Synthesis of C3 and Cs symmetric cyclic triglycerols

Article abstract of DOI:10.3987/COM-10-S(E)75

Authentic cyclic triglycerol standards have been efficiently synthesized. C₃ and C_S symmetric cyclic glycerols were effectively synthesized using intramolecular cyclization conditions and the stereochemistry of their isomers was confirmed. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)75

HETEROCYCLES, Vol. 82, No. 2, 2011
1669
HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1669 - 1674. © The Japan Institute of Heterocyclic Chemistry
Received, 28th June, 2010, Accepted, 2nd August, 2010, Published online, 3rd August, 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
Nakajima1*
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural
University, Imizu, Toyama 939-0398, Japan; E-mail: nori@pu-toyama.ac.jp
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
1,2
industrial methods. They are classified into linear, branched, and cyclic structures. Cyclic polyglycerols
3
have extra secondary alcohols and consist of several ether groups arranged in a crown ether-like ring.
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
4-10
polyglycerol standards in the literature.
We previously reported the synthesis and fine structure of
highly symmetric cyclic polyglycerols (1-4) as authentic standards.11
OBn
OBn
BnO
OBn
OBn
BnO
BnO
OBn
O
O
4
O
BnO
O
O
O
O
OBn
O
OBn
O
BnO
O
O
O
O
O
O
O
O
O
OBn
BnO
OBn
BnO
BnO
OBn
1
2
3
Figure 1. Structure of cyclic polyglycerols 1-4
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
This paper is dedicated to Professor Albert Eschenmoser on the occasion of his 85th birthday

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HETEROCYCLES, Vol. 82, No. 2, 2011
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.
OR
OR
b
RO
O
O
OH
O
O
O
O
+
OBn
OBn
OBn
60%
O
O
6: R=H
7: R=Ts (89%)
a
RO
OR RO
OR
Cs-symmetric form
C3-symmetric form
Reagents and Conditions.
(a) TsCl, Et3N, CH2Cl2; (b) NaH (4 eq.), THF (5 mM),
80°C and TLC separation.
1-C3: R = Bn
5-C3: R = H
1-Cs: R = Bn
5-Cs: R = H
1: Rf = 0.48 and Rf = 0.24 (hexane:AcOEt=3:2)
Scheme 1. Synthesis of cyclic triglycerols 1-C3 and 1-Cs
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.
OTS
O
O
(S)-10
R1O
O
OMOM
OH
OMOM
HO
O
a
OR2
OBn
O
OBn
11: R1 = R2 = iPr (71%)
12: R1 = R2 = H (98%)
9
8
b
c
d
e
13: R1 = TBDPS, R2 = H (86%)
Reagents and Conditions. (a) (S)-10, NaH, THF;
(b) 80% AcOH; (c) TBDPSCl, Et3N, DMAP, CH2Cl2;
(d) NaH, BnBr, THF; (e) TBAF, THF.
14: R1 =T BDPS, R2 = Bn (89%)
15: R1 = H, R2= Bn (96%)
Scheme 2. Synthesis of the cyclic diglycerol unit
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.

HETEROCYCLES, Vol. 82, No. 2, 2011
1671
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.
OR
R1O
OR3
h
O
O
a
OR2
15
OBn
OBn
O
O
16: R1 = R2 = iPr, R3 = MOM (66%)
17: R1 = R2 = H, R3 = MOM (92%)
18: R1 = TBDPS, R2 = H, R3 = MOM (80%)
19: R1 = TBDPS, R2 = Bn, R3 = MOM (68%)
20: R1 = H, R2 = Bn, R3 = MOM (82%)
21: R1 = Ts, R2 = Bn, R3 =MOM (89%)
22: R1 = Ts, R2 = Bn, R3 = H (90%)
b
c
O
RO
OR
d
e
f
1-C3: R = Bn (56%)
5-C3: R = H (93%)
i
g
Reagents and Conditions. (a) (S)-10, NaH, DMF; (b) 80% AcOH; (c) TBDPSCl, Et3N, DMAP, CH2Cl2; (d) NaH,
BnCl, THF; (e) TBAF, THF; (f) TsCl , Et3N, DMAP, CH2Cl2; (g) 1N HCl, MeOH; (h) NaH (4 eq), THF (5 mM), reflux,
17h; (i) Pd-C, H2, THF/EtOH=1/2.
Scheme 3. Synthesis of the C3-symmtric cyclic tri-glycerol
OR
R1O
a
h
O
O
OR3
15
OR2
OBn
OBn
O
O
23: R1 = R2 = iPr, R3 = MOM (64%)
24: R1 = R2 = H, R3 =MOM (90%)
25: R1 = TBDPS, R2 = H, R3 = MOM (70%)
26: R1 = TBDPS, R2 = Bn, R3 = MOM (86%)
27: R1 = H, R2 = Bn, R3 = MOM (92%)
28: R1 = Ts, R2 = Bn, R3 = MOM (86%)
29: R1 = Ts, R2 = Bn, R3 = H (88%)
b
O
RO
OR
c
d
e
f
1-Cs: R=Bn (55%)
5-Cs: R=H (98%)
i
g
Reagents and Conditions. (a) (R)-10, NaH, THF; (b) 80% AcOH; (c) TBDPSCl, Et3N, DMAP, CH2Cl2; (d) NaH,
BnCl, THF; (e) TBAF, THF; (f) TsCl , Et3N, DMA, CH2Cl2; (g) 1N HCl, MeOH; (h) NaH (4 eq), THF (5 mM), reflux,
17h; (i) Pd-C, H2, THF/EtOH=1/2.
Scheme 4. Synthesis of the Cs-symmetric cyclic triglycerol
1
The HNMR 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.

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HETEROCYCLES, Vol. 82, No. 2, 2011
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
1
13
accessory. H and C 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
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); [!] D 28 ꢀ2.8 (c 0.50,
(22).
MeOH): IR (neat, cm!1): 3463, 3064, 3032, 2871, 1722, 1599, 1497, 1454, 1359, 1308, 1293, 1210, 1190,
1
1175, 1095, 1059, 1028, 983, 922, 814, 793, 735, 696, 666: H NMR (400 MHz, CDCl3): "= 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,
13
quintet, J=5.2 Hz), 3.55-3.40 (7H, m), 2.34 (3H, s): C-NMR (100 MHz, CDCl3): "= 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); [!] 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,

HETEROCYCLES, Vol. 82, No. 2, 2011
1673
814, 793, 735, 696, 666; 1H NMR (400 MHz, CDCl3): "= 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):
"= 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,
1
1355, 1304, 1273, 1208, 1099, 1028, 986, 948, 910, 836, 733, 695; H NMR (400 MHz, CDCl3): "=
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): "= 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,
1
1207, 1090, 1073, 1027, 954, 908, 819, 733, 695; H NMR (400 MHz, CDCl3): "= 7.28-7.17 (15H, m),
4.53 (6H, s), 3.70-3.47 (15H, m); 13C-NMR (100 MHz, CDCl3): "= 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,
1
4/1); IR (neat, cm!1): 3308, 2868, 1726, 1653, 1460, 1361, 1261, 1138, 1067, 979; H NMR (400 MHz,
CD3OD): "= 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,

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HETEROCYCLES, Vol. 82, No. 2, 2011
9.7 Hz); 13C-NMR (100 MHz, CD3OD): "= 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): "=3.93-3.85 (3H, m), 3.67 (2H, dd, J = 3.0, 10.0 Hz), 3.69-3.52
13
(10H, m); C-NMR (100 MHz, CD3OD): "= 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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