Synthesis of furanoid and pyranoid C-1 aryl glycals by reaction of glycosyl chlorides with organolithium reagents

Furanosyl and pyranosyl chlorides react with aryllithium derivatives, obtained by directed ortho - lithiation of activated arenes, to give C-1 aryl glycals in moderate yields


Introduction
The term glycal is used to define aldose derivatives having a double bond between C-1 and C-2, e.g. 1. 1 Accordingly, C-1 glycals are Δ 1,2 unsaturated carbohydrate derivatives with a carbon substituent at the anomeric position, e.g. 2. These compounds are versatile synthetic intermediates, owing to the variety of transformations associated with their enol ether functionality, and have found ample use in the preparation of C-glycosides, e.g. 3, 2 carbohydrate mimics, 3 and natural products 4 .The preparation of C-1 glycals has been largely addressed by synthetic modifications on cyclic carbohydrate derivatives, 5 although strategies that rely on ring forming reactions from acyclic derivatives have recently emerged. 6,7Most of the synthetic routes to C-1 glycals from cyclic carbohydrate derivatives are based on the deprotonation of glycals, which was independently reported by three research groups. 8,9,10The ensuing lithiated species are then able to react with various carbon electrophiles, or with tributyltin chloride.The former approach leads directly to C-1 glycals, and the latter have been harnessed to palladium-mediated cross-coupling reactions for the key C1-C1' bond forming step. 11,12,13On the other hand, lactones have also been used as starting materials in the synthesis of C-1 glycals, 14 in this case unlike the previous one the carbohydrate functions as an electrophile.
As part of our interest in the preparation of C-1 glycals, 15 we reported, some time ago, a route to both C-aryl and C-alkyl pyranoid glycals based on the of reaction of anomeric glycosyl chlorides, e.g. 6, with commercially available organolithium reagents, where the carbohydrates exerted as the electrophilic partner. 16,17We have since evaluated the scope of the approach 18 and, in this paper, we describe the preparation of furanoid and pyranoid C-1 aryl glycals from the reaction of furanosyl and pyranosyl chlorides with aryllithium derivatives generated by directed ortho-metalation of aromatic derivatives, vide infra.Furthermore, the furanoid C-1 glycals prepared in this study can be easily transformed into homochiral 2,5-disubstituted furans.

Results and Discussion
For our study we selected compound 6, as the furanosyl chloride representative.Chloride 6 was easily prepared in two steps from D-mannose (4) by thermodynamically controlled acetonation 19 followed by anomeric chlorination 20  As pyranosyl chloride, we selected 6-deoxy derivative 15, since a related compound had been used by Tius and co-workers in their synthetic approach to vineomicinone B2 methyl ester. 21In our synthetic scheme to chloride 15, we visualized thioglycoside 12 as the key intermediate (Scheme 2a).Our synthetic scheme started with tosyl derivative prepared from thioglycoside 7, by treatment with tosyl chloride (pyridine, 0 o C) in 65% yield (Scheme 2a).From compound 8, we evaluated three different routes to 12: i) the direct treatment of tosylate 8 with lithium aluminum hydride produced triol 9, albeit in only 30% yield, from which the isopropylidene ring was installed in 60% yield; ii) a second route involving nucleophilic substitution of tosylate 8 with NaI followed by radical dehalogenation (HSnBu3, AIBN) of the ensuing iodide, gave triol 9, in 85% yield; iii) the best route proved to be acetonation of the tosylate (85% yield) followed by H4LiAl reduction (87% yield).Once we had compound 12, in hand, we proceeded with its benzylation, oxidative hydrolysis, and chlorination to gain access to glycosyl chloride 15.
Before attempting the reaction of glycosyl chlorides 6 and 15 with complex aryllithium reagents, we decided to test their reaction with, commercially available, PhLi.In agreement with our previous results, 16,18 we found they both led to the expected C-1 phenyl glycals in moderate yields (Scheme 3).We next turned our attention to the use of aryl organilithium reagents other than commercially available, PhLi.We envisaged that aryllithium derivatives generated by directed ortho-metalation, 22 could be used in the preparation of C-1 glycals.Accordingly, 2-lithio 1methoxy naphthalene generated by reaction of 1-methoxy naphthalene with t-BuLi, reacted with furanosyl chloride 6, to furnish C-1 glycal 18, in 46% yield (Scheme 4a).We also carried out the directed ortho-metalation on 2-methoxy naphthalene, and 1-naphthol, and the results are shown in Scheme 4b,c, respectively.Varying amounts of furans 19 and 21 were observed in the crude reaction mixture of chloride 6 with the lithium salts of 1-and 2-methoxynaphthalene (Scheme 4a,b).These aryl glycals proved to be highly sensitive to acid and temperature, and so the low yield of compound 22 (Scheme 4c, obtained along with 23 as an inseparable mixture) could be rationalized because of the presence of the acidic phenolic OH group.According to that, we were able to prepare homochiral furans 19 and 21, in quantitative yield from the corresponding C-1 glycals 18 and 19, upon treatment with silicagel in dichloromethane.The presence of NEt3 in the reaction work-up, and in the eluent for column chromatography, has a beneficial effect in preventing this transformation.Finally, we decided to test the reaction of lithiated of 1,5-bis(methoxyethoxy)-anthracene (26), with pyranosyl chloride 15, since the expected C-1 glycal will be related to a synthetic intermediate employed by Tius and co-workers in their approach to vineomycinone B2 methyl ester. 21e prepared compound 26 from commercially available anthrarufin (1,5-dihydroxy-9,10-anthraquinone) 24, by methoxyethoxylation followed by sodium borohydride reduction (Scheme 5a).Subsequent, lithiation (n-BuLi, THF, -78 °C to -10 °C) of 26 and reaction with chloride 15, yielded C-1 glycal 27, in 9% yield, along with hemiacetal 28 (78%).

Conclusions
C-1 Aryl glycosides can be prepared in moderate yields by the reaction of glycosyl chlorides with functionalized aryllithium derivates.The latter can be accesed by directed ortho-metalation of the corresponding activated arenes.C-1 Aryl glycals ensuing from furanosyl chloride 6, have proven to be sensitive to acid and temperature, thus evolving to the corresponding furan derivatives.

Experimental Section
General Procedures.All reactions were performed in dry flasks fitted with glass stoppers or rubber septa under a positive pressure of Ar, unless otherwise noted.Air-and moisture-sensitive liquids and solutions were transferred by syringe or stainless steel cannula.Optical rotations were determined for solutions in chloroform.Flash column chromatography was performed using 230-400 mesh silica gel.Thin-layer chromatography was conducted on Kieselgel 60 F254 (Merck).Spots were observed first under UV irradiation (254 nm) then by charring with a solution of 20 % aqueous H2SO4 (200 mL) in AcOH (800 mL).Anhydrous MgSO4 or Na2SO4 were used to dry organic solutions during workup, and evaporation of the solvents was performed under vacuum using a rotary evaporator.Solvents were dried and purified using standard methods.Unless otherwise noted 1 H and 13 C NMR spectra were recorded in CDCl3 at 300 MHz and 50 MHz, respectively.Chemical shifts are expressed in parts per million (δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: δ 7.25 ppm).Elemental analyses were carried out at the Centro Nacional de Quimica Orgánica "Manuel Lora Tamayo", Juan de la Cierva 3, 28006 Madrid, with a Heraeus CHN-Orapid elemental analyzer.

General procedure for C-1 glycal formation
A solution of the glycosyl chloride (1 mmol) in dry THF was cooled to the appropriate temperature and then treated with the corresponding organolithium reagent.After stirring for a period of time between 0.5-2 h and once TLC analyses showed total disappearance of the starting material, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl.
After partitioning between water and diethyl ether, the organic layer was dried over MgSO4 and concentrated.The residue was purified by flash chromatography.
Scheme 4. Reaction of furanosyl chloride 6 with aryl lithiums generated by directed orthometalation, and furan formation.