HETEROCYCLES

Note | Special issue | Vol. 82, No. 2, 2011, pp. 1669-1674
Received, 28th June, 2010, Accepted, 2nd September, 2010, Published online, 3rd September, 2010.
DOI: 10.3987/COM-10-S(E)75

■ Synthesis of C3 and Cs Symmetric Cyclic Triglycerols

Masahiro Hamada, Ryou Fujiwara, Takao Kishimoto, and Noriyuki Nakajima*

Biotechnology Research Center, Toyama Prefectural University, 5180 Kurokawa, Kosugi, Toyama 939-0398, Japan

Abstract

Authentic cyclic triglycerol standards have been efficiently synthesized. C3 and CS symmetric cyclic glycerols were effectively synthesized using intramolecular cyclization conditions and the stereochemistry of their isomers was confirmed.

Polyglycerols are glycerin oligomers that are easily produced and available in bulk quantities through industrial methods.1,2 They are classified into linear, branched, and cyclic structures. Cyclic polyglycerols have extra secondary alcohols and consist of several ether groups arranged in a crown ether-like ring.3 Because the oxygen atoms are well situated to coordinate with a cation located inside the ring, cyclic polyglycerols are expected to serve as a phase transfer catalysts. There are a few representative polyglycerol standards in the literature.4-10 We previously reported the synthesis and fine structure of highly symmetric cyclic polyglycerols (1-4) as authentic standards.11

When the mixture of mono-tosylates (7) obtained from the readily available tri-glycerol diol (6)12 were treated with NaH in DMF (4 mM) at 80 °C for 48h, 12-membered cyclic benzyl glycerols (1) were obtained in 38%yields.11 By examining the solvent, THF solvent increased reaction yield up to 60%. Two cyclic triglycerol benzyl ethers (1-C3 and 1-Cs) displayed different Rf values at 0.48 and 0.24 by TLC analysis, were isolated with 1/3 ratio; however, the stereochemistry of the triols, was unclear. In this paper, the stereocontrolled synthesis of both diastereomers was performed to confirm the stereochemistry of their isomers.

Starting from the (R)-solketal (8), a monoglycerol unit (9) was synthesized in five steps which consisted of methoxymethyloxy (MOM) protection, hydrolysis in 80% acetic acid (AcOH), tert-butyldiphenylsilyl (TBDPS) protection, benzyl (Bn) protection and silyl deprotection by tetrabutylammonium fluoride (TBAF). The monoglycerol unit (9) was coupled with (S)-tosyl glycigyl ether ((S)-10) to provide diglycerol (11) in 71% yield. Acid treatment with 80% AcOH removed the acetonide group in 98% yield and TBDPS protection of the primary alcohol gave alcohol (13) in 86% yield. Protection of the secondary hydroxy group with Bn group afforded benzyl ether (14) in 89% yield. The silylgroup of 14 was removed using TBAF to give diglycerol unit (15) in 96% yield.

Coupling between 15 and (S)- and (R)-10 produced triglycerol units 16 in 66% yield and 23 in 64% yield, which were converted to tri-benzyl ethers (20 and 27) in 41% and 50% yields, respectively, in four steps. Tosylation of the alcohols (20 and 27), followed by acidic hydrolysis of the MOM group gave the desired intermediates (22 and 29) in 90 and 88% yields, respectively.
The mono-tosylates (22 and 29) were treated with NaH (4 eq.) in refluxing THF (4 mM) to afford 12-membered C3- and Cs symmetric benzyl glycerols (1-C3 and 1-Cs) in 56% and 55% yields, respectively.13
Comparison between the TLC Rf values of pure C3 and CS forms and their mixtures allowed the compound observed at an Rf of 0.24 to be identified as the C3 isomer and the other compound (Rf = 0.48) as the CS form. Hydrogenation of the benzyl group smoothly proceeded to give the desired triols (5-C3 and 5-Cs) in 93% and 98% yields, respectively.

The 1HNMR spectrum of tri-glycerol 5-C3 displayed three simple sets of peaks s at 3.81, 3.67 and 3.50 ppm in 1H NMR and 13C NMR spectrum showed two sets of peaks at 74.0 and 69.2 ppm suggesting that this isomer was highly symmetric. On the other, the 5-Cs showed complicated 1H and 13CNMR spectra.
In conclusion, we established the first synthesis of cyclic polyglycerols as pure compound based on an intramolecular cyclization method. Aiming at the synthesis of optically active polyglycerols, we adopted a synthetic approach based on convergent coupling using glycerol units.

EXPERIMENTAL
All reagents used were of commercial quality. Anhydrous THF and CH2Cl2 (Kanto Chemical) were used without purification. All air- and moisture-sensitive reactions were performed under an inert gas (nitrogen or argon). Analytical TLC was conducted on precoated TLC plates (silica gel 60F254, Merck) and column chromatography was performed using silica gel 60N (70-230 mesh, Kanto Chemical). ATR-IR spectra were measured using a PerkinElmer Spectrum 100 spectrometer equipped with a Universal ATR accessory. 1H and 13C NMR spectra were recorded on a Bruker Biospin AVANCE II 400 spectrometer and a JEOL JNM LA-400 spectrometer using TMS or a solvent peaks as an internal standard (chemical shift in ppm). LR-ESI-MS spectra were recorded on an Agilent Technology 1100 LC-MSD spectrometer using MeOH or MeCN solutions in water or 0.5% HCO2H as effluents. HR-ESI-MS spectra were acuired on a Bruker Dartonics micrOTOFfocus spectrometer. Specific rotation values were measured with a Horiba polarimeter.

(2R,6R,10R)-2,6,10-O-Tribenzyl-1-O-(4-toluenesulfonyl)-4,8-dioxaundecane-1,2,6,10,11-pentaol (22). To a solution of 21 (16.7 mg, 23.6 μmol) in MeOH (1 mL) was added conc. HCl (50 μL) at 0 °C. The mixture was stirred at 60 °C for 29 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (hexane/EtOAc, 1/1) to give 22 (14.1 mg, 21.2 μmol, 90%) as a colorless oil: Rf = 0.24 (hexane/EtOAc, 1/1); [α] D 28 -2.8 (c 0.50, MeOH): IR (neat, cm−1): 3463, 3064, 3032, 2871, 1722, 1599, 1497, 1454, 1359, 1308, 1293, 1210, 1190, 1175, 1095, 1059, 1028, 983, 922, 814, 793, 735, 696, 666: 1H NMR (400 MHz, CDCl3): δ= 7.69 (2H, d, J=8.4 Hz), 7.30 -7.16 (17H, m), 4.62 (1H, d, J=12.0 Hz), 4.55 (2H, s), 4.53 (1H, d, J=12.0 Hz), 4.18 (2H, s), 4.10 (1H, dd, J=4.4 Hz, 10.8 Hz), 3.99 (1H, dd, J=5.6 Hz, 10.4 Hz), 3.68 (2H, quintet, J=5.2 Hz), 3.59 (4H, quintet, J=5.2 Hz), 3.55-3.40 (7H, m), 2.34 (3H, s): 13C-NMR (100 MHz, CDCl3): δ= 144.8, 138.4, 138.3, 137.8, 132.9, 129.8, 128.5, 128.4, 128.0, 127.80, 127.75, 127.71, 127.6 (x2), 77.9, 76.9, 76.7, 75.4, 72.4, 72.3, 72.1, 71.63, 71.56, 70.2, 69.5, 62.7, 21.6; LRMS (ESI+): m/z (%) = 687 ([M+Na]+, 100); HRMS (ESI+): calcd for C37H44NaO9S: 687.2598; found: 687.2576.

(2R,6S,10S)-2,6,10-O-Tribenzyl-1-O-(4-toluenesulfonyl)-4,8-dioxaundecane-1,2,6,10,11-pentaol (29). Yield: 88% as a colorless oil; Rf = 0.24 (hexane/EtOAc, 1/1); [α] D27 -0.3 (c 0.66, MeOH): IR (neat, cm−1): 3466, 3064, 3032, 2871, 1731, 1599, 1497, 1455, 1359, 1308, 1210, 1190, 1175, 1094, 1058, 1028, 983, 921, 814, 793, 735, 696, 666; 1H NMR (400 MHz, CDCl3): δ= 7.69 (2H, dd, J=1.6 Hz, 8.0 Hz), 7.33 -7.14 (17H, m), 4.62 (1H, d, J=12.0 Hz), 4.55 (2H, s), 4.53 (1H, d, J=11.6 Hz), 4.47 (2H, s), 4.10 (1H, dd, J=4.0 Hz, 10.4 Hz), 4.00 (1H, dd, J=6.0 Hz, 10.4 Hz), 3.70-3.65 (2H, m), 3.63-3.43 (10H, m), 3.44 (2H, dd, J=3.2 Hz, 5.6 Hz), 3.40 (1H, dd, J=5.6 Hz, 10.0 Hz), 2.34 (3H, s), 2.10-2.00 (1H, brs, OH); 13C-NMR (100 MHz, CDCl3): δ= 144.8, 138.4, 138.3, 137.8, 132.9, 129.8, 128.5, 128.4, 128.0, 127.80, 127.76, 127.72, 127.70, 127.6, 77.9, 76.9, 76.7, 75.4, 72.4, 72.3, 72.1, 71.6, 71.5, 70.2, 69.4, 62.7, 21.6; LRMS (ESI+): m/z (%) = 687 ([M+Na]+, 100); HRMS (ESI+): calcd for C37H44NaO9S: 687.2598; found: 687.2615.

C3-symmetric 1,5,9-O-Tribenzyl-3,7,11-trioxacyclododecane-1,7,11-triol (1-C3). To a solution of NaH (60% activity, 24.0 mg, 0.6 mmol) in THF (24 mL) was added dropwise with a syringe pump the THF (6 mL) solution of tri-glycerol mono-tosylate (22) (100 mg, 0.15 mmol) at 80 ˚C within 3 h. After additional stirring for 14 h, the reaction mixture was quenched with brine. The aq. solution was extracted with EtOAc and the organic phase was washed with water and brine, and dried (Na2SO4). Filtration, concentration and preparative silica gel TLC purification (hexane/EtOAc, 3/2) to afford 1-C3 (41.4 mg, 0.084 mmol, 56%) of as a colorless oil: Rf = 0.24 (hexane/EtOAc, 3/2); IR (neat, cm−1): 2865, 1497, 1454, 1355, 1304, 1273, 1208, 1099, 1028, 986, 948, 910, 836, 733, 695; 1H NMR (400 MHz, CDCl3): δ= 7.38-7.25 (15H, m), 4.61 (6H, s), 3.74 (6H, dd, J = 3.6, 9.6 Hz), 3.73 (3H, dd, J = 3.6, 7.2 Hz), 3.58 (6H, dd, J = 7.2, 9.6 Hz); 13C-NMR (100 MHz, CDCl3): δ= 138.2, 128.5, 127.8, 127.7, 74.8, 71.7, 71.0; LRMS (ESI+): m/z (%) = 516 (35), 515 ([M+Na]+, 100); HRMS (ESI+): calcd for C30H36NaO6: 515.2404; found: 515.2421.

Cs symmetric 1,5,9-O-Tribenzyl-3,7,11-trioxacyclododecane-1,7,11-triol (1-Cs). Yield: 55% as a colorless oil; Rf = 0.48 (hexane/EtOAc, 3/2): IR (neat, cm−1): 2865, 1605, 1497, 1454, 1355, 1305, 1263, 1207, 1090, 1073, 1027, 954, 908, 819, 733, 695; 1H NMR (400 MHz, CDCl3): δ= 7.28-7.17 (15H, m), 4.53 (6H, s), 3.70-3.47 (15H, m); 13C-NMR (100 MHz, CDCl3): δ= 138.1, 128.4, 127.8, 127.7, 74.6, 74.3, 71.7, 70.4, 69.9, 69.6; LRMS (ESI+): m/z (%) = 516 (32), 515 ([M+Na]+, 100); HRMS (ESI+): calcd for C30H36NaO6: 515.2404; found: 515.2425.

C3-symmetric 1,5,9-Trioxacyclododecane-3,7,11-triol (5-C3). A solution of 1-C3 (43.5 mg, 0.088 mmol) in THF/EtOH (1/2, 6 mL) was hydrogenated over 10% Pd-C (88 mg) for 25 h at rt. Filtration and concentration afforded a pale brown solid, which was purified silica gel column chromatography (CH2Cl2/MeOH = 9/1) to give 5-C3 (18.2 mg, 0.082 mmol, 93%) as an oil: Rf = 0.39 (CH2Cl2/MeOH, 4/1); IR (neat, cm−1): 3308, 2868, 1726, 1653, 1460, 1361, 1261, 1138, 1067, 979; 1H NMR (400 MHz, CD3OD): δ= 3.81 (3H, ddd, J = 3.5, 7.0, 10.4 Hz), 3.67 (6H, dd, J = 3.5, 9.7 Hz), 3.50 (6H, dd, J = 7.0, 9.7 Hz); 13C-NMR (100 MHz, CD3OD): δ= 74.0, 69.2; LRMS (ESI+): m/z (%) = 245 ([M+Na]+, 100), 223 ([M+H]+, 6); HRMS (ESI+): calcd for C9H19O6: 223.1176; found: 223.1193.

Cs symmetric 1,5,9-trioxacyclododecane-3,7,11-triol (5-Cs). Yield: 98% as an oil; Rf = 0.13 (CH2Cl2/MeOH, 4/1); IR (neat, cm−1): 3310, 2922, 2866, 1598, 1460, 1361, 1261, 1138, 1072, 979, 948, 837, 785; 1H NMR (400 MHz, CD3OD): δ=3.93-3.85 (3H, m), 3.67 (2H, dd, J = 3.0, 10.0 Hz), 3.69-3.52 (10H, m); 13C-NMR (100 MHz, CD3OD): δ= 73.7, 73.3, 69.0; LRMS (ESI+): m/z (%) = 245 ([M+Na]+, 100), 223 ([M+H]+, 9); HRMS (ESI+): calcd for C9H19O6: 223.1176; found: 223.1179.

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