Synthesis of Four Orthogonally Protected Rare l-Hexose Thioglycosides from d-Mannose by C-5 and C-4 Epimerization

Abstract

l-Hexoses are important components of biologically relevant compounds and precursors of some therapeuticals. However, they typically cannot be obtained from natural sources and due to the complexity of their synthesis, their commercially available derivatives are also very expensive. Starting from one of the cheapest d-hexoses, d-mannose, using inexpensive and readily available chemicals, we developed a reaction pathway to obtain two orthogonally protected l-hexose thioglycoside derivatives, l-gulose and l-galactose, through the corresponding 5,6-unsaturated thioglycosides by C-5 epimerization. From these derivatives, the orthogonally protected thioglycosides of further two l-hexoses (l-allose and l-glucose) were synthesized by C-4 epimerization. The preparation of the key intermediates, the 5,6-unsaturated derivatives, was systematically studied using various protecting groups. By the method developed, we are able to produce highly functionalized l-gulose derivatives in 9 steps (total yields: 21–23%) and l-galactose derivatives in 12 steps (total yields: 6–8%) starting from d-mannose.

1. Introduction

l-Sugars are key constituents of many biorelevant natural products such as polysaccharides, glycopeptides, and terpene or steroid glycosides (Figure 1) [1]. For example, l-guluronic acid is found in alginates (I) [2,3,4,5,6], the cell walls polysaccharides of brown algae, and l-gulose is a component of the potent antitumor antibiotic Bleomycin A2 (II) produced by Streptomyces verticillus [7,8,9]. The tetracyclic triterpene Datiscoside C (III), which is isolated from Datisca glomerata, contains a 6-deoxy-l-alloside [10], while l-galactose can be found in the A side chain of the pectic polysaccharide rhamnogalacturonan II (IV) [11]. l-Glucose is a major component of littoralisone isolated from Verbena littoralis, which has a nerve growth factor potentiating activity [12,13]. Apoptolidine A (V) macrolide antibiotic, isolated from Nocardiopsis species and used to initiate selective apoptosis of tumor cells, contains a 6-deoxy-l-glucose [14,15,16]. Furthermore, l-iduronic acid is a key component of the important mammalian glycosaminoglycans heparin, heparan sulfate, and dermatan sulfate [17,18,19].

l-Hexoses are rare sugars, much less common in nature than their enantiomers, the d-hexoses, and are thus very expensive [20], which prevents the exploitation of their biological potential. Therefore, it is important to produce l-sugars from common carbohydrates by cost-effective and high-yielding synthetic routes. To meet the demand of l-sugars, various strategies have been developed for their synthesis [20,21,22,23,24], including C-5 epimerization of readily available d-sugars [25,26,27,28,29,30,31,32,33,34,35,36,37], homologation of carbohydrates with shorter chains [38,39,40,41,42], de novo synthetic routes [43,44,45,46,47,48,49,50], head to tail inversion [51,52,53,54,55,56], site selective epimerization [57,58], C-H activation [59,60], and enzymatic synthesis [61,62]. However, there are very few approaches that provide the l-sugars as glycosyl donors, e.g., in form of thioglycosides, ready for glycosylation [60,63,64,65,66]. Thus, it is highly desirable to develop new methods to produce rare sugars directly in the form of functionalized glycosyl donors suitable for oligosaccharide synthesis.

Herein, we present the synthesis of four l-sugars, the l-gulose, -allose, -galactose, and -glucose, as their highly functionalized thioglycosides from a cheaply accessible d-mannosyl thioglycoside, using the elimination-hydroboration-oxidation-based C-5 epimerization as the key transformation. The synthesis of l-sugars by hydroboration/oxidation of d-sugar-derived 5-enopyranosides has been extensively studied on α-O-glycosides, focusing mainly on d-glucosides, and to a lesser extent also on sugars of other configurations. (Scheme 1A) [25,26,67]. Recently, we have successfully extended the scope of this method to thioglycosides derived from d-glucose, thus giving direct, rapid access to l-idose glycosyl donors. (Scheme 1B) [65,66]. We demonstrated that the α-anomeric configuration is crucial and the bulky C-4 substituent is advantageous for the high l-ido selectivity and that, despite the sensitivity of sulfur to oxidation, the over-oxidation into sulfoxide is negligible [65,66]. On the basis of these results, we envisioned the expeditious synthesis of l-gulose and l-galactose donors starting from d-mannosyl and d-altrosyl thioglycosides, which are readily accessible from one of the cheapest sugars, d-mannose. Subsequent protecting group manipulation and stereoselective C-4 epimerization by either the Mitsunobu reaction or oxidation/stereoselective reduction were planned to obtain l-allose and l-glucose in the form of their thioglycosides (Scheme 1C).

The most common anomeric leaving group, thiophenyl, was chosen as the aglycone, and the incorporation of ether and ester protecting groups (that are non-participating and participating groups) into the C-2 position was also devised to make the resulting l-thioglycosides suitable for the synthesis of either α- or β-glycosides. Our synthetic design requires 5,6-unsaturated pyranosides as key intermediates on which hydroboration/oxidation can be performed. A well-documented method for preparing the pyranosyl exocyclic alkene is the base-mediated elimination of the corresponding 6-deoxy-6-iodo-glycosides, for which silver(I) fluoride (AgF) [68], potassium tert-butoxide (t-BuOK) [69], sodium hydride (NaH) [70], and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) [71,72,73,74] reagents are the most commonly used. However, monitoring of this dehydroiodination step is notoriously difficult, and it often suffers from unwanted side reactions [65,66] that may be exacerbated in the presence of base-sensitive ester protecting groups. Therefore, special attention was paid to optimizing this elimination step to make the whole synthetic procedure reliable and efficient.

While the hydroboration of d-glucoside-derived enopyranosides has been studied extensively [25,26,75,76,77], only two publications have so far addressed the hydroboration of the corresponding mannosides [25,67]. The BH₃·THF-mediated C-5 epimerization of 5-enomannoside 8 was reported to proceed with moderate diastereoselectivity [25], probably due to the steric hindrance by the C-2 substituent which hampers attack of the reagent from the β-face (Scheme 1A). A much higher l-gulo:d-manno ratio could be achieved using catecholborane and RhCl(PPh₃)₃ catalysis (Wilkinson’s catalyst), but the protecting group pattern of mannoside alkenes also proved to be an important factor in l-gulo selectivity (11→12) [67]. As our goal was to produce highly functionalized, orthogonally protected thioglycoside donors via cost-effective routes, we focused on exploiting the stereoselectivity-enhancing effects of the different protecting groups and tried to avoid the use of expensive metal catalysts.

2. Results

First, the two key transformations, elimination and hydroboration/oxidation, were tested on the ether protected derivative 25, which was obtained from the known phenyl 1-thio-α-d-mannoside derivative 23 [78,79] (Scheme 2). Regioselective reductive 4,6-acetal opening of compound 23 gave the primary alcohol 24, treatment of which with Ph₃P, iodine, and imidazole afforded the 6-iodo-mannoside 25. For the next dehydroiodination reaction, our choice was DBU as a commonly used elimination reagent, which is compatible with both ester and ether protecting groups.

Treatment of 25 with DBU (4 equiv.) in dry THF at reflux temperature (70 °C) for 5 h gave the expected unsaturated product 26, however, only with moderate yield (43%) due to the incomplete conversion of 25 and formation of by-product 27 (

Table 1. Optimization of the DBU mediated elimination reaction of 25.

Solvent	Reagent	Temperature (°C)	Time (h)	Yield (%)
THF	DBU (4 equiv.)	70	5 [a]	26: 43 27: 12 [a]
Toluene	DBU (4 equiv.)	110	2	26: 40 27: 22
THF	DBU (4 equiv.)	70	24	26: 53 27: 28

^[a] Remaining 25 was detected by TLC but was not isolated.

). The latter sugar-amidinium salt, which results from a nucleophilic substitution of iodine 25 by DBU, is quite an unusual product. Bicyclic amidine DBU features poor nucleophilicity and strong basicity [80,81,82], and although there are an increasing number of examples of it reacting as a nucleophilic agent [83,84,85], this behavior has so far not been observed in HI elimination reactions. At the same time, similar 6-deoxy-6-ammonium salts of carbohydrates have already been prepared, which have been investigated as chiral ionic liquids [86] or antibacterial agents [87,88], however, they do not contain the DBU but the remarkably more nucleophilic DABCO (1,4-diazabicyclo[2.2.2]octane) at the primary position of pyranosides.

In order to improve the yield of 26, the elimination reaction was carried out in dry toluene at elevated temperature (110 °C). After 2 h under reflux, higher conversion of the starting iodide was observed, however, the yield of 26 remained moderate (40%) and the ratio of 27 to 26 increased, indicating that the higher temperature favored the competing nucleophilic substitution rather than elimination. Changing back the solvent to THF and increasing the reaction time to 24 h yielded the expected 5,6-unsaturated derivative with 53% yield, but, unfortunately, the formation of the unwanted DBU-sugar conjugate 27 could not be suppressed.

The C-5 epimerization of 26 was performed by hydroboration with BH₃·THF complex followed by oxidation with H₂O₂ under previously optimized conditions, using 10 equiv. of the borane reagent [25,26,65,66,67]. Although the yield of the expected l-gulo-configured product 28 was only 53%, a sufficiently high l-guloside: d-mannoside ratio was observed (28:24~5:1), so it was considered worthwhile to investigate the C-5 epimerization of 1-thiomannoside alkenes having other protecting group patterns.

2.1. Synthesis of l-Gulose and l-Allose Derivatives from d-Mannose

In order to thoroughly investigate the effect of ether and ester protecting groups on the production of l-hexoses, three different substitution patterns were installed on phenyl 1-thio-α-d-mannopyranoside. In each case, (2-naphthyl)methyl ether (NAP) was introduced to the C-4 position. The 2,3-hydroxyl groups, on the other hand, were masked in varying ways, using either di-O-benzyl or di-O-benzoyl or 2-O-benzoyl-3-O-benzyl protection (Scheme 3). First, the 4,6-O-(2-naphthyl)methylene derivative of phenyl α-1-thio-d-mannoside (29) [89,90,91] was prepared from d-mannose, as a suitable starting material, in four steps using routine transformations. On route to the alternating ether–ester protecting group combination, the 3-O-benzyl-protected derivative 30 was formed by preparing the temporary 2,3-O-stannylene acetal derivative using dibutyltin oxide in dry toluene, followed by its reaction with BnBr and CsF. Position C-2 of 30 was esterified with BzCl in dry pyridine to give the expected 2-O-benzoyl-3-O-benzyl protected compound 31. Alkylation of 29 with BnBr under basic conditions gave the 2,3-di-O-benzyl derivative 32. The ester groups at positions 2 and 3 of diol 29 were formed with BzCl in dry pyridine to give 33. In compounds 31, 32, and 33, the primary hydroxyl group was liberated by regioselective reductive ring-opening reaction of the 4,6-acetal with BH₃·THF/TMSOTf reagent combination in dry dichloromethane. The expected 6-OH derivatives 34, 35, and 36 were obtained in excellent yields with complete regioselectivity. Subsequently, the primary alcohols were converted to the 6-iodo derivatives 37, 38, and 39 by treatment with triphenylphosphine, iodine, and imidazole. Since the DBU-induced elimination did not work satisfactorily in the model reaction of 25, the elimination reactions of 37–39 were studied using the three most common dehydrohalogenating reagents: NaH, DBU, and AgF.

The NaH induced elimination of the fully ether-protected mannoside 37 resulted in the expected 5,6-unsaturated 40 with an excellent, 91% yield (Scheme 4).

Treatment of 37 with DBU led to, again, the simultaneous formation of the desired alkene derivative 40 and the 6-amidinium by-product 41 in a ~5:4 ratio. The HI elimination using AgF produced the exocyclic alkene derivative in high efficacy, however, a small amount of the corresponding 6-deoxy-6-fluoro derivative 42 was also obtained due to a concomitant nucleophilic substitution reaction on compound 37.

The next tested compound was the 2,3-di-O-benzoyl derivative 38 (Scheme 5). In the NaH-mediated reaction, instead of the fully protected exocyclic alkene, the unsaturated 2,3-diol 43 was formed since, as expected, the ester groups were cleaved under the used strongly basic conditions. Unfortunately, the yield of 43 was only 17%, and the 3,6-anhydro derivative 44 was isolated as the major product with 59% yield. The predominant formation of 44 in this reaction indicates that the ester-cleavage preceded the elimination reaction and the 6-iodo-2,3-diol intermediate formed rather suffered an intramolecular nucleophilic substitution by the 3-OH than an E2 elimination reaction by NaH.

The DBU-induced elimination reaction gave the expected 5,6-unsaturated compound 45 in good yield (66%). A nucleophilic substitution reaction by DBU was also observed, although to a slightly lesser extent than for the fully ether protected 25 and 37, resulting in the quaternary amidinium salt 46 in 31% yield.

Dehydroiodination with AgF gave the expected compound 45 in moderate yield of 55%, and a double eliminated derivative (47) was isolated as the by-product. Formation of the 3-phenylthio glycal derivative 47 can be explained by elimination of the 3-OBz group followed by an allylic rearrangement reaction of the intermediate 2,3-unsaturated thioglycoside [92].

In the case of the 2-O-benzoyl-3-O-benzyl protected 39, only the 2,6-anhydro derivative 48 was formed in the elimination with NaH, in excellent yield (99%) (Scheme 6).

Using DBU as the eliminating agent, the expected unsaturated compound 49 was isolated in moderate yield (54%), and the amidinium by-product (50) was formed again in a competitive nucleophilic substitution reaction. For this derivative (39), the elimination reaction elicited by AgF gave the best result, the expected exocyclic alkene 49 was obtained in 87% yield and no by-product formation was observed.

After successful preparation of the 5,6-unsaturated derivatives, the C-5 epimerization reactions were performed on all three mannose-derived exocyclic alkenes (Scheme 7). The epimerization process included hydroboration with BH₃·THF complex in dry THF followed by oxidation with 30% H₂O₂, and hydrolysis of the resulting boronic acid ester under alkaline conditions with satd. NaHCO₃ solution. The conversion of 40, 45, and 49 into l-series proceeded with acceptable-to-high stereoselectivity, producing the expected l-gulopyranosides 51, 52, and 53 with good to excellent yields. The protecting group patterns noticeably affected both the yield and stereoselectivity of the C-5 epimerization. While only a 5.4 to 1 l-gulo:d-manno ratio was obtained with the fully ether protected 40, the l-gulo ratio significantly increased to 9.3:1 by changing the 2,3-benzyl groups into benzoyls in 45.

The highest yield and the best l-gulo selectivity was achieved from 49 having the benzoyl group at position C-2. It is hypothesized that the C-2 ester group delivers the borane to the top face through coordination to the carbonyl group, and this promotes hydride donation from the upper side to the C-5 carbon. The d-manno derivatives (34, 35, and 36) were also isolated from the reaction mixtures which can be recycled and converted to the l-gulo configured product in three steps (iodination, elimination, C-5 epimerization).

The l-gulo derivatives (51, 52, 53) were converted to the corresponding l-allopyranosides by oxidation/reduction-based C-4 epimerization in four steps (Scheme 8). First, the (2-naphthyl)methyl group was moved from position 4 to the primary position via a DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) mediated oxidative acetal ring closure under strictly anhydrous conditions followed by a reductive acetal opening with BH₃·Me₃N/AlCl₃ reagent combination of the obtaining 54, 55, and 56.

The latter reaction gave the required 4-OH products 57, 58, and 59 in a regioselective way with excellent yields. Oxidation of the free hydroxyl groups using pyridinium chlorochromate (PCC) in dry CH₂Cl₂ provided the expected 4-keto derivatives 60, 61, and 62 in good yields. The final reductive transformation was performed with l-selectride, because reduction of ulosides with l-selectride [93] at low temperature has been reported to give cis vicinal diols with high selectivity [64,94]. Reduction of compounds 60 and 62 with l-selectride occurred, indeed, with high stereoselectivity producing the expected equatorial 4-OH-containing l-allopyranosides 63 and 65 in excellent yields. However, reduction of the 2,3-di-O-benzoyl derivative 61 resulted in an inseparable 5:1 mixture of the l-gulo (58) and l-allo (64) configured products. The epimeric ratio was determined on the basis of the ¹H NMR spectrum showing the H-3 l-gulo signal at 5.75 ppm and H-3 l-allo signal at 6.10 ppm. The high allo-selectivity in the reduction of 63 and 65 can be explained by the Cram’s chelation model [95]. In the present case, the metal coordinates to the carbonyl and O-3, hindering the attack by the reagent from the top-face, thus the hydride attacks from the bottom-face resulting selectively in the allo-epimers. The low and opposite stereoselectivity observed in the reduction of 61 was surprising, but literature survey revealed similar examples when no chelate control was observed during the reduction in the presence of an adjacent ester group [64,96,97]. The probable cause is that an ester protected oxygen lacks chelating ability due to the electron-withdrawing properties of the ester group. In the case of 61, coordination of the metal to O-6 might be possible at the bottom-side, facilitating the attack of the hydride from the upper-side.

2.2. Synthesis of l-Galactose and l-Glucose Derivatives from d-Mannose through d-altrose

After successful conversion of highly functionalized d-mannosides to l-gulopyranosyl and l-allopyranosyl donors, our attention turned to the synthesis of l-galacto and l-gluco derivatives, which is achievable from d-mannose through d-altrose. First, mannoside 29 was converted to the functionalized d-altrose thioglycosides 72 and 73 ready for the elimination reactions (Scheme 9). The C-2 hydroxyl group of diol 29 was selectively protected with a benzoyl group via introduction of a cyclic orthobenzoate to the 2,3-cis diol followed by regioselective orthoester opening under acidic conditions to give the axial ester 66 in an acceptable yield. Oxidation-stereoselective reduction was applied for C-3 epimerization, taking advantage of the inability of the C-2 benzoyl group to form chelates thereby favouring the hydride attack from the sterically less crowded β-side and providing the required trans diol. Oxidation of the free hydroxyl of 66 with PCC followed by reduction of the keto derivative with NaBH₄ indeed predominantly inverted the configuration of C-3 group to give the needed d-altro configured product 67 with 58% yield. This compound was converted to the 2,3-di-O-benzylated derivative 68 in two steps including Zemplén deacylation and benzylation of the liberated hydroxyls using NaH and BnBr. A dibenzoylated derivative was also formed from 67 by esterification with BzCl in dry pyridine to give the expected 2,3-di-O-benzoyl derivative 69 in good yield.

The C-6-OH group of the fully protected compounds (68, 69) was liberated by regioselective reductive ring-opening reactions using the BH₃·THF/TMSOTf reagent combination. The primary hydroxyl in the resulting 70 and 71 was converted to a good leaving group by the treatment of Ph₃P, iodine, and imidazole to give the C-6-iodide derivatives 72 and 73 in excellent yields.

As in the case of mannosides, the dehydroiodination of altropyranosides 72 and 73 was studied using three different reagents: NaH, DBU, and AgF (Scheme 10). In the elimination reaction of the fully ether protected 72 with NaH, the expected 5,6-unsaturated compound 74 was formed in excellent yield. This exocyclic alkene was also obtained in the DBU-induced reaction with acceptable yield (58%), however, the DBU-conjugated amidinium salt 75, formed in a concomitant nucleophilic replacement reaction, was also isolated from the reaction mixture in 41% yield. The dehydrohalogenation by AgF proceeded much more slowly than in the case of the d-manno configured molecule. Even after a reaction time of 48 h, the unsaturated 74 was only obtained in moderate 52% yield. No by-product was isolated from this reaction, but 19% of the starting 72 was recovered.

Treatment of the 2,3-di-O-benzoylated derivative 73 with NaH led to, similarly to the d-mannose case, deacylation followed by dehydroiodination and concomitant formation of a 2,6-anhydro-altroside (77) by an intramolecular replacement of the 6-iodide (Scheme 11). Here, in contrast to the manno case, the 5,6-unsaturated 76 was isolated as the major product with 43% yield, and the 2,6-anhydrosugar by-product 77 was formed only in 22% yield.

The diol 76 was efficiently converted to the required 78 by routine esterification with benzoyl chloride. In the DBU-induced reaction, formation of the expected alkene 78 was accompanied, as in the previous reactions, by a nucleophilic substitution reaction leading to the quaternary amidinium salt 79 (42%). The AgF mediated reaction yielded the expected 5,6-unsaturated 78 in a moderate yield (53%), and by-product 47, derived from a secondary elimination of 78 to a 2,5-dienoside followed by an allylic rearrangement reaction, was also isolated. Importantly, this compound was identical to those formed from mannoside 38 under the same conditions.

After successfully synthesizing the 5,6-unsaturated 74 and 78, C-5 epimerization was performed on both derivatives using the hydroboration/oxidation reaction described previously (Scheme 12).

The expected l-galacto configured products were formed in the reactions in good yields (80, 81) and the corresponding d-altrose epimers were not detected in the reaction mixtures. As observed for mannoside-derived alkenes, C-5 epimerization was more efficient with ester protection than with ether protection. Following the epimerization scheme developed for l-guloside, the obtained l-galacto derivatives (80, 81) were converted to the corresponding l-gluco epimers (86, 87) in three steps (Scheme 13).

First, as before, in a combination of a DDQ-mediated oxidative acetal cyclization (82, 83) and a regioselective reductive ring-opening reaction, the NAP group at position C-4 was moved to position C-6, thus releasing the 4-OH group (84, 85). The 4,6-acetalated l-galacto derivative 83 was produced in crystalline form and its structure was confirmed by X-ray diffraction study (Figure 2).

In the presence of a chelating adjacent C-3-O-benzyl group to the resulting keto function after oxidation of 84, the oxidation/reduction would result in reformation of the galactose isomer due to chelation to O-3 at the bottom face of the pyranose ring. Therefore, our attention turned to Mitsunobu isomerization as an appropriate method to convert the 3,4-cis diol of 84 and 85 to the required trans diol structure [64]. The Mitsunobu epimerization of C-4-OH was performed with p-nitrobenzoic acid, triphenylphosphine (Ph₃P), and diisopropyl azodicarboxylate (DIAD) reagents in dry toluene. In the case of the ether-protected derivative, the fully protected product 86 with the desired l-gluco configuration was obtained in good yield. However, the 2,3-O-benzoyl-containing compound (85) could only be converted to the expected l-gluco configured product 87 in a moderate yield of 51%. We observed that an elimination reaction also took place producing the 4-deoxy-4,5-unsaturated derivative 88 as a by-product. This compound was formed by E2 elimination of the antiperiplanar 5-H_axial and the oxyphosphonium ion intermediate, which is presumably facilitated by the ester groups [64,98,99].

3. Materials and Methods

3.1. General Information

Optical rotations were measured at room temperature on a Perkin-Elmer 241 automatic polarimeter. TLC analysis was performed on Kieselgel 60 F₂₅₄ (Merck Millipore, Burlington, MA, USA) silica-gel plates with visualization by immersing in a sulphuric-acid solution (5% in EtOH) followed by heating. Column chromatography was performed on silica gel 60 (Merck 0.063–0.200 mm). Organic solutions were dried over MgSO₄ and concentrated under vacuum. ¹H and J-modulated ¹³C NMR spectroscopy (¹H: 400 and 500 MHz; ¹³C: 100.28 and 125.76 MHz) were performed on Bruker DRX-400 and Bruker Avance II 500 spectrometers at 25 °C. Chemical shifts are referenced to SiMe₄ or sodium 3-(trimethylsilyl)-1-propanesulfonate (DSS, δ = 0.00 ppm for ¹H nuclei) and to residual solvent signals (CDCl₃: δ = 77.16 ppm, CD₃OD: δ = 49.15 ppm for ¹³C nuclei). ESI-TOF MS spectra were recorded by a microTOF-Q type QqTOFMS mass spectrometer (Bruker) in the positive ion mode using MeOH as the solvent. HRMS measurements were carried out on a maXis II UHR ESI-QTOF MS instrument (Bruker) in positive ionization mode. The following parameters were applied for the electrospray ion source: capillary voltage: 3.6 kV; end plate offset: 500 V; nebulizer pressure: 0.5 bar; dry gas temperature: 200 °C; and dry gas flow rate: 4.0 L/min. Constant background correction was applied for each spectrum. The background was recorded before each sample by injecting the blank sample matrix (solvent). Na-formate calibrant was injected after each sample, which enabled internal calibration during data evaluation. Mass spectra were recorded by otofControl version 4.1 (build: 3.5, Bruker) and processed by Compass DataAnalysis version 4.4 (build: 200.55.2969). Deposition Number 2163274 for compound 83 contains the supplementary crystallo-graphic data for this paper (see Supplementary Materials). These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service.

3.2. General Methods

3.2.1. General Method A for Iodination (25, 37, 38, 39, 72, 73)

To the solution of the corresponding 6-OH compound (24, 34, 35, 36, 70, and 71) (2.662 mmol) in dry toluene (24 mL), triphenylphosphine (1.05 g, 3.993 mmol, 1.5 equiv.), imidazole (544 mg, 7.986 mmol, 3.0 equiv.), and iodine (946 mg, 3.727 mmol, 1.4 equiv.) were added. The reaction mixture was stirred at 75 °C for 30 min then cooled to room temperature. To the stirred mixture, NaHCO₃ (1.0 g) in water (14 mL) was added at room temperature. After 5 min, 10% aqueous solution of Na₂S₂O₃ (25 mL) was added and the mixture was diluted with EtOAc (250 mL) and washed with H₂O (2 × 75 mL). The organic layer was separated, dried, filtered, and concentrated.

3.2.2. General Method B for Elimination of Iodide with DBU (26, 40, 45, 49, 74, 78)

To the solution of the appropriate 6-iodide compound (25, 37, 38, 39, 72, and 73) (0.427 mmol), dry THF (10 mL) heated to 75 °C and DBU (254 μL, 1.708 mmol, 4.0 equiv.) was added. The reaction mixture was stirred at 75 °C for 24 h. When the TLC showed complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure.

3.2.3. General Method C for Hydroboration and Oxidation (28, 51, 52, 53, 80, 81)

To the solution of the appropriate 5,6-unsaturated compound (26, 40, 45, 49, 74, and 78) (0.969 mmol) in dry THF (2.5 mL), BH₃·THF complex (1M in THF, 10.1 mL, 9.690 mmol, 10.0 equiv.) was added. The reaction mixture was stirred at 0 °C for 1.5 h. After 1.5 h, 30% aqueous solution of H₂O₂ (2.5 mL) and saturated aqueous solution of NaHCO₃ (8.7 mL) were added. The reaction mixture was stirred at room temperature for 50 min (28) or 2 h (51, 52, 53, 80, 81). The mixture was diluted with EtOAc (150 mL) and washed with saturated aqueous solution of NH₄Cl (2 × 25 mL), H₂O (25 mL) and saturated aqueous solution of NaCl (25 mL) until neutral pH. The organic layer was dried and concentrated.

3.2.4. General Method D for Stereoselective Ring Opening with BH₃·THF/TMSOTf (34, 35, 36, 70, 71)

To a solution of the appropriate acetal (31, 32, 33, 68, and 69) (0.500 mmol) in dry CH₂Cl₂ (5.0 mL), BH₃·THF complex (1M in THF, 2.5 mL, 2.500 mmol, 5.0 equiv.) and TMSOTf (14 μL, 0.075 mmol, 0.15 equiv.) were added at 0 °C and the reaction mixture was stirred under argon for 1.5 h (34), 2 h (36, 70, 71), or 2.5 h (35) at room temperature. Next, Et₃N (1.0 mL) was added, followed by careful addition of MeOH until the H₂ evolution ceased. The mixture was concentrated, and the residue was coevaporated with MeOH (3 × 10 mL).

3.2.5. General Method E for Elimination of Iodide with NaH (40, 43, 48, 74, 76)

A vigorously stirred solution of the corresponding 6-iodide compound (37, 38, 39, 72, and 73) (0.703 mmol) in dry DMF (4.6 mL) was cooled to 0 °C, NaH (2.812 mmol, 4.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 5 h (43), 6 h (48), or 24 h (40, 74, 76). After the complete disappearance of the starting material, MeOH (0.5 mL) was added, and the mixture was concentrated. The residue was dissolved in CH₂Cl₂ (50 mL) and washed with H₂O (2 × 10 mL). The organic layer was separated, dried, filtered and concentrated.

3.2.6. General Method F for Elimination of Iodide with AgF (40, 45, 49, 74, 78)

A solution of the appropriate 6-iodide compound (37, 38, 39, 72, and 73) (0.427 mmol) in dry pyridine (5.0 mL) under argon atmosphere AgF (270 mg, 2.135 mmol, 5.0 equiv.) was added and the mixture was stirred at room temperature for 24 h (40, 45, 49) or 48 h (74, 78) in dark. After that time, the reaction mixture was diluted with Et₂O (100 mL), and the solution was filtered through a pad of Cellite, washed with Et₂O, and concentrated.

3.2.7. General Method G for Ring Closing with DDQ (54, 55, 56, 82, 83)

To a vigorously stirred solution of the corresponding 6-OH compound (51, 52, 53, 80, and 81) (1.402 mmol) in dry CH₂Cl₂ (42 mL), DDQ (478 mg, 2.104 mmol, 1.5 equiv.) and 4 Å MS (400 mg) were added and the reaction mixture was stirred for 2 h at 0 °C. After 2 h, the mixture was diluted with CH₂Cl₂ (350 mL), filtered, washed with a saturated aqueous solution of NaHCO₃ (2 × 65 mL) and H₂O (2 × 65 mL). The organic layer was then dried, filtered and concentrated.

3.2.8. General Method H for Stereoselective Ring Opening with Me₃N·BH₃/AlCl₃ (57, 58, 59, 84, 85)

To a solution of the appropriate 4,6-acetal (54, 55, 56, 82, and 83) (0.145 mmol) in dry THF (500 μL), 4 Å MS (111 mg) and Me₃N·BH₃ (64 mg, 0.874 mmol, 6.0 equiv.) were added and the reaction mixture was stirred for 30 min at room temperature. After 30 min, the reaction mixture was cooled to 0 °C and AlCl₃ (117 mg, 0.874 mmol, 6.0 equiv.) was added, the cooling medium was removed, and the mixture was stirred at room temperature for 1 h. After 1 h, the reaction mixture was diluted with CH₂Cl₂ (100 mL) and washed with H₂O (2 × 15 mL). The organic layer was dried, filtered, and concentrated.

3.2.9. General Method I for Oxidation with PCC (60, 61, 62)

To the solution of the corresponding 4-OH compound (57, 58, and 59) (0.270 mmol) in dry CH₂Cl₂ (3.5 mL), 4 Å MS (10 p.) and PCC (233 mg, 1.080 mmol, 4.0 equiv.) were added under argon and stirred for 5 h at room temperature. After 5 h, the reaction mixture was diluted with n-hexane/Et₂O = 1:1 (5.0 mL) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure.

3.2.10. General Method J for Reduction with l-Selectride (63, 64, 65)

l-Selectride (1.0 M in THF; 254 µL, 0.254 mmol, 1.5 equiv.) was added to a solution of the corresponding 4-keto compound (60, 61, and 62) (0.169 mmol) in dry THF (2.0 mL) at −78 °C under argon. The reaction mixture was stirred at –78 °C for 1 h, then the temperature was raised to −20 °C over a period of 1 h. Subsequently, the reaction was quenched with water, and the mixture was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic extracts were washed with saturated aqueous solution of NaHCO₃ and brine, dried, filtered, and concentrated.

3.2.11. General Method K for C-4 Epimerization by Mitsunobu Reaction (86, 87)

To the solution of the appropriate 4-OH compound (84 and 85) (0.040 mmol) in toluene (440 μL) Ph₃P (0.242 mmol, 6.0 equiv.), p-nitrobenzoic acid (0.242 mmol, 6.0 equiv.) and diisopropyl azodicarboxylate (0.242 mmol, 6.0 equiv.) were added. The mixture was stirred at room temperature under argon atmosphere for 15 h. Subsequently, the reaction was quenched with saturated aqueous solution of NaHCO₃, and the mixture was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic extracts were washed with water (10 mL), dried, filtered, and concentrated.

3.2.12. Synthesis of l-Gulose and l-Allose Derivatives from d-Mannose

Phenyl 2,4-di-O-benzyl-3-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (24). The acetal derivative 23 [79] (2.53 g, 4.272 mmol) was dissolved in anhydrous CH₂Cl₂ (38.5 mL) and anhydrous Et₂O (13 mL). LiAlH₄ (729 mg, 19.224 mmol, 4.5 equiv.) was added, and then a solution of AlCl₃ (2.57 g, 19.224 mmol, 4.5 equiv.) in anhydrous Et₂O (13 mL) was added. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with EtOAc (86 mL) and H₂O (21.5 mL), the precipitated solid was filtered through a pad of Celite, and the filter cake was washed with ethyl acetate. The filtrate was washed with water (2 × 25 mL), dried over MgSO₄, filtered and concentrated. The crude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give 24 (2.01 g, 79%) as a colorless syrup. [α]_D²⁵ +51.2 (c 0.54, CHCl₃); R_f 0.38 (7:3 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 7.84–7.26 (22H, arom.), 5.51 (s, 1H, H-1), 4.99 (d, J = 10.9 Hz, 1H, BnCH₂a), 4.81–4.67 (m, 5H, BnCH₂b, BnCH₂, NAPCH₂), 4.14–4.12 (m, 1H, H-5), 4.07 (t, J = 9.3 Hz, 1H, H-4), 4.02 (s, 1H, H-2), 3.96 (d, J = 8.9 Hz, 1H, H-3), 3.86–3.80 (m, 2H, H-6-a,b), 1.83 (t, J = 6.2 Hz, 1H, C-6-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 138.4, 137.9, 135.7, 134.0, 133.4, 133.1 (6C, 6 × C_q arom.), 132.0–126.0 (22C, arom.), 86.1 (1C, C-1), 80.2 (1C, C-3), 76.5 (1C, C-2), 75.5 (1C, NAPCH₂), 74.9 (1C, C-4), 73.4 (1C, C-5), 72.4 (2C, 2 × BnCH₂), 62.3 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₆NaO₅S [M + Na]⁺ 615.2176; found: 615.2168.

Phenyl 2,4-di-O-benzyl-6-deoxy-6-iodo-3-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (25). Compound 24 (1.94 g, 3.270 mmol) was converted to 25 according to general Method A. The crude product was purified by silica gel chromatography (8:2 n-hexane/EtOAc) to give 25 (1.52 g, 66%) as a colorless syrup. [α]_D²⁵ + 50.5 (c 0.21, CHCl₃); R_f 0.72 (7:3 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 7.84–7.22 (22H, arom.), 5.58 (s, 1H, H-1), 5.04 (d, J = 10.9 Hz, 1H, BnCH₂a), 4.74–4.72 (m, 4H, NAPCH₂, BnCH₂), 4.64 (d, J = 12.3 Hz, 1H, BnCH₂b), 4.04 (s, 1H, H-2), 3.96–3.93 (m, 3H, H-3, H-4, H-5), 3.53 (d, J = 10.3 Hz, 1H, H-6a), 3.43 (dd, J = 5.1 Hz, J = 10.4 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 138.4, 137.9, 135.5, 134.2, 133.4, 133.1 (6C, 6 × C_q arom.), 131.8–126.0 (22C, arom.), 85.9 (1C, C-1), 79.9, 78.7 (2C, C-3, C-4), 76.5 (1C, C-2), 75.7 (1C, NAPCH₂), 72.2 (1C, C-5), 72.2, 72.1 (2C, 2 × BnCH₂), 7.1 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₅INaO₄S [M + Na]⁺ 725.1193; found: 725.1195.

Phenyl 2,4-di-O-benzyl-3-O-(2′-naphthyl)methyl-1-thio-α-d-lyxo-hex-5-enopyranoside (26) and 8-N-[phenyl 2,4-di-O-benzyl-6-deoxy-6-yl-3-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside]-1,8-diazabicyclo(5.4.0)undec-7-ene-iodide (27).

Reaction I.: Compound 25 (439 mg, 0.625 mmol) was converted to 26 according to general Method B using DBU (372 µL, 2.500 mmol, 4.0 equiv.) and refluxed (70 °C) for 5 h. The crude product was purified by silica gel chromatography (8:2 n-hexane/acetone) to give 26 (155 mg, 43%) as a colorless syrup and 27 (45 mg, 12%) as a colorless syrup.

Reaction II.: To a solution of compound 25 (323 mg, 0.460 mmol) in dry toluene (4.0 mL), DBU (274 µL, 1.839 mmol, 4.0 equiv.) was added and the mixture was stirred for 2 h at 110 °C. The reaction mixture was diluted with CH₂Cl₂ (100 mL), washed with 10% aqueous solution of Na₂S₂O₃ (20 mL), 1M aqueous solution of HCl (2 × 20 mL), saturated aqueous solution of NaHCO₃ (20 mL), and H₂O (2 × 20 mL) until neutral pH. The organic layer was dried over MgSO₄, filtered, and concentrated. The crude product was purified by silica gel chromatography (8:2 n-hexane/acetone → 9:1 CH₂Cl₂/MeOH) to give 26 (107 mg, 40%) as a colorless syrup and 27 (73 mg, 22%) as a light yellow syrup.

Reaction III.: Compound 25 (328 mg, 0.467 mmol) was converted to 26 according to general Method B using DBU (278 µL, 1.868 mmol, 4.0 equiv.) and refluxed for 24 h. The crude product was purified by silica gel chromatography (8:2 n-hexane/acetone → 9:1 CH₂Cl₂/MeOH) to give 26 (141 mg, 53%) as a colorless syrup and 27 (94 mg, 28%) as a light yellow syrup.

Data of 26: [α]_D²⁵ +53.5 (c 0.14, CHCl₃); R_f 0.43 (8:2 n-hexane/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 7.81–7.22 (m, 22H, arom), 5.48 (d, J = 4.7 Hz, 1H, H-1), 4.86–4.60 (m, 8H, H-6a,b, 2 × BnCH₂, NAPCH₂), 4.29 (d, J = 7.5 Hz, 1H, H-4), 4.02 (d, J = 3.3 Hz, 1H, H-2), 3.94 (dd, J = 1.6 Hz, J = 7.2 Hz, 1H, H-3) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 154.5 (1C, C-5), 138.2, 137.9, 135.8, 133.7, 133.3, 133.1 (6C, 6 × C_q arom.), 132.0–125.9 (22C, arom.), 99.1 (1C, C-6), 86.4 (1C, C-1), 77.3 (1C, C-3), 76.3 (1C, C-4), 76.0 (1C, C-2), 73.1, 72.8 (3C, 2 × BnCH₂, NAPCH₂) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₄NaO₄S [M + Na]⁺ 597.2070; found: 597.2070.

Data of 27: [α]_D²⁵ +66.7 (c 0.24, CHCl₃); R_f 0.49 (9:1 CH₂Cl₂/MeOH); ¹H NMR (400 MHz, MeOD) δ = 7.85–7.26 (m, 22H, arom.), 5.83 (s, 1H, H-1), 5.00–4.63 (m, 6H, 2 × BnCH₂, NAPCH₂), 4.17–4.15 (m, 1H, H-2), 4.06 (td, J = 1.7 Hz, J = 9.4 Hz, 1H, H-5), 3.97 (dd, J = 3.0 Hz, J = 9.1 Hz, 1H, H-3), 3.75 (t, J = 9.5 Hz, 1H, H-4), 3.69–3.60 (m, 2H, H-6a,b), 3.54–3.46 (m, 2H, NCH₂ DBU), 3.25–3.16 (m, 4H, 2 × NCH₂ DBU), 2.70–2.59 (m, 2H, CH₂ DBU), 1.67–1.27 (m, 8H, 4 × CH₂ DBU) ppm; ¹³C NMR (100 MHz, MeOD) δ = 168.5 (1C, C_q DBU), 139.5, 139.3, 136.7, 134.7, 134.5, 134.1 (6C, 6 × C_q arom.), 132.3–127.2 (22C, arom.), 85.2 (1C, C-1), 80.9 (1C, C-3), 77.1, 76.9 (2C, C-2, C-4), 76.1, 73.8, 72.7 (3C, 2 × BnCH₂, NAPCH₂), 72.3 (1C, C-5), 56.0, 55.7, 50.0, 49.6 (4C, C-6, 3 × NCH₂ DBU), 29.2, 29.1, 26.8, 23.8, 20.7 (5C, 5 × CH₂ DBU) ppm; UHR ESI-QTOF: m/z calcd for C₄₆H₅₁N₂O₄S [M]⁺ 727.3564; found: 727.3568.

Phenyl 2,4-di-O-benzyl-3-O-(2′-naphthyl)methyl-1-thio-β-l-gulopyranoside (28). Compound 26 (190 mg, 0.331 mmol) was converted to 28 according to general Method C. The crude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give 28 (104 mg, 53%) as a colorless syrup and 24 (24 mg, 12%) as a colorless syrup. [α]_D²⁵ +11.4 (c 0.21, CHCl₃); R_f 0.33 (6:4 n-hexane/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 7.82–6.94 (m, 22H, arom.), 5.27 (d, J = 9.8 Hz, 1H, H-1), 4.84–4.14 (m, 6H, 2 × BnCH₂, NAPCH₂), 3.98 (d, J = 4.5 Hz, 1H, H-5), 3.84–3.80 (m, 1H, H-6a), 3.76 (s, 2H, H-2, H-3), 3.50 (d, J = 8.4 Hz, 1H, H-6b), 3.39 (s, 1H, H-4), 1.91 (s, 1H, C-6-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 138.0, 137.6, 135.6, 134.1, 133.2, 133.1 (6C, 6 × C_q arom.), 131.7–126.1 (22C, arom.), 84.2 (1C, C-1), 76.0 (1C, C-5), 75.3 (1C, C-4), 75.1 (1C, C-3), 73.6, 73.1, 72.2 (3C, 2 × BnCH₂, NAPCH₂), 72.7 (1C, C-2), 62.5 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₆NaO₅S [M + Na]⁺ 615.2176; found: 615.2174.

Phenyl 3-O-benzyl-4,6-O-(2′-naphthyl)methylidene-1-thio-α-d-mannopyranoside (30). To a solution of compound 29 [91] (4.09 g, 10.00 mmol) in dry toluene (71 mL), dibutyltin oxide (3.644 g, 15.00 mmol, 1.5 equiv.) was added. The solution was refluxed (110 °C) under argon atmosphere for 4 h. Then, after cooling to room temperature, the solvent was evaporated to dryness and the crude product was dried on high vacuum for 2 h. The residue was dissolved in dry DMF (36 mL), and CsF (3.04 g, 2.001 mmol) and BnBr (1.78 mL, 15.00 mmol, 1.5 equiv.) were added. The reaction mixture was stirred at 90 °C for 24 h. The reaction mixture was filtered and evaporated to dryness. The residue was dissolved in EtOAc (250 mL) and washed with H₂O (2 × 25 mL). The organic layer was separated, dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by crystallization from acetone/n-hexane to give 30 (3.59 g, 73%) as white crystals. [α]_D²⁵ +244.2 (c 0.19, CHCl₃); M.p. = 194–197 °C (acetone/n-hexane); R_f 0.32 (7:3 n-hexane/acetone); ¹H NMR (400 MHz, CDCl₃) δ = 7.98–7.20 (m, 17H, arom.), 5.75 (s, 1H, H_ac), 5.59 (s, 1H, H-1), 4.88 (d, J = 11.8 Hz, 1H, BnCH₂a), 4.74 (d, J = 11.8 Hz, 1H, BnCH₂b), 4.38 (td, J = 4.8 Hz, J = 9.7 Hz, 1H, H-5), 4.26–4.21 (m, 3H), 3.98 (dd, J = 3.2 Hz, J = 9.5 Hz, 1H), 3.90 (t, J = 10.2 Hz, 1H), 3.02 (d, J = 5.3 Hz, 1H, C-2-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 137.8, 134.9, 133.7, 133.4, 133.0 (5C, 5 × C_q arom.), 131.8–123.9 (17C, arom.), 101.9 (1C, C_ac), 88.0 (1C, C-1), 79.2, 75.9, 71.5, 64.8 (4C, C-2, C-3, C-4, C-5), 73.3 (1C, BnCH₂), 68.7 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₀H₂₈NaO₅S [M + Na]⁺ 523.1550; found: 523.1545.

Phenyl 2-O-benzoyl-3-O-benzyl-4,6-O-(2′-naphthyl)methylidene-1-thio-α-d-mannopyranoside (31). To a stirred solution of compound 30 (3.48 g, 5.807 mmol) in dry pyridine (15 mL), BzCl (0.85 mL, 7.259 mmol, 1.25 equiv./OH) was added at 0 °C and the reaction mixture was stirred for 24 h at room temperature. After 24 h, the mixture was diluted with CH₂Cl₂ (300 mL), washed with H₂O (2 × 75 mL), 1M aqueous solution of H₂SO₄ (2 × 75 mL), H₂O (2 × 75 mL), saturated aqueous solution of NaHCO₃ (2 × 75 mL), and H₂O (2 × 75 mL) until neutral pH. The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (7:3 n-hexane/acetone) to give 31 (3.56 g, 72%) as a colorless syrup. [α]_D²⁵ + 73.3 (c 0.34, CHCl₃); R_f 0.52 (7:3 n-hexane/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 8.12–7.20 (m, 22H, arom.), 5.87 (s, 1H, H_ac), 5.85 (s, 1H, H-2), 5.64 (s, 1H, H-1), 4.76 (q, J = 12.2 Hz, 2H, BnCH₂), 4.49–4.47 (m, 1H, H-5), 4.36–4.32 (m, 2H, H-4, H-6a), 4.17 (d, J = 9.6 Hz, 1H, H-3), 3.97 (t, J = 10.1 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.8 (1C, C_q Bz), 137.8, 134.9, 133.8, 133.2, 133.1, 129.7 (6C, 6 × C_q arom.), 133.5–123.9 (22C, arom.), 102.0 (1C, C_ac), 87.4 (1C, C-1), 79.1 (1C, C-4), 74.4 (1C, C-3), 72.3 (1C, BnCH₂), 72.0 (1C, C-2), 68.7 (1C, C-6), 65.4 (1C, C-5) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₂NaO₆S [M + Na]⁺ 627.1812; found: 627.1819.

Phenyl 2,3-di-O-benzyl-4,6-O-(2′-naphthyl)methylidene-1-thio-α-d-mannopyranoside (32). To a solution of compound 29 [91] (3.99 g, 9.840 mmol) in dry DMF (43 mL), NaH (60%, 984 mg, 24.60 mmol, 1.25 equiv./OH) was added in portions at 0 °C. After 30 min at that temperature, BnBr (2.8 mL, 23.61 mmol, 1.25 equiv./OH) was added and the mixture was stirred for 24 h at room temperature. Next, MeOH (5.0 mL) was added, the reaction mixture was stirred for 15 min, and the solvents were evaporated. The residue was dissolved in CH₂Cl₂ (300 mL) and washed in H₂O (3 × 50 mL) until neutral pH. The organic layer was dried over MgSO₄ and concentrated. The crude product was purified by silica gel chromatography (9:1 n-hexane/acetone) to give 32 (3.75 g, 65%) as a colorless syrup. [α]_D²⁵ + 116.5 (c 0.36, CHCl₃); R_f 0.29 (9:1 n-hexane/acetone); ¹H NMR (400 MHz, CDCl₃) δ = 8.00–7.22 (m, 22H, arom.), 5.80 (s, 1H, H_ac), 5.53 (d, J = 1.2 Hz, 1H, H-1), 4.83 (d, J = 12.2 Hz, 1H, BnCH₂a), 4.73 (s, 2H, BnCH₂), 4.67 (d, J = 12.2 Hz, 1H, BnCH₂b), 4.41–4.33 (m, 2H, H-5, H-6a), 4.27 (dd, J = 4.4 Hz, J = 10.2 Hz, 1H, H-6b), 4.07 (dd, J = 1.3 Hz, J = 3.1 Hz, 1H, H-2), 4.00 (dd, J = 3.2 Hz, J = 9.4 Hz, 1H, H-3), 3.94 (t, J = 9.8 Hz, 1H, H-4) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 138.5, 137.9, 135.1, 133.9, 133.7, 133.1 (6C, 6 × C_q arom.), 131.8–123.9 (22C, arom.), 101.8 (1C, C_ac), 87.3 (1C, C-1), 79.3, 78.2, 76.4 (3C, C-2, C-3, C-4), 73.2, 73.1 (2C, 2 × BnCH₂), 68.7 (1C, C-6), 65.6 (1C, C-5) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₄NaO₅S [M + Na]⁺ 613.2019; found: 613.2039.

Phenyl 2,3-di-O-benzoyl-4,6-O-(2′-naphthyl)methylidene-1-thio-α-d-mannopyranoside (33). To a stirred solution of compound 29 [91] (4.10 g, 10.10 mmol) in pyridine (25 mL), BzCl (2.92 mL, 25.20 mmol, 1.25 equiv./OH) was added at 0 °C and the reaction mixture was stirred for 24 h at room temperature. After 24 h, the mixture was diluted with CH₂Cl₂ (300 mL), washed with H₂O (150 mL), 1M aqueous solution of H₂SO₄ (2 × 150 mL), H₂O (150 mL), saturated aqueous solution of NaHCO₃ (2 × 150 mL), and H₂O (150 mL) until neutral pH. The organic layer was separated, dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (7:3 n-hexane/acetone) to give 33 (4.38 g, 71%) as a colorless syrup. [α]_D²⁵ − 15.7 (c 0.22, CHCl₃); R_f 0.46 (7:3 n-hexane/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 8.10–7.23 (m, 22H, arom.), 5.99 (dd, J = 1.3 Hz, J = 3.4 Hz, 1H, H-2), 5.86 (dd, J = 3.4 Hz, J = 10.3 Hz, 1H, H-3), 5.84 (s, 1H, H_ac), 5.70 (d, J = 1.1 Hz, 1H, H-1), 4.69 (td, J = 4.8 Hz, J = 9.8 Hz, 1H, H-5), 4.48 (t, J = 9.9 Hz, 1H, H-6a), 4.38 (dd, J = 4.9 Hz, J = 10.4 Hz, 1H, H-4), 4.03 (t, J = 10.3 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.6, 165.4 (2C, 2 × C_q Bz), 134.5, 133.8, 133.0, 129.7, 129.6 (6C, 6 × C_q arom.), 133.8–123.9 (22C, arom.), 102.3 (1C, C_ac), 87.2 (1C, C-1), 77.2, 72.6, 69.4, 65.5 (4C, C-2, C-3, C-4, C-5), 68.8 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₀NaO₇S [M + Na]⁺ 641.1604; found: 641.1603.

Phenyl 2,3-di-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (34). Compound 32 (3.46 g, 5.850 mmol) was converted to 34 according to general Method D. The crude product was purified by silica gel chromatography (7:3 n-hexane/acetone) to give 34 (3.44 g, 99%) as a colorless syrup. [α]_D²⁵ + 81.4 (c 0.37, CHCl₃); R_f 0.39 (7:3 n-hexane/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 7.81–7.27 (m, 22H, arom.), 5.52 (s, 1H, H-1), 5.10 (d, J = 11.1 Hz, 1H, BnCH₂a), 4.83 (d, J = 11.0 Hz, 1H, BnCH₂b), 4.69 (s, 2H, NAPCH₂), 4.65 (s, 2H, BnCH₂), 4.17–4.15 (m, 1H, H-5), 4.10 (t, J = 9.3 Hz, 1H, H-4), 4.02 (s, 1H, H-2), 3.92 (d, J = 8.9 Hz, 1H, H-3), 3.86–3.82 (m, 2H, H-6-a,b), 1.88 (s, 1H, C-6-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 138.2, 137.9, 135.9, 134.0, 133.4, 133.1 (6C, 6 × C_q arom.), 132.0–126.0 (22C, arom.), 86.2 (1C, C-1), 80.2 (1C, C-3), 76.5 (1C, C-2), 75.4 (1C, NAPCH₂), 74.5 (1C, C-4), 73.4 (1C, C-5), 72.5, 72.3 (2C, 2 × BnCH₂), 62.3 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₆NaO₅S [M + Na]⁺ 615.2176; found: 615.2196.

Phenyl 2,3-di-O-benzoyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (35). Compound 33 (4.83 g, 7.788 mmol) was converted to 35 according to general Method D. The crude product was purified by silica gel chromatography (65:35 n-hexane/acetone) to give 35 (4.16 g, 95%) as a colorless syrup. [α]_D²⁵ +8.1 (c 0.32, CHCl₃); R_f 0.46 (6:4 n-hexane/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 8.01–7.24 (m, 22H, arom.), 5.86 (d, J = 1.3 Hz, 1H, H-2), 5.79 (dd, J = 3.2 Hz, J = 8.9 Hz, 1H, H-3), 5.65 (s, 1H, H-1), 4.89 (s, 2H, NAPCH₂), 4.44–4.41 (m, 2H, H-4, H-5), 3.96 (s, 2H, H-6a,b), 1.92 (s, 1H, H-6-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.5, 165.4 (2C, 2 × C_q Bz), 135.1, 133.3, 133.2, 133.1, 129.6 (6C, 6 × C_q arom.), 133.6–126.1 (22C, arom.), 86.2 (1C, C-1), 75.3 (1C, NAPCH₂), 73.3, 73.0 (2C, C-4, C-5), 72.7 (1C, C-3), 72.6 (1C, C-2), 61.8 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₂NaO₇S [M + Na]⁺ 643.1761; found: 643.1742.

Phenyl 2-O-benzoyl-3-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (36). Compound 31 (3.56 g, 5.899 mmol) was converted to 36 according to general Method D. The crude product was purified by silica gel chromatography (7:3 n-hexane/acetone) to give 36 (2.82 g, 79%) as a colorless syrup. [α]_D²⁵ + 68.6 (c 0.29, CHCl₃); R_f 0.42 (7:3 n-hexane/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 8.06–7.24 (m, 22H, arom.), 5.86 (s, 1H, H-2), 5.59 (d, J = 0.9 Hz, 1H, H-1), 5.11–4.62 (m, 4H, NAPCH₂, BnCH₂), 4.29–4.27 (m, 1H, H-5), 4.12–4.11 (m, 2H, H-3, H-4), 3.90–3.87 (m, 2H, H-6a,b), 1.82 (t, J = 6.6 Hz, 1H, C-6-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.7 (1C, C_q Bz), 137.8, 135.7, 133.4, 133.2, 129.8 (6C, 6 × C_q arom.), 133.5–126.1 (22C, arom.), 86.6 (1C, C-1), 78.6 (1C, C-3), 75.5 (1C, NAPCH₂), 74.2 (1C, C-4), 73.2 (1C, C-5), 71.9 (1C, BnCH₂), 70.9 (1C, C-2), 62.2 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₄NaO₆S [M + Na]⁺ 629.1968; found: 629.2028.

Phenyl 2,3-di-O-benzyl-6-deoxy-6-iodo-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (37). Compound 34 (3.38 g, 5.702 mmol) was converted to 37 according to general Method A. The crude product was purified by silica gel chromatography (8:2 n-hexane/acetone) to give 37 (3.12 g, 78%) as a colorless syrup. [α]_D²⁵ +57.3 (c 0.63, CHCl₃); R_f 0.42 (8:2 n-hexane/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 7.82–7.22 (m, 22H, arom.), 5.59 (s, 1H, H-1), 5.15 (d, J = 11.1 Hz, 1H, BnCH₂a), 4.88 (d, J = 11.1 Hz, 1H, BnCH₂b), 4.73 (d, J = 12.3 Hz, 1H, BnCH₂a), 4.65 (d, J = 12.2 Hz, 1H, BnCH₂b), 4.61 (s, 2H, NAPCH₂), 4.03 (s, 1H, H-2), 3.97–3.94 (m, 2H, H-4, H-5), 3.91–3.90 (m, 1H, H-3), 3.54 (d, J = 10.3 Hz, 1H, H-6a), 3.44 (dd, J = 5.4 Hz, J = 10.5 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 138.1, 137.9, 135.8, 134.3, 133.4, 133.2 (6C, 6 × C_q arom.), 131.7–126.1 (22C, arom.), 86.0 (1C, C-1), 79.9 (1C, C-3), 78.8 (1C, C-4), 76.4 (1C, C-2), 75.7 (1C, NAPCH₂), 72.2 (1C, C-5), 72.1, 72.1 (2C, 2 × BnCH₂), 7.1 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₅INaO₄S [M + Na]⁺ 725.1193; found: 725.1183.

Phenyl 2,3-di-O-benzoyl-6-deoxy-6-iodo-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (38). Compound 35 (4.08 g, 5.588 mmol) was converted to 38 according to general Method A. The crude product was purified by silica gel chromatography (7:3 n-hexane/acetone) to give 38 (3.77 g, 79%) as a colorless syrup. [α]_D²⁵ + 24.1 (c 0.22, CHCl₃); R_f 0.53 (7:3 n-hexane/acetone); ¹H NMR (400 MHz, CDCl₃) δ = 8.13–7.23 (m, 22H, arom.), 5.92 (s, 1H), 5.80 (dd, J = 2.6 Hz, J = 9.5 Hz, 1H), 5.68 (s, 1H), 4.95 (s, 2H, NAPCH₂), 4.32 (d, J = 9.4 Hz, 1H), 4.14–4.09 (m, 1H), 3.69 (dd, J = 3.8 Hz, J = 10.9 Hz, 1H, H-6a), 3.59–3.57 (m, 1H, H-6b) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 165.4, 165.3 (2C, 2 × C_q Bz), 134.9, 133.2, 133.1, 133.0, 129.5, 129.4 (6C, 6 × C_q arom.), 133.6–125.9 (22C, arom.), 86.1 (1C, C-1), 75.7 (1C, NAPCH₂), 77.7, 72.5, 72.3, 70.9 (4C, C-2, C-3, C-4, C-5), 8.6 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₁INaO₆S [M + Na]⁺ 753.0778; found: 753.0758.

Phenyl 2-O-benzoyl-3-O-benzyl-6-deoxy-6-iodo-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (39). Compound 36 (2.77 g, 3.868 mmol) was converted to 39 according to general Method A. The crude product was purified by silica gel chromatography (8:2 n-hexane/acetone) to give 39 (3.23 g, 99%) as a colorless syrup. [α]_D²⁵ + 0.6 (c 0.14, CHCl₃); R_f 0.43 (8:2 n-hexane/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 8.16–7.24 (m, 22H, arom.), 5.90 (s, 1H, H-2), 5.62 (s, 1H, H-1), 5.15–4.60 (m, 4H, NAPCH₂, BnCH₂), 4.11 (d, J = 8.9 Hz, 1H, H-3), 4.02 (t, J = 9.1 Hz, 1H, H-4), 3.95 (d, J = 8.0 Hz, 1H, H-5), 3.61 (dd, J = 4.2 Hz, J = 10.8 Hz, 1H, H-6a), 3.54 (dd, J = 2.1 Hz, J = 10.7 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.7 (1C, C_q Bz), 137.6, 135.6, 133.5, 133.2, 129.8 (6C, 6 × C_q arom.), 133.5–126.1 (22C, arom.), 86.5 (1C, C-1), 78.4 (1C, C-4), 78.3 (1C, C-3), 75.8 (1C, NAPCH₂), 71.8 (1C, BnCH₂), 71.1 (1C, C-5), 70.6 (1C, C-2), 8.5 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₃INaO₅S [M + Na]⁺ 739.0985; found: 739.0992.

Phenyl 2,3-di-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-lyxo-hex-5-enopyranoside (40). Compound 37 (300 mg, 0.427 mmol) was converted to 40 according to general Method E. The crude product was purified by silica gel chromatography (8:2 n-hexane/acetone) to give 40 (224 mg, 91%) as a colorless syrup. [α]_D²⁵ + 62.6 (c 0.19, CHCl₃); R_f 0.38 (8:2 n-hexane/acetone); ¹H NMR (400 MHz, CDCl₃) δ = 7.79–7.18 (m, 22H, arom.), 5.51 (d, J = 4.7 Hz, 1H, H-1), 4.86–4.57 (m, 8H, H-6a,b, 2 × BnCH₂, NAPCH₂), 4.32 (d, J = 7.6 Hz, 1H, H-4), 4.04 (t, J = 3.5 Hz, 1H, H-2), 3.92 (dd, J = 2.1 Hz, J = 7.6 Hz, 1H, H-3) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 154.4 (1C, C-5), 138.2, 137.8, 135.6, 133.7, 133.3, 133.0 (6C, 6 × C_q arom.), 131.8–125.8 (22C, arom.), 99.1 (1C, C-6), 86.3 (1C, C-1), 77.3 (1C, C-3), 76.1 (1C, C-4), 75.8 (1C, C-2), 72.8, 72.7, 72.6 (3C, 2 × BnCH₂, NAPCH₂) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₄NaO₄S [M + Na]⁺ 597.2070; found: 597.2058.

Phenyl 2,3-di-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-lyxo-hex-5-enopyranoside (40) and 8-N-[phenyl 2,3-di-O-benzyl-6-deoxy-6-yl-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside]-1,8-diazabicyclo(5.4.0)undec-7-ene-iodide (41). Compound 37 (300 mg, 0.427 mmol) was converted to 40 according to general Method B. The crude product was purified by silica gel chromatography (7:3 CH₂Cl₂/n-hexane → 9:1 CH₂Cl₂/MeOH) to give 40 (117 mg, 48%) as a colorless syrup and 41 (175 mg, 38%) as a light yellow syrup.

Data of 41: [α]_D²⁵ + 67.7 (c 0.30, CHCl₃); R_f 0.49 (9:1 CH₂Cl₂/MeOH); ¹H NMR (500 MHz, CDCl₃) δ = 7.86–7.27 (m, 22H, arom.), 5.60 (s, 1H, H-1), 5.11–4.61 (m, 6H, 2 × BnCH₂, NAPCH₂), 4.07 (t, J = 9.3 Hz, 1H, H-5), 3.97 (s, 1H, H-2), 3.92–3.87 (m, 2H, H-3, H-6a), 3.77 (t, J = 9.3 Hz, 1H, H-4), 3.63–3.53 (m, 3H, H-6b, NCH₂ DBU), 3.46–3.40 (m, 4H, 2 × NCH₂ DBU), 2.77–2.63 (m, 2H, CH₂ DBU), 1.77–1.43 (m, 8H, 4 × CH₂ DBU) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 167.1 (1C, C_q DBU), 137.5, 134.9, 133.2, 133.0, 132.7 (6C, 6 × C_q arom.), 130.8–126.1 (22C, arom.), 84.5 (1C, C-1), 79.8 (1C, C-3), 75.6 (2C, C-2, C-4), 75.4, 72.7, 72.1 (3C, 2 × BnCH₂, NAPCH₂), 55.7 (1C, NCH₂ DBU), 55.0 (1C, C-6), 49.4, 48.2 (2C, 2 × NCH₂ DBU), 28.8, 28.2, 25.7, 22.5, 19.7 (5C, 5 × CH₂ DBU) ppm; UHR ESI-QTOF: m/z calcd for C₄₆H₅₁N₂O₄S [M]⁺ 727.3564; found: 727.3562.

Phenyl 2,3-di-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-lyxo-hex-5-enopyranoside (40) and Phenyl 2,3-di-O-benzyl-6-deoxy-6-fluoro-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (42). Compound 37 (300 mg, 0.427 mmol) was converted to 40 according to general Method F. The crude product was purified by silica gel chromatography (7:3 CH₂Cl₂/n-hexane) to give 40 (210 mg, 86%) as a colorless syrup and 42 (14 mg, 6%) as a colorless syrup.

Data of 42: [α]_D²⁵ + 60.6 (c 1.44, CHCl₃); R_f 0.33 (7:3 CH₂Cl₂/n-hexane); ¹H NMR (500 MHz, CDCl₃) δ = 7.84–7.25 (m, 22H, arom.), 5.59 (d, J = 1.3 Hz, 1H, H-1), 5.14–4.54 (m, 8H, H-6a,b, 2 × BnCH₂, NAPCH₂), 4.26 (ddd, J = 2.7 Hz, J = 10.0 Hz, J = 27.4 Hz, 1H, H-5), 4.12 (t, J = 9.6 Hz, 1H, H-4), 4.03 (dd, J = 1.8 Hz, J = 2.9 Hz, 1H, H-2), 3.91 (dd, J = 3.0 Hz, J = 9.3 Hz, 1H, H-3) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 138.1, 137.8, 135.8, 134.3, 133.4, 133.1 (6C, 6 × C_q arom.), 131.4–126.1 (22C, arom.), 86.0 (1C, C-1), 82.3 (1C, J_C,F = 172.9 Hz, H-6), 80.2, 76.2 (2C, C-2, C-3), 75.2 (1C, NAPCH₂), 74.9 (1C, J_C,F = 6.6 Hz, C-5), 72.4 (1C, C-4), 72.2 (2C, 2 × BnCH₂) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₅FNaO₄S [M + Na]⁺ 617.2132; found: 617.2123.

Phenyl 4-O-(2′-naphthyl)methyl-1-thio-α-d-lyxo-hex-5-enopyranoside (43) and Phenyl 3,6-anhydro-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (44) Compound 38 (300 mg, 0.411 mmol) was converted to 43 according to general Method E. The crude product was purified by silica gel chromatography (1:1 n-hexane/EtOAc) to give 43 (21 mg, 17%) as a colorless syrup and 44 (95 mg, 59%) as a colorless syrup.

Data of 43: [α]_D²⁵ +70.4 (c 0.28, CHCl₃); R_f 0.42 (1:1 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 7.84–7.26 (m, 12H, arom.), 5.29 (d, J = 6.2 Hz, 1H, H-1), 4.95 (s, 1H, H-6a), 4.89 (d, J = 11.9 Hz, 1H, NAPCH₂a), 4.79 (s, 1H, H-6b), 4.59 (d, J = 11.9 Hz, 1H, NAPCH₂b), 4.15–4.13 (m, 2H, H-2, H-3), 4.10 (d, J = 5.6 Hz, 1H, H-4), 2.53, 2.49 (2 × s, 2H, H-2-OH, H-3-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 153.8 (1C, C-5), 135.2, 133.4, 133.2, 132.5 (4C, 4 × C_q arom.), 132.3–125.8 (12C, arom.), 101.1 (1C, C-6), 87.6 (1C, C-1), 76.9 (1C, C-4), 71.5 (1C, NAPCH₂), 70.3 (1C, C-3), 68.5 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for C₂₃H₂₂NaO₄S [M + Na]⁺ 417.1131; found: 417.1136.

Data of 44: [α]_D²⁵ + 40.7 (c 0.28, CHCl₃); R_f 0.28 (1:1 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 7.83–7.09 (m, 12H, arom.), 4.93 (d, J = 8.7 Hz, 1H, H-1), 4.78 (d, J = 11.9 Hz, 1H, NAPCH₂a), 4.61 (d, J = 11.9 Hz, 1H, NAPCH₂b), 4.47 (t, J = 2.8 Hz, 1H, H-5), 4.32 (dd, J = 0.8 Hz, J = 6.0 Hz, 1H, H-3), 4.12 (d, J = 10.9 Hz, 1H, H-6a), 3.99 (dd, J = 2.7 Hz, J = 6.0 Hz, 1H, H-4), 3.93 (dd, J = 2.7 Hz, J = 10.8 Hz, 2H, H-2, H-6b), 3.91 (t, J = 8.0 Hz, H-2), 2.46 (s, 1H, H-2-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 134.7, 133.2, 133.1, 132.7 (4C, 4 × C_q arom.), 132.5–125.7 (12C, arom.), 85.6 (1C, C-1), 77.4 (1C, C-4), 76.9 (1C, C-3), 74.2 (1C, C-5), 71.9 (1C, NAPCH₂), 69.5 (1C, C-6), 67.6 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for C₂₃H₂₂NaO₄S [M + Na]⁺ 417.1131; found: 417.1129.

Phenyl 2,3-di-O-benzoyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-lyxo-hex-5-enopyranoside (45) and 8-N-[phenyl 2,3-di-O-benzoyl-6-deoxy-6-yl-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside]-1,8-diazabicyclo(5.4.0)undec-7-ene-iodide (46). Compound 38 (2.3 g, 3.150 mmol) was converted to 45 according to general Method B. The crude product was purified by silica gel chromatography (7:3 CH₂Cl₂/n-hexane → 95:5 CH₂Cl₂/MeOH) to give 45 (1.25 g, 66%) as a colorless syrup and 46 (773 mg, 31%) as a light yellow syrup.

Data of 45: [α]_D²⁵ − 13.7 (c 0.27, CHCl₃); R_f 0.28 (7:3 CH₂Cl₂/n-hexane); ¹H NMR (400 MHz, CDCl₃) δ = 7.89–7.25 (m, 22H, arom.), 5.84–5.82 (m, 1H, H-2), 5.78 (dd, J = 3.2 Hz, J = 8.1 Hz, 1H, H-3), 5.63 (d, J = 4.6 Hz, 1H, H-1), 5.03 (s, 1H, H-6a), 5.00 (s, 1H, H-6b), 4.96 (d, J = 12.0 Hz, 1H, NAPCH₂a), 4.75 (d, J = 12.0 Hz, 1H, NAPCH₂b), 4.50 (d, J = 8.1 Hz, 1H, H-4) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 165.2 (2C, 2 × C_q Bz), 153.4 (1C, C-5) 134.9, 133.3, 133.2, 132.5, 129.5, 129.4 (6C, 6 × C_q arom.), 133.5–126.1 (22C, arom.), 100.9 (1C, C-6), 86.1 (1C, C-1) 74.0 (1C, C-4), 72.6 (1C, NAPCH₂), 70.6 (2C, C-2, C-3) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₀NaO₆S [M + Na]⁺ 625.1655; found: 625.1665.

Data of 46: [α]_D²⁵ + 27.4 (c 0.19, CHCl₃); R_f 0.31 (95:5 CH₂Cl₂/MeOH); ¹H NMR (500 MHz) δ = 8.05–7.26 (m, 22H, arom.), 5.86 (dd, J = 1.6 Hz, J = 3.1 Hz, 1H, H-2), 5.81 (d, J = 1.1 Hz, 1H, H-1), 5.78 (dd, J = 3.2 Hz, J = 9.4 Hz, 1H, H-3), 4.90 (d, J = 3.2 Hz, 2H, NAPCH₂), 4.42 (t, J = 9.3 Hz, 1H, H-5), 4.23 (d, J = 15.0 Hz, 1H, H-6a), 4.12 (t, J = 9.6 Hz, 1H, H-4), 3.97 (dd, J = 9.7 Hz, J = 15.8 Hz, 1H, H-6b), 3.68–3.41 (m, 6H, 3 × NCH₂ DBU), 2.80–2.79 (m, 2H, CH₂ DBU), 1.94–1.56 (m, 8H, 4 × CH₂ DBU) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 167.6 (1C, C_q DBU), 165.4, 165.3 (2C, 2 × C_q Bz), 134.2, 133.1, 132.3, 129.0, 128.9 (6C, 6 × C_q arom.), 133.9–126.1 (22C, arom.), 84.6 (1C, C-1), 75.9 (1C, NAPCH₂), 75.0 (1C, C-4), 72.5 (1C, C-3), 72.1 (1C, C-5), 71.6 (1C, C-2), 55.8 (1C, NCH₂ DBU), 55.6 (1C, C-6), 49.5, 48.5 (2C, 2 × NCH₂ DBU), 29.3, 28.5, 25.8, 22.7, 19.9 (5C, 5 × CH₂ DBU) ppm; UHR ESI-QTOF: m/z calcd for C₄₆H₄₇N₂O₆S [M]⁺ 755.3149; found: 755.3147.

Phenyl 2,3-di-O-benzoyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-lyxo-hex-5-enopyranoside (45) and 1,5-anhydro-2-O-benzoyl-3,6-dideoxy-4-O-(2′-naphthyl)methyl-3-S-phenyl-3-thio-α-d-erythro-hex-1,5-dienitol (47). Compound 38 (300 mg, 0.411 mmol) was converted to 45 according to general Method F. The crude product was purified by silica gel chromatography (7:3 CH₂Cl₂/n-hexane) to give 47 (24 mg, 9%) as a colorless syrup and 45 (154 mg, 55%) as a colorless syrup.

Data of 47: [α]_D²⁵ −18.8 (c 0.25, CHCl₃); R_f 0.60 (7:3 CH₂Cl₂/n-hexane); ¹H NMR (400 MHz, CDCl₃) δ = 7.94–7.27 (m, 17H, arom.), 6.54 (s, 1H, H-1), 5.19 (d, J = 6.3 Hz, 1H, H-4), 5.08 (s, 2H, NAPCH₂), 5.00 (s, 1H, H-6a), 4.69 (s, 1H, H-6b), 4.09 (dd, J = 1.0 Hz, J = 6.3 Hz, 1H, H-3) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 164.9 (1C, C_q Bz), 148.5 (1C, C-5), 147.0 (1C, C-2), 133.8, 133.4, 133.2, 133.0, 129.5 (5C, 5 × C_q arom.), 133.6–125.1 (17C, arom.), 94.1 (1C, C-6), 93.6 (1C, C-4), 92.8 (1C, C-1), 69.7 (1C, NAPCH₂), 46.4 (1C, C-3) ppm; ESI-TOF-MS: m/z calcd for C₃₀H₂₄NaO₄S [M + Na]⁺ 503.1288; found: 503.1281.

Phenyl 2,6-anhydro-3-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside (48). Compound 39 (310 mg, 0.433 mmol) was converted to 48 according to general Method E. The crude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give 48 (209 mg, 99%) as a colorless syrup. [α]_D²⁵ + 64.7 (c 0.15, CHCl₃); R_f 0.37 (7:3 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 8.09–7.20 (m, 17H, arom.), 5.68 (s, 1H, H-1), 4.81–4.52 (m, 4H, NAPCH₂, BnCH₂), 4.20–4.12 (m, 4H, H-2, H-3, H-5, H-6a), 3.813 (d, J = 9.8 Hz, 1H, H-6b), 3.73 (s, 1H, H-4) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 137.6, 135.3, 134.3, 133.3, 133.1 (5C, 5 × C_q arom.), 133.7–126.0 (17C, arom.), 86.9 (1C, C-1), 80.6 (1C, C-4), 78.9 (1C, C-3), 71.0, 70.6 (2C, NAPCH₂, BnCH₂), 69.9 (1C, C-2), 69.7 (1C, C-5), 66.8 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₀H₂₈NaO₄S [M + Na]⁺ 507.1601; found: 507.1626.

Phenyl 2-O-benzoyl-3-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-lyxo-hex-5-enopyranoside (49) and 8-N-[phenyl 2-O-benzoyl-3-O-benzyl-6-deoxy-6-yl-4-O-(2′-naphthyl)methyl-1-thio-α-d-mannopyranoside]-1,8-diazabicyclo(5.4.0)undec-7-ene-iodide (50).

Reaction I.: Compound 39 (336 mg, 0.469 mmol) was converted to 49 according to general Method B. The crude product was purified by silica gel chromatography (7:3 CH₂Cl₂/n-hexane → 95:5 CH₂Cl₂/MeOH) to give 49 (149 mg, 54%) as a colorless syrup and 50 (118 mg, 29%) as a light yellow syrup.

Reaction II.: Compound 39 (1.388 g, 1.938 mmol) was converted to 49 according to general Method F. The crude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give 49 (991 mg, 87%) as a colorless syrup.

Data of 49: [α]_D²⁵ + 40.9 (c 0.35, CHCl₃); R_f 0.60 (7:3 CH₂Cl₂/n-hexane); ¹H NMR (400 MHz, CDCl₃) δ = 8.03–7.19 (m, 22H, arom.), 5.80 (d, J = 3.5 Hz, 1H, H-2), 5.62 (d, J = 4.1 Hz, H-1), 5.00 (s, 1H, H-6a), 4.94–4.62 (m, 5H, H-6b, NAPCH₂, BnCH₂), 4.35 (d, J = 8.1 Hz, 1H, H-4), 4.12 (dd, J = 2.9 Hz, J = 8.1 Hz, 1H, H-3) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 165.5 (1C, C_q Bz), 154.2 (1C, C-5), 137.7, 135.4, 133.4, 133.1, 133.0, 129.7 (6C, 6 × C_q arom.), 133.4–126.0 (22C, arom.), 99.8 (1C, C-6), 86.3 (1C, C-1), 76.8 (1C, C-3), 75.5 (1C, C-4), 73.2, 72.5 (2C, NAPCH₂, BnCH₂), 70.6 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₂NaO₅S [M + Na]⁺ 611.1863; found: 611.1897.

Data of 50: [α]_D²⁵ + 67.3 (c 0.26, CHCl₃); R_f 0.63 (9:1 CH₂Cl₂/MeOH); ¹H NMR (400 MHz) δ = 8.08–7.25 (m, 22H, arom.), 5.82 (dd, J = 1.5 Hz, J = 2.7 Hz, 1H, H-2), 5.73 (s, 1H, H-1), 5.10–4.59 (m, 4H, NAPCH₂, BnCH₂), 4.23 (t, J = 9.4 Hz, 1H, H-5), 4.10 (dd, J = 3.1 Hz, J = 9.0 Hz, 1H, H-3), 4.04 (d, J = 15.0 Hz, 1H, H-6a), 3.79 (t, J = 9.4 Hz, 1H, H-4), 3.72 (dd, J = 9.7 Hz, J = 15.0 Hz, 1H, H-6b), 3.65–3.38 (m, 6H, 3 × NCH₂ DBU), 2.79–2.65 (m, 2H, CH₂ DBU), 1.84–1.47 (m, 8H, 4 × CH₂ DBU) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 167.1 (1C, C_q DBU), 165.4 (1C, C_q Bz), 137.0, 134.6, 133.1, 132.9, 132.1, 129.1 (6C, 6 × C_q arom.), 133.6–126.1 (22C, arom.), 84.7 (1C, C-1), 78.2 (1C, C-3), 75.4 (1C, NAPCH₂), 75.1 (1C, C-4), 71.7 (1C, C-5), 71.6 (1C, BnCH₂), 69.6 (1C, C-2), 55.6 (1C, NCH₂ DBU), 55.3 (1C, C-6), 49.3, 48.2 (2C, 2 × NCH₂ DBU), 29.0, 28.2, 25.6, 22.4, 19.7 (5C, 5 × CH₂ DBU) ppm; UHR ESI-QTOF: m/z calcd for C₄₆H₄₉N₂O₅S [M]⁺ 741.3357; found: 741.3357.

Phenyl 2,3-di-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-β-l-gulopyranoside (51). Compound 40 (574 mg, 1.000 mmol) was converted to 51 according to general Method C. The crude product was purified by silica gel chromatography (65:35 n-hexane/EtOAc) to give 34 (70 mg, 12%) as a colorless syrup and 51 (385 mg, 65%) as a colorless syrup.

Data of 51: [α]_D²⁵ + 3.1 (c 0.35, CHCl₃); R_f 0.40 (65:35 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 7.85–7.17 (m, 22H, arom.), 5.24 (d, J = 9.6 Hz, 1H, H-1), 4.68–4.33 (m, 6H, 2 × BnCH₂, NAPCH₂), 3.98–3.95 (m, 1H, H-5), 3.89–3.86 (m, 1H, H-6a), 3.80–3.76 (m, 2H, H-2, H-3), 3.53 (td, J = 4.2 Hz, J = 11.5 Hz, 1H, H-6b), 3.45 (dd, J = 1.2 Hz, J = 3.5 Hz, 1H, H-4), 1.78 (d, J = 8.5 Hz, 1H, H-6-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 138.0, 137.8, 135.1, 134.1, 133.0 (6C, 6 × C_q arom.), 131.5–125.8 (22C, arom.), 84.1 (1C, C-1), 76.0 (1C, C-5), 75.2 (1C, C-4), 74.8 (1C, C-2), 73.2, 72.8, 72,4 (3C, 2 × BnCH₂, NAPCH₂), 72.6 (1C, C-3), 62.3 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₆NaO₅S [M + Na]⁺ 615.2176; found: 615.2183.

Phenyl 2,3-di-O-benzoyl-4-O-(2′-naphthyl)methyl-1-thio-β-l-gulopyranoside (52). Compound 45 (1.15 g, 1.909 mmol) was converted to 52 according to general Method C. The crude product was purified by silica gel chromatography (65:35 n-hexane/EtOAc) to give 35 (100 mg, 8%) as a colorless syrup and 52 (870 mg, 74%) as a colorless syrup.

Data of 52: [α]_D²⁵ + 108.0 (c 0.10, CHCl₃); R_f 0.32 (65:35 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 8.01–7.26 (m, 22H, arom.), 6.02 (s, 1H, H-3), 5.57 (dd, J = 2.8 Hz, J = 10.3 Hz, 1H, H-2), 5.39 (d, J = 10.3 Hz, 1H, H-1), 5.07 (d, J = 11.9 Hz, 1H, NAPCH₂a), 4.74 (d, J = 11.9 Hz, 1H, NAPCH₂b), 4.10–4.08 (m, 1H, H-5), 3.99–3.96 (m, 1H, H-6a), 3.79 (d, J = 1.5 Hz, 1H, H-4), 3.60–3.55 (m, 1H, H-6b), 1.79 (d, J = 6.1 Hz, 1H, C-6-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 165.3, 165.1 (2C, 2 × C_q Bz), 134.5, 133.2, 132.3, 129.6, 129.3 (6C, 6 × C_q arom.), 133.7–126.0 (22C, arom.), 83.2 (1C, C-1), 77.1 (1C, C-5), 73.5 (1C, C-4), 72.4 (1C, NAPCH₂), 67.8 (1C, C-2), 67.7 (1C, C-3), 62.3 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₂NaO₇S, [M + Na]⁺ 643.1761; found: 643.1743.

Phenyl 2-O-benzoyl-3-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-β-l-gulopyranoside (53). Compound 49 (325 mg, 0.553 mmol) was converted to 53 according to general Method C. The crude product was purified by silica gel chromatography (65:35 n-hexane/EtOAc) to give 36 (20 mg, 6%) as a colorless syrup and 53 (285 mg, 84%) as a colorless syrup.

Data of 53: [α]_D²⁵ + 35.8 (c 0.19, CHCl₃); R_f 0.41 (65:35 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 8.09–7.10 (m, 22H, arom.), 5.42–5.36 (m, 2H, H-1, H-2), 4.80–4.43 (m, 4H, NAPCH₂, BnCH₂), 4.27–4.24 (m, 1H, H-3), 4.12–4.09 (m, 1H, H-5), 3.94 (dd, J = 7.6 Hz, J = 11.2 Hz, 1H, H-6a), 3.59 (d, J = 9.1 Hz, 1H, H-6b), 3.55 (s, 1H, H-4), 1.96 (s, 1H, C-6-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.5 (1C, C_q Bz), 137.5, 134.8, 133.2, 133.1, 129.9 (6C, 6 × C_q arom.), 133.4–126.0 (22C, arom.), 83.0 (1C, C-1), 76.5 (1C, C-5), 74.4 (1C, C-4), 73.7 (1C, NAPCH₂), 72.9 (1C, C-3), 72.3 (1C, BnCH₂), 70.1 (1C, C-2), 62.6 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₄NaO₆S, [M + Na]⁺ 629.1968; found: 629.1961.

Phenyl 2,3-di-O-benzyl-4,6-O-(2′-naphthyl)methylidene-1-thio-β-l-gulopyranoside (54). Compound 51 (350 mg, 0.591 mmol) was converted to 54 according to general Method G. The crude product was purified by silica gel chromatography (7:3 n-hexane/acetone) to give 54 (267 mg, 77%) as a colorless syrup. [α]_D²⁵ + 7.5 (c 0.16, CHCl₃); R_f 0.36 (8:2 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 7.89–7.21 (m, 22H, arom.), 5.63 (s, 1H, H_ac), 5.30 (d, J = 9.8 Hz, 1H, H-1), 4.83–4.60 (m, 5H, H-6a, 2 × BnCH₂), 4.11 (d, J = 3.7 Hz, 1H, H-5), 4.04 (dd, J = 1.4 Hz, J = 12.4 Hz, 1H, H-6b), 3.95–3.93 (m, 1H, H-4), 3.88 (s, 1H, H-3), 3.85 (dd, J = 2.6 Hz, J = 10.0 Hz, 1H, H-2) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 138.3, 138.1, 135.4, 133.9, 133.2, 133.0 (6C, 6 × C_q arom.), 132.9–124.2 (22C, arom.), 101.3 (1C, C_ac), 83.4 (1C, C-1), 77.3 (1C, C-5), 74.6 (1C, C-4), 74.2 (1C, C-2), 73.8, 72.7 (2C, 2 × BnCH₂), 69.8 (1C, C-6), 67.7 (1C, C-3) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₄NaO₅S [M + Na]⁺ 613.2019; found: 613.2019.

Phenyl 2,3-di-O-benzoyl-4,6-O-(2′-naphthyl)methylidene-1-thio-β-l-gulopyranoside (55). Compound 52 (870 mg, 1.402 mmol) was converted to 55 according to general Method G. The crude product was purified by silica gel chromatography (65:35 n-hexane/EtOAc) to give 55 (719 mg, 83%) as a colorless syrup. [α]_D²⁵ + 35.0 (c 0.14, CHCl₃); R_f 0.48 (65:35 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 8.04–7.23 (m, 22H, arom.), 5.82 (s, 1H, H-3), 5.72 (s, 1H, H_ac), 5.48 (dd, J = 2.7 Hz, J = 10.2 Hz, 1H, H-2), 5.40 (d, J = 10.2 Hz, 1H, H-1), 4.50 (d, J = 12.4 Hz, 1H, H-6a), 4.32 (d, J = 2.9 Hz, 1H, H-4), 4.15 (d, J = 12.3 Hz, 1H, H-6b), 4.01 (s, 1H, H-5) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.0, 164.7 (2C, 2 × C_q Bz), 134.9, 134.0, 133.0, 130.9, 129.7, 129.5 (6C, 6 × C_q arom.), 134.2–124.2 (22C, arom.), 101.6 (1C, C_ac), 82.2 (1C, C-1), 74.2 (1C, C-4), 69.6 (1C, C-3), 69.5 (1C, C-6), 68.5 (1C, C-5), 66.7 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₀NaO₇S [M + Na]⁺ 641.1604; found: 641.1606.

Phenyl 2-O-benzoyl-3-O-benzyl-4,6-O-(2′-naphthyl)methylidene-1-thio-β-l-gulopyranoside (56). Compound 53 (270 mg, 0.445 mmol) was converted to 56 according to general Method G. The crude product was purified by silica gel chromatography (85:15 CH₂Cl₂/n-hexane) to give 56 (179 mg, 67%) as a colorless syrup. [α]_D²⁵ + 40.9 (c 0.21, CHCl₃); R_f 0.63 (85:15 CH₂Cl₂/n-hexane); ¹H NMR (400 MHz, CDCl₃) δ = 8.07–7.15 (m, 22H, arom.), 5.61 (s, 1H, H_ac), 5.44 (dd, J = 2.4 Hz, J = 10.3 Hz, 1H, H-1), 5.33 (dt, J = 3.2 Hz, J = 10.3 Hz, 1H, H-2), 4.58 (s, 2H, BnCH₂), 4.37 (d, J = 12.3 Hz, 1H, H-6a), 4.18 (s, 1H, H-3), 4.11 (d, J = 3.5 Hz, 1H, H-4), 4.01–3.98 (m, 1H, H-6b), 3.89 (s, 1H, H-5) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 164.9 (1C, C_q Bz), 137.6, 135.2, 133.8, 132.8, 131.6 (6C, 6 × C_q arom.), 133.5–124.1 (22C, arom.) 101.2 (1C, C_ac), 81.9 (1C, C-1), 75.0 (1C, C-3), 74.6 (1C, C-4), 73.8 (1C, BnCH₂), 69.5 (1C, C-6), 68.9 (1C, C-2), 67.9 (1C, C-5) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₂NaO₆S, [M + Na]⁺ 627.1812; found: 627.1822.

Phenyl 2,3-di-O-benzyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-gulopyranoside (57). Compound 54 (250 mg, 0.423 mmol) was converted to 57 according to general Method H. The crude product was purified by silica gel chromatography (65:35 n-hexane/EtOAc) to give 57 (200 mg, 80%) as a colorless syrup. [α]_D²⁵ + 24.4 (c 0.18, CHCl₃); R_f 0.46 (65:35 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 7.79–7.16 (m, 22H, arom.), 5.26 (d, J = 10.0 Hz, 1H, H-1), 4.74–4.48 (m, 6H, 2 × BnCH₂, NAPCH₂), 4.06 (t, J = 3.8 Hz, 1H, H-5), 3.96 (s, 1H, H-4), 3.90 (t, J = 3.6 Hz, 1H, H-3), 3.83 (dd, J = 2.9 Hz, J = 9.9 Hz, 1H, H-2), 3.81 (dd, J = 3.4 Hz, J = 10.3 Hz, 1H, H-6a), 3.75 (dd, J = 4.4 Hz, J = 10.6 Hz, 1H, H-6b), 3.43 (s, 1H, C-4-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 138.2, 137.9, 134.9, 134.0, 133.1, 132.9 (6C, 6 × C_q arom.), 131.5–125.5 (22C, arom.), 84.7 (1C, C-1), 75.4 (1C, C-2), 74.7 (1C, C-3), 73.9 (1C, C-5), 73.7, 73.3, 72.5 (3C, 2 × BnCH₂, NAPCH₂), 70.9 (1C, C-6), 70.0 (1C, C-4) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₆NaO₅S [M + Na]⁺ 615.2176; found: 615.2181.

Phenyl 2,3-di-O-benzoyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-gulopyranoside (58). Compound 55 (90 mg, 0.145 mmol) was converted to 58 according to general Method H. The crude product was purified by silica gel chromatography (65:35 n-hexane/EtOAc) to give 58 (78 mg, 86%) as a colorless syrup. [α]_D²⁵ + 43.5 (c 0.17, CHCl₃); R_f 0.34 (7:3 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 7.99–7.21 (m, 22H, arom.), 5.77 (t, J = 3.5 Hz, 1H, H-3), 5.60 (dd, J = 3.3 Hz, J = 10.4 Hz, 1H, H-2), 5.36 (d, J = 10.4 Hz, 1H, H-1), 4.76 (d, J = 3.3 Hz, 2H, NAPCH₂), 4.23 (t, J = 4.4 Hz, 1H, H-5), 4.14 (d, J = 3.5 Hz, 1H, H-4), 3.91 (d, J = 4.7 Hz, 2H, H-6a,b), 3.47 (s, 1H, H-4-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 165.1, 164.9 (2C, 2 × C_q Bz), 135.0, 133.3, 133.1, 132.5, 129.5, 129.4 (6C, 6 × C_q arom.), 133.6–125.8 (22C, arom.), 83.8 (1C, C-1), 75.5 (1C, C-5), 74.1 (1C, NAPCH₂), 70.7 (1C, C-3), 70.3 (1C, C-6), 69.1 (1C, C-4), 67.1 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₂NaO₇S [M + Na]⁺ 643.1761; found: 643.1762.

Phenyl 2-O-benzoyl-3-O-benzyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-gulopyranoside (59). Compound 56 (428 mg, 0.708 mmol) was converted to 59 according to general Method H. The crude product was purified by silica gel chromatography (65:35 n-hexane/EtOAc) to give 59 (373 mg, 87%) as a colorless syrup. [α]_D²⁵ + 20.4 (c 0.23, CHCl₃); R_f 0.44 (65:35 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 8.08–7.19 (m, 22H, arom.), 5.39 (dd, J = 2.7 Hz, J = 10.4 Hz, 1H, H-2), 5.36 (d, J = 10.4 Hz, 1H, H-1), 4.82–4.56 (m, 4H, NAPCH₂, BnCH₂), 4.20 (t, J = 4.2 Hz, 1H, H-5), 4.12–4.11 (m, 1H, H-3), 4.03 (t, J = 4.1 Hz, 1H, H-4), 3.90 (dd, J = 4.1 Hz, J = 10.6 Hz, 1H, H-6a), 3.85 (dd, J = 4.4 Hz, J = 10.6 Hz, 1H, H-6b), 3.23 (d, J = 4.3 Hz, 1H, C-4-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 165.1 (1C, C_q Bz), 137.8, 135.1, 133.1, 132.9, 129.7 (6C, 6 × C_q arom.), 133.2–125.6 (22C, arom.) 83.6 (1C, C-1), 76.5 (1C, C-3), 74.6 (1C, C-5), 73.8, 73.6 (2C, NAPCH₂, BnCH₂), 70.6 (1C, C-6), 69.5 (1C, C-4), 69.1 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₄NaO₆S, [M + Na]⁺ 629.1968; found: 629.1954.

Phenyl 2,3-di-O-benzyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-ribo-hexopyranos-4-uloside (60). Compound 57 (160 mg, 0.270 mmol) was converted to 60 according to general Method I. The crude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give 60 (107 mg, 67%) as a colorless syrup. [α]_D²⁵ + 1.2 (c 0.17, CHCl₃); R_f 0.55 (7:3 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 7.81–7.17 (m, 22H, arom.), 5.16 (d, J = 2.6 Hz, 1H, H-1), 4.73–4.54 (m, 6H, 2 × BnCH₂, NAPCH₂), 4.46 (d, J = 3.5 Hz, 1H, H-3), 4.32–4.29 (m, 1H, H-5), 4.19 (t, J = 3.0 Hz, 1H, H-2), 3.88 (qd, J = 3.4 Hz, J = 10.8 Hz, 2H, H-6a,b) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 206.0 (1C, C-4), 137.4, 137.3, 135.5, 133.3, 133.1, 132.2 (6C, 6 × C_q arom.), 133.0–125.7 (22C, arom.), 86.4 (1C, C-1), 82.5 (1C, C-5), 82.1 (1C, C-3), 80.1 (1C, C-2), 73.7, 73.3, 72.8 (3C, 2 × BnCH₂, NAPCH₂), 69.6 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₄NaO₅S [M + Na]⁺ 613.2019; found: 613.2011.

Phenyl 2,3-di-O-benzoyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-ribo-hexopyranos-4-uloside (61). Compound 58 (69 mg, 0.112 mmol) was converted to 61 according to general Method I. The crude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give 61 (50 mg, 73%) as a colorless syrup. [α]_D²⁵ − 17.5 (c 0.12, CHCl₃); R_f 0.34 (7:3 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 7.98–7.24 (m, 22H, arom.), 6.12 (dd, J = 2.8 Hz, J = 4.2 Hz, 1H, H-2), 6.07 (d, J = 4.2 Hz, 1H, H-3), 5.31 (d, J = 2.7 Hz, 1H, H-1), 4.77 (s, 2H, NAPCH₂), 4.51 (t, J = 3.8 Hz, 1H, H-5), 4.00 (d, J = 3.9 Hz, 2H, H-6a,b) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 201.0 (1C, C-4), 165.0, 164.7 (2C, 2 × C_q Bz), 135.3, 133.4, 133.2, 131.3, 128.9 (6C, 6 × C_q arom.), 133.9–125.7 (22C, arom.), 85.9 (1C, C-1), 83.4 (1C, C-5), 74.7, 74.4 (2C, C-2, C-3), 73.9 (1C, NAPCH₂), 69.5 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₀NaO₇S [M + Na]⁺ 641.1604; found: 641.1607.

Phenyl 2-O-benzoyl-3-O-benzyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-ribo-hexopyranos-4-uloside (62). Compound 59 (342 mg, 0.563 mmol) was converted to 62 according to general Method I. The crude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give 62 (196 mg, 58%) as a colorless syrup. [α]_D²⁵ − 16.2 (c 0.08, CHCl₃); R_f 0.42 (7:3 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 7.97–7.16 (m, 22H, arom.), 5.85 (t, J = 4.0 Hz, 1H, H-2), 5.22 (d, J = 3.9 Hz, 1H, H-1), 4.67 (d, J = 2.3 Hz, 2H, NAPCH₂), 4.55 (d, J = 12.2 Hz, 1H, BnCH₂a), 4.46–4.40 (m, 3H, H-3, H-5, BnCH₂b), 3.92 (d, J = 3.6 Hz, 2H, H-6) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 203.9 (1C, C-4), 165.0 (1C, C_q Bz), 136.7, 135.2, 133.2, 133.0, 131.3, 129.1 (6C, 6 × C_q arom.), 133.6–125.6 (22C, arom.), 85.1 (1C, C-1), 82.4 (1C, C-5), 79.3 (1C, C-3), 73.8 (1C, C-2), 73.7, 72.2 (2C, NAPCH₂, BnCH₂), 69.4 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₂NaO₆S, [M + Na]⁺ 627.1812; found: 627.1809.

Phenyl 2,3-di-O-benzyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-allopyranoside (63). Compound 60 (100 mg, 0.169 mmol) was converted to 63 according to general Method J. The crude product was purified by silica gel chromatography (65:35 n-hexane/EtOAc) to give 63 (98 mg, 98%) as a colorless syrup. [α]_D²⁵ + 10.7 (c 0.29, CHCl₃); R_f 0.33 (65:35 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 7.78–7.19 (m, 22H, arom.), 5.20 (d, J = 7.1 Hz, 1H, H-1), 5.05 (d, J = 9.7 Hz, 1H, BnCH₂a), 4.72–4.60 (m, 4H, NAPCH₂, BnCH₂), 4.56 (d, J = 10.8 Hz, 1H, BnCH₂b), 4.05 (s, 1H, H-3), 3.83–3.81 (m, 2H, H-4, H-6a), 3.69–3.67 (m, 1H, H-6b), 3.54–3.51 (m, 1H, H-5), 3.44 (d, J = 8.3 Hz, 1H, H-2), 2.40 (s, 1H, C-4-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 138.4, 137.6, 135.9, 134.2, 133.3, 133.0 (6C, 6 × C_q arom.), 131.6–125.8 (22C, arom.), 84.0 (1C, C-1), 78.4 (1C, C-2), 77.5 (1C, C-3), 76.7 (1C, C-5), 75.3, 73.6, 73.1 (3C, 2 × BnCH₂, NAPCH₂), 70.2 (1C, C-6), 68.1 (1C, C-4) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₆NaO₅S [M + Na]⁺ 615.2176; found: 615.2132.

Phenyl 2,3-di-O-benzoyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-gulopyranoside (58) and Phenyl 2,3-di-O-benzoyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-allopyranoside (64). Compound 61 (27 mg, 0.044 mmol) was converted to 64 according to general Method J. The crude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give mixture of 58 and 64 (22 mg, 81%, inseparable mixture of the l-gulo and the l-allo configured compounds, ratio of l-gulo (58): l-allo (64) = 5:1 based on the ¹H NMR spectra (H-3 l-gulo: 5.75 ppm and H-3 l-allo: 6.10 ppm) as a colorless syrup.

Data of 64: R_f 0.36 (7:3 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 8.01–7.21 (m, 22H, arom.), 6.10 (t, J = 2.9 Hz, 1H, H-3), 5.27 (dd, J = 2.8 Hz, J = 10.2 Hz, 1H, H-2), 5.10 (d, J = 9.9 Hz, 1H, H-1), 4.78–4.67 (m, 2H, NAPCH₂), 4.36 (ddd, J = 2.2 Hz, J = 5.4 Hz, J = 10.3 Hz, 1H, H-5), 3.82 (dd, J = 3.3 Hz, J = 6.5 Hz, 1H, H-4), 3.79 (dd, J = 2.2 Hz, J = 11.0 Hz, 1H, H-6a), 3.71 (dd, J = 5.5 Hz, J = 11.0 Hz, 1H, H-6b), 2.43 (d, J = 3.6 Hz, 1H, C-4-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 133.4–125.9 (22C, arom.), 85.5 (1C, C-1), 75.0 (1C, C-5), 74.1 (1C, NAPCH₂), 70.3 (1C, C-3), 68.9 (1C, C-6), 68.1 (1C, C-4), 67.7 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₂NaO₇S [M + Na]⁺ 643.1761; found: 643.1828.

Phenyl 2-O-benzoyl-3-O-benzyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-allopyranoside (65). Compound 62 (174 mg, 0.287 mmol) was converted to 65 according to general Method J. The crude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give 65 (155 mg, 89%) as a colorless syrup. [α]_D²⁵ + 25.9 (c 0.17, CHCl₃); R_f 0.38 (7:3 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 8.09–7.18 (m, 22H, arom.), 5.33 (d, J = 10.2 Hz, 1H, H-1), 4.99 (d, J = 10.0 Hz, 1H, H-2), 4.83 (d, J = 11.4 Hz, 1H, BnCH₂a), 4.75 (s, 2H, NAPCH₂), 4.56 (d, J = 11.4 Hz, 1H, BnCH₂b), 4.30 (s, 1H, H-3), 3.94–3.93 (m, 1H, H-5), 3.88 (d, J = 10.5 Hz, 1H, H-6a), 3.79–3.72 (m, 2H, H-4, H-6b), 2.44 (d, J = 9.3 Hz, 1H, C-4-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.3 (1C, C_q Bz), 137.9, 135.7, 133.4, 133.1, 132.7, 129.6 (6C, 6 × C_q arom.), 133.6–125.8 (22C, arom.), 82.5 (1C, C-1), 77.9 (1C, C-3), 76.9 (1C, C-5), 75.8, 73.8 (2C, NAPCH₂, BnCH₂), 71.7 (1C, C-2), 70.4 (1C, C-6), 68.5 (1C, C-4) ppm; ESI-TOF-MS: m/z calcd for C₃₇H₃₄NaO₆S, [M + Na]⁺ 629.1968; found: 629.1964.

3.2.13. Synthesis of l-Galactose and l-Glucose Derivatives from d-Altrose

Phenyl 2-O-benzoyl-4,6-O-(2′-naphthyl)methylidene-1-thio-α-d-mannopyranoside (66). To a solution of compound 29 [91] (2.5 g, 6.096 mmol) in dry CH₃CN (85 mL), we added triethyl-orthobenzoate (2.22 mL, 9.753 mmol, 1.6 equiv.) and stirred for 15 min. After 15 min at that temperature, CSA (425 mg, 1.828 mmol, 0.30 equiv.) was added and the mixture was stirred for 2 h at room temperature. After that, the solvents were evaporated. The residue was dissolved in AcOH (80%, 40 mL) at 0 °C and stirred for 15 min. The reaction mixture was neutralized with NaHCO₃, extracted with CH₂Cl₂ (3 × 100 mL), and the organic phases was washed with H₂O (3 × 50 mL) until neutral pH. The organic layer was dried over MgSO₄ and concentrated. The crude product was purified by silica gel chromatography (7:3 n-hexane/acetone) to give 66 (1.81 g, 57%) as a colorless syrup. [α]_D²⁵ −6.2 (c 0.13, CHCl₃); R_f 0.42 (7:3 n-hexane/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 8.11–7.24 (m, 17H, arom.), 5.83 (s, 1H, H_ac), 5.75 (dd, J = 1.3 Hz, J = 3.5 Hz, 1H, H-2), 5.64 (d, J = 1.0 Hz, 1H, H-1), 4.49 (td, J = 4.9 Hz, J = 9.8 Hz, 1H, H-5), 4.39 (dt, J = 3.7 Hz, J = 9.8 Hz, 1H, H-3), 4.33 (dd, J = 4.9 Hz, J = 10.3 Hz, 1H, H-6a), 4.18 (t, J = 9.7 Hz, 1H, H-4), 3.95 (t, J = 10.3 Hz, 1H, H-6b), 2.56 (dd, J = 4.1 Hz, J = 9.4 Hz, 1H, C-3-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 166.1 (1C, C_q Bz), 134.5, 133.9, 133.2, 133.1, 129.6 (5C, 5 × C_q arom.), 133.7–123.8 (17C, arom.), 102.6 (1C, C_ac), 87.2 (1C, C-1), 79.8 (1C, C-4), 74.3 (1C, C-2), 68.7 (1C, C-6), 68.3 (1C, C-3), 64.9 (1C, C-5) ppm; ESI-TOF-MS: m/z calcd for: C₃₀H₂₆NaO₆S [M + Na]⁺ 537.1342; found: 537.1348.

Phenyl 2-O-benzoyl-4,6-O-(2′-naphthyl)methylidene-1-thio-α-d-altropyranoside (67). Compound 66 (5.68 g, 11.05 mmol) was converted to 3-ulose according to general Method I. The crude product was purified by silica gel chromatography (6:4 n-hexane/EtOAc) to give the 3-ulose derivative (4.37 g, 77%) as a colorless syrup. [α]_D²⁵ + 112.0 (c 0.15, CHCl₃); R_f 0.39 (7:3 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 8.15–7.20 (m, 17H, arom.), 5.92 (s, 1H, H-1), 5.81 (s, 1H, H_ac), 5.54 (s, 1H, H-2), 4.98 (d, J = 9.7 Hz, 1H, H-4), 4.77–4.75 (m, 1H, H-5), 4.41–4.30 (m, 1H, H-6a), 4.05 (t, J = 10.0 Hz, 1H, H-6b) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 193.4 (1C, C-3), 164.8 (1C, C_q Bz), 133.8, 133.7, 132.9, 131.4 (5C, 5 × C_q arom.), 134.1–123.8 (17C, arom.), 102.2 (1C, C_ac), 88.6 (1C, C-1), 81.9 (1C, C-4), 78.6 (1C, C-2), 69.1 (1C, C-6), 68.1 (1C, C-5) ppm; ESI-TOF-MS: m/z calcd for: C₃₀H₂₄NaO₆S [M + Na]⁺ 535.1186; found: 535.1210.

To the solution of the 3-ulose compound (4.44 g, 8.669 mmol) in dry MeOH (53.6 mL), NaBH₄ (492 mg, 13.00 mmol, 1.5 equiv.) was added and the reaction mixture was stirred for 1 h at room temperature. After 1 h the mixture was neutralized with 60% AcOH (6 mL) and concentrated, then the residue was coevaporated with MeOH (3 × 100 mL). The crude product was purified by silica gel chromatography (CH₂Cl₂) to give 67 (2.61 g, 58%) as a white foam and 66 (710 mg, 16%) as a colorless syrup.

Data of 67: [α]_D²⁵ +167.0 (c 0.10, CHCl₃); R_f 0.40 (CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ = 8.08–7.25 (m, 17H, arom.), 5.90 (s, 1H, H_ac), 5.62 (d, J = 3.2 Hz, 1H, H-2), 5.55 (s, 1H, H-1), 4.93 (td, J = 5.1 Hz, J = 10.1 Hz, 1H, H-5), 4.44 (dd, J = 5.1 Hz, J = 10.3 Hz, 1H, H-6a), 4.38 (s, 1H, H-3), 4.17 (dd, J = 2.9 Hz, J = 9.8 Hz, 1H, H-4), 3.97 (t, J = 10.4 Hz, 1H, H-6b), 2.58 (d, J = 1.7 Hz, 1H, C-3-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 165.0 (1C, C_q Bz), 136.1, 134.5, 133.9, 133.0, 129.3 (5C, 5 × C_q arom.), 133.7–123.8 (17C, arom.), 102.5 (1C, C_ac), 86.3 (1C, C-1), 77.4 (1C, C-4), 74.1 (1C, C-2), 69.1 (1C, C-6), 66.9 (1C, C-3), 59.6 (1C, C-5) ppm; ESI-TOF-MS: m/z calcd for: C₃₀H₂₆NaO₆S [M + Na]⁺ 537.1342; found: 537.1389.

Phenyl 2,3-di-O-benzyl-4,6-O-(2′-naphthyl)methylidene-1-thio-α-d-altropyranoside (68). To the solution of compound 67 (888 mg, 1.728 mmol) in MeOH (21 mL), NaOMe (55 mg) was added, and the reaction mixture was stirred for 24 h at room temperature. After 24 h the reaction mixture was neutralized by Amberlite IR-120 (H⁺) ion-exchange resin, then it was filtered, washed with MeOH, and concentrated. The crude product was reacted in the further reaction without purification (R_f 0.35 (6:4 n-hexane/EtOAc)). To a solution of the crude product (709 mg, 1.728 mmol), dry DMF (7.3 mL) at 0 °C NaH (60%, 173 mg, 4.320 mmol, 1.25 equiv./-OH) was added in portions. After 30 min stirring at this temperature, BnBr (513 μL, 4.320 mmol, 1.25 equiv./-OH) was added, and the reaction mixture was allowed to warm up to room temperature and stirred for 24 h. After completion of the reaction, MeOH (20 mL) was added. The reaction mixture was stirred for 15 min, then the solvents were evaporated. The residue was diluted with CH₂Cl₂ (500 mL), washed with H₂O (3 × 100 mL), dried over MgSO₄, filtered, and concentrated. The crude product was purified by silica gel chromatography (8:2 n-hexane/EtOAc) to give 68 (796 mg, 78% for two steps) as a yellow syrup. [α]_D²⁵ −145.0 (c 0.12, CHCl₃); R_f 0.49 (8:2 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 7.96–7.25 (m, 22H, arom.), 5.75 (s, 1H, H_ac), 5.49 (s, 1H, H-1), 4.88–4.85 (m, 2H, H-5, BnCH₂a), 4.74 (d, J = 12.5 Hz, 1H, BnCH₂b), 4.61 (d, J = 11.9 Hz, 1H, BnCH₂a), 4.52 (d, J = 11.9 Hz, 1H, BnCH₂b), 4.37 (dd, J = 5.0 Hz, J = 10.0 Hz, 1H, H-6a), 4.18 (d, J = 9.5 Hz, 1H, H-4), 4.03–4.01 (m, 2H, H-2, H-3), 3.89 (t, J = 10.3 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 138.5, 137.4, 137.3, 135.3, 133.8, 133.1 (6C, 6 × C_q arom.), 130.8–124.0 (22C, arom.), 102.5 (1C, C_ac), 86.4 (1C, C-1), 78.9 (1C, C-2), 77.7 (1C, C-4), 73.5 (1C, C-3), 73.2, 72.4 (2C, 2 × BnCH₂), 69.4 (1C, C-6), 60.3 (1C, C-5) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₄NaO₅S [M + Na]⁺ 613.2019; found: 613.2014.

Phenyl 2,3-di-O-benzoyl-4,6-O-(2′-naphthyl)methylidene-1-thio-α-d-altropyranoside (69). To a stirred solution of compound 67 (892 mg, 1.735 mmol) in dry pyridine (4.7 mL), BzCl (252 µL, 2.169 mmol, 1.25 equiv.) was added at 0 °C and the reaction mixture was stirred for 24 h at room temperature. After 24 h the mixture was diluted with CH₂Cl₂ (100 mL), washed with H₂O (25 mL), 1M aqueous solution of H₂SO₄ (2 × 25 mL), H₂O (25 mL), saturated aqueous solution of NaHCO₃ (2 × 25 mL), and H₂O (25 mL) until neutral pH. The organic layer was separated, dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (7:3 → 8:2 CH₂Cl₂/n-hexane) to give 69 (887 mg, 83%) as a colorless syrup. [α]_D²⁵ + 174.2 (c 0.12, CHCl₃); R_f 0.49 (7:3 CH₂Cl₂/n-hexane); ¹H NMR (500 MHz, CDCl₃) δ = 8.34–7.23 (m, 22H, arom.), 5.88 (s, 1H, H_ac), 5.83 (s, 1H, H-3), 5.72 (s, 1H, H-2), 5.61 (s, 1H, H-1), 5.05 (td, J = 5.2 Hz, J = 9.9 Hz, 1H, H-5), 4.47 (dd, J = 5.0 Hz, J = 10.3 Hz, 1H, H-6a), 4.38 (d, J = 9.6 Hz, 1H, H-4), 3.99 (t, J = 10.4 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.4, 164.9 (2C, 2 × C_q Bz), 135.2, 134.5, 133.8, 133.0, 129.5, 129.2 (6C, 6 × C_q arom.), 133.9–123.7 (22C, arom.), 102.3 (1C, C_ac), 86.5 (1C, C-1), 75.6 (1C, C-4), 72.6 (1C, C-2), 69.3 (1C, C-6), 67.3 (1C, C-3), 60.7 (1C, C-5) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₀NaO₇S [M + Na]⁺ 641.1604; found: 641.1608.

Phenyl 2,3-di-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-altropyranoside (70). Compound 68 (750 mg, 1.270 mmol) was converted to 70 according to general Method D. The crude product was purified by silica gel chromatography (65:35 n-hexane/EtOAc) to give 70 (660 mg, 88%) as a colorless syrup. [α]_D²⁵ + 140.0 (c 0.17, CHCl₃); R_f 0.48 (65:35 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 7.83–7.12 (m, 22H, arom.), 5.44 (s, 1H, H-1), 4.73–4.33 (m, 7H, H-5, NAPCH₂, 2 × BnCH₂), 3.96–3.94 (m, 2H, H-2, H-4), 3.93–3.88 (m, 2H, H-6a,b), 3.83 (s, 1H, H-4), 1.89 (s, 1H, C-6-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 138.0, 137.5, 137.4, 135.6, 133.4, 133.1 (6C, 6 × C_q arom.), 131.1–126.0 (22C, arom.), 86.2 (1C, C-1), 77.4 (1C, C-2), 72.8 (1C, C-4), 72.6 (1C, C-3), 72.2, 72.2, 71.7 (3C, NAPCH₂, 2 × BnCH₂), 68.6 (1C, C-5), 62.7 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₆NaO₅S [M + Na]⁺ 615.2176; found: 615.2173.

Phenyl 2,3-di-O-benzoyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-altropyranoside (71). Compound 69 (823 mg, 1.331 mmol) was converted to 71 according to general Method D. The crude product was purified by silica gel chromatography (65:35 n-hexane/EtOAc) to give 71 (728 mg, 88%) as a colorless syrup. [α]_D²⁵ +131.8 (c 0.11, CHCl₃); R_f 0.49 (6:4 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 8.35–7.25 (m, 22H, arom.), 5.94 (s, 1H, H-3), 5.59 (d, J = 3.1 Hz, 1H, H-2), 5.56 (s, 1H, H-1), 4.93 (d, J = 11.5 Hz, 1H, NAPCH₂a), 4.77–4.72 (m, 2H, H-5, NAPCH₂b), 4.14 (dd, J = 2.7 Hz, J = 9.9 Hz, 1H, H-4), 3.97 (d, J = 11.6 Hz, 1H, H-6a), 3.91–3.87 (m, 1H, H-6b), 1.86 (t, J = 6.2 Hz, 1H, C-6-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.6, 164.9 (2C, 2 × C_q Bz), 135.4, 134.7, 133.3, 133.2, 129.5, 129.1 (6C, 6 × C_q arom.), 133.7–126.2 (22C, arom.), 86.1 (1C, C-1), 72.5 (1C, C-2), 71.5 (1C, NAPCH₂), 70.5 (1C, C-4), 68.6 (1C, C-5), 66.1 (1C, C-3), 62.5 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₂NaO₇S [M + Na]⁺ 643.1761; found: 643.1821.

Phenyl 2,3-di-O-benzyl-6-deoxy-6-iodo-4-O-(2′-naphthyl)methyl-1-thio-α-d-altropyranoside (72). Compound 70 (650 mg, 1.095 mmol) was converted to 72 according to general Method A. The crude product was purified by silica gel chromatography (4:6 → 8:2 CH₂Cl₂/n-hexane) to give 72 (665 mg, 87%) as a white foam. [α]_D²⁵ + 93.3 (c 0.12, CHCl₃); R_f 0.57 (7:3 CH₂Cl₂/n-hexane); ¹H NMR (500 MHz, CDCl₃) δ = 7.85–7.19 (m, 22H, arom.), 5.51 (s, 1H, H-1), 4.72–4.48 (m, 5H, NAPCH₂, 2 × BnCH₂a, BnCH₂b), 4.40 (t, J = 6.8 Hz, 1H, H-5), 4.36 (d, J = 12.2 Hz, 1H, BnCH₂b), 4.01 (d, J = 1.9 Hz, 1H, H-2), 3.81–3.79 (m, 2H, H-3, H-4), 3.64–3.62 (m, 1H, H-6a), 3.47 (dd, J = 6.5 Hz, J = 10.6 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 137.8, 137.7, 137.6, 135.3, 133.3, 133.1 (6C, 6 × C_q arom.), 131.0–126.1 (22C, arom.), 86.2 (1C, C-1), 77.2 (1C, C-2), 76.7 (1C, C-3), 72.5, 72.0, 71.6 (3C, NAPCH₂, 2 × BnCH₂), 72.1 (1C, C-4), 67.5 (1C, C-5), 8.7 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₅INaO₄S [M + Na]⁺ 725.1193; found: 725.1195.

Phenyl 2,3-di-O-benzoyl-6-deoxy-6-iodo-4-O-(2′-naphthyl)methyl-1-thio-α-d-altropyranoside (73). Compound 71 (676 mg, 1.089 mmol) was converted to 73 according to general Method A. The crude product was purified by silica gel chromatography (1:1 → 8:2 CH₂Cl₂/n-hexane) to give 73 (759 mg, 95%) as a colorless syrup. [α]_D²⁵ + 99.2 (c 0.13, CHCl₃); R_f 0.46 (8:2 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 8.34–7.26 (m, 22H, arom.), 5.95 (s, 1H, H-3), 5.64 (s, 1H, H-2), 5.59 (s, 1H, H-1), 4.96 (d, J = 11.1 Hz, 1H, NAPCH₂a), 4.72 (d, J = 11.1 Hz, 1H, NAPCH₂b), 4.46–4.43 (m, 1H, H-5), 4.02 (d, J = 9.2 Hz, 1H, H-4), 3.64 (d, J = 10.6 Hz, 1H, H-6a), 3.52 (dd, J = 5.7 Hz, J = 10.5 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.5, 164.8 (2C, 2 × C_q Bz), 135.6, 134.4, 133.3, 129.3, 129.1 (6C, 6 × C_q arom.), 133.7–126.3 (22C, arom.), 86.3 (1C, C-1), 74.5 (1C, C-4), 72.4 (1C, C-2), 71.7 (1C, NAPCH₂), 67.3 (1C, C-5), 65.6 (1C, C-3), 8.3 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₁INaO₆S [M + Na]⁺ 753.0778; found: 753.0792.

Phenyl 2,3-di-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-arabino-hex-5-enopyranoside (74).

Reaction I.: Compound 72 (218 mg, 0.310 mmol) was converted to 74 according to general Method E. The crude product was purified by silica gel chromatography (7:3 CH₂Cl₂/n-hexane) to give 74 (151 mg, 85%) as a colorless syrup.

Reaction II.: Compound 72 (201 mg, 0.286 mmol) was converted to 74 according to general Method F. The crude product was purified by silica gel chromatography (7:3 CH₂Cl₂/n-hexane) to give 72 (31 mg, 19%) as a colorless syrup and 74 (85 mg, 52%) as a colorless syrup.

Data of 74: [α]_D²⁵ + 50.8 (c 0.12, CHCl₃); R_f 0.47 (8:2 CH₂Cl₂/n-hexane); ¹H NMR (500 MHz, CDCl₃) δ = 7.85–7.20 (m, 22H, arom.), 4.96 (d, J = 7.5 Hz, 1H, H-1), 4.91 (s, 1H, H-6a), 4.91–4.59 (m, 6H, NAPCH₂, 2 × BnCH₂), 4.53 (s, 1H, H-6b), 4.13–4.10 (m, 2H, H-2, H-4), 3.67 (dd, J = 3.1 Hz, J = 8.0 Hz, 1H, H-3) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 153.9 (1C, C-5), 138.2, 138.1, 135.4, 134.3, 133.4, 133.1 (6C, 6 × C_q arom.), 131.9–126.0 (22C, arom.), 100.2 (1C, C-6), 88.6 (1C, C-1), 80.0 (1C, C-3), 77.1 (1C, C-2), 74.9, 72.1, 69.9 (3C, NAPCH₂, 2 × BnCH₂), 73.3 (1C, C-4) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₄NaO₄S [M + Na]⁺ 597.2070; found: 597.2051.

Phenyl 2,3-di-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-arabino-hex-5-enopyranoside (74) and 8-N-[phenyl 2,3-di-O-benzyl-6-deoxy-6-yl-4-O-(2′-naphthyl)methyl-1-thio-α-d-altropyranoside]-1,8-diazabicyclo(5.4.0)undec-7-ene-iodide (75). Compound 72 (215 mg, 0.306 mmol) was converted to 74 according to general Method B. The crude product was purified by silica gel chromatography (7:3 CH₂Cl₂/n-hexane → 95:5 CH₂Cl₂/MeOH) to give 74 (102 mg, 58%) as a colorless syrup and 75 (107 mg, 41%) as a light yellow syrup.

Data of 75: [α]_D²⁵ + 120.8 (c 0.13, CHCl₃); R_f 0.44 (7:3 CH₂Cl₂/MeOH); ¹H NMR (500 MHz, CDCl₃) δ = 7.86–7.17 (m, 22H, arom.), 5.51 (s, 1H, H-1), 4.69–4.41 (m, 7H, H-5, NAPCH₂, 2 × BnCH₂), 4.00 (dd, J = 1.6 Hz, J = 15.3 Hz, 1H, H-6a), 3.94 (d, J = 3.4 Hz, 1H, H-2), 3.86 (t, J = 3.0 Hz, 1H, H-3), 3.68 (dd, J = 2.8 Hz, J = 9.9 Hz, 1H, H-4), 3.64–3.39 (m, 7H, H-6b, 3 × NCH₂ DBU), 2.84–2.68 (m, 2H, CH₂ DBU), 1.84–1.80 (m, 2H, CH₂ DBU), 1.61–1.47 (m, 6H, 3 × CH₂ DBU) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 167.2 (1C, C_q DBU), 137.2, 137.0, 136.1, 134.4, 133.0, 132.9 (6C, 6 × C_q arom.), 129.4–125.9 (22C, arom.), 84.5 (1C, C-1), 76.4 (1C, C-2), 73.4 (1C, C-4), 72.5, 72.3, 70.9 (3C, NAPCH₂, 2 × BnCH₂), 71.0 (1C, C-3), 66.5 (1C, C-5), 55.5 (1C, C-6), 55.0, 49.4, 48.0 (3C, 3 × NCH₂ DBU), 28.9, 28.1, 25.6, 22.5, 19.7 (5C, 5 × CH₂ DBU) ppm; UHR ESI-QTOF: m/z calcd for C₄₆H₅₁N₂O₄S [M]⁺ 727.3564; found: 727.3572.

Phenyl 4-O-(2′-naphthyl)methyl-1-thio-α-d-arabino-hex-5-enopyranoside (76) and Phenyl 2,6-anhydro-4-O-(2′-naphthyl)methyl-1-thio-α-d-altropyranoside (77). Compound 73 (254 mg, 0.347 mmol) was converted to 76 according to general Method E. The crude product was purified by silica gel chromatography (97:3 → 9:1 CH₂Cl₂/acetone) to give 76 (60 mg, 43%) as a white foam and 77 (30 mg, 22%) as a white foam.

Data of 76: [α]_D²⁵ +34.3 (c 0.14, CHCl₃); R_f 0.17 (97:3 CH₂Cl₂/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 7.81–7.21 (m, 12H, arom.), 4.94 (s, 1H, H-6a), 4.77 (d, J = 11.7 Hz, 1H, NAPCH₂a), 4.64 (d, J = 9.3 Hz, 1H, H-1), 4.55 (s, 1H, H-6b), 4.43 (d, J = 11.7 Hz, 1H, NAPCH₂b), 4.03 (d, J = 3.5 Hz, 1H, H-4), 3.87 (t, J = 9.1 Hz, 1H, H-2), 3.65 (d, J = 6.3 Hz, 1H, H-3), 3.06 (s, 2H, C-2-OH, C-3-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 154.0 (1C, C-5), 134.9, 133.3, 133.1, 132.0 (4C, 4 × C_q arom.), 132.7–125.9 (12C, arom.), 102.0 (1C, C-6), 88.9 (1C, C-1), 76.7 (1C, C-4), 73.6 (1C, C-3), 70.1 (1C, NAPCH₂), 69.5 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for: C₂₃H₂₂NaO₄S [M + Na]⁺ 417.1131; found: 417.1131.

Data of 77: [α]_D²⁵ +227.3 (c 0.12, CHCl₃); R_f 0.54 (97:3 CH₂Cl₂/acetone); ¹H NMR (500 MHz, CDCl₃) δ = 7.86–7.23 (m, 12H, arom.), 5.72 (t, J = 1.5 Hz, 1H, H-1), 4.93 (s, 2H, NAPCH₂), 4.28–4.24 (m, 1H, H-5), 4.18 (dd, J = 2.7 Hz, J = 10.4 Hz, 1H, H-6a), 4.07 (s, 1H, H-3), 4.05 (dd, J = 1.9 Hz, J = 3.6 Hz, 1H, H-2), 3.88 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H, H-4), 3.73 (s, 1H, C-3-OH), 3.71 (d, J = 4.2 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 136.5, 134.6, 133.3, 133.2 (4C, 4 × C_q arom.), 131.2–125.8 (12C, arom.), 85.8 (1C, C-1), 72.5 (1C, NAPCH₂), 72.2 (1C, C-4), 70.2 (1C, C-2), 68.0 (1C, C-3), 66.3 (1C, C-6), 66.1 (1C, C-5) ppm; ESI-TOF-MS: m/z calcd for: C₂₃H₂₂NaO₄S [M + Na]⁺ 417.1131; found: 417.1144.

Phenyl 2,3-di-O-benzoyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-arabino-hex-5-enopyranoside (78). To a stirred solution of compound 76 (60 mg, 0.150 mmol) in dry pyridine (1.0 mL), BzCl (52 µL, 0.449 mmol, 1.5 equiv.) was added at 0 °C and the reaction mixture was stirred for 24 h at room temperature. After 24 h the mixture was diluted with CH₂Cl₂ (50 mL), washed with H₂O (15 mL), 1M aqueous solution of H₂SO₄ (2 × 15 mL), H₂O (15 mL), saturated aqueous solution of NaHCO₃ (2 × 15 mL), and H₂O (15 mL) until neutral pH. The organic layer was separated, dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (8:2 CH₂Cl₂/n-hexane) to give 78 (57 mg, 63%) as a colorless syrup. [α]_D²⁵ + 10.8 (c 0.12, CHCl₃); R_f 0.45 (7:3 CH₂Cl₂/n-hexane); ¹H NMR (500 MHz, CDCl₃) δ = 8.08–7.23 (m, 22H, arom.), 5.96 (dd, J = 7.2 Hz, J = 7.8 Hz, 1H, H-2), 5.48 (dd, J = 3.2 Hz, J = 8.0 Hz, 1H, H-3), 5.25 (d, J = 7.0 Hz, 1H, H-1), 5.05 (s, 1H, H-6a), 4.87 (d, J = 12.6 Hz, 1H, NAPCH₂a), 4.81 (s, 1H, H-6b), 4.63 (d, J = 12.6 Hz, 1H, NAPCH₂b), 4.43 (d, J = 3.2 Hz, 1H, H-4) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.8, 165.1 (2C, 2 × C_q Bz), 152.8 (1C, C-5), 135.0, 133.3, 133.1, 129.4 (6C, 6 × C_q arom.), 133.5–125.7 (22C, arom.), 101.3 (1C, C-6), 87.6 (1C, C-1), 73.1 (1C, C-4), 72.1 (1C, C-3), 70.3 (1C, NAPCH₂), 69.3 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₀NaO₆S [M + Na]⁺ 625.1655; found: 625.1654.

Phenyl 2,3-di-O-benzoyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-arabino-hex-5-enopyranoside (78) and 8-N-[phenyl 2,3-di-O-benzoyl-6-deoxy-6-yl-4-O-(2′-naphthyl)methyl-1-thio-α-d-altropyranoside]-1,8-diazabicyclo(5.4.0)undec-7-ene-iodide (79). Compound 73 (257 mg, 0.351 mmol) was converted to 78 according to general Method B. The crude product was purified by silica gel chromatography (7:3 CH₂Cl₂/n-hexane → 9:1 CH₂Cl₂/MeOH) to give 78 (105 mg, 50%) as a white foam and 79 (130 mg, 42%) as a light yellow syrup.

Data of 79: [α]_D²⁵ + 75.0 (c 0.16, CHCl₃); R_f 0.54 (9:1 CH₂Cl₂/MeOH); ¹H NMR (500 MHz, CDCl₃) δ = 8.31–7.27 (m, 22H, arom.), 5.96 (s, 1H, H-3), 5.72 (s, 1H, H-1), 5.58 (d, J = 3.1 Hz, 1H, H-2), 4.92 (d, J = 11.2 Hz, 1H, NAPCH₂a), 4.77 (d, J = 11.2 Hz, 1H, NAPCH₂b), 4.71 (t, J = 9.6 Hz, 1H, H-5), 4.16 (d, J = 15.5 Hz, 1H, H-6a), 3.99 (dd, J = 2.5 Hz, J = 9.8 Hz, 1H, H-4), 3.76 (dd, J = 9.7 Hz, J = 15.7 Hz, 1H, H-6b), 3.67–3.49 (m, 6H, 3 × NCH₂ DBU), 2.87–2.74 (m, 2H, CH₂ DBU), 1.92–1.83 (m, 2H, CH₂ DBU), 1.66–1.56 (m, 6H, 3 × CH₂ DBU) ppm; ¹³C NMR (125 MHz, CDCl₃), δ = 167.5 (1C, C_q DBU), 165.0, 164.7 (2C, 2 × C_q Bz), 134.3, 133.6, 133.0, 132.9, 128.8, 128.3 (6C, 6 × C_q arom.), 133.8–126.2 (22C, arom.), 84.6 (1C, C-1), 71.6 (1C, C-4), 71.2 (1C, C-2), 71.1 (1C, NAPCH₂), 67.3 (1C, C-5), 64.9 (1C, C-3), 55.2 (1C, C-6), 55.7, 49.4, 48.4 (3C, 3 × NCH₂ DBU), 29.1, 28.2, 25.7, 22.7, 19.8 (5C, 5 × CH₂ DBU) ppm; UHR ESI-QTOF: m/z calcd for C₄₆H₄₇N₂O₆S [M]⁺ 755.3149; found: 755.3154.

Phenyl 2,3-di-O-benzoyl-4-O-(2′-naphthyl)methyl-1-thio-α-d-arabino-hex-5-enopyranoside (78) and 1,5-anhydro-2-O-benzoyl-3,6-dideoxy-4-O-(2′-naphthyl)methyl-3-S-phenyl-3-thio-α-d-erythro-hex-1,5-dienytol (47). Compound 73 (234 mg, 0.320 mmol) was converted to 78 according to general Method F. The crude product was purified by silica gel chromatography (7:3 CH₂Cl₂/n-hexane) to give 78 (103 mg, 53%) as a white foam and 47 (20 mg, 10%) as a colorless syrup.

Phenyl 2,3-di-O-benzyl-4-O-(2′-naphthyl)methyl-1-thio-β-l-galactopyranoside (80). Compound 74 (143 mg, 0.249 mmol) was converted to 80 according to general Method C. The crude product was purified by silica gel chromatography (55:45 n-hexane/EtOAc) to give 80 (100 mg, 68%) as a colorless syrup. [α]_D²⁵ + 7.0 (c 0.10, CHCl₃); R_f 0.41 (55:45 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 7.84–7.17 (m, 22H, arom.), 5.12–4.65 (m, 6H, NAPCH₂, 2 × BnCH₂), 4.66 (d, J = 9.6 Hz, 1H, H-1), 3.99 (t, J = 9.4 Hz, 1H, H-2), 3.88–3.84 (m, 2H, H-4, H-6a), 3.61 (dd, J = 2.7 Hz, J = 9.2 Hz, 1H, H-3), 3.53–3.49 (m, 1H, H-6b), 3.45–3.42 (m, 1H, H-5), 1.84 (d, J = 4.7 Hz, 1H, C-6-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 138.3, 138.2, 135.8, 134.1, 133.2, 133.1 (6C, 6 × C_q arom.), 131.6–126.2 (22C, arom.), 87.8 (1C, C-1), 84.4 (1C, C-3), 79.0 (1C, C-5), 77.6 (1C, C-2), 75.8, 74.4, 73.2 (3C, NAPCH₂, 2 × BnCH₂), 73.4 (1C, C-4), 62.4 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₆NaO₅S [M + Na]⁺ 615.2176; found: 615.2189.

Phenyl 2,3-di-O-benzoyl-4-O-(2′-naphthyl)methyl-1-thio-β-l-galactopyranoside (81). Compound 78 (193 mg, 0.319 mmol) was converted to 81 according to general Method C. The crude product was purified by silica gel chromatography (55:45 n-hexane/EtOAc) to give 81 (152 mg, 76%) as a colorless syrup. [α]_D²⁵ − 68.3 (c 0.12, CHCl₃); R_f 0.40 (55:45 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 7.98–7.26 (m, 22H, arom.), 5.93 (t, J = 9.9 Hz, 1H, H-2), 5.38 (d, J = 9.9 Hz, 1H, H-3), 4.97 (d, J = 9.9 Hz, 1H, H-1), 4.90 (d, J = 11.8 Hz, 1H, NAPCH₂a), 4.68 (d, J = 11.8 Hz, 1H, NAPCH₂b), 4.24 (s, 1H, H-4), 3.98–3.95 (m, 1H, H-6a), 3.81 (t, J = 5.6 Hz, 1H, H-5), 3.65–3.63 (m, 1H, H-6b), 1.73 (d, J = 6.0 Hz, 1H, C-6-OH) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 166.0, 165.4 (2C, 2 × C_q Bz), 134.9, 133.2, 133.1, 132.8, 129.7, 129.0 (6C, 6 × C_q arom.), 133.6–126.1 (22C, arom.), 86.7 (1C, C-1), 79.3 (1C, C-5), 76.1 (1C, C-3), 75.0 (1C, NAPCH₂), 74.0 (1C, C-4), 68.6 (1C, C-2), 62.1 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₂NaO₇S [M + Na]⁺ 643.1761; found: 643.1768.

Phenyl 2,3-di-O-benzyl-4,6-O-(2′-naphthyl)methylidene-1-thio-β-l-galactopyranoside (82). Compound 80 (85 mg, 0.144 mmol) was converted to 82 according to general Method G. The crude product was purified by silica gel chromatography (CH₂Cl₂) to give 82 (68 mg, 80%) as a colorless syrup. [α]_D²⁵ − 30.0 (c 0.12, CHCl₃); R_f 0.47 (6:4 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 7.98–7.14 (m, 22H, arom.), 5.61 (s, 1H, H_ac), 4.73–4.69 (m, 4H, 2 × BnCH₂), 4.61 (d, J = 9.6 Hz, 1H, H-1), 4.37 (dd, J = 1.2 Hz, J = 12.3 Hz, 1H, H-6a), 4.16 (d, J = 3.3 Hz, 1H, H-4), 3.97 (dd, J = 1.3 Hz, J = 12.3 Hz, 1H, H-6b), 3.93 (t, J = 9.4 Hz, 1H, H-2), 3.62 (dd, J = 3.4 Hz, J = 9.2 Hz, 1H, H-3), 3.35 (s, 1H, H-5) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 138.6, 138.3, 135.4, 133.9, 133.0, 132.9 (6C, 6 × C_q arom.), 132.8–124.4 (22C, arom.), 101.5 (1C, C_ac), 86.7 (1C, C-1), 81.5 (1C, C-3), 75.3 (2C, C-2, BnCH₂), 73.9 (1C, C-4), 71.9 (1C, BnCH₂), 70.0 (1C, C-5), 69.6 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₄NaO₅S [M + Na]⁺ 613.2019; found: 613.2054.

Phenyl 2,3-di-O-benzoyl-4,6-O-(2′-naphthyl)methylidene-1-thio-β-l-galactopyranoside (83). Compound 81 (149 mg, 0.239 mmol) was converted to 83 according to general Method G. The crude product was purified by silica gel chromatography (6:4 n-hexane/EtOAc) to give 83 (115 mg, 78%) as a white crystal. [α]_D²⁵ − 111.0 (c 0.10, CHCl₃); M.p.: 226–228 °C (EtOAc/n-hexane); R_f 0.44 (6:4 n-hexane/EtOAc); ¹H NMR (400 MHz, CDCl₃) δ = 7.99–7.19 (m, 22H, arom.), 5.85 (t, J = 9.9 Hz, 1H, H-2), 5.61 (s, 1H, H_ac), 5.40 (dd, J = 3.4 Hz, J = 9.9 Hz, 1H, H-3), 4.94 (d, J = 9.8 Hz, 1H, H-1), 4.61 (d, J = 3.2 Hz, 1H, H-4), 4.43 (dd, J = 0.9 Hz, J = 12.2 Hz, 1H, H-6a), 4.06 (dd, J = 1.1 Hz, J = 12.3 Hz, 1H, H-6b), 3.66 (s, 1H, H-5) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 166.3, 165.0 (2C, 2 × C_q Bz), 135.1, 133.7, 132.8, 131.2, 129.7, 129.1 (6C, 6 × C_q arom.), 133.8–124.2 (22C, arom.), 101.2 (1C, C_ac), 85.3 (1C, C-1), 74.1 (1C, C-3), 73.8 (1C, C-4), 69.9 (1C, C-5), 69.2 (1C, C-6), 67.2 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₀NaO₇S [M + Na]⁺ 641.1604; found: 641.1616.

Phenyl 2,3-di-O-benzyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-galactopyranoside (84). Compound 82 (59 mg, 0.099 mmol) was converted to 84 according to general Method H. The crude product was purified by silica gel chromatography (98:2 CH₂Cl₂/acetone) to give 84 (40 mg, 68%) as a colorless syrup. [α]_D²⁵ + 8.0 (c 0.15, CHCl₃); R_f 0.35 (98:2 CH₂Cl₂/acetone); ¹H NMR (400 MHz, CDCl₃) δ = 7.84–7.20 (m, 22H, arom.), 4.84–4.66 (m, 6H, NAPCH₂, 2 × BnCH₂), 4.65 (d, J = 9.8 Hz, 1H, H-1), 4.11 (d, J = 1.7 Hz, 1H, H-4), 3.87–3.79 (m, 2H, H-6a,b), 3.76 (t, J = 9.3 Hz, 1H, H-2), 3.63 (t, J = 5.7 Hz, 1H, H-5), 3.58 (dd, J = 3.2 Hz, J = 8.9 Hz, 1H, H-3), 2.56 (s, 1H, C-4-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 138.3, 137.8, 135.5, 134.0, 133.4, 133.1 (6C, 6 × C_q arom.), 131.9–125.9 (22C, arom.), 87.8 (1C, C-1), 82.7 (1C, C-3), 77.2 (1C, C-5), 77.1 (1C, C-2), 75.9, 74.0, 72.3 (3C, NAPCH₂, 2 × BnCH₂), 69.9 (1C, C-6), 67.1 (1C, C-4) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₆NaO₅S [M + Na]⁺ 615.2176; found: 615.2161.

Phenyl 2,3-di-O-benzoyl-6-O-(2′-naphthyl)methyl-1-thio-β-l-galactopyranoside (85). Compound 83 (107 mg, 0.173 mmol) was converted to 85 according to general Method H. The crude product was purified by silica gel chromatography (98:2 CH₂Cl₂/acetone) to give 85 (68 mg, 64%) as a white foam. [α]_D²⁵ −7 7.0 (c 0.10, CHCl₃); R_f 0.32 (98:2 CH₂Cl₂/acetone); ¹H NMR (400 MHz, CDCl₃) δ = 7.98–7.19 (m, 22H, arom.), 5.82 (t, J = 9.9 Hz, 1H, H-2), 5.34 (dd, J = 2.9 Hz, J = 9.8 Hz, 1H, H-3), 4.96 (d, J = 10.0 Hz, 1H, H-1), 4.74 (s, 2H, NAPCH₂), 4.43 (s, 1H, H-4), 3.94–3.92 (m, 1H, H-5), 3.89–3.87 (m, 2H, H-6a,b), 2.86 (s, 1H, C-4-OH) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 166.0, 165.4 (2C, 2 × C_q Bz), 135.2, 133.4, 133.2, 132.7, 129.6, 129.2 (6C, 6 × C_q arom.), 133.5–125.8 (22C, arom.), 86.7 (1C, C-1), 77.4 (1C, C-5), 75.7 (1C, C-3), 74.0 (1C, NAPCH₂), 69.7 (1C, C-6), 68.4 (1C, C-4), 68.1 (1C, C-2) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₂NaO₇S [M + Na]⁺ 643.1761; found: 643.1779.

Phenyl 2,3-di-O-benzyl-6-O-(2′-naphthyl)methyl-4-O-(4′-nitrobenzoyl)-1-thio-β-l-glucopyranoside (86). Compound 84 (24 mg, 0.040 mmol) was converted to 86 according to general Method K. The crude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give 86 (18 mg, 60%) as a colorless syrup. [α]_D²⁵ + 12.0 (c 0.10, CHCl₃); R_f 0.63 (7:3 n-hexane/EtOAc); ¹H NMR (500 MHz, CDCl₃) δ = 7.95–7.03 (m, 26H, arom.), 5.31 (t, J = 9.4 Hz, 1H, H-4), 4.95–4.52 (m, 7H, H-1, NAPCH₂, 2 × BnCH₂), 3.80 (t, J = 9.1 Hz, 1H, H-3), 3.76–3.73 (m, 1H, H-5), 3.71–3.66 (m, 2H, H-6a,b), 3.64 (t, J = 9.3 Hz, 1H, H-2) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 163.7, 150.2 (2C, 2 × C_q p-NO₂-Bz), 137.9, 137.8, 135.0, 134.9, 133.5, 133.0 (6C, 6 × C_q arom.), 132.2–123.2 (26C, arom.), 88.0 (1C, C-1), 83.5 (1C, C-3), 81.0 (1C, C-2), 77.0 (1C, C-5), 75.7, 75.5, 73.8 (3C, NAPCH₂, 2 × BnCH₂), 72.6 (1C, C-4), 70.1 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for: C₄₄H₃₉NNaO₈S [M + Na]⁺ 764.2289; found: 764.2139.

Phenyl 2,3-di-O-benzoyl-6-O-(2′-naphthyl)methyl-4-O-(4′-nitrobenzoyl)-1-thio-β-l-glucopyranoside (87) and Phenyl 2,3-di-O-benzoyl-6-O-(2′-naphthyl)methyl-4-deoxy-1-thio-α-d-threo-hex-4-enopyranoside (88). Compound 85 (40 mg, 0.063 mmol) was converted to 87 according to general Method K. The crude product was purified by silica gel chromatography (CH₂Cl₂) to give 87 (25 mg, 51%) as a colorless syrup and 88 (7 mg, 18%) as a colorless syrup.

Data of 87: [α]_D²⁵ + 20.9 (c 0.11, CHCl₃); R_f 0.55 (CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ = 7.96–7.26 (m, 26H, arom.), 5.85 (t, J = 9.4 Hz, 1H, H-3), 5.56 (t, J = 9.7 Hz, 1H, H-4), 5.51 (t, J = 9.7 Hz, 1H, H-2), 5.05 (d, J = 10.0 Hz, 1H, H-1), 4.64 (s, 2H, NAPCH₂), 4.07–4.05 (m, 1H, H-5), 3.84–3.78 (m, 2H, H-6a,b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.9, 165.2, 163.7, 150.4 (4C, 2 × C_q Bz, 2 × C_q p-NO₂-Bz), 134.9, 134.4, 133.0, 132.1, 129.3, 128.8 (6C, 6 × C_q arom.), 133.5–123.3 (26C, arom.), 86.6 (1C, C-1), 77.4 (1C, C-5), 74.4 (1C, C-3), 73.9 (1C, NAPCH₂), 71.3 (1C, C-4), 70.6 (1C, C-2), 69.5 (1C, C-6) ppm; ESI-TOF-MS: m/z calcd for: C₄₄H₃₅NNaO₁₀S [M + Na]⁺ 792.1874; found: 792.1800.

Data of 88: [α]_D²⁵ + 49.5 (c 0.62, CHCl₃); R_f 0.41 (CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ = 8.20–7.26 (m, 22H, arom.), 5.86 (s, 1H, H-1), 5.75 (s, 1H, H-2), 5.54 (s, 2H, H-3, H-4), 4.78 (dd, J = 11.8 Hz, J = 30.2 Hz, 2H, NAPCH₂), 4.18 (d, J = 13.3 Hz, 1H, H-6a), 4.10 (d, J = 13.1 Hz, 1H, H-6b) ppm; ¹³C NMR (125 MHz, CDCl₃) δ = 165.6, 165.5 (2C, 2 × C_q Bz), 152.0 (1C, C-5), 135.9, 135.3, 134.5, 129.9, 129.2 (6C, 6 × C_q arom.), 133.7–126.0 (22C, arom.), 97.3 (1C, C-4), 84.0 (1C, C-1), 72.5 (1C, NAPCH₂), 70.0 (1C, C-2), 69.6 (1C, C-6), 64.9 (1C, C-3) ppm; ESI-TOF-MS: m/z calcd for: C₃₇H₃₀NaO₆S [M + Na]⁺ 625.1655; found: 625.1632.

4. Conclusions

We have successfully developed an efficient synthetic route for the preparation of four rare l-hexoses (l-gulose, l-galactose, l-allose, and l-glucose) in the form of orthogonally protected thioglycosides, starting from the cheap d-mannose, using the most readily available chemicals and most cost-effective transformations possible. The preparation of the 5,6-unsaturated derivatives, required for the C-5 epimerization, was investigated systematically in the presence of ether and ester protecting groups. We have found that the outcome of the elimination reactions is strongly dependent on both the protecting group pattern, the sugar configuration, and the reagent applied. For the fully ether protected derivative, elimination with NaH reagent led to the best yields. AgF-induced dehydrohalogenation proceeded efficiently from ester-bearing compounds, however, in the case of C-3 ester group, a glycal by-product has also been formed due to elimination and subsequent allylic rearrangement. The only example for such an intriguing side reaction has previously been observed in photoinitiated thiol-ene reaction of 2,3-unsaturated α-thioglycosides [38]. In DBU-induced reactions, significant amounts of amidinium salt by-products were formed in all cases, regardless of the type and configuration of the protecting groups. C-5 epimerization could be performed with good stereoselectivity for all derivatives, but the yields were significantly higher for ester-protected derivatives than for ether protected ones. Oxidation-reduction-based C-4 epimerization of vicinal trans diols to vicinal cis diols was performed with good stereoselectivity in the presence of an ether protecting group adjacent to the keto functionality. The same method yielded vicinal trans diol in the presence of an ester group adjacent to the oxo group, which was exploited during the d-mannose to d-altrose conversion. The Mitsunobu inversion proved to be suitable for the preparation of equatorial trans diols, but an undesired elimination side reaction was also observed in the presence of an adjacent ester group. All designed l-hexoses were successfully prepared in 9–15 steps (total yields for l-gulose: 21–23%; for l-galactose: 6–8%; for l-allose: 6–8%; for l-glucose: 2–3%) as thioglycosides suitable for the synthesis of oligosaccharides, which can facilitate the synthesis of biologically active molecules.