Synthesis of cyclic polyglycerols

Article abstract of DOI:10.3987/com-06-s(o)44

Authentic standards of cyclic polyglycerol, with well-defined structures and degrees of polymerization from 3 to 6 cyclic oligomers, have been efficiently synthesized. The intramolecular cyclization conditions gave cyclic glycerols more effectively than intermolecular coupling conditions.

Full text of DOI:10.3987/com-06-s(o)44

HETEROCYCLES, Vol. 69, 2006
107
HETEROCYCLES, Vol. 69, 2006, pp. 107 - 111. © The Japan Institute of Heterocyclic Chemistry
Received, 2nd July, 2006, Accepted, 21st August, 2006, Published online, 25th August, 2006. COM-06-S(O)44
SYNTHESIS OF CYCLIC POLYGLYCEROLS
Takahiro Kawagishi,1 Kimio Yoshikawa,1 Makoto Ubukata,2 Masahiro Hamada,1
and Noriyuki Nakajima1*
1Biotechnology Research Center, Toyama Prefectural University, Imizu, Toyama
939-0398, JAPAN, e-mail: nori@pu-toyama.ac.jp
2Graduate School of Agriculture, Hokkaido University, Kita-ku, Sapporo
060-8589, Japan
Abstract – Authentic standards of cyclic polyglycerol, with well-defined
structures and degrees of polymerization from 3 to 6 cyclic oligomers, have been
efficiently synthesized. The intramolecular cyclization conditions gave cyclic
glycerols more effectively than intermolecular coupling conditions.
Polyglycerols are oligomers of glycerol (glycerin). Their fatty acid esters (PGE) are generally dispersible
in water and soluble in oil. They are widely using in food additives, cosmetic materials and toiletries as
surfactants.1 Although polyglycerols is readily available in bulk quantities by industrial manufacture, the
reaction requires drastic conditions, including high temperature and alkaline media. Therefore,
commercially available polyglycerols are very complicated oligomeric mixtures and undefined molecular
composition with difficult characterization.2
OBn
O
OBn
BnO
OBn
OBn
BnO
BnO
OBn
O
O
4
O
BnO
O
O
OBn
O
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
We therefore focused our attention on the synthesis of single and fine structure of highly cyclic
polyglycerols (1-4) as an authentic standard. There are a few representative standards of polyglycerols in
the literature.3-8 Linear polyglycerols, dimer to pentamer, have previously been prepared either by direct

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HETEROCYCLES, Vol. 69, 2006
synthesis involving bishydroxylation of diallyl ether5 and 1,3-di-O-allylglycerol6 or by coupling of
D,L-α,β-isopropylideneglycerol (solketal (5)) with either its tosylate8 or with glycidyl solketal ether.9-11
Rollin et al. reviewed recent synthesis of linear, branched and cyclic polyglycerol standards.12
In order to couple only between primary positions, we used three units of glycerol (8, 11 and 17) as the
useful synthetic intermediates. Commercially available mono-glycerol unit (8) has a benzyl (Bn) group,
di-glycerol unit (11) has two Bn groups and tri-glycerol unit (17) has three Bn groups at each secondary
positions. Di-glycerol unit (11) was made from solketal (5) which was changed to MEM ether (6) in 5
steps with 67% overall yield. After methoxyethoxymethyl (MEM) ether (6) was converted into tosylate 7
in 88% yield, its coupling with solketal (5) provided di-glycerol (9) in 62% yield. The acetonide group at
terminal position is convertible to Bn group to give 10 in 62% by four steps; hydrolysis in 80% AcOH,
tert-butyldiphenylsilyl (TBDPS) protection, benzylation and silyl deprotection by tetrabutylammonium
fluoride (TBAF). Finally acid hydrolysis of MEM group gave desired di-glycerol unit (11) in 90% yield.
The corresponding di-tosylate (12) was synthesized in 88% yield under usual conditions.
5 steps
b
HO
MEMO
O
R1O
OR2
O
O
O
O
OBn
67 %
62 %
OBn
6: R1 = MEM,R2 = H
7: R1 = MEM,R2 = Ts
8: R1 = R2 = H
9
5
a, 88 %
g
c - g
MEMO
O
OH
RO
O
OR
90 %
62 %
OBn
OBn
OBn
OBn
10
11: R = H
12: R = Ts
a, 88 %
reagent and conditions: a. TsCl, Et3N, CH2Cl2; b. 5, NaH, DMSO/THF; c. 80%
AcOH; d. TBDPS-Cl, DMAP, Et3N, CH2Cl2; e. BnBr, NaH, THF; f. TBAF, THF;
g. HCl, MeOH, 80 °C.
Scheme 1. Synthesis of di-glycerol units
Tri-glycerol unit (13) was synthesized from the coupling of solketal (5) and epichlorohydrin in the
presence of tetrabutylammonium bisulfate in 80% yield. Obtained secondary hydroxy group was
protected with Bn group to give 14 in 93% yield, its acetonide groups were removed by acid treatment
and following primary alcohols were protected with TBDPS group to give diol (16) in 95% yield. Two
secondary hydroxy groups were protected with Bn group and TBDPS groups were deprotected to afford
desired benzyl tri-glycerol (17). The corresponding di-tosylate (18) was synthesized in 89% yield under
usual conditions.

HETEROCYCLES, Vol. 69, 2006
109
c
a
O
O
O
RO
O
O
OR
O
5
O
O
OR
OH
OH
BnO
100 %
80 %
13: R = H
14: R = Bn
15: R = H
16: R = TBDPS
b, 93 %
d, 95 %
b, e, 80 %
RO
BnO
O
BnO
O
BnO
OR
reagent and conditions: a.epichlorohydrine,
HSO4Bu4N, 40% NaOH/hexane/toluene; b. BnBr,
NaH, THF; c. 80% AcOH; d. TBDPS-Cl, DMAP,
Et3N, CH2Cl2; e.TBAF, THF f. TsCl, Et3N, CH2Cl2.
17: R = H
18: R = Ts
f, 89 %
Scheme 2. Synthesis of tri-glycerol units
Three glycerol (8, 11 and 17) are in hands as the useful synthetic intermediates. We first tried 1:1
condensation of di-tosylates and diols. The synthesis of cyclic trimer to pentamer has been reported by
1:1 condensation of bis-epoxide or di-triflate with di-nucleophiles.13
Table 1. Synthesis of cyclic glycerols by intermolecular coupling
OBn
NaH
DMF
+
TsO
O
OBn
OTs
OBn
HO
OH
OBn
O
O
n
m
O
OBn
BnO
o
Entry
Tosylate, Alcohol,
n
oligomer ,
o
Cyclic
oligomer
Yield, %
m
1
2
3
4
1
2
2
2
12
18
18
18
1
1
2
3
8
8
11
17
1, Trimer
2, Tetramer
3, Pentamer
4, Hexamer
1
2
3
4
13
19
10
7
When di-glycerol di-tosylate (12) and mono-glycerol (8) were treated with NaH in DMF at 60 °C for 12 h,
cyclic tri-glycerol (1) was obtained in 13% yield. Under the same reaction conditions, tetramer (2) was
obtained from the coupling of tri-glycerol di-tosylate (18) and 8. Pentamer (3) and hexamer (4) were
obtained in 10% and 7% yields from the coupling of tri-glycerol di-tosylate (18) with alcohols (11 and
17). Linear hexamer (19) was recovered in 9% yield as the by-product of cyclization. When recovered
linear hexa-glycerol (19) was treated with NaH in DMF at 80 °C for 2 days, cyclic hexa-glycerol (4) was
obtained in 70% yield (Table 2, Entry 4).
On the base of this result, we made linear glycerols mono-tosylates (20, 22 and 24) to apply NaH-
mediated cyclization. After diol (17) was selectively converted into tosylate (20), which was coupled with
5 and following 4 step sequences (hydrolysis in 80% AcOH, TBDPS protection, benzylation and
deprotection by TBAF) to provide tetra-glycerol (21). Under the same reaction pathway, penta-glycerol

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HETEROCYCLES, Vol. 69, 2006
(23) was obtained from tetra-glycerol mono-tosylate (22).
b - f
b - f
HO
HO
O
O
OR
OBn
HO
HO
O
O
OR
56 %
62 %
2
OBn
OBn
OBn
OBn
OBn
17: R = H
20: R = Ts
21: R = H
22: R = Ts
a, 50 %
a, 59 %
O
O
4
OTs
O
O
3
OR
OBn
OBn
19
OBn
OBn
OBn
OBn
23: R = H
24: R = Ts
a, 29 %
reagent and conditions: a. TsCl, Et3N, CH2Cl2; b. 5, NaH, DMSO/THF; c. 80% AcOH;
d. TBDPS-Cl, DMAP, Et3N, CH2Cl2; e. BnBr, NaH, THF; f. TBAF, THF
Scheme 3. Synthesis of precursors of intramolecular cyclization
When the mono-tosylates (20, 22 and 24) were treated with NaH in DMF14 (4 mM) at 80 °C for 2 days,
12-, 16-, and 20-membered cyclic benzyl glycerols (1, 2,15 and 316) were obtained in 38%, 38% and 54%
yields, respectively.
Table 2. Synthesis of cyclic glycerols by intramolecular cyclization
OBn
NaH, DMF (4 mM)
O
O
HO
BnO
O
O
OTs
n
80°C, 2 days
BnO
BnO
O
OBn
BnO
n
Entry
Tosylate,
n
oligomer ,
Cyclic
oligomer
Yield, %
n
1
2
3
4
1
2
3
4
1
2
3
4
20
22
24
19
1
2
3
4
38
38
54
70
We have established cyclic polyglycerol synthesis based on the intramolecular NaH-mediated
cyclization method. The intermolecular coupling methodology of di-tosylate and diol was also studied to
find efficient synthesis of cyclic polyglycerols. Taking into account the synthesis of optically active
polyglycerols as a next project, we adopted the synthetic approach based on convergent coupling by use
of glycerol unit.

HETEROCYCLES, Vol. 69, 2006
111
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15. The corresponding glycerols of 1, 2 were synthesized by hydrogenolysis on Pd(OH)2 in EtOH in
98% and 83% yield, respectively.
16. Typical procedure for the synthesis of 3: The DMF (10 mL) solution of penta-glycerol mono-
tosylate (24) (40 mg, 0.04 mmol) and NaH (60% activity, 9.6 mg, 0.24 mmol) was stirred for 48 h
at 80 °C. The reaction mixture was quenched with sat. aq. ammonium chloride. The aq. solution
was extracted with EtOAc and the combined organic phase were washed with brine, and dried
(Na2SO4). Filtration, concentration and silica gel column purification (hexane/EtOAc, 7/3) to give
17.9 mg (54 %) of 3 as a colorless oil. Data for 3:1H-NMR (400 MHz, CDCl3) 7.32-7.30 (25H, m,
HC(Ar)), 4.64(10H, s, CH2), 3.67-3.57 (25H, m); IR (neat, cm-1) 3854 (w), 3713 (w), 3063 (w),
3031 (w), 2869 (m), 2349 (w), 1497 (w), 1455 (m), 1350 (w), 1306 (w), 1266 (w), 1208 (w), 1109
(s), 1028 (w), 735 (s), 696 (s); FAB-MS (m/z) 847 (17), 846 (74), 845 (100), 844 ([M+Na]+, 100), 843
(9), 842 (13), 823 (6), 822 (MH+, 13), 821 (3), 820 (4), 752 (42), 735 (53), 615 (66), 451 (29), 409 (11), 289
(32), 181(31), 91(100), 77 (19).