Synthesis of branched heptaglycerol bearing eight hydroxyl groups with four cyclic protecting groups

Article abstract of DOI:10.1055/s-2007-984890

A large series of branched oligoglycerols, BGL07 (heptamer) with cyclic protecting groups, was synthesized. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984890

LETTER
2091
Synthesis of Branched Heptaglycerol Bearing Eight Hydroxyl Groups with
Four Cyclic Protecting Groups
S
ynthesis of Branc
i
hedH
e
s
ptaglycer
o
l
o Nemoto,* Masaki Kamiya, Yuki Minami, Takaaki Araki, Tomoyuki Kawamura
Division of Pharmaceutical Chemistry, Institute of Health Biosciences, Graduate School of the University of Tokushima, 1-78 Sho-machi,
Tokushima 770-8505, Japan
Fax +81(88)6337284; E-mail: nem@ph.tokushima-u.ac.jp
Received 16 May 2007
the secondary alcohol at the apex position is used to a
Abstract: A large series of branched oligoglycerols, BGL07
create covalent bond with a lipophilic compound, and four
(heptamer) with cyclic protecting groups, was synthesized.
primary hydroxyl groups at the branched termini confer
Key words: glycerol, water solubility, branched-type, cyclic pro-
water solubility.
tecting groups, oligomer, hydroxyl group
However, the preparation of large analogues bearing fur-
ther repetitive linkages, such as 5, a precursor of hepta-
glyceryl derivatives BGL07 has yet to be reported.4,5
Linear macromolecules consist of a number of bifunction-
alized units such as ethylene glycol1a or 1,3-linked glycer-
HO Bn
ol;1b in contrast, branched macromolecules2 consist of
O
ECH =
(epichlorohydrin)
trifunctionalized (or further functionalized) units. Such
oligomers or macromolecules have been synthesized
using 3,3¢-dichloroisobutene,2a lactic acid,2b and imino-
diacetic acid with serinol.2c These have attracted much
attention due to the unique molecular skeleton which may
show novel properties and evaluations.2
Cl
ECH
OBn
OH
HO
OH
BGL01
OBn
ECH
3
The glyceryl unit is one of the simplest trifunctionalized
molecules. The preparation of compounds bearing a sin-
gle glyceryl unit at each dendrimeric terminus such as 1
has been reported2 (Figure 1). In contrast, compounds
such as 2, which bear repetitive branched glyceryl (BGL)
units, have not been reported except in our previous pa-
pers dealing with BGL.3 It is often difficult to create ether
linkage in high yield (especially at sterically hindered
positions) since the alkoxy anion often behaves as a base
rather than a nucleophile, and its nucleophilicity is gener-
ally weaker than that of carbanions or electron-negative
heteroatom species.
OH
OBn
apex
O
O
O
OH
OH
OBn
OBn
terminus
HO
4
O
OH
OBn
BGL03
ECH
OH
OH
OH
OBn
OBn
OBn
O
O
O
O
O
O
Despite this, we succeeded in preparing 4,3a,b a precursor
of triglyceryl derivatives BGL03 (Scheme 1). In BGL03,
O
O
O
O
OH
OH
OBn
OBn
HO
OH
OH
OH
OBn
OBn
OBn
5
OH
OH
O
O
OH
HO
X
OH
X
BGL07
OH
HO
O
O
X
X
OH
OH
Scheme 1
X
OH
HO
HO
X
OH
n
Alkoxy anions 7 and 8 were sufficiently reactive towards
glycidyl ether 6 to afford 3 and 4, respectively
(Scheme 2). However, it was likely that the nucleophilic-
ity of alkoxy anion 9 would be remarkably reduced by the
presence of four benzyl groups, in which the anion is
swathed.
OH
2
1
a molecule bearing
ONE glyceryl unit
at each terminus
a molecule bearing
repetitive glyceryl units
X = O, N, etc.
Figure 1 Two types of branched oligo- or polyglycerols
In order to increase the nucleophilicity of the triglyceryl
unit, preparation of an alternative molecule with reduced
steric hindrance around the secondary alkoxy anion is a
potential solution.
SYNLETT 2007, No. 13, pp 2091–2095
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-984890; Art ID: U05007ST
© Georg Thieme Verlag Stuttgart · New York
1
3
.0
8
.2
0
0
7

2092
H. Nemoto et al.
LETTER
(Table 1,10 entry 1). In the case of reaction from 11b to
12b, we noticed that anhydrous conditions generally gave
better results than our previous use of aqueous conditions.
Typical results obtained using sodium hydride as a base
are summarized (entries 2–4, 6–9). For the reaction of
11a, performing the reaction with no solvent gave the best
result (entry 1). When solvents were used, better results
were obtained at higher temperature (entries 2–4). Since
11b is not a liquid, the same reaction condition as entry 1
could not be examined (entry 5). By using THF (bp 65°C)
as a solvent, desired 12b was not obtained but the corre-
sponding glycidyl ether was detected (entry 6). In reflux-
ing 1,2-dimethoxyethane (DME, bp 85 °C), 12b was
obtained with good reproducibility (entry 7). The reaction
in refluxing cyclopentyl methyl ether (CPME, bp 106 °C)
gave lower yield of 12b than in DME in spite of its higher
boiling point (entry 8). Finally, in refluxing 1,4-dioxane
(bp 101 °C), best result for 12b was obtained (entry 9)
among we have examined (entries 6–9). The synthesis of
12b may require both high temperature and polarity of
solvent as well as 12a.
–
RO
O
O
–
O
–
Bn
7
7–9
ECH
RO
OBn
6
O
OBn
OBn
OBn
BnO
OBn
8
–
O
O
9
Scheme 2
In this paper, we report the first synthesis of protected
heptaglyceryl derivatives. The 1,3-protected cyclic
glycerols 10a6 and 10b7 were chosen as starting materials
instead of 1,3-dibenzyl glycerol (3) (Scheme 3). It is ex-
pected that the presence of six-membered rings would re-
duce the conformational flexibility of the whole molecule.
Furthermore, the total molecular weights of 11a (320.38)
and 11b (416.46) are each less than that of 4 (600.74).
R1
O
The details of the syntheses of 12a (entry 1) and 12b
(entry 9) are as follows.
O
R2
R1
R2
O
O
O
O
ECH
To a vigorously stirred mixture of 11a (6.00 g, 18.7
mmol), TBAI (0.30 g, 0.90 mmol), finely ground KOH in
a mortar (0.93 g, 14.0 mmol), and water (1.0 mL) was
added ECH (0.43 g, 4.70 mmol) slowly and dropwise. The
resulting mixture was stirred for 48 hours at 80 °C, then
poured into water (100 mL), and extracted with dichloro-
methane (3 × 20 mL). The combined organic layers were
dried over anhydrous potassium carbonate, and concen-
trated in vacuo. The residue was purified by silica gel col-
umn chromatography with diethyl ether–methanol (15:1)
as an eluent to afford 12a11 as a pale yellow oil (2.71 g,
3.89 mmol, 57% yield10) and the starting material 11a
(1.62 g, 5.05 mmol, 27% recovered yield10).
HO
HO
KOH, TBAI
H2O
R1
R2
O
10a,b
O
11a,b
R1
O
O
R2
O
O
O
O
R1
R2
O
O
ECH
base
O
O
HO
BGL07
R1
R2
O
O
a: R1 = R2 = Me
b: R1 = Ph, R2= H
R1
R2
O
To a solution of 11b (2.807 g, 6.74 mmol) in anhydrous
1,4-dioxane (5 mL) was added sodium hydride (0.441 g,
10.1 mmol). After the mixture has been stirred for 30 min-
utes at room temperature, ECH (0.26 mL, 3.37 mmol) was
added slowly. The resulting solution was refluxed for 48
hours, poured into water (100 mL), and extracted with
ethyl acetate (5 × 80 mL). The combined organic layers
were washed with brine, dried over anhydrous potassium
carbonate, and concentrated in vacuo. The residue was
purified by silica gel flash column chromatography using
diethyl ether–methanol (100:5 to 100:10) as an eluent to
afford 12b12 (1.219 g, 1.37 mmol, 54% yield10) and 11b
(0.713 g, 1.71 mmol, 25% recovered10).
Next, we demonstrated the synthesis of 1416 which bears
an activated ester at the apex position for covalent bond
formation with various lipophilic materials, as shown in
Scheme 4.17,18 A similar procedure to that used for benzyl
ethers 3 and 4 (tosylation, azidation, and reduction)3f
afforded amines 13a in 63% yield from 12a. The same
procedure was applied to 12b to afford 13b in 85% yield.
The amine 13a was then transformed to 14a in 74% yield
12a,b
O
Scheme 3
Triglycerol 11a8 was easily obtained from 10a in 56%
yield under the conditions previously reported for a simi-
lar reaction [epichlorohydrin (ECH), tetrabutylammoni-
um iodide (TBAI), H2O, and KOH].3a,b Another
triglycerol 11b9 was also obtained in 73% yield from 10b
in the same manner.
Compound 12a was obtained from 11a in 10% yield on
our first attempt, using the same conditions. The yield was
low but of appreciable value, since our previous attempts
to prepare compounds of this type, and even a detection of
octabenzyl ether 5 from 4 had failed entirely. The identi-
fication of 12a encouraged us to continue with further
optimization of the reaction.
After attempting the reaction under various conditions
(changing the base, solvent, temperature, counter alkali-
metal cation, phase-transfer catalyst, or ratio of ECH and
11), the yield of 12a from 11a was improved at 80 °C
Synlett 2007, No. 13, 2091–2095 © Thieme Stuttgart · New York

LETTER
Synthesis of Branched Heptaglycerol
2093
Table 1 Preparation of 12 from 11 and ECH with Sodium Hydride
In conclusion, a branched heptaglycerol skeleton was first
synthesized by choosing an appropriate protecting group.
The successful synthesis of the triply repetitive glycerol
oligomer is probably due to the reduction of both confor-
mational flexibility and molecular weight compared to
species used in previous preparation. We now have a
larger series of branched oligoglycerols allowing more
flexible and practical research into BGL modification of
lipophilic compounds.
in Various Solvents at Refluxa
Entry
11
Solvent
Recovered yield Yield of 12
of 11 (%)
(%)
57
5
1b
2
3
4
5
6
7
8
9
11a
Neat
27
37
38
55
n.e.
–
11a
THF
11a
DME
26
33
n.e.
0d
11a
MeCN
Neat
Acknowledgment
11bc
11b
11be
11be
11be
We thank Kyowa Hakko Kogyo Co. Ltd. for financial support, and
Mr. Jun-ya Kikuishi, Ms. Shiho Yanagida, and Ms. Satomi Yuzawa
for participation in the earlier work.
THF
DME
27
20
25
40
36
55
CPME
1,4-Dioxane
References and Notes
(1) (a) Serebryakov, E. P.; Abylgaziev, R. I. Bull. Acad. Sci.
USSR Div. Chem. Sci. (Engl. Transl.) 1985, 34, 1916.
(b) Fröling, A. Chem. Phys. Lipids 1990, 53, 289. (c)Urata,
K.; Takaishi, N. J. Am. Oil Chem. Soc. 1994, 71, 1027.
(d) Engler, G.; Ulsperger, E. J. J. Prakt. Chem. 1974, 316,
325.
a Compound 11 (4.0 equiv),14,15 ECH (1.0 equiv), NaH (1.2 equiv),
reflux, 48 h.
b Reaction carried out with TBAI, KOH, and H2O at 80 °C.
c Since 11b was not a liquid but gummy solid, reaction could not be
carried out without solvent (n.e. = not examined).
d Formation of 12b was not observed but the corresponding glycidyl
ether was detected.13
(2) (a) Jayaraman, M.; Frêcher, M. J. J. Am. Chem. Soc. 1998,
120, 12996. (b) Carnahan, M. A.; Grinstaff, M. W. J. Am.
Chem. Soc. 2001, 123, 2905. (c) Wang, Y. A.; Li, J. J.;
Chen, H.; Peng, X. J. Am. Chem. Soc. 2002, 124, 2293.
(3) Our previous papers on BGL: (a) Nemoto, H.; Wilson, J. G.;
Nakamura, H.; Yamamoto, Y. J. Org. Chem. 1992, 57, 435.
(b) Nemoto, H.; Wilson, J. G.; Nakamura, H.; Yamamoto, Y.
J. Org. Chem. 1995, 60, 1478. (c) Nemoto, H.; Iwamoto, S.;
Nakamura, H.; Yamamoto, Y. Chem. Lett. 1993, 465.
(d) Yamamoto, Y.; Asao, N.; Meguro, M.; Tsukada, N.;
Nemoto, H.; Sadayori, N.; Wilson, J. G. J. Chem. Soc.,
Chem. Commun. 1993, 1201. (e) Nemoto, H.; Cai, J.;
Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1994, 577.
(f) Nemoto, H.; Cai, J.; Iwamoto, S.; Yamamoto, Y. J. Med.
Chem. 1995, 38, 1673. (g) Yamamoto, Y.; Cai, J.;
e 2.0 Equiv of 11b were used.15
in one step using the asymmetric glutaric acid based dual-
activated ester 1519 with diisopropylethylamine (DIPEA)
in CH2Cl2. Meanwhile, a stepwise procedure, involving
treatment of glutaric anhydride with triethylamine (Et3N)
followed by condensation reaction with N-hydroxysuc-
cinimide (HOSu) using ethyl 2-(N,N-dimethylamino)pro-
pyl carbodiimide (EDC) afforded 14b in 57% yield from
13b.
13a
14a: one-step procedure
R1
O
O
O
O
O
R2
O
, DIEPA, CH Cl
Cl
O
2
2
N
O
R1
O
15
O
R2
12a,
12b
O
O
H2N
R1
O
R2
O
13b
14b: two-step (one-pot) procedure
O
O
O
O
O
R1
O
, Et3N, THF
1)
O
R2
O
2) HOSu, EDC, THF
13a: 63% yield
13b: 85% yield
HOSu = N-hydroxysuccinimide
R1
R2
O
O
O
O
R1
R2
O
O
O
O
O
O
a: R1 = R2 = Me
b: R1 = Ph, R2 = H
O
O
N
N
O
R1
R2
H
O
O
O
O
R1
R2
14a: 74% yield
14b: 57% yield
O
O
Scheme 4
Synlett 2007, No. 13, 2091–2095 © Thieme Stuttgart · New York

2094
H. Nemoto et al.
LETTER
Nakamura, H.; Sadayori, N.; Asao, N.; Nemoto, H. J. Org.
Chem. 1995, 60, 3352. (h) Takagaki, M.; Ono, K.; Oda, Y.;
Kikuchi, H.; Nemoto, H.; Iwamoto, S.; Cai, J.; Yamamoto,
Y. Cancer Res. 1996, 56, 2017. (i) Nemoto, H.; Kikuishi, J.;
Yanagida, S.; Kawano, T.; Yamada, M.; Harashima, H.;
Kiwada, H.; Shibuya, M. Bioorg. Med. Chem. Lett. 1999, 9,
205. (j) Nemoto, H.; Araki, T.; Kamiya, M.; Kawamura, T.;
Hino, T. Eur. J. Org. Chem. 2007, 3003.
(8) Preparation of 11a
To a vigorously stirred mixture of 10a (500 mg, 3.78 mmol),
TBAI (61.0 mg, 0.19 mmol), finely ground KOH in a mortar
(187.3 mg, 2.84 mmol), and H2O (0.04 mL) was added ECH
(87.5 mg, 0.95 mmol) slowly and dropwise. After stirring for
40 h at 60 °C, the resulting mixture was diluted with EtOAc,
and the resulting suspension was filtered. The filtrate was
dried over anhyd K2CO3, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
using hexane–EtOAc (1:3) as an eluent to afford 11a as a
colorless oil (169.7 mg, 0.53 mmol, 56% yield) and 10a (250
mg, 1.89 mmol, 50% recovered). FT-IR (KBr): 518, 561,
731, 829, 949, 1016, 1086, 1124, 1120, 1254, 1333, 1377,
1452, 1473, 2879, 2973, 3442 cm–1. 1H NMR (400 MHz,
CDCl3): d = 4.04–3.89 (m, 5 H), 3.83–3.73 (m, 4 H), 3.63–
3.51 (m, 4 H), 3.49–3.41 (m, 2 H), 2.81 (br s, 1 H), 1.43 (s,
6 H), 1.41 (s, 6 H). 13C NMR (100 MHz, CDCl3): d = 98.0 (2
× C), 70.8 (2 × CH), 69.6 (2 × CH2), 69.5 (CH), 62.3 (4 ×
CH2), 23.5 (2 × CH3), 23.4 (2 × CH3). Anal. Calcd for
C15H28O7: C, 56.23; H, 8.81. Found: C, 55.88; H, 8.73.
(9) Preparation of 11b
(4) (a) In Scheme 15 of ref. 4b, the reaction of 4 and 3 with ECH
to afford a mixture of 5 (4 + 4 + ECH) and asymmetrical
pentaglycerol (4 + 3 + ECH), is drawn with a plain arrow but
not with a dotted arrow. However, the authors mention in the
main text that ‘One can imagine repeating this step to give
higher degree oligomers (pentamer, heptamer,…) with
dendrimer-like structures’ (around Scheme 15, our paper3a,b
was the only one referenced). Furthermore, no experimental
details are provided for Scheme 15. It is possible that they
misread our paper,3a,b or mistakenly used a plain arrow rather
than a dotted one. Accordingly, the preparation (either
isolation or identification) of octabenzyl ether 5 has not been
demonstrated. (b) Cassel, S.; Debaig, C.; Benvegnu, T.;
Chaimbault, P.; Lafosse, M.; Plusquellec, D.; Rollin, P. Eur.
J. Org. Chem. 2001, 875.
To a mixture of 10b (5.613 g, 31.2 mmol), TBAB (0.518 g,
1.56 mmol), finely ground KOH in a mortar (1.543 g, 31.2
mmol), and H2O (0.04 mL) was added Et2O (adequate
amount for stirring). To the resulting suspension was added
ECH (0.61 mL, 7.79 mmol) slowly and dropwise while
stirring vigorously at r.t. The mixture was then stirred for
5 h at 40 °C, for 5 h at 60 °C, and then for 17 h at 80 °C. The
mixture was poured into H2O (50 mL), and extracted with
EtOAc (5 × 50 mL). The combined organic layers were
washed with brine, dried over anhyd K2CO3, and
(5) BGL07 is a heptamer containing triply repetitive glyceryl
units. In contrast, compound 16, recently reported by us,3j
contains a doubly repetitive glyceryl unit attached to a
disparate trifunctionalized molecule (iminodiacetic acid).
This octabenzyl ether 16 should be called BGL06
(Figure 2).
OBn
O
concentrated in vacuo. The residue was purified by silica gel
column chromatography using hexane–EtOAc (1:4) as an
eluent to afford 11b (2.212 g, 5.32 mmol, 73% yield based
on conversion of 10b) and 10b (2.955 g, 16.4 mmol, 53%
recovered). FT-IR (neat): 700, 750, 800, 839, 916, 980,
1011, 1092, 1153, 1217, 1238, 1277, 1340, 1392, 1454,
2860, 2974, 3477 cm–1. 1H NMR (400 MHz, CDCl3): d =
7.54–7.43 (m, 4 H), 7.40–7.32 (m, 6 H), 5.54 (s, 2 H), 4.41–
4.31 (m, 4 H), 4.10–3.98 (m, 5 H), 3.79–3.65 (m, 4 H), 3.77–
3.67 (m, 2 H), 2.85 (d, J = 5.6 Hz, 1 H). 13C NMR (75 MHz,
CDCl3): d = 137.9 (2 × C), 128.6 (2 × CH), 127.9 (4 × CH),
125.8 (4 × CH), 100.9 (2 × CH), 70.9 (2 × CH), 69.5 (CH),
69.1 (2 × CH2), 68.7 (4 × CH2). HRMS (EI): m/z calcd for
C23H28O7 [M+]: 416.1809; found: 416.1835.
O
OBn
H
N
OBn
O
OBn
HN
OBn
O
OBn
H
N
OBn
O
O
16
OBn
(10) The recovered yield of 11 was calculated using the following
equation (Equation 1). Accordingly, 50% is the ideal value
for entries 1–6, and 0% is the ideal value for entries 7–9
(Table 1). Equation 2 was also used to calculate the yield of
12 since 12 consists of two moieties of 11 and an excess of
11 was used.
Figure 2
(6) Preparation of 10a. See: Forbes, D. C.; Ene, D. G.; Doyle,
M. P. Synthesis 1998, 879.
(7) Preparation of 10b. See: (a) Crich, D.; Beckwith, A. L. J.;
Chen, C.; Yao, Q.; Davison, I. G. E.; Longmore, R. W.;
Anaya, d. e. P. C.; Quintero-Cortes, L.; Sandoval-Ramirez,
J. J. Am. Chem. Soc. 1995, 117, 8757. (b) Carlsen Per, H. J.;
Soerbye, K.; Ulven, T.; Aasboe, K. Acta Chem. Scand. 1996,
50, 185. (c) Based on 1H NMR analysis, it is considered that
10b has a chair form bearing phenyl group at equatorial
position, and hydroxyl group at axial position. The hydroxyl
group may have electronic affinity among oxygen atoms of
the 1,3-dioxirane ring as shown in the following Figure 3.
(recovered weight of 11)
recovered yield of 11 =
(molecular weight of 11)
Equation 1
Yield of 12 =
(weight of 12 obtained)÷(molecular weight of 12 obtained)
O
H
O
O
H
(weight of starting 11) – (recovered weight of 11)
O
O
÷2
Ph
Ph
O
(molecular weight of 11)
Figure 3
Equation 2
Synlett 2007, No. 13, 2091–2095 © Thieme Stuttgart · New York

LETTER
Synthesis of Branched Heptaglycerol
2095
(11) Compound 12a: FT-IR (neat): 521, 733, 827, 941, 1084,
1120, 1252, 1286, 1375, 1454, 1651, 1716, 2877, 2991, 3417
cm–1. 1H NMR (400 MHz, CDCl3): d = 4.00–3.86 (m, 9 H),
3.80–3.50 (m, 22 H), 3.48–3.40 (m, 4 H), 1.43 (s, 12 H), 1.40
(s, 4 H). 13C NMR (100 MHz, CDCl3): d = 98.1 (4 × C), 78.7
(2 × CH), 71.9 (2 × CH2), 70.9 (4 × CH), 69.6 (CH), 68.7,
68.6 (4 × CH2), 62.4, 62.4, 62.3, 62.3 (8 × CH2), 30.9, 29.6,
24.0, 24.0, 23.1, 23.0 (8 × CH3). ESI-HRMS: m/z calcd for
C33H60O15Na [M + Na]+: 719.3830; found: 719.3832.
(12) Compound 12b: FT-IR (neat): 699, 749, 799, 841, 916, 982,
1011, 1092, 1216, 1238, 1278, 1278, 1344, 1392, 1454,
1496, 1604, 2864, 3034, 3477 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.60–7.44 (m, 8 H), 7.43–7.29 (m, 12 H), 5.60–
5.41 (s, 4 H), 4.43–4.22 (m, 8 H), 4.02–3.87 (m, 9 H), 3.85–
3.56 (m, 14 H), 3.40–3.25 (s, 4 H). 13C NMR (100 MHz,
CDCl3): d = 137.7 (4 × C), 128.0 (4 × CH), 127.3 (8 × CH),
125.4 (8 × CH), 100.2 (4 × CH), 78.1 (2 × CH), 71.0 (2 ×
CH2), 70.4 (4 × CH), 69.1 (CH), 68.2, 67.9 (8 × CH2), 67.7,
67.5 (4 × CH2). HRMS–FAB: m/z calcd for C49H61O15 [M +
H]+: 889.4018; found: 889.4010.
(15) In contrast to the reaction with 11a,14 compounds with high
molecular weight such as undecamers, were not detected
when 11b was used. Therefore, a molar ration of 11b/
ECH = 2:1 was applied.
(16) Compound 14a: pale yellow oil. FT-IR (neat): 520, 665, 754,
827, 941, 995, 1087, 1373, 1454, 1553, 1666, 1739, 1783,
1815, 2875, 2941, 2993, 3334, 3508 cm–1. 1H NMR (400
MHz, CDCl3): d = 6.63 (d, J = 8.8 Hz, 1 H), 4.18–4.08 (m, 1
H), 3.98–3.87 (m, 8 H), 3.77–3.64 (m, 10 H), 3.61–3.44 (m,
12 H), 3.42–3.33 (m, 4 H), 2.80 (s, 4 H), 2.65 (t, J = 7.2 Hz,
2 H), 2.30 (t, J = 7.2 Hz, 2 H), 2.03 (quin, J = 7.2 Hz, 2 H),
1.42–1.34 (m, 24 H). 13C NMR (100 MHz, CDCl3): d =
171.3 (C), 168.9 (2 × C), 168.1 (C), 98.1 (2 × C), 98.0 (2 ×
C), 78.7 (2 × CH), 71.0 (2 × CH), 70.9 (2 × CH), 68.8 (2 ×
CH2), 68.7 (2 × CH2), 68.6 (2 × CH2), 62.5 (4 × CH2), 62.3
(2 × CH2), 62.2 (2 × CH2), 49.3 (CH), 34.3 (CH2), 30.0
(CH2), 25.5 (2 × CH2), 23.9 (2 × CH3), 23.6 (2 × CH3), 23.6
(2 × CH3), 23.3 (2 × CH3), 20.5 (CH2). ESI-HRMS: m/z
calcd for C42H70N2O19Na [M + Na]+: 929.4470; found:
929.4470.
(13) Structure of the glycidyl ether (Figure 4):
Compound 14b: pale yellow oil. FT-IR (neat): 699, 749,
799, 1012, 1092, 1208, 1389, 1454, 1495, 1529, 1667, 1739,
1783, 1813, 2862, 3346 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.51–7.42 (m, 8 H), 7.41–7.29 (m, 12 H), 6.83–6.73 (m,
1 H), 5.48 (s, 4 H), 4.40–4.22 (m, 8 H), 4.19–4.08 (m, 1 H),
4.04–3.85 (m, 8 H), 3.82–3.46 (m, 14 H), 3.35–3.21 (m, 4
H), 2.71 (s, 4 H), 2.45 (t, 2 H, J = 8.0 Hz), 2.06 (t, 2 H, J = 8
Hz), 1.83 (quin, 2 H, J = 8.0 Hz). 13C NMR (75 MHz,
CDCl3): d = 171.4 (C), 169.5 (C), 168.1 (C), 138.1 (4 × C),
128.6 (4 × CH), 127.9 (8 × CH), 125.9 (8 × CH), 100.9,
100.8 (4 × CH), 78.6 (2 × CH), 71.1, 71.0 (4 × CH), 69.0,
68.9, 68.6, 68.5 (8 × CH2), 67.9 (2 × CH2), 49.4 (CH), 34.1
(CH2), 29.8 (CH2), 25.4 (2 × CH2), 20.3 (CH2). HRMS–
FAB: m/z calcd for C58H71N2O19 [M + H]+: 1099.4633;
found: 199.4651.
O
Ph
Ph
O
O
O
O
O
O
O
Figure 4
(14) A molar ratio 11a/ECH = 4:1 was finally applied, otherwise
nucleophilic attack by 11a to the glycidyl ether (11a + ECH)
slowed down, affording an unidentified mixture and some
identified oligomers such as an asymmetrical tetramer (11a
+ ECH + H2O) and an asymmetrical undecamer (12a + ECH
+ 11a = three of 11a + two of ECH).
(17) BGL modification of a protein: Nemoto, H.; Yamasaki, M.;
Suzawa, T.; Yamaguchi, H. WO 2004029018, 2004.
(18) BGL modification of a liposome: Nemoto, H.; Yamauchi,
M.; Kusano, H.; Kato, Y.; Yamasaki, M.; Suzawa, T. WO
2005023844, 2005.
(19) Abrams, M. J.; Bridger, G. J.; Schwartz, D. A.;
Padmanabhan, S.; Ultee, M. E. WO 9410149, 1994.
Synlett 2007, No. 13, 2091–2095 © Thieme Stuttgart · New York

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