Synthesis of novel carbohydrate based pyridinium ionic liquids and cytotoxicity of ionic liquids for mammalian cells

The large pool of naturally occurring carbohydrates with their diversity in chirality and structure led to the idea of a systematic investigation of carbohydrate based ILs. To this end, we investigated the influence of different ether groups, mainly methyl or ethyl ether, on the secondary OH groups as well as different configurations on physical properties such as melting point, thermostability and especially the influence on cell toxicity. For this investigation we chose α- and β-methyl-, β-allyl- and β-phenyl d-glucopyranose as well as four 1-deoxy-pentoses. In order to be able to classify the results, more ionic liquids with different structural motives were examined for cytotoxicity. Here, we present data that confirm the biocompatibility of such ILs consisting of naturally occurring molecules or their derivatives. The synthesized carbohydrate based ILs were tested for their suitability as additives in coatings for medical applications such as drug-eluting balloons.


1-Deoxy-D-ribofuranoside 1d
NEt 3 (6.7 mL) were stirred at room temperature overnight in dichloromethane (25 mL). The reaction mixture was evaporated. Column chromatography (PE/EA 4:1 to EA) led to products 1-4e. *yield over two steps, impure product 2d was used for this reaction.  1-4e (2.07 g, 5.5 mmol) was dissolved in dry DMF (33 mL) and cooled to 0°C. NaH (60 % dispersion in mineral oil, 1.3 eq per OH group) was added in small portions. The reaction was stirred at 0°C for 30 min, then methyl iodide (2.0 eq per OH group) was added and the reaction was stirred over night at room temperature. The solvent was evaporated, dichlormethane (100 mL) was added and the mixture was washed (3x 30 mL). Column chromatography (PE/EA 3:1) led to products 1-4f.

N-(2,3-O-Methyl-1,5-deoxy-D-ribofuranoside-5-yl)-pyridinium triflate 1i
MeO OMe O N OTf Work-up: The crude product was dissolved in dest. Water (100 mL) and washed with dichloromethane (4x 10 mL) and diethyl ether (2x 10 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added to further purify the product from remaining pyridine. The solvent was evaporated after filtration and the product was dried under high vaccum.

N-(2,3-O-Methyl-1,5-deoxy-D-lyxofuranoside-5-yl)-pyridinium triflate 2i
OMe OMe Work-up: The crude product was dissolved in dest. Water (100 mL) and washed with dichloromethane (4x 10 mL) and diethyl ether (2x 10 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added to further purify the product from remaining pyridine. The solvent was evaporated after filtration and the product was dried under high vaccum.

N-(2,3-O-Methyl-1,5-deoxy-D-xylofuranoside-5-yl)-pyridinium triflate 3i
OMe O N OTf OMe Work-up: The crude product was dissolved in dest. Water (100 mL) and washed with dichloromethane (4x 10 mL) and diethyl ether (2x 10 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added to further purify the product from remaining pyridine. The solvent was evaporated after filtration and the product was dried under high vaccum.

N-(2,3-O-Methyl-1,5-deoxy-L-arabinofuranoside-5-yl)-pyridinium triflate 4i
OMe O OTf OMe N Work-up: The crude product was dissolved in dest. Water (100 mL) and washed with dichloromethane (4x 10 mL) and diethyl ether (2x 10 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added to further purify the product from remaining pyridine. The solvent was evaporated after filtration and the product was dried under high vaccum.
Pyridine (1.07 mL, 13.3 mmol) was added. Afterwards, Tf 2 O (1.5 mL, 9.0 mmol) was added dropwise and the mixture was stirred for 10 min at 0°C. Dichloromethane (20 mL) was added and the mixture was washed with cold water (15 mL), sat. NaHCO 3 (2x 15 mL) and cold water again (15 mL). The dried organic phase contains a mixture of the 5-O-triflate intermediates, both 2,3-O-isopropylidene protected and unprotected. The mixture was directly used in the next step. Pyridine (2.15 mL, 26.6 mmol) was added and the follow-up reaction was performed at the rotary evaporator (40°C, 700 mbar). The crude product was dissolved in dest. water (100 mL) and washed with dichloromethane (4x 10 mL) and diethyl ether (2x 10 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added to further purify the product from remaining pyridine. The solvent was evaporated and the product was dried under high vaccum. This leads to a mixture of both 2,3-O-isopropylidene protected and unprotected pyridinium triflate salts. To achieve pure product 1k, a 70 % acetic acid solution (3 mL) was added and the reaction was stirred for 20 min. The mixture was codistilled with toluene until all acetic acid is removed. The crude product was again dissolved in dest. water (100 mL) and washed with dichloromethane (3x 20 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added. The solvent was evaporated after filtration and the product was dried under high vaccum, leading to 1k.
The crude product was dissolved in dest. water (100 mL) and washed with dichloromethane (4x 10 mL) and diethyl ether (2x 10 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added to further purify the product from remaining pyridine. The solvent was evaporated after filtration and the product 1x was dried under high vaccum.

5-8c and ethyl ether 5g
5-8b (5.5 mmol) was dissolved in dry DMF (33 mL) and cooled to 0°C. NaH (60 % dispersion in mineral oil, 1.3 eq per OH group) was added in small portions. The reaction was stirred at 0°C for 30 min, then methyl iodide (2.0 eq per OH group) was added and the reaction was stirred over night at room temperature. The solvent was evaporated, dichlormethane (100 mL) was added and the mixture was washed (3x 30 mL). Column chromatography (PE/EA 3:1) led to products 5-8c.

N-(Methyl-6-deoxy-2,3,4-O-methyl-β-D-glucopyranoside-6-yl)-pyridinium triflate 5f
Work-up: The crude product was dissolved in dest. Water (100 mL) and washed with dichloromethane (4x 10 mL) and diethyl ether (2x 10 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added to further purify the product from remaining pyridine. The solvent was evaporated after filtration and the product was dried under high vaccum.

N-(Allyl-6-deoxy-2,3,4-O-methyl-β-D-glucopyranoside-6-yl)-pyridinium triflate 6f
Work-up: The crude product was dissolved in dest. Water (100 mL) and washed with dichloromethane (4x 10 mL) and diethyl ether (2x 10 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added to further purify the product from remaining pyridine. The solvent was evaporated after filtration and the product was dried under high vaccum.

N-(Methyl-6-deoxy-2,3,4-O-methyl-α-D-glucopyranoside-6-yl)-pyridinium triflate 8f
OMe Work-up: The crude product was dissolved in dest. Water (100 mL) and washed with dichloromethane (4x 10 mL) and diethyl ether (2x 10 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added to further purify the product from remaining pyridine. The solvent was evaporated after filtration and the product was dried under high vaccum.

N-(Methyl-6-deoxy-2,3,4-O-ethyl-β-D-glucopyranoside-6-yl)-pyridinium triflate 5j
Work-up: The crude product was dissolved in dest. Water (100 mL) and washed with dichloromethane (4x 10 mL) and diethyl ether (2x 10 mL). The aqueous phase was evaporated. The product was then dissolved in dry methanol (10 mL) and a small amount of activated charcoal was added to further purify the product from remaining pyridine. The solvent was evaporated after filtration and the product was dried under high vaccum.