Synthesis of a Novel D-Glucose-Conjugated 15-Crown-5 Ether with a Spiro Ketal Structure

This paper describes a synthetic approach to a novel D-glucose-conjugated 15-crown-5 ether having a spiroketal structure starting from a 1-C-vinylated glucose derivative. The approach consists of the glycosylation of the vinylated glucose derivative to give an ethyleneoxy spacer derivative using bismuth(III) triflate, the conversion of the 1-C-vinyl group of the glucoside produced into a carboxylic acid group, and the intramolecular condensation between the carboxyl group and the terminal hydroxyl group in the ethyleneoxy spacer. A D-glucose-conjugated 15-crown-5 ether having a unique spiroketal structure was thus successfully synthesized.


Introduction
Crown ether molecules with saccharide moieties are interesting as chiral phase-transfer catalysts [1][2]. An enzymatic approach for synthesizing these types of crown ethers provides the cyclofructan family (cycloβ(2 1)-D-fructooligosaccharides) via the digestion of inulin. The cyclofructan contains a structurally interesting crown ether framework in its central core [3][4]. It is noteworthy that this is the OPEN ACCESS first example of saccharide-based crown ethers which have spiroketal structures. Many saccharidebased crown ether molecules have also been synthesized by chemical procedures [5][6][7]. As these chemical methods bind the original hydroxyl groups of the saccharide with an ethyleneoxy spacer, they cannot produce however crown ether compounds having spiroketal structures.
Sugar derivatives (1-C-vinylated sugars) having a vinyl group at the anomeric center, which are readily prepared by the addition of organometallic reagents, such as vinylMgX, to a suitably protected sugar lactone, are a synthetically useful tool in carbohydrate chemistry [8][9][10][11]. Our recent studies have shown that these 1-C-vinylated sugar derivatives were good precursors for preparing some fuctionalized exo-glycal derivatives [12] and naturally occurring anhydroketopyranoses [13]. For the purpose of further exploring the utility of the 1-C-vinylated sugars, we investigated the synthesis of a novel crown ether molecule from a 1-C-vinylated D-glucose derivative 1. The D-glucose-conjugated 15-crown-5 ether 2 that we designed is a dicyclic compound with a unique spiroketal structure derived from the structural characteristic of 1, i.e., its spiro carbon atom corresponds to the anomeric carbon atom. This paper describes our synthetic approach to a novel 15-crown-5 ether 2 having a spiroketal structure from a 1-C-vinylated glucose derivative (1).

Results and Discussion
The synthetic approach to compound 2 from 1 is shown in Scheme 1. It consists of the following reaction steps: 1) introduction of the ethyleneoxy spacer, tetraethyleneglycol monobenzoate (3) onto the vinylated D-glucopyranose derivative 1 by the glycosylation reaction; 2) conversion of the vinyl group at the anomeric center of 4 to a carboxyl group, and 3), intramolecular condensation between the carboxyl group and the terminal hydroxyl group in the ethyleneoxy spacer to produce the desired 2.
The glycosylation of 1 to 3 (1.3 equiv.) using bismuth(III) triflate (Bi(OTf) 3 ) (0.05 equiv.) in the presence of anhydrous CaSO 4 in dichloromethane at 0 o C for 24 h afforded the desired glucoside 4 [14], which was purified by preparative TLC (ethyl acetate/hexane = 1/2) in 81% yield. The glycosylation proceeded with an α-stereoselectivity. The high α-stereoselectivity of the glycosylation using 1 was in agreement with our previously reported observation [15]. The α-anomeric configuration of 4 was determined by the NOE interaction between the H-2 and the H-1'.
In conclusion, we have demonstrated the synthesis of a novel 15-crown-5 ether 2 having a spiro ketal structure from a 1-C-vinylated D-glucose derivative. This compound 2 is expected to function as a chiral phase-transfer catalyst.

Experimental
General 1 H-NMR (600 MHz) and 13 C-NMR (150 MHz) spectra were recorded using a JEOL ECA-600 spectrometer in CDCl 3 with TMS as the internal standard. The optical rotations were recorded by a JASCO DIP-360 digital polarimeter. The HRMS were obtained using a Mariner spectrometer (PerSeptive Biosystems Inc.). Preparative TLC was performed using Merck silica gel 60GF254. Column chromatography was conducted using silica gel 60 N (40~50 μm, Kanto Chemical Co., Inc.). Bi(OTf) 3 was purchased from Sigma-Aldrich. All anhydrous solvents were purified according to standard methods. NaHCO 3 solution (5 mL). The reaction mixture was extracted with CH 2 Cl 2 (three times), and the organic layer was washed with water and a sat. NaCl solution. After the organic layer was dried over Na 2 SO 4 , the solvent was evaporated under reduced pressure. The crude product was purified by preparative silica gel TLC (ethyl acetate/hexane = 1/2) to give 4 (311 mg, 81% yield) as a colorless oil.   , 1.2 mmol). After the reaction mixture was stirred for 24 h, the reaction was quenched by adding 2 M HCl (1 mL) and water (5 mL). The reaction mixture was then extracted with CH 2 Cl 2 (three times), and the combined organic solvent was dried over anhydrous Na 2 SO 4 . The organic solvent was filtered and evaporated under reduced pressure. The crude product was purified by preparative silica gel TLC (CHCl 3 /MeOH = 5/1) to afford 5 (194 mg, 85% yield) as a colorless oil.  After the reaction mixture was stirred for 3 h at room temperature, the reaction was quenched by adding 2 M HCl (1 mL) and water (5 mL). After the reaction mixture was extracted with CH 2 Cl 2 (three times), the combined organic solvent was dried over anhydrous Na 2 SO 4 . The organic solvent was filtered and evaporated under reduced pressure. The crude product was purified by preparative silica gel TLC (CHCl 3 /MeOH = 5/1) to afford 6 (103 mg, 83% yield) as a colorless oil.  [3,6,9,12]tetraoxatetradecan]-14'-olide (2): To a solution of 6 (20 mg, 0.027 mmol) in CH 2 Cl 2 (3 mL) were added 4-dimethylaminopyridine (5.9 mg, 0.048 mmol) and PyBOP (35 mg, 0.067 mmol). After the reaction mixture was stirred for 24 h. The reaction was then quenched by the addition of a sat. citric acid solution (5 mL). The reaction mixture was extracted with EtOAc and the organic layer was washed with water and a sat. NaCl solution. After the organic layer was dried over Na 2 SO 4 , the solvent was evaporated under reduced pressure. The crude product was purified by preparative silica gel TLC (CHCl 3 /MeOH = 20/1) to give 2 (17 mg, 84% yield) as a colorless oil.