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 first example of saccharide-based crown ethers which have spiroketal structures. Many saccharide-based 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.

Scheme 1

Synthetic approach to 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 CaSO4 in dichloromethane at 0 oC 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’.

The ozone oxidation of 4 in dichloromethane at -78 oC for 5 h and treatment with triphenylphosphine (3.4 equiv.) at room temperature for 19 h gave the crude aldehyde product. The subsequent oxidation using NaClO2 (12 equiv.)-NaH2PO4 (3 equiv.) in t-butyl alcohol-H2O (4/1) produced the carboxylic acid derivative 5, which was purified by preparative TLC (CHCl3/MeOH = 5/1) in 85% yield.

Deprotection of the benzoyl group of 5 was performed using 0.5 M NaOH/THF to afford 6 in 83% yield. The cyclization of 6 using (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluoro-phosphate (PyBOP) (2.5 equiv.) and DIEA (1.8 equiv.) in dichloromethane for 24 h afforded the desired 2, which was purified by preparative TLC (CHCl3/MeOH = 20/1) in 84% yield.

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.

Reagents and conditions: i) Bi(OTf)3 (0.05 equiv.), Bz(OCH2CH2)4OH 3 (1.3 equiv.), CH2Cl2, 0 °C, 24 h, 81%; ii) (a) O3, -78 °C, 5 h, CH2Cl2, then Ph3P (3.4 equiv.), rt, 19 h. (b) Me2C=CHMe (4.5 equiv.), NaClO2 (12 equiv.), NaH2PO4 (3 equiv.), t-BuOH-H2O, rt, 24 h, 85%; iii) 0.5 M NaOH (13 equiv.), THF, rt, 3 h, 83%; iv) PyBOP (2.5 equiv.), DIEA (1.8 equiv.), CH2Cl2, 24 h, 84%.

Experimental

General

1H-NMR (600 MHz) and 13C-NMR (150 MHz) spectra were recorded using a JEOL ECA-600 spectrometer in CDCl3 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.

11-Benzoyloxy-3,6,9-trioxaundecyl 2,3,4,6-tetra-O-benzyl-1-C-vinyl-α-D-glucopyranoside (4): To a stirred solution of Bi(OTf)3 (15 mg, 0.023 mmol) in CH2Cl2 (3.5 mL) were added tetraethyleneglycol monobenzoate (3) (165 mg, 0.55 mmol) and 2,3,4,6-tetra-O-benzyl-1-C-vinyl-α-D-glucopyranose (1) (257 mg, 0.42 mmol) in the presence of anhydrous CaSO4 (280 mg) under an Ar atmosphere. The resulting mixture was stirred at 0 oC for 24 h. The reaction was then quenched by the addition of a sat. NaHCO3 solution (5 mL). The reaction mixture was extracted with CH2Cl2 (three times), and the organic layer was washed with water and a sat. NaCl solution. After the organic layer was dried over Na2SO4, 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. [α]D25 = +3o (c 4.7, CHCl3); 1H-NMR: δ 3.34 (d, 1H, J = 9.6 Hz, H-2), 3.48-3.70 (m, 14H, H-4, Ha-6, CH2CH2), 3.76-3.79 (m, 3H, Hb-6, CH2CH2), 3.85 (m, 1H, H-5), 4.10 (t, 1H, J = 9.7 Hz, H-3), 4.43-4.91 (m, 8H, CHPh), 5.27 (dd, 1H, J = 2.0 Hz, J = 11.0 Hz, CH=CHHb), 5.54 (dd, 1H, J = 2.1 Hz, J = 17.9 Hz, CH=CHaH), 5.99 (m, 1H, CH=CH2), 7.19-7.54, 8.04-8.05 (m, 25H, Ph); 13C-NMR: δ 61.1 (CH2CH2), 64.1 (CH2CH2), 68.8 (C-6), 69.2 (CH2CH2), 70.0 (CH2CH2), 70.6 (CH2CH2), 70.64 (CH2CH2), 70.7 (CH2CH2), 71.5 (C-5), 73.4 (CH2Ph), 75.0 (CH2Ph), 75.5 (CH2Ph), 75.8 (CH2Ph), 78.5 (C-4), 83.0 (C-3), 84.3 (C-2), 99.5 (C-1), 118.8 (CH=CH2), 127.5-133.0 (Ph), 135.3 (CH=CH2), 138.1-138.4 (Ph), 166.5 (C=O); HRMS (ESI) m/z calcd for C51H58NaO11 869.3871 [M +Na]+, found 869.3865.

(11-Benzoyloxy-3,6,9-trioxaundecyl 3,4,5,7-tetra-O-benzyl-α-D-gluco-hept-2-ulopyranosid)onic acid (5): Ozone was bubbled through a stirred solution of 4 (224 mg, 0.26 mmol) in CH2Cl2 (15 mL) at -78 oC for 5 h. After triphenylphosphine (230 mg, 0.88 mmol) was added at -78 oC and the reaction temperature was raised to room temperature, the reaction mixture was stirred for 19 h. The solvent was then evaporated under reduced pressure. To a solution of the crude product in t-butyl alcohol (4 mL)-H2O (1 mL) were added NaClO2 (277 mg, 3.1 mmol), NaH2PO4 (124 mg, 0.8 mmol) and 2-methyl-2-butene (123 μL, 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 CH2Cl2 (three times), and the combined organic solvent was dried over anhydrous Na2SO4. The organic solvent was filtered and evaporated under reduced pressure. The crude product was purified by preparative silica gel TLC (CHCl3/MeOH = 5/1) to afford 5 (194 mg, 85% yield) as a colorless oil. [α]D25 = +21o (c 3.9, CHCl3); 1H-NMR: δ 3.54-4.08 (m, 20H, H-3, H-4, H-5, H-6, H-7, CH2CH2), 4.41-4.49 (m, 2H, CH2CH2), 4.51-5.28 (m, 8H, CHPh), 7.03-7.53 (m, 23H, Ph), 8.03-7.53 (d, 2H, J = 6.8 Hz, Ph); 13C-NMR: δ 64.0 (CH2CH2), 69.1 (C-7), 69.9 (CH2CH2), 70.2 (CH2CH2), 70.3 (CH2CH2), 70.4 (CH2CH2), 70.5 (CH2CH2), 70.6 (CH2CH2), 72.6 (CH2CH2), 75.19 (CH2Ph), 75.20 (CH2Ph), 75.4 (CH2Ph), 75.5 (CH2Ph), 77.6 (C-6), 80.9 (C-5), 82.7 (C-3, C-4), 99.3 (C-2), 126.0-139.2 (Ph), 166.5 (C(O)Ph), 177.7 (C-1); HRMS (ESI) m/z calcd for C50H56NaO13 887.3613 [M +Na]+, found 887.3653.

(11-Hydroxy-3,6,9-trioxaundecyl 3,4,5,7-tetra-O-benzyl-α-D-gluco-hept-2-ulopyranosid)onic acid (6): A 0.5 M NaOH solution (4 mL, 2 mmol) was added to a solution of 5 (142 mg, 0.16 mmol) in THF (4 mL). 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 CH2Cl2 (three times), the combined organic solvent was dried over anhydrous Na2SO4. The organic solvent was filtered and evaporated under reduced pressure. The crude product was purified by preparative silica gel TLC (CHCl3/MeOH = 5/1) to afford 6 (103 mg, 83% yield) as a colorless oil. [α]D25 = +25o (c 1.8, CHCl3); 1H-NMR: δ 3.37-4.00 (m, 22H, H-3, H-4, H-5, H-6, H-7, CH2CH2), 4.44-4.84 (m, 8H, CHPh), 6.94-7.43 (m, 20H, Ph); 13C-NMR: δ 60.4 (CH2CH2), 62.6 (CH2CH2), 68.5-70.4 (CH2CH2, C-7), 72.4 (CH2Ph), 73.4 (CH2Ph), 74.9 (CH2Ph), 75.3 (CH2Ph), 78.1 (C-6), 82.4 (C-5), 82.9 (C-3, C-4), 99.7 (C-2), 127.3-128.4, 137.8-138.9 (Ph), 172.3 (C-1); HRMS (ESI) m/z calcd for C43H52NaO12 783.3351 [M +Na]+, found 783.3396.

(1R)-2,3,4,6-Tetra-O-benzylspiro[1,5-anhydro-D-glucitol-1,2’-[3,6,9,12]tetraoxatetradecan]-14’-olide (2): To a solution of 6 (20 mg, 0.027 mmol) in CH2Cl2 (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 Na2SO4, the solvent was evaporated under reduced pressure. The crude product was purified by preparative silica gel TLC (CHCl3/MeOH = 20/1) to give 2 (17 mg, 84% yield) as a colorless oil. [α]D25 = +11o (c 0.15, CHCl3); 1H-NMR: δ 3.48-3.71 (m, 15H, H-4, H-5, H-6, CH2CH2), 3.73-3.75 (m, 1H, CH2CH2), 3.81 (d, 1H, J = 9.6 Hz, H-2), 3.87-3.92 (m, 1H, CH2CH2), 3.94-3.98 (m, 1H, CH2CH2), 4.00-4.05 (m, 1H, CHaHbCH2), 4.06-4.07 (m, 1H, H-3), 4.31-4.34 (m, 1H, CHaHbCH2), 4.54-4.65 (m, 4H, CHPh), 4.79-4.89 (m, 4H, CHPh), 7.16-7.35 (m, 20H, Ph); 13C-NMR: δ 63.6 (CH2CH2), 65.2 (CH2CH2), 68.3 (CH2CH2), 68.4 (C-6), 69.6 (CH2CH2), 70.1 (CH2CH2), 70.4 (CH2CH2), 70.9 (CH2CH2), 71.2 (CH2CH2), 73.41 (C-5), 73.44 (CH2Ph), 75.1 (CH2Ph), 75.2 (CH2Ph), 75.6 (CH2Ph), 78.0 (C-4), 82.2 (C-2), 82.7 (C-3), 99.7 (C-1), 127.5-128.4 (Ph), 137.9-138.5 (Ph), 173.5 (C-1’); HRMS (ESI) m/z calcd for C43H50NaO11 765.3245 [M +Na]+, found 765.3247.