Short and stereocontrolled cyclic polyglycerols synthesis using BF 3·OEt2 mediated intramolecular epoxide-opening reaction

Article abstract of DOI:10.3987/COM-12-S(N)67

We developed a new method for the stereocontrolled synthesis of cyclic oligoglycerols. Optically pure solketal and epichlorohydrin were coupled with allyl alcohol under aqueous basic conditions to construct a linear triglycerol skeleton. After subsequent steps, the epoxy alcohol (7) obtained was treated with a catalytic amount of BF₃·OEt₂ in CH ₂Cl₂ to produce in a high yield of the desired cyclic triglycerol through a regioselective, intramolecular epoxide ring-opening reaction.

Full text of DOI:10.3987/COM-12-S(N)67

HETEROCYCLES, Vol. 86, No. 2, 2012
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HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1533 - 1539. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 28th June, 2012, Accepted, 13th August, 2012, Published online, 17th August, 2012
DOI: 10.3987/COM-12-S(N)67
SHORT AND STEREOCONTROLLED CYCLIC POLYGLYCEROLS
SYNTHESIS USING BF3!OEt2 MEDIATED INTRAMOLECULAR
EPOXIDE-OPENING REACTION
Masahiro Hamada,* Takao Kishimoto, and Noriyuki Nakajima
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural
University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan; E-mail:
hamada@pu-toyama.ac.jp
Abstract – We developed a new method for the stereocontrolled synthesis of
cyclic oligoglycerols. Optically pure solketal and epichlorohydrin were coupled
with allyl alcohol under aqueous basic conditions to construct a linear triglycerol
skeleton. After subsequent steps, the epoxy alcohol (7) obtained was treated with
a catalytic amount of BF3·OEt2 in CH2Cl2 to produce in a high yield of the desired
cyclic triglycerol through a regioselective, intramolecular epoxide ring-opening
reaction.
Polyglycerols are oligomers of glycerol that can be linear, brunched, or cyclic. Cyclic polyglycerol has a
cyclic polyether skeleton tethered to three carbon atoms with regularly arranged secondary alcohols. Its
unique structure is interesting as a chiral host molecule; however, only a few reports describe its synthesis.
Dupuy and co-workers reported the synthesis of cyclic tetraglycerol via intermolecular coupling of
diepoxide with monoglycerol under the basic conditions,1 while Rollin et al. reported the synthesis of
cyclic tri-, tetra-, and penta-glycerols using Williamson’s ether synthesis.2 We also recently reported the
stereocontrolled synthesis of cyclic triglycerol through intramolecular substitution under the basic
conditions.3,4 Our synthetic pathway enable precise control of the stereochemistry; however, it comprises
many long steps. Herein, we report a new short synthetic pathway to produce cyclic triglycerol through
regioselective, intramolecular epoxide ring opening promoted by BF3·OEt2 as a single catalyst.
Optically active solketal (1) was coupled with optically active epichlorohydrin (2) and allyl alcohol under
aqueous basic conditions5 to obtain linear triglycerol 3 in 65% yield as a single isomer. Deprotection of
Dedicated with respect to Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 2, 2012
acetonide 3 using 80% aqueous AcOH followed by selective protection of the primary and secondary
alcohols gave allyl ether 5. After desilylation of 5, the allyl moiety of the resultant 6 was oxidized with
mCPBA to give epoxy alcohol 7 in 93% yield as an inseparable mixture of diastereomers (Scheme 1).
i
ii, iii
OH
O
O
O
O
+
Cl
O
O
O
OH
81%
65%
(R)-2
(S)-1
3
v
TBSO
O
O
HO
O
O
OR
iv
OR
OBn
OBn
99%
4: R = H
6
5: R = Bn
vi
93%
HO
O
O
O
OBn
OBn
7
Scheme 1. Conditions: (i) nBu4NHSO4, 50% aq. NaOH, 0 °C, 2 h then allyl alcohol rt, 1 d (65%); (ii)
80% aq. AcOH, rt, 1 d (quant); (iii) TBSCl, Et3N, DMAP, CH2Cl2, rt, 4 h (81%); (iv) NaH, BnBr, THF, rt,
2 h (89%); (v) TBAF, THF, rt, 2 h (99%); (vi) mCPBA, CH2Cl2, rt, 3 h (93%).
First, we attempted to cyclize epoxy alcohol 7 using the basic conditions described by us and Dupuy, but
the desired compound was not obtained. Therefore, the epoxy alcohol 7 was instead treated with 30 mol%
of BF3·OEt2 in CH2Cl2 to obtain the desired cyclic triglycerol (8) in a moderate yield as an inseparable
mixture of diastereomers (Table 1, entry 1). The solvent is important in this reaction, and only
halogenated hydrocarbon solvents afforded the cyclic triglycerol (entries 1-4). The concentration of
solvent also influenced the cyclic triglycerol yield (entries 1, 5, and 6). In 5 mM of CH2Cl2, the amount of
BF3·OEt2 did not affect to the reaction yield (entries 7 and 8). Interestingly, the use of an equimolecular
amount of BF3·OEt2 afforded the desired cyclic triglycerol with only a 58% yield (entry 9).6ꢀ
OBn
BF3·OEt2
O
O
HO
O
O
O
solvent
rt
OBn
OBn
O
BnO
OH
7
8
Scheme 2

HETEROCYCLES, Vol. 86, No. 2, 2012
1535
Table 1. BF3·OEt2-mediated intramolecular epoxide ring opening
a
BF3·OEt2 (eq)
Entry
Solvent (mM)
Time (h)
8 (Yield, %)
1
2
3
4
5
6
7
8
9
0.3
0.3
0.3
0.3
0.3
0.3
0.2
0.5
1.1
CH2Cl2 (30)
DMF (10)
24
9
41
0
toluene (10)
1,2-DCE (10)b
CH2Cl2 (20)
CH2Cl2 (10)
CH2Cl2 (5)
CH2Cl2 (5)
CH2Cl2 (10)
24
11
12
5
0
40
56
81
79
86
58
3
7
4
a Isolated yield. b 1,2-dichloroethane.
The use of SnCl4 or TiCl4 as a Lewis-acidic catalyst decreased the regioselectivity and resulted in a
complex mixture including trace amounts of undesired primary alcohol 9 (Scheme 3). In contrast, epoxy
alcohol 10, which is protected by a t-butykdiphenylsilyl (TBDPS) group rather than a benzyl (Bn) group
in the secondary alcohol, produced cyclic triglycerol 11 (Scheme 4) with a 63% yield after treatment
under standard conditions (Table 1, entry 6).
OBn
OBn
SnCl4
O
O
O
O
O
O
HO
O
O
O
OH
CH2Cl2
rt
OBn
OBn
BnO
OH BnO
7
8
9 (not isolated)
Scheme 3
OTBDPS
O
BF3·OEt2 (0.2 eq)
O
HO
O
O
O
CH2Cl2 (5 mM)
rt, 8 h
OTBDPS OTBDPS
O
TBDPSO
OH
10
11 (63%)
Scheme 4
Subsequently, the synthesized cyclic trigricerol 8 was oxidized with Dess-Martin periodinane (DMP) to
give the corresponding ketone 12 with a 48% yield. Ketone 12 was reduced by L-selectride to regenerate
alcohol 8 as a 3:1 mixture of diastereomers (Scheme 5). The major product had an all-syn (C3-form)
1
configuration, which was determined by HPLC analysis7 and inspection of the H-NMR spectrum after
benzylation of the hydroxy group.

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HETEROCYCLES, Vol. 86, No. 2, 2012
OBn
OBn
OBn
i
48%
ii
O
O
O
O
O
O
O
O
73%
O
BnO
OH
BnO
O
BnO
OH
8
12
all syn-8
dr = 3 : 1
Scheme 5. Conditions: (i) DMP, CH2Cl2, rt, 1 d (48%); (ii) L-selectride, THF, -78 °C, 2 h (73%).
In conclusion, we developed a short synthetic pathway to the stereocontrolled cyclic triglycerol. The key
reaction is the BF3·OEt2-mediated intramolecular epoxide opening. Our method provides a very simple,
highly regioselective route to medium-sized polyether skeletons. This reaction is a synthetic tool for the
synthesis of natural and synthetic products containing macro polyether rings.
EXPERIMENTAL
1H NMR spectra were recorded in CDCl3 with TMS as an internal reference using a Bruker Biospin
AVANCE-II 400 operating at 400 MHz. 13C NMR spectra were recorded in CDCl3 with remnant solvent
as an internal reference using the Bruker Biospin AVANCE-II 400 operating at 100 MHz. IR spectra
were measured using a PerkinElmer FT-IR Spectrum 100 spectrometer. Low-resolution (LR) and
high-resolution (HR) electrospray ionization (ESI) mass spectra (MS) were measured using Agilent
LC-MSD 1100 series and Bruker Daltonics micrOTOF forcus spectrometers, respectively. Thin-layer
chromatography (TLC) was performed on a Merck Silica gel 60F254 plate. Column chromatography was
performed using Kanto Chemical Silica gel 60N (0.063-0.230 mm). All of the organic solvents used in
this study were obtained dehydrated from Kanto Chemical and were used. All chemicals used in this
study were commercially obtained. All air- and moisture-sensitive reactions were carried out under argon
atmosphere.
(2S,6S)-1,2-O-Isopropylidene-4,8-dioxaundeca-10-en-6-ol (3). To a mixture of (R)-epichlorohydrin (2,
4.14 g, 44.7 mmol) and nBu4NHSO4 (1.01 g, 2.98 mmol) in 50% aqueous NaOH (20 mL) was added
(S)-solketal (1, 3.94 g, 29.8 mmol) at 0 °C. The mixture was stirred for 2 h at the same temperature before
allyl alcohol (8.65 g, 0.15 mol) was added. The mixture was stirred for 1 day at rt, and then diluted with
ice water. The mixture was extracted with EtOAc. The combined extracts were washed with brine and
dried over Na2SO4. After filtration, the solvent was removed by evaporation. The residue was purified by
column chromatography on silica gel (hexane : EtOAc = 3 : 2 then 1 : 1) to give 3 (4.83 g, 65%) as a
colorless oil; Rf 0.39 (hexane : EtOAc = 2 : 3); IR (neat) cm-1 3466, 2986, 2873, 1719, 1455, 1371, 1253,
1213, 1076, 1050, 974, 909, 839, 793, 759; 1H NMR (CDCl3) ! 1.37 (s, 3H), 1.43 (s, 3H), 2.59 (br d, J =

HETEROCYCLES, Vol. 86, No. 2, 2012
1537
3.5 Hz, 1H), 3.44-3.61 (m, 6H), 3.74 (dd, J = 8.3 and 6.4 Hz, 1H), 3.98 (br d, J = 3.2 Hz, 1H), 4.02 (dt, J
= 5.6 and 1.4 Hz, 2H), 4.06 (dd, J = 8.3 and 6.5 Hz, 1H), 4.28 (quint, J = 5.5 Hz, 1H), 5.20 (dq, J = 10.4
and 1.4 Hz, 1H), 5.28 (dq, J = 17.2 and 1.6 Hz, 1H), 5.90 (ddt, J = 17.2, 10.5, and 5.6 Hz, 1H); 13C NMR
(CDCl3) ! 25.39, 26.74, 66.59, 69.50, 71.10, 72.37, 72.47,72.87, 74.69, 109.50, 117.31, 134.46; LRMS
m/z 264 (M++Na, 38), 247 (M++H, 100), 189 (31); HRMS calcd for C12H35O5 247.1540: Found 247.1544.
(2S,6S)-1-tert-Butyldimethylsilyloxy-4,8-dioxaundeca-10-ene-2,6-diol (4). Acetonide 3 (4.30 g, 17.5
mmol) was treated with 80% aqueous AcOH (40 mL) for 7 h at rt. The mixture was concentrated by
evaporation to give the corresponding triol (3.70 g, quant.) as a colorless oil. This compound was used in
next step without further purification.
To a solution of the triol (3.60 g, 17.4 mmol), Et3N (8.83 g, 87.3 mmol), and DMAP (426 mg, 3.49 mmol)
in CH2Cl2 (170 mL) was added TBDMSCl (3.95 g, 26.2 mmol) at 0 °C. The mixture was stirred for 23 h
at rt before saturated aqueous NH4Cl was added. The mixture was extracted with CH2Cl2, and the organic
layer was washed with brine, dried over Na2SO4, and concentrated by evaporation. The residue was
purified by column chromatography on silica gel (hexane : EtOAc = 1 : 1) to give the title compound 4
(4.51 g, 81%) as a colorless oil; Rf 0.50 (hexane : EtOAc = 3 : 7); IR (neat) cm-1 3405, 2953, 2928, 2857,
1
1472, 1463, 1361, 1252, 1084, 1005, 926, 834, 775, 667; H NMR (CDCl3) ! 0.07 (s, 6H), 0.90 (s, 9H),
2.72 (br s, 1H), 2.79 (br s, 1H), 3.45-3.67 (m, 9H), 3.83 (br, 1H), 3.99 (br, 1H), 4.02 (dt, J = 5.6 and 1.3
Hz, 2H), 5.20, (dq, J = 10.4 and 1.3 Hz, 1H), 5.28 (dq, J = 15.7 and 1.5 Hz, 1H), 5.90 (ddt, J = 17.2, 10.4,
and 5.7 Hz, 1H); 13C NMR (CDCl3) ! -5.41, 18.29, 25.87, 63.93, 69.56, 70.72, 71.18, 72.38, 72.44, 72.79,
117.33, 134.45; LRMS m/z 321 (M++H, 14), 207 (100); HRMS calcd for C15H32O5SiNa 343.1911 : Found
343.1889.
(6S,10S)-11-tert-Butyldimethylsilyloxy-6,10-dibenzyloxy-4,8-dioxaundecene (5). To a suspension of
NaH (60% in oil, 2.25 g, 56.2 mol) in THF (50 ml) was added a solution of 4 (4.50 g, 14.0 mmol) in THF
(20 mL) at 0 °C. The mixture was stirred for 40 min at rt before BnBr (7.20 g, 42.1 mmol) was added at
0 °C. The reaction mixture was stirred for 2 h at rt. The reaction was quenched with 50% aqueous THF,
and concentrated by evaporation. The residue was diluted with water, and the organic materials were
extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, and
concentrated by evaporation. The residue was purified by column chromatography on silica gel (hexane :
EtOAc = 15 : 1) to give 5 (6.23 g, 89%) as a colorless oil; Rf 0.38 (hexane : EtOAc = 4 : 1); IR (neat) cm-1
2928, 2856, 1496, 1471, 1454, 1252, 1091, 1027, 923, 834, 776, 733, 695, 668; 1H NMR (CDCl3) ! 0.04
(s, 6H), 0.89 (s, 9H), 3.49-3.66 (m, 8H), 3.68 (s, 1H), 3.69 (d, J = 1.0 Hz, 1H), 3.75 (quint, J = 5.1 Hz,
1H), 3.99 (dt, J = 5.5 and 1.5 Hz, 1H), 4.686 (s, 2H), 4.695 (s, 2H), 5.16 (dq, J = 10.4 and 1.4 Hz, 1H),
13
5.26 (dq, J = 17.2 and 1.7 Hz, 1H), 5.89 (ddt, J =17.2, 10.4, and 5.5 Hz, 1H), 7.24-7.36 (m, 2H); C
NMR (CDCl3) ! -5.42, -5.37, 18.29, 25.91, 63.19, 70.42, 71.68, 71.77, 72.29, 72.33, 77.17, 77.22, 78.89,

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HETEROCYCLES, Vol. 86, No. 2, 2012
116.86, 127.44, 127.48, 127.68, 127.72, 128.28, 134.77, 138.74, 138.86; LRMS m/z 520 (M++H2O, 100);
HRMS calcd for C29H45O5Si 501.3031: Found 501.3029.
(2R,6S)-2,6-Dibenzyloxy-4,8-dioxaundeca-10-en-1-ol (6). To a solution of 5 (1.78 g, 3.55 mmol) in
THF (12 mL) was added TBAF (1.0 M in THF, 5.33 mL, 5.33 mmol) at 0 °C. The solution was stirred for
2 h at rt, and concentrated by evaporation. The residual oil was purified by column chromatography on
silica gel (hexane : EtOAc = 3 : 2) to give 6 (1.37 g, 99%) as a colorless oil; Rf 0.54 (hexane : EtOAc = 2 :
3); IR (neat) cm-1 3457, 3064, 3030, 2866, 1736, 1496, 1454, 1348, 1207, 1087, 1059, 1027, 996,922, 734,
1
696; H NMR (CDCl3) ! 2.21 (br, 1H), 3.48-3.69 (m, 10H), 3.99 (dt, J = 4.2 and 1.4 Hz, 2H), 4.54-4.71
(m, 4H, CH2Ph), 4.14 (dd, J = 10.4 and 1.5 Hz, 1H), 4.21 (dd, J =17.3 and 1.6 Hz, 1H), 5.89 (ddt, J =
13
17.2, 10.4, and 5.6 Hz, 1H), 7.24-7.36 (m, 10H, Ph-H); C NMR (CDCl3) ! 62.78, 70.02, 71.56, 71.65,
71.83, 72.10, 72.27, 72.34, 73.43, 77.85, 117.00, 127.58, 127.70, 127.74, 127.76, 128.32, 128.41, 128.45,
134.63, 138.27, 138.50; LRMS m/z 409 (M++Na, 8), 404 (M++H2O, 100), 387 (M++H, 38); HRMS calcd
for C23H30O5Na 409.1985: Found 409.1996.
(2R,6S)-2,6-Dibenzyloxy-10,11-epoxy-4,8-dioxaundecan-1-ol (7). To a solution of allyl ether 6 (549 mg,
1.42 mmol) in CHCl3 (7 mL) was added mCPBA (294 mg, 1.70 mmol) at 0 °C. The mixture was stirred
for 24 h at rt before saturated aqueous NaHCO3 was added at 0 °C in order to quench. The organic
materials were extracted with EtOAc, and combined extracts were washed with 1 N HCl, H2O, and brine,
dried over Na2SO4, and concentrated by evaporation. The residue was purified by column
chromatography on silica gel (hexane : EtOAc = 1 : 1 then 3 : 7) to give 7 (532 mg, 93%) as a colorless
oil with inseparable mixture of diastereomers; Rf 0.29 (hexane : EtOAc = 2 : 3); IR (neat) cm-1 3444, 2920,
2870, 1718, 1496, 1454, 1347, 1273, 1208, 1090, 1027, 907, 848, 736, 697; 1H NMR (CDCl3) ! 2.17 (br,
1H), 2.58-2.60 (m, 1H), 2.78 (t, J = 4.6 Hz, 1H), 3.11-3.16 (m, 1H), 3.35-3.41 (m, 1H), 3.55-3.68 (m, 8H),
13
3.71-3.79 (m, 3H), 4.55-4.71 (m, 4H, -CH2Ph), 7.25-7.36 (m, 10H, Ph-H); C NMR (CDCl3) ! 44.14,
50.82, 62.74, 71.22, 71.30, 71.56, 71.60, 72.08, 72.11 72.29, 72.31, 76.96, 77.85, 127.64, 127.77, 128.36,
128.47, 138.26,138.41; LRMS m/z 425 (M++Na, 9), 420 (M++H2O, 100), 403 (M++H, 11); HRMS calcd
for C23H30O6Na 425.1935: Found 425.1948.
General Procedure for the Intramolecular Epoxide-Opening Reaction of 7 (Table 1, Entry 6). To a
solution of 7 (402 mg, 1.00 mmol) in CH2Cl2 (100 mL) was added BF3·OEt2 (42.5 mg, 0.30 mmol) at 0 °C.
The solution was stirred for 5 h at rt, and concentrated by evaporation. The residue was purified by
column chromatography on silica gel (hexane : EtOAc = 1 : 1 then 2 : 3) to give a 1:1 diastereomeric
mixture of 8 (324 mg, 81%) as a colorless oil; Rf 0.33 (hexane : EtOAc = 3 : 7); IR (neat) cm-1 3419, 2867,
1
1718, 1496, 1453, 1270, 1091, 1070, 1026, 970, 737, 714, 697; H NMR (CDCl3) ! 2.34 (br, 1H),
13
3.49-3.85 (m, 15H), 4.59 (s, 4H), 7.26-7.36 (m, 10H); C NMR (CDCl3) ! 68.80, 69.05, 70.13, 70.89,

HETEROCYCLES, Vol. 86, No. 2, 2012
1539
71.03, 71.06, 71.73, 71.79,72.13, 74.76, 74.83, 127.74, 127.77, 128.42, 138.08, 138.11; LRMS m/z 425
(M++Na, 2), 420 (M++H2O, 100), 403 (M++H, 9); HRMS calcd for C23H31O6 403.2115: Found 403.2109.
5,10-Dibenzyloxy-3,7,10-trioxacyclododecanone (12). To a solution of 8 (124 mg, 0.31 mmol) in
CH2Cl2 (3 mL) was added DMP (196 mg, 0.46 mmol) at rt. The mixture was stirred for 2 h at the same
temperature before 2-propanol (4 mL) was added in order to quench, and concentrated by evaporation.
The residue was diluted with EtOAc, and the solution was washed with saturated aqueous NaHCO3, water,
and brine, dried over Na2SO4, and concentrated by evaporation. The residue was purified by column
chromatography on silica gel (hexane : EtOAc = 1 : 1) to give 12 (59 mg, 48%) as a colorless oil; Rf 0.64
(hexane : EtOAc = 3 : 7); IR (neat) cm-1 2869, 1730, 1496, 1454, 1354, 1305, 1267, 1104, 1074, 1027,
982, 949, 916, 735, 696; 1H NMR (CDCl3) ! 3.56-3.70 (m, 9H), 3.76 (dd, J = 11.5 and 5.1 Hz, 1H), 4.18
(ABq, JAB = 15.6 Hz, 4H), 4.60 (ABq, JAB = 12.1 Hz, 4H), 7.27-7.36 (m, 10H); 13C NMR (CDCl3) ! 68.96,
69.02, 71.62, 71.79, 73.42, 73.92, 74.90, 75.11, 127.80, 127.87, 127.90, 128.46, 137.86, 208.38; LRMS
m/z 423 (M++Na, 2), 418 (M++H2O, 100), 401 (M++H, 2); HRMS calcd for C23H29O6 401.1959: Found
401.1951.
Stereoselective Reduction of Ketone 12. To a solution of 12 (20 mg, 0.05 mmol) in THF (0.6 mL) was
added L-selectride (1.0 M in THF, 0.06 mL, 0.06 mmol) at -78 °C. The mixture was stirred for 2 h at the
same temperature before 1 N HCl was added. After warming to rt, the reaction mixture was extracted
with EtOAc, and combined extracts were washed with brine, dried over Na2SO4, and concentrated by
evaporation. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 1 : 1
the 2 : 3) to give 8 (14 mg, 73%) as a colorless oil. All characterized data were corresponded with above
data.
REFERENCES (AND NOTES)
1. M. F. Sebban, P. Vottero, A. Alagui, and C. Dupuy, Tetrahedron Lett., 2000, 41, 1019.
2. S. Cassel, C. Debaig, T. Benvegnu, P. Chaimbault, M. Lafosse, D. Plusquellec, and P. Rollin, Eur. J.
Org. Chem., 2001, 875.
3. T. Kawagishi, K. Yoshikawa, M. Ubukata, M. Hamada, and N. Nakajima, Heterocycles, 2006, 69,
107.
4. M. Hamada, R. Fujiwara, T. Kishimoto, and N. Nakajima, Heterocycles, 2010, 82, 1669.
5. M. Lemaire, G. Jeminet, J.–G. Gourcy, and G. Dauphin, Tetrahedron: Asymmetry, 1993, 4, 2101.
6. In these cases, polymerized products were not observed.
7. HPLC conditions; Cosmosil AR-II (Nacarai Tesque); eluent = MeCN : 0.5% aq. HCO2H (65 : 35),
flow rate = 0.5 mL/min; " = 254 nm; retention times = 19.5 and 21.8 min (all syn).