MOP and EE Protecting Groups in Synthesis of α- or β-Naphthyl-C-Glycosides from Glycals.

The development of effective protection strategies is essential in the synthesis of complex carbohydrates and glycomimetics. This article describes a versatile four-stage protocol for the synthesis of α- or β-aryl-C-glycosides from unprotected d-glycals using two acetal protecting groups, ethoxyethyl and methoxypropyl, which are stable under harsh basic conditions and convenient for the C-1 metalation of glycals. Their stability was investigated in subsequent cross-coupling reactions with 1-iodonaphthalene followed by oxidative/reductive transformations to naphthyl-C-glycosides.

Introduction

Recent development of glycobiology[1] has increased the need for the synthesis of structurally defined carbohydrates and their analogues. Among them, C-glycosides[2] are important analogues of carbohydrates, which exhibit high stability toward chemical and enzymatic hydrolysis and include many bioactive natural products[3] and commercial drugs.[4] Because of their stability and broad range of biological activities, access to C-glycosides is of great importance.

Several common synthetic approaches,[2e,2f,3b] including methods using cationic, anionic, or radical sugar species, as well as methods using de novo construction of the sugar or aromatic moiety for the synthesis of aryl-C-glycoside scaffolds, were used in the past. However, these methods are often hard to carry out stereoselectively and are not universal across sugar substrates. Therefore, alternative approaches including transition-metal-mediated cross-coupling reactions[2e,2f,3b] (Heck, Suzuki, Stille, and Negishi-type reactions) have been developed for the synthesis of C-glycosides employing metalated glycals and aromatic electrophiles as key starting materials. Nevertheless, the preparation of 1-metalated glycals usually relies upon the lithiation of the C-1 position of protected glycals by a strong base. Lithiation conditions are harsh, and some common protecting groups such as benzyl[5a] or tert-butyldimethylsilyl (TBS)[5b,5c] ethers compete for lithiation. Several protecting groups that survive the metalation of glycals by t-BuLi have been gradually developed (triisopropylsilyl,[6] di-tert-butylsilylene,[6b,6c,7] TBS,[5,6c,8]tert-butyldiphenylsilyl,[5a,9] triethylsiyl,[10] methoxymethyl (MOM),[7,11] and isopropylidene[11,12]), but they all suffer from one or more disadvantages, which precludes their general applicability (Figure ). These include, for example, the requirement of 3–6 equiv of t-BuLi for glycal deprotonation, presumably due to complexation effects. Besides that, the deprotection of silyl ethers with tetra-n-butylammonium fluoride is usually complicated by problems in separating the product from tetrabutylammonium salts. Moreover, silyl ethers are not universal protecting groups across pyranoid substrates (d-glucal, d-galactal, etc.), which makes it necessary to discover the efficient combination of protecting groups for each application. Next, silyl groups are quite expensive for multigram synthesis and the combination of MOM and isopropylidene groups requires multistep protection. Finally, silyl ether-protected cross-coupling products are often inconvenient for further transformation to α- or β-C-glycosides, presumably due to the bulkiness of the protecting groups and for ring-strain reasons.[6b,13] In view of the aforementioned, it is obvious that the development of alternative protection strategies would facilitate progress in the synthesis of aryl-C-glycosides from glycals.

Figure 1

Protecting groups that survive metalation of d-glucal and d-galactal by t-BuLi.

Results and Discussion

We have found that the utilization of rarely used ethoxyethyl[14] (EE) or methoxypropyl[15] (MOP) acetal protecting groups (Figure ) offers several advantages. Although these protecting groups have been used for orthogonal protection in carbohydrate chemistry, their use for glycals has not yet been described. Specifically, EE and MOP protecting groups are cheap and enable mild conditions for their introduction and removal. Nevertheless, they are stable under strong basic conditions. This article suggests that EE and MOP can be universal protecting groups across pyranoid glycals and convenient for further transformation of cross-coupling products to the corresponding α- or β-C-glycosides.

First, we investigated the reaction conditions for the preparation of fully protected glycals 2a–b and 3a–b. Specifically, we investigated commercially available d-glucal 1a and d-galactal 1b, which reacted under standard conditions with 2-methoxypropene[16] or ethyl vinyl ether[17] in the presence of pyridinium tosylate, yielding fully protected glycals 2a–b and 3a–b in 79–95% yields. Remarkably, the reaction of 2-methoxypropene with cis-1,2-diol such as d-galactal 1b leads to the formation of isopropylidene acetal on the secondary hydroxyls (3a), whereas the reaction with trans-1,2-diol such as d-glucal 1a introduces MOP groups selectively. In the reaction with ethyl vinyl ether, no such selectivity has been observed and per-EE products have been obtained in both cases (Scheme ). Surprisingly, the subsequent reaction of 3a with t-BuLi formed racemic open-chain enone 4 in 81% yield (the enantiomeric composition was determined by derivatization by (S)-Mosher’s acid and NMR analysis (see Supporting Information (SI) Chapter 2, Scheme )).

Scheme 1

Preparation of MOP- and EE-Protected d-Glycals 2a–b and 3a–b,

2-Methoxypropene, Py·TsOH, dichloromethane (DCM), or dimethylformamide (DMF); 0–25 °C; 1–12 h.

Ethyl vinyl ether, Py·TsOH, DCM; 0–25 °C; 1.5–12 h.

Scheme 2

Reaction of 3a with t-BuLi

Next, since the protection of glycals with ethyl vinyl ether produced fully protected glycals as a mixture of eight possible diastereoisomers, it was crucial to find a simple and efficient method to prove the structure of these compounds by NMR. Therefore, we first attempted to deprotect EE glycals 2b and 3b using 5% (v/v) trifluoroacetic acid (TFA) in MeOH-d4 directly in the NMR tube; however, this method suffered from partial decomposition of substrates. Fortunately, switching the 5% TFA to 10% (v/v) CD3COOD in MeOH-d4 and heating the mixture to 50 °C for 0.75–2 h in the NMR tube enabled the complete cleavage of EE groups. Using this in situ deprotection protocol, we were able to confirm the structure of EE-protected compounds by NMR (for details, see the SI, Chapter 4).

Since our interest was focused on the synthesis of C-glycosides using Suzuki and Stille reactions, fully protected d-glucals 2a–b and d-galactal 3b were converted into 1-lithiated intermediates by treatment with t-BuLi and then reacted with Bu3SnCl or iPrOBPin, followed by quenching with water. In all cases (Table , entries 1–6), the reaction proceeded cleanly, providing the desired compounds 5a–b, 6a–b, 7, and 8 in almost quantitative yields (Table ). The deprotonation of vinylic C1–H by t-BuLi usually requires 3–6 equiv of base.[18] Therefore, it was important to find the optimal lithiation conditions for the preparation of organometalated glycals with EE and MOP protecting groups. We performed a series of lithiation experiments on protected d-glucals 2a–b with t-BuLi, followed by deuteration with D2O. In both cases, direct deprotonations of C1–H required 3.5 equiv of t-BuLi (see the SI, Chapter 1). No evidence of competing deprotonation on MOP or EE protecting groups was observed.

Table 1

Preparation of Metalated Glycals 5a–b or 6a–b and 7–8

entry	derivative	PG	E+	E	product, yield (%)
1	d-glucal, 2a	MOP	iPrOBPin	BPin	5a, (94)a
2	d-glucal, 2a	MOP	Bu3SnCl	SnBu3	6a, (93)b
3	d-glucal, 2b	EE	iPrOBPin	BPin	5b, (81)a
4	d-glucal, 2b	EE	Bu3SnCl	SnBu3	6b, (90)b
5	d-galactal, 3b	EE	iPrOBPin	BPin	7, (90)a
6	d-galactal, 3b	EE	Bu3SnCl	SnBu3	8, (69)b

Crude product.

Isolated yield.

In our systematic study of EE and MOP protecting groups, we also tested the performance of the substituted glycals 5a–b, 6a–b, 7, and 8 in cross-coupling reactions. As model reactions, we investigated Suzuki–Miyaura and Stille reactions with 1-iodonaphthalene (Table ). The Suzuki–Miyaura reaction of 1-pinacolboronates 5a, 5b, and 7 was performed under our previously published conditions[6c] (conditions A). In all cases, the expected cross-coupling products 9a, 9b, and 10 were obtained in high yields of 72–93% (Table , entries 1, 3, and 5).

Table 2

Preparation of Protected 1-Naphthyl-C-glycals 9a–b and 10

entry	derivative	PG	E	conditions	product, yield (%)a
1	5a	MOP	BPin	A	9a, (86)
2	6a	MOP	SnBu3	B	9a, (76)
3	5b	EE	BPin	A	9b, (79)
4	6b	EE	SnBu3	B	9b, (93)
5	7	EE	BPin	A	10, (72)
6	8	EE	SnBu3	B	10, (87)
7	2b	EE	H	C	9b, (43)
8	2b	EE	H	D	9b, (20)

Isolated yield; reaction conditions: (A) Pd(PPh3)2Cl2, 1,2-dimethoxyethane (DME), Na2CO3, 80 °C; (B) Pd(PPh3)4, toluene, 120 °C; (C) (1) t-BuLi, InCl3, tetrahydrofuran (THF), (2) Pd(Ph3P)2Cl2, reflux; (D) (1) t-BuLi, ZnCl2, THF, (2) Pd(Ph3P)4.

The Stille reaction was carried out under standard conditions.[19] Specifically, Pd(PPh3)4 was used as a catalyst and the reaction was heated at 120 °C for 12 h in toluene as the solvent. In these cases, the corresponding 1-stannylglycals 6a, 6b, and 8 were again converted to naphthyl-C-glycals 9a, 9b, and 10 in high yields of 72–86% (Table , entries 2, 4, and 6). Finally, we decided to prove the compatibility of the EE protecting groups of 2b in Negishi-type[20] and In-mediated[6a] coupling reactions with 1-iodonaphthalene (Table , entries 7 and 8). In both cases, the cross-coupling product 9b was isolated in 20–43% yields. These low yields were probably caused by the instability of EE protecting groups in the presence of zinc and indium Lewis acids after quenching with water.

In the next step, we investigated whether these protected cross-coupling products 9a, 9b, and 10 with a reactive endocyclic double bond can be deprotected without damaging the glycal double bond. To our surprise, the fully protected gluco derivative 9a with MOP protecting groups was converted to free enol ether 12 by stirring in the mixture of 1% acetic acid and THF overnight. Similarly, the free cross-coupling product 12 was achieved after the treatment of the EE-protected derivative 9b with a mixture of 20% aqueous acetic acid and THF (Scheme ).

Scheme 3

Transformations of the Glucal Double Bond to α- or β-Aryl-C-glucosides 11 or 13,

1% AcOH/THF (1:1).

20% AcOH/THF (1:1).

Since the control of the stereochemistry of C-glycosides is essential for the preparation of the desired stereoisomer, it was necessary to confirm that the EE- and MOP-protected derivatives 9a–b are stable during stereoselective transformations,[6c,21] leading to α- or β-aryl-C-glycosides. Compounds 9a and 9b with MOP and EE protecting groups served as model compounds. It was found that hydroboration of the double bond in 9a and 9b with the BH3·THF complex followed by oxidation with alkaline hydrogen peroxide and deprotection with diluted acetic acid in THF gave directly aryl-β-C-glycoside 11 as a single stereoisomer in high overall yields (Scheme ). The opposite anomer, naphthyl-α-C-glycoside 13, was obtained by epoxidation of the double bond with dimethyldioxirane (DMDO), followed by the cleavage of the formed epoxide ring with lithiumtriethylborohydride (LiBEt3H). The stereochemical outcome of these transformations is consistent with results previously reported on the substituted glucal unit bearing benzyl ether[21,22b] or silyl ether[6b,6c] protection. The reactions mentioned above were also carried out with the free cross-coupling product 12; after hydroboration, β-C-glycoside 11 was obtained in high 84% yield (Scheme ). On the other hand, the transformation of 12 to α-anomer 13 failed.

Finally, the protected 1-naphthylgalactal 10 was subjected to subsequent stereoselective transformation. As we assumed, hydroboration of derivative 10 with the BH3.THF complex and deprotection with a mixture of 20% aqueous acetic acid and THF provided free aryl-β-C-glycoside 14 in 69% overall yield (Scheme ).

Scheme 4

Preparation of Aryl-C-galactosides 14 and 16,

10% AcOH in MeOH.

20% AcOH/MeOH (1:1).

Additionally, we also tested the Werz protocol,[22] which was supposed to lead to β-aryl-C-galactoside 14 using DIBAL-H and LiAlH4 for the opening of the epoxide ring. In both of these cases, the expected derivative 14 was obtained after deprotection. The free aryl-β-C-glycoside 14 was also obtained by the hydroboration of the free cross-coupling product 15. As before, we decided to transform the coupled product 10 to the opposite naphthyl-α-C-glycoside. Although the product of the DMDO epoxidation of derivative 10 was confirmed, the subsequent opening of the formed epoxide ring with lithiumtriethylborohydride failed and derivative 16 with an opened galactose ring was isolated under the standard deprotection conditions. Even though various attempts to modify reaction conditions, workup procedures, and hydride sources were made, the desired α-C-galactoside with a closed sugar ring was not obtained (Scheme ).

Conclusions

In conclusion, we have introduced ethoxyethyl and methoxypropyl acetals as effective protecting groups for a straightforward and stereoselective synthesis of α- or β-naphthyl-C-glycosides. We have established that uniformly EE- and MOP-protected d-glycals are compatible with harsh basic conditions and are universal protecting groups for both d-glucal and d-galactal. Their stability was also proven in the subsequent Pd-catalyzed cross-coupling reactions and the ensuing oxidative−reductive transformation. We have also found that the complete removal of all EE or MOP groups is high yielding and effective under mild acidic conditions. We assume that this work can be extended to the synthesis of a wide range of aryl-C-glycosides.

Experimental Section

General Experiment

All reactions using anhydrous conditions were performed using flame-dried apparatus under an atmosphere of argon. Standard inert techniques were used in handling all air and moisture sensitive reagents. Anhydrous THF and CH2Cl2 were obtained by distillation using CaH2 as a drying agent. Other anhydrous solvents were used directly as received from commercial suppliers. All other solvents were used as supplied (Analytical or high-performance liquid chromatography grade), without prior purification. Reagents were purchased from various commercial suppliers and used as supplied, unless otherwise indicated. Distilled water was used for chemical reactions. “Hexane” refers to the fraction of hexane boiling in the range 68–72 °C. Brine refers to a saturated solution of sodium chloride. Anhydrous magnesium sulfate (MgSO4) was used as a drying agent after reaction workup, as indicated.

Solution of DMDO in acetone was obtained according to a literature procedure,[23] stored at −20 °C under argon atmosphere, and used in 2 days after distillation at the latest. Column chromatography was carried out using Material Harvest silica gel (pore size 60 Å, mesh 230–400 (40–63 μm)). Thin-layer chromatography (TLC) was carried out using Merck TLC Silica gel 60 F254 aluminum plates. Visualization of the TLC plates was achieved using a UV lamp Spektroline-ENF-240/F (Spectronics Corporation Westbury) (λmax = 254 nm) and/or by spraying with cerium(IV) sulfate solution (1% in 10% H2SO4). Mobile phases are reported in relative composition (e.g., hexane/EtOAc 1:1 v/v). All 1H and 13C NMR spectra were recorded using a Bruker Avance III 400 (401.0 MHz for 1H; 100.8 MHz for 13C) or Bruker Avance III 500 (500.0 MHz for 1H; 125.7 MHz for 13C) spectrometers. 1H and 13C resonances were fully assigned using H,H-COSY, H,C-HSQC, and H,C-HMBC techniques. All chemical shifts are quoted on the δ scale in ppm and referenced using residual 1H solvent signal in 1H NMR spectra (δ(CHCl3) = 7.26 ppm, δ(CD2HOD) = 3.31 ppm, δ(CD2HCOCD3) = 2.05 ppm, and δ(CD2HSOCD3) = 2.50 ppm) and 13C solvent signal in 13C NMR spectra (δ(CDCl3) = 77.0 ppm, δ(CD3OD) = 49.0 ppm, δ(CD3COCD3) = 29.8 ppm, and δ((CD3)2SO) = 29.7 ppm). Coupling constant (J) is reported in Hz with the following splitting abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. IR spectra were recorded on a Thermo Scientific Nicolet 6700 spectrometer. Absorption maxima (υmax) are reported in wavenumbers (cm–1).

High-resolution mass spectra were measured on a LTQ Orbitrap XL (Thermo Fisher Scientific) spectrometer using electrospray ionization technique. Nominal and exact m/z values are reported in Daltons.

Optical rotations were measured on an AUTOPOL IV (Rudolph Research Analytical,) polarimeter at temperature 20 °C and 589 nm sodium line with a path length l of 1.0 dm. Concentration c is given in g/100 mL. Specific rotation values are reported as a unitless number with implied units of (deg mL)/(g dm). Melting points (mp) were recorded on a Kofler hot-stage microscope and are reported uncorrected in degrees Celsius (°C).

1,5-Anhydro-3,4,6-tri-O-(2-methoxypropan-2-yl)-d-arabino-hex-1-enitol (2a)

To a stirred solution of d-glucal 1a (5 g, 34.21 mmol, 1 equiv) in anhydrous CH2Cl2 (50 mL) were added 2-methoxypropene (19.66 mL, 205.28 mmol, 6 equiv) and Pyr·TsOH (860 mg, 3.42 mmol, 0.10 equiv) at 0 °C under an argon atmosphere. The resulting heterogeneous reaction mixture was stirred for 3 h at the same temperature, during which it turned homogeneous. Et3N (5 mL) was added, and the resulting mixture was stirred for another 20 min at room temperature (RT) and then diluted with CH2Cl2 (300 mL). The organic layer was washed with H2O (3 × 200 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 15:1, 1% Et3N) to give MOP-glucal 2a (10.46 g, 84%) as a colorless oil: R = 0.47 (hexane/EtOAc 4:1); [α]D20 −28.6 (c 0.3, CHCl3); 1H NMR (401.0 MHz, DMSO-d6): 1.24, 1.245, 1.25, 1.29, 1.30 (5 × s, 18H, (CH3)2C); 3.09, 3.15 (2 × s, 9H, CH3O); 3.47 (dd, 1H, J6b,6a = 10.7, J6b,5 = 4.3, H-6b); 3.67 (dd, 1H, J6a,6b = 10.7, J6a,5 = 8.2, H-6a); 3.80 (dt, 1H, J3,2 = 5.3, J3,4 = J3,5 = 2.0, H-3); 3.94 (td, 1H, J4,3 = J4,5 = 2.0, J4,2 = 1.6, H-4); 4.14 (ddt, 1H, J5,6a = 8.2, J5,6b = 4.3, J5,4 = 2.0, H-5); 4.75 (ddd, 1H, J2,1 = 6.4, J2,3 = 5.3, J2,4 = 1.6, H-2); 6.38 (d, 1H, J1,2 = 6.4, H-1); 13C NMR (100.8 MHz, DMSO-d6): 24.3, 24.5, 25.0, 25.05, 25.08, 25.2 ((CH3)2C); 47.8, 48.7, 49.0 (CH3O); 58.9 (CH2-6); 61.6 (CH-3); 67.2 (CH-4); 76.9 (CH-5); 99.5, 100.3 ((CH3)2C); 100.4 (CH-2); 101.0 ((CH3)2C); 143.5 (CH-1); IR (CHCl3): νmax 3069, 2996, 2945, 2832, 1647, 1464, 1382, 1373, 1250, 1184, 1151, 1097, 1070, 1044, 1027, 1014, 909, 864, 839, 572, 528, 505 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C18H34O7Na 385.2197, found 385.2198.

1,5-Anhydro-3,4,6-tri-O-(ethoxyethyl)-d-arabino-hex-1-enitol (2b)

To a stirred solution of d-glucal 1a (2 g, 13.69 mmol, 1 equiv) in anhydrous CH2Cl2 (30 mL) were added ethyl vinyl ether (7.86 mL, 82.11 mmol, 6 equiv) and Pyr·TsOH (344 mg, 1.37 mmol, 0.10 equiv) at 0 °C under an argon atmosphere. The resulting heterogeneous reaction mixture was stirred for 20 h at room temperature, during which it turned homogeneous. The resulting mixture was diluted with CH2Cl2 (250 mL). The organic layer was washed with H2O (3 × 200 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 6:1 to 3:1) to give EE-glucal 2b (4.7 g, 95%) as a colorless oil: R = 0.53 (hexane/EtOAc 3:1); 1H NMR (401.0 MHz, CDCl3): 1.16–1.21 (m, 9H, CHCH2O); 1.28–1.34 (m, 9H, CHCH); 3.43–3.94 (m, 8H, H-4,6, CH3CHO); 4.03–4.20 (m, 2H, H-3,5); 4.69–5.00 (m, 4H, H-2, CH3CH); 6.35–6.43 (m, 1H, H-1); 13C NMR (100.8 MHz, CDCl3): 15.19, 15.22, 15.24, 15.27, 15.28, 15.30, 15.31 (CH3CH2O); 19.73, 19.76, 19.77, 19.78, 19.80, 19.83, 20.30, 20.31, 20.33, 20.34, 20.42, 20.44, 20.51, 20.55, 20.57, 20.58, 20.60 (CH3CH); 59.84, 59.87, 59.88, 60.41, 60.43, 60.57, 60.81, 60.84, 60.86, 60.97, 61.03, 61.06, 61.18, 61.26, 61.27, 61.29, 61.35, 61.40, 61.54, 61.79 (CH3CH2O); 62.68, 63.14, 63.16, 63.22, 63.31, 63.86, 63.89 (CH2-6); 67.47, 67.80, 69.18, 69.32, 70.26, 70.63, 70.73, 70.85, 71.12, 71.14, 71.18, 71.37, 71.38, 72.22, 72.49 (CH-3,4); 76.38, 76.41, 76.47, 76.81, 76.84, 76.98 (CH-5); 97.31, 97.32, 97.50, 98.63, 98.83, 99.05, 99.12, 99.43, 99.45, 99.56, 99.58, 99.63, 99.68, 99.73, 99.77, 99.82, 99.85, 99.93, 99.95, 100.05, 100.11, 100.17, 100.28, 100.35, 100.52, 100.79, 100.86, 100.93 (CH-2, CH3CH); 144.00, 144.09, 144.24 (CH-1); IR (CHCl3): νmax 3070, 2981, 2933, 2898, 2886, 1948, 1445, 1383, 1341, 1239, 1131, 1096, 1084, 1055, 971, 949, 930, 877, 844, 819 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C18H34O7Na 385.2197, found 385.2198.

1,5-Anhydro-2-deoxy-3,4-O-isopropylidene-6-O-(2-methoxypropan-2-yl)-d-lyxo-hex-1-enitol (3a)

To a stirred solution of d-galactal 1b (2 g, 13.69 mmol, 1 equiv) in anhydrous DMF (15 mL) were added 2-methoxypropene (3.93 mL, 41.06 mmol, 3 equiv) and Pyr·TsOH (172 mg, 684 μmol, 0.05 equiv) at 0 °C under an argon atmosphere. The resulting mixture was stirred for 1 h at the same temperature, and then another portion of 2-methoxypropene (2.62 mL, 27.37 mmol, 2 equiv) was added. The reaction mixture was stirred for another 2 h at 0 °C. Et3N (3 mL) was added, and the resulting mixture was diluted with EtOAc (200 mL) and then washed with H2O (300 mL). The aqueous phase was washed with EtOAc (3 × 150 mL), and the combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 15:1 to 10:1, 1% Et3N) to give product 3a (2.78 g, 79%) as a pale yellow oil: R = 0.65 (hexane/EtOAc 3:1); [α]D20 −3.2 (c 0.4, CHCl3); 1H NMR (401.0 MHz, DMSO-d6): 1.26 (q, 3H, 4J = 0.6, (CH3)2C); 1.27 (s, 6H, (CH3)2C); 1.34 (q, 3H, 4J = 0.6, (CH3)2C); 3.11 (s, 3H, CH3O); 3.50–3.62 (m, 2H, H-6); 3.99 (ddd, 1H, J5,6 = 7.0, 5.7, J5,4 = 1.5, H-5); 4.29 (dtd, 1H, J4,3 = 6.1, J4,2 = J4,5 = 1.5, J4,1 = 0.4, H-4); 4.63 (dd, 1H, J3,4 = 6.1, J3,2 = 2.9, H-3); 4.71 (ddd, 1H, J2,1 = 6.2, J2,3 = 2.9, J2,4 = 1.5, H-2); 6.41 (dd, 1H, J1,2 = 6.2, J1,4 = 0.4, H-1); 13C NMR (100.8 MHz, DMSO-d6): 24.39, 24.40, 26.9, 28.3 ((CH3)2C); 60.7 (CH2-6); 68.1 (CH-3); 72.3 (CH-4); 73.7 (CH-5); 99.8 ((CH3)2C); 102.8 (CH-2); 109.6 ((CH3)2C); 144.5 (CH-1); IR (CHCl3): νmax 3442, 3065, 2989, 2940, 2892, 2831, 1727, 1648, 1459, 1437, 1380, 1371, 1260, 1239, 1214, 1185, 1164, 1153, 1126, 1088, 1068, 1054, 1032, 993, 868, 843, 755, 720, 676, 661, 597, 560, 536, 500 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C13H22O5Na 281.1359, found 281.1360.

1,5-Anhydro-2-deoxy-3,4,6-tri-O-(ethoxyethyl)-d-lyxo-hex-1-enitol (3b)

To a stirred solution of d-galactal 1a (5 g, 34.21 mmol, 1 equiv) in anhydrous CH2Cl2 (40 mL) were added ethyl vinyl ether (26.21 mL, 273.71 mmol, 8 equiv) and Pyr·TsOH (860 mg, 3.42 mmol, 0.10 equiv) at 0 °C under an argon atmosphere. The resulting heterogeneous reaction mixture was stirred for 20 h at room temperature, during which it turned homogeneous. The resulting mixture was diluted with CH2Cl2 (200 mL). The organic layer was washed with H2O (3 × 150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 10:1 to 4:1) to give EE-galactal 3b (10.75 g, 87%) as a colorless oil: R = 0.41 (hexane/EtOAc 4:1); 1H NMR (500.0 MHz, CDCl3): 1.16–1.21 (m, 9H, CH3CH2O); 1.29–1.36 (m, 9H, CH3CH); 3.43–4.00 (m, 8H, H-6, CH3CH2O); 4.00–4.38 (m, 3H, H-3,4,5); 4.68–4.87 (m, 3H, CH3CH); 4.88–5.06 (m, 1H, H-2); 6.29–6.37 (m, 1H, H-1); 13C NMR (125.7 MHz, CDCl3): 15.22, 15.23, 15.24, 15.25, 15.27, 15.28, 15.31, 15.32, 15.34, 15.36, 15.39, 15.41 (CH3CH2O); 19.81, 19.82, 19.84, 19.88, 19.90, 19.94, 19.99, 20.00, 20.01, 20.06, 20.08, 20.13, 20.15, 20.17, 20.24, 20.29, 20.37, 20.39, 20.41, 20.42 (CH3CH); 59.48, 59.49, 59.68, 59.80, 59.84, 60.01, 60.17, 60.57, 60.67, 60.69, 61.03, 61.06, 61.12, 61.19, 61.21, 61.33, 61.34 (CH3CH2O); 61.62, 61.74, 61.82, 62.00, 62.58, 62.63, 63.66, 64.18 (CH2-6); 66.71, 68.04, 68.34, 68.52, 69.56, 69.67, 69.93 (CH-3,4); 75.61, 75.77, 75.82, 76.06, 76.34, 76.40, 76.57, 76.70 (CH-5); 98.13, 98.15, 99.59, 99.63, 99.73, 99.70, 99.73, 99.76, 99.80, 99.91, 99.93, 99.97, 100.01, 100.07, 100.11, 100.16, 100.21, 100.31, 100.87, 100.92, 100.97, 100.98 (CH-2, CH3CH); 143.64, 143.80, 143.81, 143.87, 144.04, 144.05 (CH-1); IR (CHCl3): νmax 3069, 2980, 2933, 2898, 1644, 1484, 1454, 1445, 1394, 1383, 1340, 1298, 1254, 1235, 1134, 1094, 1082, 1055, 1030, 950, 931, 880, 844, 819, 698; HRMS (ESI) m/z [M + Na]+ calcd for C18H34O7Na 385.2197, found 385.2197.

rac-(E)-6-Hydroxy-1-((2-methoxypropan-2-yl)oxy)-7,7-dimethyloct-2-en-4-one (4)

To a stirred solution of compound 3a (0.5 g, 1.94 mmol, 1 equiv) in anhydrous THF (10 mL) was added t-BuLi (3.99 mL, 6.77 mmol, 3.5 equiv, 1.7 M in pentane) dropwise over 15 min at −78 °C under an argon atmosphere. The reaction mixture was stirred for 10 min at −78 °C and then for 2 h at 0 °C. After warming to RT, Et3N (2 mL) was added and the resulting mixture was diluted with EtOAc (100 mL). The organic phase was washed with sat. aq NaHCO3 (200 mL) and H2O (2 × 200 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 8:1 to 5:1, 1% Et3N) to give enone 4 (854 mg, 81%) as racemic mixture of enantiomers: R = 0.44 (hexane/EtOAc 3:1); [α]D20 9.4 (c 0.3, CHCl3); 1H NMR (500.0 MHz, DMSO-d6): 0.83 (s, 9H, ((CH3)3)C); 1.29 (s, 6H, (CH3)2C); 2.52 (dd, 1H, 2J = 15.3, 3J = 2.7, CHaHCHOH); 2.60 (dd, 1H, 2J = 15.3, 3J = 9.5, CHHbCHOH); 3.08 (s, 3H, CH3O); 3.60 (ddd, 1H, 3J = 9.5, 5.9, 2.8, CH2CHOH); 4.09 (dd, 2H, 3J = 4.3, 4J = 2.1, CH–CH=CH); 4.54 (d, 1H, 3J = 5.9, CH2CHOH); 6.32 (dt, 1H, 3J = 16.0, 4J = 2.1, CH2–CH=CH); 6.84 (dt, 1H, 3J = 16.0, 4.3, CH2–CH=CH); 13C NMR (125.7 MHz, DMSO-d6): 24.4 ((CH3)3C); 26.0 ((CH3)2C); 35.0 ((CH3)3C); 42.9 (CH2CHOH); 48.2 (CH3O); 59.7 (CH2–CH=CH); 74.5 (CH2CHOH); 100.1 ((CH3)2C); 129.2 (CH2–CH=CH); 143.7 (CH2–CH=CH); 199.8 (CO); IR (CHCl3): νmax 3054, 2989, 2956, 2909, 2879, 2873, 1690, 1665, 1634, 1480, 1466, 1381, 1368, 1292, 1192, 1065, 969 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C14H26O4Na 281.1723, found 281.1723.

(1,5-Anhydro-2-deoxy-3,4,6-tri-O-(2-methoxypropan-2-yl)-d-arabino-hex-1-enitolyl)boronic Acid Pinacol Ester (5a)

To a stirred solution of MOP-glucal 2a (1 g, 2.76 mmol, 1 equiv) in anhydrous THF (20 mL) was added t-BuLi (5.68 mL, 9.66 mmol, 3.5 equiv, 1.7 M in pentane) dropwise over 10 min at −78 °C under argon atmosphere. The reaction mixture was stirred for 10 min at −78 °C and then for 1 h at 0 °C. Subsequently, the resulting mixture was again cooled to −78 °C and iPrOBpin (2.25 mL, 11.04 mmol, 4 equiv) was added dropwise over 10 min. The mixture was allowed to warm gradually to RT over 3 h and stirred overnight. The reaction was quenched by the addition of H2O (5 mL) and extracted between EtOAc (200 mL) and H2O (200 mL). The organic layer was washed with H2O (2 × 200 mL), dried over MgSO4, filtered, and concentrated in vacuo to give crude product 5a (1.27 g, 94%) as a pale yellow oil, which was used without further purification for the next step: [α]D20 −17.9 (c 0.3, CHCl3); IR (CHCl3): νmax 2995, 2985, 2957, 2833, 1644, 1468, 1447, 1402, 1391, 1381, 1373, 1330, 1235, 1144, 1144, 1099, 1099, 1079, 1049, 1027, 966, 866 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C24H45O9BNa 511.3049, found 511.3051.

(1,5-Anhydro-2-deoxy-3,4,6-tri-O-(ethoxyethyl)-d-arabino-hex-1-enitolyl)boronic Acid Pinacol Ester (5b)

To a stirred solution of EE-glucal 2b (3 g, 8.28 mmol, 1 equiv) in anhydrous THF (20 mL) was added t-BuLi (17.04 mL, 28.97 mmol, 3.5 equiv, 1.7 M in pentane) dropwise over 10 min at −78 °C under argon atmosphere. The reaction mixture was stirred for 10 min at −78 °C and then for 1 h at 0 °C. Subsequently, the resulting mixture was again cooled to −78 °C and iPrOBpin (6.75 mL, 33.11 mmol, 4 equiv) was added dropwise over 5 min. The mixture was allowed to warm gradually to RT over 3 h and stirred overnight. The reaction was quenched by the addition of H2O (5 mL) and extracted between EtOAc (150 mL) and H2O (100 mL). The organic layer was washed with H2O (2 × 100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give crude product 5b (3.26 g, 81%) as a pale yellow oil, which was used without further purification for the next step: IR (CHCl3): νmax 3614, 3574, 2982, 2935, 1732, 1642, 1480, 1405, 1396, 1382, 1374, 1340, 1141, 1135, 1095, 1084, 1055, 1055, 962, 861 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C24H45O9BNa 511.3049, found 511.3055.

1,5-Anhydro-2-deoxy-3,4,6-tri-O-(2-methoxypropan-2-yl)-1-(tri-n-butylstannyl)-d-arabino-hex-1-enitol (6a)

To a stirred solution of MOP-glucal 2a (3 g, 8.28 mmol, 1 equiv) in anhydrous THF (20 mL) was added t-BuLi (17.04 mL, 28.97 mmol, 3.5 equiv, 1.7 M in pentane) dropwise over 15 min at −78 °C under argon atmosphere. The reaction mixture was stirred for 10 min at −78 °C and then for 1 h at 0 °C. Subsequently, the resulting mixture was again cooled to −78 °C and Bu3SnCl (8.98 mL, 31.11 mmol, 4 equiv) was added dropwise over 10 min. The mixture was allowed to warm gradually to RT over 3 h and stirred for 2 h. Et3N (5 mL) was added, and the resulting mixture was stirred for another 20 min at RT and then diluted with EtOAc (250 mL). The organic layer was washed with NaHCO3 (250 mL), H2O (250 mL), and brine (250 mL), dried over MgSO4, and filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 20:1, 1% Et3N) to give product 6a (5.02, 93%) as a light-yellow oil: R = 0.69 (hexane/EtOAc 3:1); [α]D20 −44.6 (c 0.3, CHCl3); 1H NMR (401.0 MHz, DMSO-d6): 0.86 (t, 9H, Jvic = 7.3, CHCH2CH2CH2Sn); 0.85–0.94 (m, 6H, CH3CH2CH2CHSn); 1.21–1.34 (m, 24H, (CH3)2C, CH3CHCH2CH2Sn); 1.40–1.62 (m, 6H, CH3CH2CHCH2Sn); 3.08, 3.14 (2 × s, 9H, CH3O); 3.52 (dd, 1H, J6b,6a = 10.3, J6b,5 = 5.1, H-6b); 3.59 (dd, 1H, J6a,6b = 10.3, J6a,5 = 7.5, H-6a); 3.72 (dt, 1H, J3,2 = 5.1, J3,4 = J3,5 = 2.1, H-3); 3.91 (td, 1H, J4,3 = J4,5 = 2.1, J4,2 = 1.6, H-4); 4.07 (ddt, 1H, J5,6a = 7.5, J5,6b = 5.2, J5,3 = J5,4 = 2.1, H-5); 4.79 (dd, 1H, J2,3 = 5.1, J2,4 = 1.6, H-2); 13C NMR (100.8 MHz, DMSO-d6): 9.4 (CH3CH2CH2CH2Sn); 13.8 (CH3CH2CH2CH2Sn); 24.6, 24.4, 25.0, 25.1, 25.1, 25.3 ((CH3)2C); 26.7 (CH3CH2CH2CH2Sn); 28.6 (CH3CH2CH2CH2Sn); 47.8, 48.5, 48.8 (CH3O); 59.2 (CH2-6); 61.9 (CH-3); 67.6 (CH-4); 76.8 (CH-5); 99.4; 100.2, 100.8 ((CH3)2C); 111.5 (CH-2); 162.3 (C-1); IR (CHCl3): νmax 2994, 2958, 2932, 2827, 1465, 1433, 1381, 1373, 1151, 1104, 1072, 1011, 891, 870, 857, 843, 824, 515 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C30H60O7NaSn 675.3253, found 675.3260.

1,5-Anhydro-2-deoxy-3,4,6-tri-O-(ethoxyethyl)-1-(tri-n-butylstannyl)-d-arabino-hex-1-enitol (6b)

To a stirred solution of EE-glucal 2b (2 g, 5.52 mmol, 1 equiv) in anhydrous THF (15 mL) was added t-BuLi (11.36 mL, 19.31 mmol, 3.5 equiv, 1.7 M in pentane) dropwise over 10 min at −78 °C under argon atmosphere. The reaction mixture was stirred for 20 min at −78 °C and then for 3 h at 0 °C. Subsequently, the resulting mixture was again cooled to −78 °C and Bu3SnCl (5.99 mL, 22.07 mmol, 4 equiv) was added dropwise over 10 min. The mixture was allowed to warm gradually to RT over 3 h and stirred for 1 h. Et3N (5 mL) was added, and the resulting mixture was stirred for another 30 min at RT and then diluted with EtOAc (100 mL). The organic layer was washed with sat. aq NaHCO3 (50 mL), H2O (100 mL), and brine (250 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 20:1, 1% Et3N) to give product 6b (2.89, 81%) as a yellow oil: R = 0.65 (hexane/EtOAc 4:1); 1H NMR (401.0 MHz, CDCl3): 0.83–0.96 (m, 15H, CHCH2CH2CHSn); 1.16–1.21 (m, 9H, CHCH2O); 1.26–1.35 (m, 15H, CHCH, CH3CHCH2CH2Sn); 1.42–1.61 (m, 6H, CH3CH2CHCH2Sn); 3.41–4.00 (m, 10H, H-4,5,6, CH3CH); 4.03–4.24 (m, 1H, H-3); 4.65–5.05 (m, 1H, H-2); 13C NMR (100.8 MHz, CDCl3): 9.57, 9.60, 9.62 (CH3CH2CH2CH2Sn); 13.65, 13.66 (CH3CH2CH2CH2Sn); 15.28, 15.30, 15.31, 15.35, 15.38 (CH3CH2O); 19.83, 19.85, 19.90, 19.93, 19.96, 20.00, 20.40, 20.44, 20.57, 20.59, 20.60, 20.71, 20.75, 20.80, 20.82, 20.84, 20.97, 21.01 (CH3CH); 27.19, 27.20 (CH3CH2CH2CH2Sn); 28.88 (CH3CH2CH2CH2Sn); 59.67, 59.73, 59.76, 59.82, 60.37, 60.40, 60.44, 60.47, 60.63, 60.64, 60.65, 60.68, 60.80, 60.82, 60.99, 61.09, 61.41, 61.49, 61.59, 61.62, 61.82, 61.93, 62.34 (CH3CH2O); 63.35, 63.46, 64.03, 64.21, 64.26, 64.85, 65.03 (CH2-6); 69.26, 70.05, 71.15, 71.38, 71.60, 71.72, 71.74, 71.93, 72.00, 72.10, 72.24, 72.40, 73.25, 74.12, 75.27, 75.66, 76.56, 76.75, 76.92, 77.05, 77.20, 77.25, 77.29, 77.36 (CH-3,4,5); 97.29, 97.31, 97.48, 97.51, 99.59, 99.83, 99.86, 99.91, 99.92, 99.96, 99.99, 100.01, 100.23, 100.27, 100.30, 100.33, 100.41, 100.55, 100.58 (CH3CH); 109.87, 110.18, 110.26, 110.32, 111.83, 111.95, 112.14, 112.36 (CH-2); 163.90, 164.07, 164.16, 164.22, 164.25, 164.27, 164.36 (C-1); IR (CHCl3): νmax 2979, 2931, 2897, 2852, 1606, 1464, 1457, 1379, 1246, 1131, 1097, 1097, 1055, 1055, 1030 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C30H60O7NaSn 675.3253, found 675.3255.

(1,5-Anhydro-2-deoxy-3,4,6-tri-O-(ethoxyethyl)-d-lyxo-hex-1-enitolyl)boronic Acid Pinacol Ester (7)

To a stirred solution of EE-galactal 3b (2 g, 5.52 mmol, 1 equiv) in anhydrous THF (15 mL) was added t-BuLi (11.36 mL, 19.31 mmol, 3.5 equiv, 1.7 M in pentane) dropwise over 5 min at −78 °C under argon atmosphere. The reaction mixture was stirred for 5 min at −78 °C and then for 30 h at 0 °C. Subsequently, the resulting mixture was again cooled to −78 °C and iPrOBpin (4.50 mL, 22.07 mmol, 4 equiv) was added dropwise over 5 min. The mixture was allowed to warm gradually to RT over 3 h and stirred overnight. The reaction was quenched by the addition of H2O (5 mL) and extracted between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with H2O (2 × 200 mL), dried over MgSO4, filtered, and concentrated in vacuo to give crude product 7 (2.42 g, 90%) as a red-brown oil, which was used without further purification for the next step: IR (CHCl3): νmax 2981, 2936, 1477, 1471, 1402, 1391, 1391, 1382, 1374, 1296, 1167, 1138, 1112, 1094, 1083, 1008, 866, 851, 851 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C24H45O9BNa 511.3049, found 511.3051.

1,5-Anhydro-2-deoxy-3,4,6-tri-O-(ethoxyethyl)-1-(tri-n-butylstannyl)-d-lyxo-hex-1-enitol (8)

To a stirred solution of EE-galactal 3b (2.5 g, 6.90 mmol, 1 equiv) in anhydrous THF (15 mL) was added t-BuLi (14.20 mL, 24.14 mmol, 3.5 equiv, 1.7 M in pentane) dropwise over 5 min at −78 °C under argon atmosphere. The reaction mixture was stirred for 5 min at −78 °C and then for 30 min at 0 °C. Subsequently, the resulting mixture was again cooled to −78 °C and Bu3SnCl (7.48 mL, 27.59 mmol, 4 equiv) was added dropwise over 10 min. The mixture was allowed to warm gradually to RT over 3 h and stirred for 2 h. The resulting mixture was diluted with EtOAc (150 mL) and washed with sat. aq NaHCO3 (100 mL), H2O (100 mL), and brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 15:1, 1% Et3N) to give product 8 (3.10, 69%) as a red-brown oil: R = 0.80 (hexane/EtOAc 3:1); 1H NMR (401.0 MHz, acetone-d6): 0.90 (t, 9H, Jvic = 7.3, CHCH2CH2CH2Sn); 0.94–1.01 (m, 6H, CH3CH2CH2CHSn); 1.10–1.18 (m, 9H, CHCH2O); 1.22–1.29 (m, 9H, CHCH); 1.30–1.40 (m, 6H, CH3CHCH2CH2Sn); 1.47–1.69 (m, 6H, CH3CH2CHCH2Sn); 3.40–3.91 (m, 8H, H-6, CH3CHO); 3.94–4.38 (m, 3H, H-3,4,5); 4.65–5.13 (m, 4H, H-2, CH3CH); 13C NMR (100.8 MHz, acetone-d6): 10.10, 10.12, 10.13, 10.14 (CH3CH2CH2CH2Sn); 13.94, 13.96, 13.97 (CH3CH2CH2CH2Sn); 15.71, 15.73, 15.75, 15.78, 15.82 (CH3CH2O); 20.29, 20.30, 20.45, 20.50, 20.53, 20.61, 20.66, 20.72, 20.76, 20.79, 20.83, 20.87, 20.93, 21.08, 21.09 (CH3CH); 27.79, 27.80, 27.82, 27.84 (CH3CH2CH2CH2Sn); 29.60, 29.61 (CH3CH2CH2CH2Sn); 60.19, 60.24, 60.62, 60.75, 60.78, 60.93, 60.98, 61.11, 61.21, 61.22, 61.26, 61.31, 61.35, 61.39, 62.04, 62.08, 62.14 (CH3CH2O); 63.68, 64.29, 64.79, 64.81, 65.29, 65.55, 65.73 (CH2-6); 69.93, 69.98, 70.05, 70.98, 71.22, 71.40, 76.82, 76.94, 77.12, 77.28, 77.37, 77.75, 77.81 (CH-3,4,5); 99.34, 99.47, 100.18, 100.25, 100.27, 100.35, 100.39, 100.45, 100.62, 100.72, 100.77, 100.79, 100.88, 100.92, 101.00 (CH3CH); 112.10, 112.29, 112.33, 112.91, 112.95, 113.11 (CH-2); 163.08, 163.11, 163.28, 163.31, 163.32 (C-1); IR (CHCl3): νmax 3040, 2978, 2959, 2931, 2920, 2900, 2872, 1855, 1600, 1483, 1465, 1457, 1445, 1417, 1395, 1379, 1293, 1176, 1133, 1096, 1096, 1082, 1068, 1056, 843, 650, 599, 510 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C30H60O7NaSn 675.3253, found 675.3254.

General Procedure A: Suzuki Reactions of MOP- and EE-Protected Glycal Pinacol Boronates

To a stirred solution of pinacol boronate (2 equiv) in 1,2-dimethoxyethane (DME) were added 1-iodonaphthalene (1 equiv), Pd(PPh3)2Cl2 (0,05 equiv), and 2 M Na2CO3 (DME/2 M Na2CO3 4:1) under argon atmosphere. The reaction mixture was heated to 80 °C and stirred for 3 h. After TLC analysis showed complete consumption of the starting material, the mixture was cooled to RT, diluted with EtOAc, extracted with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 10:1 to 6:1).

General Procedure B: Stille Reactions of MOP- and EE-Protected Glycal Stannanes

To a solution of stannane (1 equiv) in anhydrous toluene were added 1-iodonaphthalene (1.5 equiv) and Pd(PPh3)4 (0.05 equiv) under an argon atmosphere. The reaction mixture was stirred under reflux at 125 °C for 5 h. After TLC analysis showed complete consumption of the starting material, the mixture was cooled to RT, filtered through a short plug of celite, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 10:1 to 6:1).

(1,5-Anhydro-2-deoxy-3,4,6-tri-O-(2-methoxypropan-2-yl)-d-arabino-hex-1-enitolyl)naphthalene (9a)

From 5a: Following the general procedure A, boronate 5a (1.5 g, 3.07 mmol, 2 equiv), 1-iodonaphthalene (0.22 mL, 1.53 mmol, 1 equiv), Pd(PPh3)2Cl2 (54 mg, 77 μmol, 0.05 equiv) in DME (12 mL), and 2 M Na2CO3 (3 mL) were used. The reaction mixture was stirred at 80 °C for 3 h. After completion of the reaction, the residue was purified by column chromatography on silica gel (hexane/EtOAc 10:1 to 6:1) to give product 9a (568 mg, 76%) as a pale yellow oil.

From 6a: Following the general procedure B, stannane 6a (220 mg, 338 μmol, 1 equiv), 1-iodonaphthalene (74 μL, 507 μmol, 1.5 equiv), and Pd(PPh3)4 (20 mg, 17 μmol, 0.05 equiv) in toluene (7 mL) were used. The reaction mixture was stirred at 125 °C for 5 h. After completion of the reaction, the residue was purified by column chromatography on silica gel (hexane/EtOAc 10:1 to 6:1) to give product 9a (142 mg, 86%) as a pale yellow oil: R = 0.51 (hexane/EtOAc 3:1); [α]D20 −27.6 (c 0.3, CHCl3); 1H NMR (401.0 MHz, DMSO-d6): 1.26, 1.31, 1.32, 1.36, 1.42 (5 × s, 18H, (CH3)2C); 3.05, 3.20, 3.23 (3 × s, 3 × 3H, CH3O); 3.63 (dd, 1H, J6b,6a = 10.9, J6b,5 = 3.6, H-6b); 3.97 (dd, 1H, J6a,6b = 10.9, J6a,5 = 8.5, H-6a); 4.07–4.13 (m, 2H, H-3,); 4.45 (ddt, 1H, J5,6 = 8.5, 3.6, J5,3 = J5,4 = 1.9, H-5); 5.06 (dd, 1H, J2,3 = 5.5, J2,4 = 1.5, H-2); 7.45–7.57 (m, 4H, H-2,3,6,7-naphth); 7.87–7.97 (m, 2H, H-4,5-naphth); 8.31–8.40 (m, 1H, H-8-naphth); 13C NMR (100.8 MHz, DMSO-d6): 24.39, 24.50, 25.11, 25.19, 25.26 ((CH3)2C); 47.99, 48.79, 49.10 (CH3O); 59.03 (CH2-6); 62.95 (CH-3); 66.77 (CH-4); 78.29 (CH-5); 99.63, 100.47 ((CH3)2C); 100.69 (CH-2); 101.08 ((CH3)2C); 125.43, 126.10, 126.12, 126.13, 126.33 (CH-2,3,6,7-naphth); 128.21, 129.02 (CH-4,5-naphth); 130.95 (C-8a-naphth); 133.29 (C-4a-naphth); 134.75 (C-1-naphth); 152.26 (C-1); IR (CHCl3): νmax 3049, 2995, 2962, 2945, 2886, 2832, 1662, 1508, 1463, 1435, 1435, 1382, 1373, 1258, 1151, 1105, 1095, 1071, 1015, 958, 901, 864, 853, 853, 835, 819, 527, 499 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C28H40O7Na 511.2666, found 511.2667.

(1,5-Anhydro-2-deoxy-3,4,6-tri-O-(ethoxyethyl)-d-arabino-hex-1-enitolyl)naphthalene (9b)

From 5b: Following the general procedure A, boronate 5b (2.01 g, 4.11 mmol, 2 equiv), 1-iodonaphthalene (0.3 mL, 2.05 mmol, 1 equiv), Pd(PPh3)2Cl2 (72 mg, 103 μmol, 0.05 equiv) in DME (16 mL), and 2 M Na2CO3 (4 mL) were used. The reaction mixture was stirred at 80 °C for 3 h. After completion of the reaction, the residue was purified by column chromatography on silica gel (hexane/EtOAc 10:1 to 6:1) to give product 9b (931 mg, 93%) as a pale yellow oil.

From 6b: Following the general procedure B, stannane 6b (2 g, 3.07 mmol, 1 equiv), 1-iodonaphthalene (0.67 mL, 4.60 mmol, 1.5 equiv), and Pd(PPh3)4 (177 mg, 153 μmol, 0.05 equiv) in toluene (15 mL) were used. The reaction mixture was stirred at 125 °C for 5 h. After completion of the reaction, the residue was purified by column chromatography on silica gel (hexane/EtOAc 10:1 to 6:1) to give product 9b (1.19 g, 79%) as a pale yellow oil.

Preparation of 9b Using Indium Cross-Coupling Reaction

To a stirred solution of EE-glucal 2b (200 mg, 552 μmol, 1 equiv) in anhydrous THF (5 mL) was added t-BuLi (0.49 mL, 828 μmol, 1.7 M in pentane, 1.5 equiv) dropwise over 5 min at −78 °C under argon. The reaction mixture was stirred for 15 min at −78 °C and then for 1 h at 0 °C. Subsequently, the resulting mixture was again cooled to −78 °C and transferred via cannula to the solution of InCl3 (61 mg, 276 μmol, 0.5 equiv) in THF (4 mL) at −78 °C. The reaction was stirred for 30 min at −78 °C and then allowed to warm to RT. 1-Iodonaphthalene (0.12 mL, 828 μmol, 1.5 equiv) and Pd(Ph3P)2Cl2 (12 mg, 17 μmol, 0.03 equiv) were added, and the resulting mixture was heated to reflux at 70 °C overnight. The mixture was diluted with toluene (10 mL), MeOH (5 mL), filtered over a plug of Celite, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (toluene/acetone 20:1) to give product 9b (115 mg, 43%) as a pale yellow oil.

Preparation of 9b Using Negishi Cross-Coupling Reaction

To a stirred solution of EE-glucal 2b (200 mg, 552 μmol, 1 equiv) in anhydrous THF (5 mL) was added t-BuLi (1.14 mL, 1.93 mmol, 1.7 M in pentane, 3.5 equiv) dropwise over 5 min at −78 °C under argon. The reaction mixture was stirred for 15 min at −78 °C and then for 1 h at 0 °C. Then, a solution of freshly fused ZnCl2 (301 mg, 2.21 mmol, 4 equiv) in THF (4 mL) was added at 0 °C. In a separate flask, Pd(PPh3)4 (32 mg, 28 μmol, 0.05 equiv) and 1-iodonaphthalene (97 μL, 662 μmol, 1.2 equiv) were dissolved in THF (1 mL), giving a red-brown solution. To this solution was transferred the solution containing the organozinc compound via cannula at RT and stirred for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and filtered over a plug of Celite. The filtrate was washed with H2O (2 × 50 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc 6:1) to give product 9b (54 mg, 20%) as a pale yellow oil: R = 0.37 (hexane/EtOAc 4:1); 1H and 13C NMR spectra of 9b were analyzed after in situ deprotection by 10% CD3COOD in CD3OD (see SI Chapter 4), and NMR spectra were compared with the spectra of unprotected derivative 12; IR (CHCl3): νmax 3061, 3050, 2980, 2933, 2899, 2887, 2875, 2860, 2855, 1662, 1593, 1580, 1508, 1484, 1466, 1445, 1397, 1382, 1241, 1130, 1096, 1084, 1056, 868, 844, 694 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C28H40O7Na 511.2666, found 511.2666.

(1,5-Anhydro-2-deoxy-3,4,6-tri-O-(ethoxyethyl)-d-lyxo-hex-1-enitolyl)naphthalene (10)

From 7: Following the general procedure A, boronate 7 (1.35 g, 2.76 mmol, 2 equiv), 1-iodonaphthalene (0.20 mL, 1.38 mmol, 1 equiv), Pd(PPh3)2Cl2 (48 mg, 69 μmol, 0.05 equiv) in DME (12 mL), and 2 M Na2CO3 (3 mL) were used. The reaction mixture was stirred at 80 °C for 3 h. After completion of the reaction, the residue was purified by column chromatography on silica gel (hexane/EtOAc 8:1, 1% Et3N) to give product 10 (584 mg, 87%) as a pale yellow oil.

From 8: Following the general procedure B, stannane 8 (800 mg, 1.23 mmol, 1 equiv), 1-iodonaphthalene (0.27 mL, 1.84 mmol, 1.5 equiv), and Pd(PPh3)4 (71 mg, 61 μmol, 0.05 equiv) in toluene (15 mL) were used. The reaction mixture was stirred at 125 °C for 5 h. After completion of the reaction, the residue was purified by column chromatography on silica gel (hexane/EtOAc 8:1, 1% Et3N) to give product 10 (432 mg, 72%) as a pale yellow oil: R = 0.38 (hexane/EtOAc 4:1); 1H and 13C NMR spectra of 10 were analyzed after in situ deprotection by 10% CD3COOD in CD3OD (see SI Chapter 4), and NMR spectra were compared with the NMR of unprotected derivative 15; IR (CHCl3): νmax 3090, 3062, 3049, 2981, 2933, 2898, 2874, 1661, 1621, 1593, 1581, 1508, 1483, 1456, 1446, 1395, 1381, 1134, 1112, 1100, 1084, 1056, 861, 804, 640 cm–1; HRMS (ESI) [M + Na]+m/z calcd for C28H40O7Na 511.2666, found 511.2667.

(1,5-Anhydro-2-deoxy-d-arabino-hex-1-enitolyl)naphthalene (12)

From 9a: The derivative 9a (250 mg, 512 μmol) was dissolved in the mixture of THF (5 mL) and 1% AcOH (5 mL). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (2 × 50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH 8:1) to give product 12 (127 mg, 91%) as a colorless oil.

From 9b: The derivative 9b (180 mg, 368 μmol) was dissolved in the mixture of THF (5 mL) and 20% AcOH (5 mL). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (2 × 50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH 8:1) to give product 12 (90 mg, 90%) as a colorless oil: R = 0.61 (CHCl3/MeOH 3:1); [α]D20 −11.9 (c 0.3, MeOH); 1H NMR (401.0 MHz, CD3OD): 3.84 (dd, 2H, J4,5 = 9.8, J4,3 = 7.1, H-4); 3.93 (dd, 1H, J6b,6a = 12.3, J6b,5 = 5.3, H-6b); 4.00 (dd, 1H, J6a,6b = 12.3, J6a,5 = 2.6, H-6a); 4.10 (ddd, 1H, J5,4 = 9.8, J5,6 = 5.3, 2.6, H-5); 4.37 (dd, 1H, J3,4 = 7.1, J3,4 = 2.5, H-3); 5.02 (d, 1H, J2,3 = 2.5, H-2); 7.43 (dd, 1H, J3,4 = 8.3, J3,2 = 7.0, H-3-naphth); 7.44–7.52 (m, 2H, H-6,7-naphth); 7.55 (dd, 1H, J2,3 = 7.0, J2,4 = 1.3, H-2-naphth); 7.82–7.87 (m, 2H, H-4,5-naphth); 8.23 (m, 1H, H-8-naphth); 13C NMR (100.8 MHz, CD3OD): 62.3 (CH2-6); 71.0 (CH-4); 71.5 (CH-3); 81.3 (CH-5); 105.4 (CH-2); 126.0 (CH-3-naphth); 126.9, 127.00, 127.2 (CH-6,7,8-naphth); 127.8 (CH-2-naphth); 129.2 (CH-5-naphth); 130.2 (CH-4-naphth); 132.6 (C-8a-naphth); 135.0, 135.1 (C-1,4a-naphth); 155.0 (C-1); IR (CHCl3): νmax 3278, 1659, 1621, 1590, 1509, 1400, 1253, 1108, 1067, 1067, 1047, 800 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C16H16O4Na 295.0941, found 295.0941.

(1,5-Anhydro-2-deoxy-d-lyxo-hex-1-enitolyl)naphthalene (15)

EE-protected derivative 10 (186 mg, 381 μmol) was dissolved in 10% AcOH in MeOH (10 mL). The reaction mixture was heated to 40 °C and stirred for 1.5 h. After cooling to RT, toluene (30 mL) was added and the solution was evaporated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH 12:1 to 10:1, 1% Et3N) to give product 15 (61 mg, 59%) as a colorless oil: R = 0.68 (CHCl3/MeOH 5:1); [α]D20 −6.2 (c 0.4, MeOH); 1H NMR (401.0 MHz, CD3OD): 3.90 (dd, 1H, J6b,6a = 11.5, J6b,5 = 5.8, H-6b); 3.94 (dd, 1H, J6a,6b = 11.5, J6a,5 = 6.6, H-6a); 4.06 (ddd, 1H, J4,3 = 4.7, J4,2 = 1.9, J4,5 = 1.1, H-4); 4.24 (ddt, 1H, J5,6 = 6.6, 5.8, J5,3 = J5,4 = 1.1, H-5); 4.59 (dd, 1H, J3,4 = 4.7, J3,2 = 2.4, H-3); 4.93 (dd, 1H, J2,3 = 2.4, J2,1 = 1.9, H-2); 7.43 (dd, 1H, J3,4 = 8.4, J3,2 = 7.0, H-3-naphth); 7.43–7.50 (m, 2H, H-6,7-naphth); 7.55 (dd, 1H, J2,3 = 7.0, J2,4 = 1.4, H-2-naphth); 7.82–7.87 (m, 2H, H-4,5-naphth); 8.28 (m, 1H, H-8-naphth); 13C NMR (100.8 MHz, CD3OD): 62.6 (CH2-6); 66.1 (CH-4); 66.6 (CH-3); 79.6 (CH-5); 104.6 (CH-2); 126.0 (CH-3-nphth); 126.8 (CH-6-naphth); 127.0 (CH-7-naphth); 127.3 (CH-8-naphth); 127.6 (CH-2-naphth); 129.0 (CH-5-naphth); 130.0 (CH-4-naphth); 132.8 (C-8a-naphth); 135.1 (C-4a-naphth); 135.5 (C-1-naphth); 155.0 (C-1); IR (CHCl3): νmax 3361, 1060, 1592, 1508, 1085, 959, 893, 852 cm–1; HRMS (ESI) m/z [M + Na]+ calculated for C16H16O4Na 295.0941, found 295.0941.

Transformations of Endocyclic Double Bond: General Procedure C: Hydroboration

To a stirred solution of 1-naphthylglycal (1 equiv) in anhydrous THF was added BH3·THF (1 M in THF, 10 equiv) dropwise at 0 °C under argon atmosphere. The reaction mixture was stirred for 2.5 h and 30% NaOH and 30% H2O2 were added slowly, and the resulting mixture was stirred for 1 h at 0 °C and then for another 2 h at RT. The reaction mixture was diluted with EtOAc and washed with H2O (3×). The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was dissolved in the mixture of hexane/EtOAc (3:1) and filtered over a plug of silica gel and evaporated in vacuo. The protected alcohol was confirmed by HRMS and used directly for deprotection (general procedure E or F).

General Procedure D: Epoxidation/LiBHEt3 Opening

To a stirred solution of 1-naphthylglycal (1 equiv) in CH2Cl2 was added freshly distilled solution of DMDO[23] (approx. 0.06 M in acetone, 1.1 equiv) at 0 °C under argon atmosphere. The reaction mixture was stirred for 30 min at 0 °C. Thereafter, the solvent was removed under reduced pressure without heating, codistilled with toluene (3 × 20 mL), and dried for 1 h under vacuum. The residue was dissolved in anhydrous THF, and LiBHEt3 (1 M in THF, 40 equiv) was added at 0 °C under argon atmosphere. The reaction mixture was stirred for 30 min at 0 °C and then for 1.5 h at RT. The resulting mixture was diluted with Et2O and washed with H2O (3×). The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The protected alcohol was confirmed by HRMS and used directly for deprotection (general procedure E or F).

General Procedure E: Deprotection for MOP

MOP-protected derivative was dissolved in the mixture of THF and 1% aqueous AcOH (1:1) and stirred at RT overnight. The solution was diluted with H2O (10 mL) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH) to give corresponding C-glycoside.

General Procedure F: Deprotection for EE

EE-protected derivative was dissolved in the mixture of THF and 20% aqueous AcOH (1:1) and stirred at RT overnight. The solution was diluted with H2O (10 mL) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH) to give corresponding C-glycoside.

1-(β-d-Glucopyranosyl)naphthalene (11)

From 9a: Following the general procedure C, the MOP-protected derivative 9a (100 mg, 205 μmol, 1 equiv), BH3·THF (2.05 mL, 2.05 mmol, 1 M in THF, 10 equiv), and THF (5 mL) were used. The mixture was stirred for 2.5 h at 0 °C. Then, 30% NaOH (2 mL) and 30% H2O2 (2 mL) were used and resulting mixture was stirred for 1 h at 0 °C and then for 2 h at RT. After completion of the reaction, crude 1-(3,4,6-tri-O-(2-methoxypropan-2-yl)-β-d-glucopyranosyl)naphthalene (R = 0.71 (CHCl3/MeOH 5:1); HRMS (ESI) m/z [M + Na]+ calcd for C28H42O8Na 529.2772, found 529.2772) was obtained. Following the general procedure E, the MOP-C-glycoside, THF (5 mL), and 1% AcOH (5 mL) were used. After completion of the reaction, the residue was purified by column chromatography on silica gel (CHCl3/MeOH 6:1) to give product 11 (107 mg, 78%) as a colorless foam.

From 9b: Following the general procedure C, the MOP-protected derivative 9b (230 mg, 471 μmol, 1 equiv), BH3·THF (4.71 mL, 4.71 mmol, 1 M in THF, 10 equiv), and THF (7 mL) were used. The mixture was stirred for 2.5 h at 0 °C. Then, 30% NaOH (5 mL) and 30% H2O2 (5 mL) were used and resulting mixture was stirred for 1 h at 0 °C and then for 2 h at RT. After completion of the reaction, crude 1-(3,4,6-tri-O-(ethoxyethyl)-β-d-glucopyranosyl)naphthalene (R = 0.57 (hexane/EtOAc 2:1); HRMS (ESI) m/z [M + Na]+ calcd for C28H42O8Na 529.2772, found 529.2772) was obtained. Following the general procedure E, the EE-C-glycoside, THF (10 mL), and 20% AcOH (10 mL) were used. After completion of the reaction, the residue was purified by column chromatography on silica gel (CHCl3/MeOH 6:1) to give product 11 (49 mg, 82%) as a colorless foam.

From 12: Following the general procedure C, the derivative 12 (150 mg, 551 μmol, 1 equiv), BH3·THF (5.51 mL, 5.51 mmol, 1 M in THF, 10 equiv), and THF (5 mL) were used. The mixture was stirred for 2.5 h at 0 °C. Then, 30% NaOH (3 mL) and 30% H2O2 (3 mL) were used and the resulting mixture was stirred for 1 h at 0 °C and then for 2 h at RT. The reaction mixture was diluted with acetone (10 mL) and stirred for 10 min. Then, the formed solid was filtered over a plug of Celite, the plug was washed with MeOH (20 mL), and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH 6:1) to give 11 (134 mg, 84%) as a colorless foam: R = 0.22 (CHCl3/MeOH 5:1); [α]D20 9.1 (c 0.3, MeOH); 1H NMR (401.0 MHz, CD3OD): 3.51–3.60 (m, 2H, H-4,5); 3.64 (t, 1H, J3,2 = J3,4 = 8.6, H-3); 3.74 (dd, 1H, J6b,6a = 12.0, J6b,5 = 5.6, H-6b); 3.82 (dd, 1H, J2,1 = 9.6, J2,3 = 8.6, H-2); 3.91 (dd, 1H, J6a,6b = 12.0, J6a,5 = 1.9, H-6a); 4.94 (d, 1H, J1,2 = 9.6, H-1); 7.42–7.55 (m, 3H, H-3,6,7-naphth); 7.67 (dd, 1H, J2,3 = 7.2, J2,4 = 1.4, H-2-naphth); 7.83 (dt, 1H, J4,3 = 8.4, J4,2 = J4,5 = 1.4, H-4-naphth); 7.86 (m, 1H, H-5); 8.31 (m, 1H, H-8); 13C NMR (100.8 MHz, CD3OD): 63.2 (CH2-6); 72.0 (CH-4); 75.8 (CH-2); 80.1 (CH-3); 80.4 (CH-1); 82.5 (CH-5); 125.6 (CH-8-naphth); 126.2 (CH-3-naphth); 126.4 (CH-6-naphth); 126.77 (CH-2-naphth); 126.80 (CH-7-naphth); 129.5, 129.6 (CH-4,5-naphth); 133.5 (C-8a-naphth); 135.4 (C-4a-naphth); 136.3 (C-1-naphth); IR (KBr): νmax 3375, 2924, 1618, 1598, 1512, 1398, 1084, 1084, 1043, 1027, 802 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C16H18O5Na 313.1046, found 313.1048. Previously published NMR data were measured in CDCl3.

1-(β-d-Galactopyranosyl)naphthalene (14)

From 10: Following the general procedure C, the EE-protected derivative 10 (100 mg, 205 μmol, 1 equiv), BH3·THF (2.05 mL, 2.05 mmol, 1 M in THF, 10 equiv), and THF (5 mL) were used. The mixture was stirred for 2.5 h at 0 °C. Then, 30% NaOH (5 mL) and 30% H2O2 (5 mL) were used and the resulting mixture was stirred for 1 h at 0 °C and then for 2 h at RT. After completion of the reaction, crude 1-(3,4,6-tri-O-(ethoxyethyl)-β-d-galactopyranosyl)naphthalene (R = 0.32 (hexane/EtOAc 2:1); HRMS (ESI) m/z [M + Na]+ calcd for C28H42O8Na 529.2772, found 529.2773) was obtained. Following the general procedure F, the EE-C-glycoside, THF (5 mL), and 20% AcOH (5 mL) were used. After completion of the reaction, the residue was purified by column chromatography on silica gel (CHCl3/MeOH 6:1) to give product 14 (41 mg, 69%) as a white solid.

From 15: Following the general procedure C, the derivative 15 (100 mg, 367 μmol, 1 equiv), BH3·THF (3.67 mL, 3.67 mmol, 1 M in THF, 10 equiv), and THF (5 mL) were used. The mixture was stirred for 2.5 h at 0 °C. Then, 30% NaOH (3 mL) and 30% H2O2 (3 mL) were used and the resulting mixture was stirred for 1 h at 0 °C and then for 2 h at RT. The reaction mixture was diluted with acetone (10 mL) and stirred for 10 min. Then, the formed solid was filtered over a plug of Celite, the plug was washed with MeOH (20 mL), and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH 6:1) to give 14 (80 mg, 75%) as a white solid: R = 0.20 (CHCl3:MeOH 5:1); mp 106–112 °C (acetone) [α]D20 12.2 (c 0.3, MeOH); 1H NMR (401.0 MHz, CD3OD): 3.72 (dd, 1H, J3,2 = 9.2, J3,4 = 3.3, H-3); 3.75–3.86 (m, 3H, H-5,6); 4.08 (dd, 1H, J4,3 = 3.3, J4,5 = 0.9, H-4); 4.20 (dd, 1H, J2,1 = 9.6, J2,3 = 9.2, H-2); 4.81 (d, 1H, J1,2 = 9.6, H-1); 7.41–7.53 (m, 3H, H-3,6,7-naphth); 7.68 (dd, 1H, J2,3 = 7.2, J2,4 = 1.3, H-2-naphth); 7.83 (dt, 1H, J4,3 = 8.2, J4,2 = J4,5 = 1.3, H-4-naphth); 7.86 (m, 1H, H-5); 8.46 (m, 1H, H-8); 13C NMR (100.8 MHz, CD3OD): 63.1 (CH2-6); 71.2 (CH-4); 72.6 (CH-2); 76.8 (CH-3); 80.8 (CH-5); 82.0 (CH-1); 126.08 (CH-8-naphth); 126.11 (CH-3-naphth); 126.40 (CH-6-naphth); 126.71 (CH-7-naphth); 127.4 (CH-2-naphth); 129.5 (CH-5-naphth); 129.6 (CH-4-naphth); 133.5 (C-8a-naphth); 135.5 (C-4a-naphth); 136.4 (C-1-naphth); IR (MeOH): νmax 3361, 1599, 1512, 1179, 1083, 1048, 1013, 950, 847 cm–1; HRMS (ESI) m/z [M + Na]+ calcd for C16H18O5Na 313.1046, found 313.1047.

1-(α-d-Glucopyranosyl)naphthalene (13)

From 9a: Following the general procedure D, the MOP-protected derivative 9a (200 mg, 409 μmol, 1 equiv), DMDO (7.50 mL, 450 μmol, 0.06 M in acetone, 1.1 equiv), and CH2Cl2 (5 mL) were used. The mixture was stirred for 30 min at 0 °C. After completion of the epoxidation step, the residue LiBHEt3 (16.37 mL, 16.37 mmol, 1 M in THF, 40 equiv) and THF (5 mL) were used. The reaction mixture was stirred for 30 min at 0 °C and then for 1.5 h at RT. After completion of the reaction, crude 1-(3,4,6-tri-O-(2-methoxypropan-2-yl)-α-d-glucopyranosyl)naphthalene (R = 0.47 (hexane/EtOAc 3:1); HRMS (ESI) [M + Na]+m/z calcd for C28H42O8Na 529.2772, found 529.2772) was obtained. Following the general procedure E, the MOP-C-glycoside, THF (5 mL), and 1% AcOH (5 mL) were used. After completion of the reaction, the residue was purified by column chromatography on silica gel (CHCl3/MeOH 8:1) to give product 13 (76 mg, 64%) as a colorless oil.

From 9b: Following the general procedure D, the EE-protected derivative 9b (140 mg, 287 μmol, 1 equiv), DMDO (5.25 mL, 315 μmol, 0.06 M in acetone, 1.1 equiv), and CH2Cl2 (5 mL) were used. The mixture was stirred for 30 min at 0 °C. After completion of the epoxidation step, the residue LiBHEt3 (11.46 mL, 11.46 mmol, 1 M in THF, 40 equiv) and THF (5 mL) were used. The reaction mixture was stirred for 30 min at 0 °C and then for 1.5 h at RT. After completion of the reaction, crude 1-(3,4,6-tri-O-(ethoxyethyl)-α-d-glucopyranosyl)naphthalene (R = 0.53 (CHCl3/MeOH 3:1); HRMS (ESI) m/z [M + Na]+ calcd for C28H42O8Na 529.2772, found 529.2773) was obtained. Following the general procedure F, the EE-C-glycoside, THF (5 mL), and 20% AcOH (5 mL) were used. After completion of the reaction, the residue was purified by column chromatography on silica gel (CHCl3/MeOH 8:1) to give product 13 (57 mg, 69%) as a colorless oil: R = 0.63 (CHCl3/MeOH 3:1); [α]D20 42.4 (c 0.3, CHCl3); 1H NMR (401.0 MHz, CD3OD): 3.51 (ddd, 1H, J5,4 = 6.9, J5,6 = 6.1, 3.3, H-5); 3.61–3.69 (m, 2H, H-4,6b); 3.88 (dd, 1H, J6a,6b = 12.0, J6a,5 = 6.1, H-6a); 4.08 (dd, 1H, J2,3 = 7.1, J2,1 = 4.2, H-2); 4.23 (dd, 1H, J3,2 = 7.1, J3,4 = 6.4, H-3); 5.89 (d, 1H, J1,2 = 4.2, H-1); 7.42–7.57 (m, 3H, H-3,6,7-naphth); 7.82 (d, 1H, J4,3 = 8.2, H-4-naphth); 7.88 (m, 1H, H-5-naphth); 7.98 (dt, 1H, J2,3 = 7.3, J2,4 = J2,5 = 1.1, H-2-naphth); 8.28 (m, 1H, H-8-naphth); 13C NMR (100.8 MHz, CD3OD): 62.1 (CH2-6); 71.7 (CH-4); 72.3 (CH-1); 73.8 (CH-2); 74.4 (CH-3); 77.9 (CH-5); 125.2 (CH-8-naphth); 125.6 (CH-3-naphth); 126.4 (CH-6-naphth); 126.9 (CH-7-naphth); 128.1 (CH-2-naphth); 129.2 (CH-4-naphth); 129.8 (CH-5-naphth); 133.0 (C-8a-naphth); 134.4 (C-1-naphth); 135.5 (CH-4-naphth); IR (CHCl3): νmax 3606, 3530, 3412, 2928, 1626, 1600, 1592, 1509, 1463, 1401, 1059, 811 cm–1; HRMS (ESI) m/z [M – H]− calcd for C16H17O5 289.1082, found 289.1080.

(2S,3R,4S,5R)-1-(Naphthalen-1-yl)hexane-1,2,3,4,5,6-hexaol (16)

Following the general procedure D, the EE-protected derivative 10 (180 mg, 368 μmol, 1 equiv), DMDO (6.75 mL, 405 μmol, 0.06 M in acetone, 1.1 equiv), and CH2Cl2 (5 mL) were used. The mixture was stirred for 30 min at 0 °C. After completion of the epoxidation step, the residue LiBHEt3 (14.74 mL, 14.74 mmol, 1 M in THF, 40 equiv) and THF (5 mL) were used. The reaction mixture was stirred for 30 min at 0 °C and then for 1.5 h at RT. After completion of the reaction, crude (2S,3R,4S,5R)-1-(naphthalen-1-yl)hexane-(3,4,6-tri-O-(ethoxyethyl)-1,2,3,4,5,6-hexaol) (R = 0.26 (hexane/EtOAc 5:1); HRMS (ESI) m/z [M + Na]+ calcd for C28H44O9Na 547.2878, found 547.2880) was obtained. Following the general procedure F, the hexanol, THF (5 mL), and 20% AcOH (5 mL) were used. After completion of the reaction, the residue was purified by column chromatography on silica gel (CHCl3/MeOH 5:1) to give product 16 (59 mg, 52%) as a colorless oil: R = 0.15 (CHCl3/MeOH 5:1); 1H NMR (500.0 MHz, DMSO-d6): 3.31–3.42 (m, 2H, H-6, overlapped with water signal); 3.49 (bd, 1H, J3,4 = 9.5, H-3); 3.74 (bt, 1H, J5,6 = 6.2, H-5); 3.90 (d, 1H, J4,3 = 9.5, H-4); 4.01 (bd, 1H, J2,1 = 7.8, H-2); 4.15 (bs, 1H, OH-3); 4.21 (bs, 2H, OH-2,5); 4.51 (bs, 1H, OH-6); 4.69 (bs, 1H, OH-4); 5.37 (d, 1H, J1,2 = 7.8, H-1); 5.68 (bs, 1H, OH-1); 7.43–7.53 (m, 3H, H-3,6,7-naphth); 7.64 (dd, 1H, J2,3 = 7.3, J2,4 = 1.3, H-2-naphth); 7.79 (d, 1H, J4,3 = 8.2, H-4-naphth); 7.89 (m, 1H, H-5-naphth); 8.26 (m, 1H, H-8-naphth); 13C NMR (125.7 MHz, DMSO-d6): 63.5 (CH2-6); 69.1 (CH-4); 69.3 (CH-3); 70.2 (CH-5); 71.2 (CH-1); 72.4 (CH-2); 124.7 (CH-2-naphth); 124.8 (CH-8-naphth); 125.3, 125.4, 125.5 (CH-3,6,7-naphth); 127.1 (CH-4-naphth); 128.5 (CH-5-naphth); 131.7 (C-8a-naphth); 133.4 (CH-4a-naphth); 140.9 (C-1-naphth); HRMS (ESI) m/z [M + Na]+calcd for C16H20O6Na 331.1152, found 331.1152.