CH2Cl2–MeOH) to give compound 20 as a white amorphous solid (1.00 g, 1.14 mmol, 93%). TLC (10:1 CH2Cl2–MeOH): Rf 0.5; mp 234–236 °C; [α]D −36.7 (c 0.5, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 7.53–7.24 (m, 15 H, ArH), 7.21 (d, 2 H, ArH), 7.04 (d, 2 H, ArH), 6.82 (dd, 4 H, ArH), 6.67 (d, 1 H, NH), 5.52 (s, 1 H, PhCH), 5.16 (d, 1 H, ArCH2O), 5.11 (d, 1 H, ArCH2O), 4.90 (d, 1 H, H-1I, J1, 2 = 7.8 Hz), 4.89 (d, 1 H, ArCH2O), 4.60 (d, 1 H, ArCH2O), 4.48 (s, 2 H, ArCH2O), 4.29–4.24 (m, 1 H, H-6I), 4.16–4.13 (dd, 1 H, H-6II), 3.90–3.87 (m, 1 H, H-5I), 3.79 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 3.70–3.67 (m, 2 H, H-2I, H-3II), 3.64–3.60 (m, 1 H, H-6I), 3.54 (dd, 1 H, H-3I), 3.47–3.34 (m, 5 H, H-6II, H-5II, H-1II, H-2II, H-4II), 2.04–1.98 (m, 1 H, H-4I), 1.81–1.76 (m, 1 H, CH2), 1.57 (s, 3 H, COCH3), 1.39–1.36 (m, 1 H, CH2); 13C NMR (62.5 MHz, CDCl3): δ 171.4, 159.2, 155.3, 151.3, 137.9, 137.2, 136.8, 129.8, 129.4, 129.3, 129.1, 129.0, 128.8, 128.5, 128.3, 128.2, 127.9, 126.3, 118.4, 114.5, 113.7, 102.9, 101.7, 83.1, 83.0, 82.7, 76.8, 74.5, 74.0, 73.2, 70.1, 69.1, 69.0, 64.8, 55.6, 55.2, 53.5, 41.6, 28.9, 22.5; ESIMS (positive-ion): m/z 876.3 [M + H], 893.3 [M + NH4], 898.2 [M + Na], 914.3 [M + K]. Anal. Calcd for C51H57NO12 (876.01): C, 69.93; H, 6.56; N, 1.60. Found: C, 69.86; H, 6.66; N, 1.67.

3.18 p-Methoxyphenyl C-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1→4a)-4a-carba-β-D-glucopyranosiduronic acid (21)

To a solution of compound 20 (505 mg, 0.58 mmol) in CH2Cl2 (20 mL) and H2O (1 mL) was added DDQ (308 mg, 1.1 equiv). The reaction was stirred at room temperature for 1.5 h, after which time the mixture was washed with satd NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried with anhyd Na2SO4 and evaporated to dryness. To a solution of the resulting white solid in CH2Cl2 (6 mL) and H2O (1 mL) were added sequentially NaBr (2.66 mg), Bu4NBr (2.66 mg), TEMPO (2.66 mg), a satd NaHCO3 solution (1.33 mL), and a 5% solution of NaOCl (1.73 mL) at 0 °C. After 2 h the reaction was quenched with MeOH (1.5 mL), neutralized with 1 M HCl, and extracted with CH2Cl2. The combined organic extracts were dried with anhyd MgSO4 and then concentrated to dryness. To a solution of the residue in 20:1 EtOAc and MeOH (10 mL) was added Pd(OH)2/C (20%, 50 mg), and the reaction was stirred in an H2 atmosphere (1 atm) for 60 h at room temperature. At the end of this time the reaction mixture was filtered through Celite and concentrated to dryness. The residue was submitted to silica gel chromatography (20:1:1 CH2Cl2–MeOH–AcOH) to give compound 21 as a white solid (61 mg, 0.12 mmol, 21%). 1H NMR (600 MHz, CD3OD): δ 7.07 (d, 2 H, ArH), 6.82 (d, 2 H, ArH), 4.73 (d, 1 H, H-1I, J1, 2 = 7.8 Hz), 3.90–3.82 (m, 2 H, H-6II, H-5I), 3.73 (s, 3 H, OCH3), 3.61–3.56 (m, 1 H, H-6II), 3.56–3.50 (dd, 1 H, H-4II), 3.46 (t, 1 H, H-2I), 3.40–3.27 (m, 4 H, H-3I, H-2II, H-5II, H-3II), 3.26–3.21(m, 1 H, H-1II), 2.03–1.92 (m, 1 H, H-4I), 1.99 (s, 3 H, COCH3), 1.81–1.72 (m, 1 H, CH2), 1.68–1.56 (m, 1 H, CH2). 13C NMR (62.5 MHz, CD3OD): δ 174.3, 156.5, 153.0, 119.4, 115.5, 103.5, 81.3, 77.5, 77.2, 76.1, 75.1, 72.3, 63.0, 57.2, 56.2, 43.0, 30.0, 23.1. ESIMS (negative-ion): Calcd for C22H31NO12 501.1846; Found: 501.1840 [M]; 500.1773 ([M – H] (calcd 500.1768).

Supplementary Material

01

Supplementary data

Crystallographic data, excluding structure factors, have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication with CCDC No. 646876. Copies of the data can be obtained free of charge on application with the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax +44-1223-336-033; e-mail: deposit@ccdc.cam.ac.uk). Supplementary data (NMR spectra for all compounds, mass spectrum for 21) for this paper are available online at doi: xxxxxxxx.

Footnotes

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Associated Data

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Supplementary Materials

01

Supplementary data

Crystallographic data, excluding structure factors, have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication with CCDC No. 646876. Copies of the data can be obtained free of charge on application with the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax +44-1223-336-033; e-mail: deposit@ccdc.cam.ac.uk). Supplementary data (NMR spectra for all compounds, mass spectrum for 21) for this paper are available online at doi: xxxxxxxx.

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