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

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.

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 αor 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-iodoglycosides, 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 BH 3 ·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(PPh 3 ) 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.

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 Ph 3 P, 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. Scheme 2. Preparation of the 5,6-unsaturated 26 from SPh-α-D-mannopyranoside and its conversion to L-gulose series by hydroboration/oxidation. 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). 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.

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 BH 3 ·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.  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 BH 3 ·THF complex in dry THF followed by oxidation with 30% H 2 O 2 , and hydrolysis of the resulting boronic acid ester under alkaline conditions with satd. NaHCO 3 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 BH 3 ·Me 3 N/AlCl 3 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 CH 2 Cl 2 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 1 H 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. 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 NaBH 4 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 BH 3 ·THF/TMSOTf reagent combination. The primary hydroxyl in the resulting 70 and 71 was converted to a good leaving group by the treatment of Ph 3 P, 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 DBUinduced 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 (Ph 3 P), and diisopropyl azodicarboxylate (DIAD) reagents in dry toluene. In the case of the etherprotected 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-4,5unsaturated 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].

General Information
Optical rotations were measured at room temperature on a Perkin-Elmer 241 automatic polarimeter. TLC analysis was performed on Kieselgel 60 F 254 (Merck, 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 MgSO 4 and concentrated under vacuum. 1 H and J-modulated 13 C NMR spectroscopy ( 1 H: 400 and 500 MHz; 13 C: 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 SiMe 4 or sodium 3-(trimethylsilyl)-1-propanesulfonate (DSS, δ = 0.00 ppm for 1 H nuclei) and to residual solvent signals (CDCl 3 : δ = 77.16 ppm, CD 3 OD: δ = 49.15 ppm for 13 C 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, Billerica, MA, USA) 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  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, NaHCO 3 (1.0 g) in water (14 mL) was added at room temperature. After 5 min, 10% aqueous solution of Na 2 S 2 O 3 (25 mL) was added and the mixture was diluted with EtOAc (250 mL) and washed with H 2 O (2 × 75 mL). The organic layer was separated, dried, filtered, and concentrated.

General Method H for Stereoselective Ring Opening with Me 3 N·BH 3 /AlCl 3 (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 Me 3 N·BH 3 (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 AlCl 3 (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 CH 2 Cl 2 (100 mL) and washed with H 2 O (2 × 15 mL). The organic layer was dried, filtered, and concentrated. 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 CH 2 Cl 2 (3 × 25 mL). The combined organic extracts were washed with saturated aqueous solution of NaHCO 3 and brine, dried, filtered, and concentrated.

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) Ph 3 P (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 NaHCO 3 , and the mixture was extracted with CH 2 Cl 2 (3 × 25 mL). The combined organic extracts were washed with water (10 mL), dried, filtered, and concentrated. (24). The acetal derivative 23 [79] (2.53 g, 4.272 mmol) was dissolved in anhydrous CH 2 Cl 2 (38.5 mL) and anhydrous Et 2 O (13 mL). LiAlH 4 (729 mg, 19.224 mmol, 4.5 equiv.) was added, and then a solution of AlCl 3 (2.57 g, 19.224 mmol, 4.5 equiv.) in anhydrous Et 2 O (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 H 2 O (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 MgSO 4 , 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.   [91] (2.5 g, 6.096 mmol) in dry CH 3 CN (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 NaHCO 3 , extracted with CH 2 Cl 2 (3 × 100 mL), and the organic phases was washed with H 2 O (3 × 50 mL) until neutral pH. The organic layer was dried over MgSO 4 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. To the solution of the 3-ulose compound (4.44 g, 8.669 mmol) in dry MeOH (53.6 mL), NaBH 4 (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 (CH 2 Cl 2 ) to give 67 ( (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 CH 2 Cl 2 (500 mL), washed with H 2 O (3 × 100 mL), dried over MgSO 4 , 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. able 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.