A quantitative investigation of the water-solubilizing properties of branched oligoglycerols

Article abstract of DOI:10.1002/ejoc.200601036

Water solubility and partition-coefficient measurements have been conducted on already known monobenzoylated octamethylenediamine-containing branched oligoglycerols. A new oligoglycerol, a hexamer bearing eight primary hydroxy groups, has also been prepar

Full text of DOI:10.1002/ejoc.200601036

FULL PAPER
DOI: 10.1002/ejoc.200601036
A Quantitative Investigation of the Water-Solubilizing Properties of Branched
Oligoglycerols
Hisao Nemoto,*[a] Takaaki Araki,[a] Masaki Kamiya,[a] Tomoyuki Kawamura,[a] and
Tomoaki Hino[b]
Keywords: Solvolysis / Glycerols / Hydroxylation / Oligomers / Iminodiacetic acid
Water solubility and partition-coefficient measurements have
geometric progression with the number of hydroxy groups
been conducted on already known monobenzoylated octa- and the water solubility of the hexamer derivative was at
methylenediamine-containing branched oligoglycerols.
A
least half a million times greater than that of the propan-
amide derivative.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
new oligoglycerol, a hexamer bearing eight primary hydroxy
groups, has also been prepared and its properties examined.
Water solubility was found to increase in an approximately
sis[13,14] of water-soluble p-boronophenylalanines[14] and
studies of their effects on melanoma cells[15,16] have also
been carried out and liposomes constructed with modified
β-cholestanol using 1 or 2 have been prepared.[17] Through-
out these studies, we found that not only was BGL modifi-
cation helpful in increasing water solubility, but it also
changed the pharmacokinetic and/or pharmacodynamic be-
havior of the original material 5.
BGLs are designed to have certain characteristic chemi-
cal features: (1) BGL derivatives such as 1 or 2 are water-
soluble under a wider range of pH conditions than com-
pounds possessing ammonium cations or sulfonate anions
because of the number of neutral functionalities (hydroxy
groups); (2) BGL derivatives possess polar primary hydroxy
groups that cause dissolution in water more effectively than
the ether functionality in poly(ethylene glycols); (3) because
the BGL moiety has no asymmetric center,[18] a water-solu-
ble derivative such as 1 or 2 cannot be a mixture of dia-
stereomers even if the target molecule 5 contains asymmet-
ric center(s). We have devoted considerable effort to increas-
ing the number of concrete examples of BGL modification.
However, until now, a systematic and quantitative review
of water solubilization by BGL modification has not been
carried out.
Introduction
Water solubility is a frequent requirement of compounds
for medicinal use. To administer poorly water-soluble com-
pounds, the usual method is to pretreat the compound with
amphiphilic materials[1] to form a solid dispersion,[1a,1b] an
inclusion complex,[1c,1d] micelles,[1e,1f] liposomes,[1g,1h] or a
nanosuspension,[1i,1j] and much research has been carried
out in this area. Most of these publications describe the
utilization of weak noncovalent interactions, but there have
been few reviews on water solubilization by covalent bond
formation with hydrophilic moieties.[2] However, for exam-
ple, papers on the chemical modification of a famous anti-
cancer agent, paclitaxel,[3] by covalent bond formation with
carboxylate,[4] poly(ethylene glycols),[5] or saccharides[6]
have recently been published independently. Oligoglycer-
ols[7,8] can be classified among these water-solubilizing
agents. We have developed a series of water-solubilizing
agents, branched glycerols (BGLs),[9] and demonstrated the
synthesis and properties of compounds bearing these moie-
ties.[9–17] As shown in Scheme 1, a lipophilic material 5 un-
dergoing BGL modification can be converted into the
water-soluble analogue 1 or 2.
We have applied the methodology shown in Scheme 1 to
a 1,2-dicarbadodecaborane(12) derivative, which is an ex-
Furthermore, the partition coefficients of BGL-modified
tremely water-insoluble boron cluster.[9–12] The synthe- molecules have not been measured until now. Although
water solubilization is useful as a practical technology for
many different purposes, we concentrate here on its applica-
[a] Department of Molecular Design and Synthesis, Division of
tion in medicinal uses. It is well known that extreme water
solubility in certain medicinal compounds can result in a
disturbance of the membrane permeation process. For this
reason, the regulation of water solubility is important in
terms of both administration and permeation.[19] Therefore,
it is desirable to know the partition coefficients of BGL-
modified compounds.
Pharmaceutical Chemistry, Institute of Health Biosciences,
Graduate School of The University of Tokushima,
1-78-1, Sho-machi, Tokushima 770-8505, Japan
Fax: +81-88-633-7284
E-mail: nem@ph.tokushima-u.ac.jp
[b] The College of Pharmacy Kinjo Gakuin University,
2-1723 Ohmori, Moriyama, Nagoya 463-8521, Japan
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 3003–3011
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H. Nemoto, T. Araki, M. Kamiya, T. Kawamura, T. Hino
FULL PAPER
Scheme 1. General scheme of BGL modification.
TFA by the usual extraction procedure to afford the crude
amine, which was converted into 13d using succinic anhy-
dride and pyridine. Octaol 19 was obtained from 13d in the
same manner as 16 from 13a.
Results and Discussion
In this paper we report the quantitative values of the
water solubility and the partition coefficients of BGL deriv-
atives and related compounds. Monobenzoylated octame-
thylenediamine (8) was chosen[20,21] as a representative ex-
ample (Scheme 2). The derivatives 16–19, prepared with the
purpose of measuring water-solubilizing properties, are
shown in a rectangular frame in Scheme 2. In addition, pro-
panamide 10, a non-hydroxylated derivative, and the hydro-
chloride salt 9 were examined for comparison.
An Alternative BGL Modification Pathway
The procedure in Scheme 2 was outlined from the view-
point of the BGL moiety. From the viewpoint of the com-
pound undergoing BGL modification, however, 8 was con-
verted into 16–19 in two steps: (i) covalent bond formation
(condensation of –NH2 and –CO2Su) and (ii) deprotection
of the resulting benzyl ethers 15a–15d. This two-step path-
way, (i) + (ii), is conceptualized in the upper part of
Scheme 3. We employed this pathway, starting from 8 (cor-
responding to 5) and yielding 15a–15d (corresponding to
20) as 8 fortunately contains no functionalities that are sen-
Synthesis
Benzamide 8 was prepared according to the previously sitive to debenzylation conditions. Furthermore, complete
reported method.[21] Propanamide 10 was prepared from 8 purification of 15a–15d (corresponding to 21) was easily
and propionyl chloride with pyridine (Py). O-Benzylethano- carried out just prior to the formation of the final product
lamine (11a) was converted into 13a by reaction with suc- 23. However, if 5 contains sensitive functional groups such
cinic anhydride in pyridine. Carboxylic acid 13a was con- as a benzylic ether, a benzylic amine, an unsaturated bond,
verted into 14a by using N-hydroxysuccinimide (HOSu), 1- or an S–S bond, an alternative method for the synthesis of
[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochlo- 23 from 5 must be developed. Although replacement of the
ride (EDC), and triethylamine (Et3N) in THF (reaction C). benzyl protecting group with a different type of protecting
Amide 15a was obtained from the condensation reaction group is a practical way of solving this problem, a judicious
between 14a and 8 in THF. Reductive debenzylation of ben- choice of protecting group may often be made to suit each
zyl ether 15a in the presence of a catalytic amount of palla- occasion.
dium hydroxide (10% on carbon) [Pd(OH)2/C] in methanol
Hence, we also examined the one-step pathway (iv) from
under hydrogen afforded 16. Diol 17 and 18 were obtained 5 to 23, as shown in the lower part of Scheme 3. Once 22
starting from 11b (= 6B)[13] and 11c (= 7B),[9] respectively, has been independently prepared in advance by step (iii),
in the same manner. A condensation reaction between N- the final target 23 can be obtained from 5 in one step. As
tert-butyloxycarbonylated
iminodiacetic
acid
[Boc- a representative example, we demonstrated the synthesis of
N(CH2CO2H)2][8c] and 7B (= 11c)[9] was carried out with 19 (corresponding to 23) starting from 14d (corresponding
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexaflu- to 22) (Scheme 4): the four benzyl groups of 14d were
orophosphate (PyBOP) and N,N-diisopropylethylamine deprotected in the presence of a catalytic amount of
(DIEA) to afford octabenzyl ether[22] 12d. Deprotection of Pd(OH)2/C in ethanol under hydrogen at room temperature
Boc in 12d was carried out with trifluoroacetic acid (TFA) to afford 24 in quantitative yield. Note that the N–O bond
in dichloromethane (CH2Cl2) followed by the removal of of the OSu moiety was not affected at all. A condensation
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Eur. J. Org. Chem. 2007, 3003–3011

Water-Solubilizing Properties of Branched Oligoglycerols
FULL PAPER
Scheme 2.
Scheme 3. Two pathways for the BGL modification of 5.
Eur. J. Org. Chem. 2007, 3003–3011
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H. Nemoto, T. Araki, M. Kamiya, T. Kawamura, T. Hino
FULL PAPER
reaction between 8 and 24 afforded 19 in excellent yield. diluted with water to prepare solutions of appropriate con-
Accordingly, either one- or two-step BGL modification can centration for the measurement of ultraviolet spectra. The
be chosen depending on the situation.
partition coefficients of 10 and 16–19 were calculated based
on the strength of the 256 nm signal of the dilute solutions.
Broadly speaking, water solubility was found to increase
in a geometric progression according to the number of hy-
droxy groups. Tetrahydroxylated derivative 18 was approxi-
mately 5000 times more water-soluble than the control com-
pound 10 and the water solubility of the octahydroxylated
derivative 19 was at least half a million times greater than
that of 10. Note that the water solubility of neutral mole-
cules such as 18 and 19 is greater than that of the ionic
compound 9. Accordingly, it was concluded that the level
of water solubility is influenced by the number of primary
hydroxy groups in the BGL moiety. Furthermore, the ob-
served partition coefficients indicate that BGL modification
never causes complete loss of lipophilicity in these sub-
strates but instead results in amphiphilicity.
Scheme 4.
Measurement of Water-Solubilizing Properties and
Partition Coefficients
Each compound (9, 10, and 16–19) was placed in an ap-
propriate amount of water and the mixture was shaken well Conclusion
for half an hour. The resulting suspension was allowed to
Measurement of the water solubility of the representative
stand for half an hour and then filtered using a membrane
filter (pore size 0.45 µ) to remove excess solute, including
invisible tiny grains and any micelles that may have formed.
Each filtrate, which consisted of a saturated solution, was
diluted with water to prepare a solution of appropriate con-
centration for measuring the strength of ultraviolet absorp-
tion at 256 nm by the benzamide moiety. In the case of 19,
a saturated solution was not prepared because 19 was found
to be too soluble in water. Instead, a solution of 19 that
was approximately one hundred times more concentrated
than a saturated solution of 18 was prepared. The water
solubilities of 9, 10, and 16–19, calculated based on the
strength of the 256 nm signal obtained with the dilute solu-
tions, are listed in Table 1.
BGL derivatives indicates that the BGL family exhibits
high-performance water solubilization despite having small
numbers of glycerol units. Accordingly, BGL modification
is shown to be an efficient method for converting water-
insoluble compounds into water-soluble ones. In addition,
based on the measured partition coefficients, it seems that
BGL modification, rather than removing the lipophilicity
of the original compound, results in amphiphilicity, so that
BGL derivatives may be well suited to membrane permea-
tion. In conclusion, the values reported herein will be useful
for regulating the water solubility and partition coefficients
of target molecules based on the use of available BGL
modification agents.
Table 1. Water solubilities and partition coefficients of BGL deriva-
tives and related compounds.
Experimental Section
Com-
Number Number of Water solu- Partition coef-
pound
of OH
groups
glycerol
units
bility
ficient (1-oc-
tanol/water)
General Experimental Methods: Melting points were determined
using a Yanagimoto Micro melting point apparatus and are uncor-
rected. IR spectra were recorded with a Perkin-Elmer 1720 or Jasco
FT-IR/420 spectrometer with data listed in cm–1. 1H and 13C NMR
spectra were measured with a JEOL JMN-AL300 spectrometer at
300 and 75 MHz or a JEOL AL-400 spectrometer at 400 and
100 MHz, respectively, in [D]chloroform and chemical shifts are
given as the δ value in ppm measured relative to the internal tet-
ramethylsilane standard at 25 °C unless otherwise noted. High-res-
olution mass spectra (HRMS) were measured with a JEOL JMS-
DX303 spectrometer. UV spectra were measured with a Hitachi U-
3310 spectrometer. Methanol was distilled from magnesium meth-
oxide. Pyridine (Py), N,N-diisopropylethylamine (DIEA), and tri-
ethylamine (Et3N) were distilled from potassium hydroxide. Dichlo-
romethane (CH2Cl2) was distilled from phosphorus pentaoxide.
Anhydrous tetrahydrofuran (THF) was purchased from Kanto
Chemicals. N,N-Dimethylformamide (DMF) was distilled from
[molL–1]
9
salt
0
1
2
4
0
0
2.5ϫ10–2
7.7ϫ10–5
3.0ϫ10–4
6.5ϫ10–3
2.1ϫ10–2
Ͼ 3.3ϫ101
–
10
16
17
18
19
54.05
4.44
3.57
0[a]
1
3
6
2.01
8
Ͻ 10–5
[a] Compound 16 contains one ethylene glycol unit instead of glyc-
erol.
The partition coefficients of 10 and 16–19 were also mea-
sured. Each compound (1.0 mmol) was dissolved in water/
octanol (5 mL/5 mL), the mixture was shaken for 30 min,
and then allowed to stand for 30 min. The aqueous layers
were treated with a centrifugal separator to remove tiny
drops of organic solvent and the aqueous solutions were barium oxide at 20 Torr.
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Water-Solubilizing Properties of Branched Oligoglycerols
FULL PAPER
N-[8-(Phenylcarbonylamino)octyl]propanamide (10): Propionyl chlo-
ride (0.34 mL, 3.86 mmol) and Py (0.57 mL, 7.02 mmol) were
added to a solution of 8 (1.0 g, 3.51 mmol) in CH2Cl2 (50 mL) at
0 °C. The mixture was stirred at room temperature for 4 h, poured
into HCl (aq) (1 , 50 mL), and extracted with CH2Cl2
(50 mLϫ3). The combined organic layers were washed with a satu-
rated aqueous solution of sodium hydrogen carbonate [NaHCO3
(aq)] and then brine, dried with anhydrous magnesium sulfate
(MgSO4), and concentrated in vacuo. The residue was purified by
silica gel column chromatography (eluted with ethyl acetate) to af-
ford 10 as a colorless solid (662.3 mg, 2.18 mmol, 62% yield); m.p.
3-{N-[2-{2-(Phenylmethoxy)-1-[(phenylmethoxy)methyl]ethoxy}-1-
({2-(phenylmethoxy)-1-[(phenylmethoxy)methyl]ethoxy}methyl)-
ethyl]carbamoyl}propanoic Acid (13c): Yield from 11c: 699.3 mg,
1.00 mmol, 100%. A colorless oil. FTIR (neat): ν = 3324, 3062,
˜
3031, 2867, 1784, 1732, 1540, 1454, 1206, 1095, 907, 739, 698 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 7.36–7.25 (m, 20 H, 4ϫC6H5-
15), 6.82 (d, J = 8.0 Hz, 1 H, NH-11), 4.50 (s, 4 H, 2ϫCH2-14),
4.50 (s, 4 H, 2ϫCH2-14), 4.16–4.09 (m, 1 H, CH-12), 3.82–3.50
(m, 14 H, 2ϫCH2-13, 2ϫCH-16, 4ϫCH2-17), 2.44 (t, J = 6.5 Hz,
2 H, CH2-9), 2.06 (t, J = 6.5 Hz, 2 H, CH2-10) ppm; COOH signal
not clearly observed. 13C NMR (CDCl3, 75 MHz): δ = 175.3 (C),
172.0 (C), 137.9 (2 ϫ C), 137.7 (2 ϫ C), 128.2 (4 ϫ CH), 128.2
(4ϫCH), 127.7 (4ϫCH), 127.6 (4ϫCH), 127.5 (2ϫCH), 127.4
95–96 °C (recrystallized from hexane/ethyl acetate). FTIR (KBr): ν
˜
= 3313, 3057, 2935, 2851, 1632, 1538, 1466, 692, 1313, 924,
1
715 cm–1. H NMR (CDCl3, 400 MHz): δ = 7.77 (d, J = 7.5 Hz, 2 (2 ϫ CH), 78.9 (2 ϫ CH), 73.4 (2 ϫ CH2), 73.2 (2 ϫ CH2), 70.5
H, 2ϫCH-3), 7.49 (t, J = 7.5 Hz, 1 H, CH-1), 7.42 (t, J = 7.5 Hz,
2 H, 2ϫCH-2), 6.38 (br., 1 H, NH-4), 5.71 (br., 1 H, NH-8), 3.44
(2ϫCH2), 69.9 (2ϫCH2), 68.4 (2ϫCH2), 49.6 (CH), 30.1 (CH2),
30.0 (CH2) ppm. FAB-MS: m/z = 700 [M + H]+. FAB-HRMS:
(q, J = 7.0 Hz, 2 H, CH2-5), 3.22 (q, J = 7.0 Hz, 2 H, CH2-7), 2.19 calcd. for C41H50NO9 [M + H]+ 700.3486; found 700.3468.
(q, J = 7.5 Hz, 2 H, CH2-9), 1.68–1.29 [m, 12 H, (CH2)6-6], 1.15
(t, J = 7.5 Hz, 3 H, CH3-10) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 174.0 (C), 167.6 (C), 134.8 (C), 131.3 (CH), 128.5 (2ϫCH), 126.9
2-[(tert-Butoxy)-N-({N-[2-{2-(phenylmethoxy)-1-[(phenylmethoxy)-
methyl]ethoxy}-1-({2-(phenylmethoxy)-1-[(phenylmethoxy)-
(2ϫCH), 40.0 (CH2), 39.5 (CH2), 29.7 (CH2), 29.6 (CH2), 29.5
methyl]ethoxy}methyl)ethyl]carbamoyl}methyl)carbonylamino]-N-[2-
(CH2), 29.0 (CH2), 29.0 (CH2), 26.8 (CH2), 26.7 (CH2), 10.0 (CH3)
{2-(phenylmethoxy)-1-[(phenylmethoxy)methyl]ethoxy}-1-({2-(phen-
ylmethoxy)-1-[(phenylmethoxy)methyl]ethoxy}methyl)ethyl]acet-
amide (12d): PyBop (15.6 g, 30.01 mmol) was added to a mixture
ppm. EI-MS: m/z = 304 [M]+. EI-HRMS: calcd. for C18H28N2O2
[M]+ 304.2151; found 304.2157.
of BocN(CH2 CO2 H)2 (3.50 g, 15.01 mmol), 7B (19.8 g,
General Procedure for the Reaction of Amines 11a–11c with Succinic
33.02 mmol), and DIEA (10.46 mL, 60.03 mmol) in DMF (50 mL)
Anhydride: Succinic anhydride (150.1 mg, 1.5 mmol) was added in
at room temperature. The mixture was stirred at room temperature
portions to a solution of an amine 11 (1.0 mmol) in Py (2.0 mL) at
for 3 h, poured into potassium hydrogen sulfate (5% aqueous solu-
0 °C. The resulting mixture was stirred at 100 °C for 3–4 h, cooled
tion, 100 mL), and extracted with ethyl acetate (3ϫ100 mL). The
to room temperature, poured into HCl (aq), and extracted with
combined organic layers were washed with NaHCO3 (aq) and then
CH2Cl2 (3ϫ20 mL). The combined organic layers were washed
brine, dried with MgSO4, and concentrated in vacuo. The residue
with brine, dried with MgSO4, and concentrated in vacuo. The resi-
was purified by silica gel column chromatography (eluted with hex-
due was purified by silica gel column chromatography (eluted with
ane/ethyl acetate, 3:2) to afford 12d as a colorless oil (18.66 g,
hexane/ethyl acetate, 1:3) to afford the carboxylic acid.
13.36 mmol, 89% yield). FTIR (neat): ν = 3031, 2866, 1702, 698,
˜
1668, 1454, 1252, 1098, 737 cm–1. H NMR (CDCl3, 400 MHz): δ
1
3-{N-[2-(Phenylmethoxy)ethyl]carbamoyl}propanoic Acid (13a):
Yield from 11a: 203.6 mg, 0.81 mmol, 81%. A colorless solid; m.p.
= 7.83 (d, J = 8.0 Hz, 1 H, one of NH-11), 7.31–7.19 (m, 41 H,
8ϫC6H5-15, one of NH-11), 4.48 (s, 16 H, 8ϫCH2-14), 4.19–4.08
(m, 2 H, 2ϫCH-12), 3.81–3.40 (m, 32 H, 4ϫCH2-13, 4ϫCH-16,
8 ϫ CH2-17, 2 ϫ CH2-18), 1.36 (s, 9 H, Boc) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 169.4 (C), 169.2 (C), 154.9 (C), 138.3
(2ϫC), 138.3 (4ϫC), 138.2 (2ϫC), 128.3, 127.8, 127.7, 127.6, and
127.5 (40 ϫ CH), 80.9 (C), 79.0 (2 ϫ CH), 78.8 (2 ϫ CH), 73.4
(2ϫCH2), 73.4 (2 ϫCH2), 73.3 (4 ϫCH2), 70.4 (2 ϫCH2), 70.3
(2ϫCH2), 70.1 (2 ϫCH2), 70.0 (2 ϫCH2), 68.6 (2 ϫCH2), 68.5
(2 ϫ CH2), 53.2 (CH2), 52.4 (CH2), 49.6 (CH), 49.6 (CH), 28.2
(3 ϫ CH3) ppm. FAB-MS: m/z = 1396 [M + H]+. FAB-HRMS:
calcd. for C83H102N3O16 [M + H]+ 1396.7260; found 1396.7271.
75–76 °C (recrystallized from hexane/ethyl acetate). FTIR (KBr): ν
˜
= 3302, 3079, 2877, 1709, 1554, 1430, 1207, 1134, 918, 741,
698 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.42–7.31 (m, 5 H,
C6H5-15), 6.20 (t, J = 5.0 Hz, 1 H, NH-11), 4.54 (s, 2 H, CH2-14),
3.59 (t, J = 5.0 Hz, 2 H, CH2-12), 3.49 (t, J = 5.0 Hz, 2 H, CH2-
13), 2.69 (t, J = 7.0 Hz, 2 H, CH2-9), 2.51 (t, J = 7.0 Hz, 2 H, CH2-
10) ppm; COOH signal not clearly observed. 13C NMR (CDCl3,
75 MHz): δ = 175.8 (C), 172.5 (C), 137.4 (C), 128.1 (2ϫCH), 127.5
(2ϫCH), 127.5 (CH), 72.6 (CH2), 68.2 (CH2), 39.1 (CH2), 30.2
(CH2), 29.2 (CH2) ppm. EI-MS: m/z = 251 [M]+. EI-HRMS: calcd.
for C13H17NO4 251.1158; found 251.1210.
3-(N-{2-(Phenylmethoxy)-1-[(phenylmethoxy)methyl]ethyl}-
3-[N,N-Bis({N-[2-{2-(phenylmethoxy)-1-[(phenylmethoxy)-
carbamoyl)propanoic Acid (13b): Yield from 11b: 274.8 mg, methyl]ethoxy}-1-({2-(phenylmethoxy)-1-[(phenylmethoxy)-
0.74 mmol, 74%. A colorless solid; m.p. 93–95 °C (recrystallized methyl]ethoxy}methyl)ethyl]carbamoyl}methyl)carbamoyl]propanoic
from hexane/ethyl acetate). FTIR (KBr): ν = 3307, 3062, 2858, Acid (13d): Trifluoroacetic acid (5 mL) was added to a solution of
˜
1
1728, 1644, 1544, 1453, 1204, 1107, 831, 751, 700 cm–1. H NMR
(CDCl3, 400 MHz): δ = 7.37–7.25 (m, 10 H, 2ϫC6H5-15), 6.09 (d, The mixture was stirred at room temperature for 20 h, poured into
J = 8.0 Hz, 1 H, NH-11), 4.50 (s, 4 H, 2ϫCH2-14), 4.32–4.25 (m, NaHCO3 (aq), and extracted with CH2Cl2 (3ϫ50 mL). The com-
1 H, CH-12), 3.64 (dd, J = 14.5, 4.0 Hz, 2 H, 2ϫone of CH2-13), bined organic layers were dried with MgSO4 and concentrated in
12d (2.0 g, 1.43 mmol) in CH2Cl2 (45 mL) at room temperature.
3.54 (dd, J = 14.5, 5.5 Hz, 2 H, 2ϫone of CH2-13), 2.57 (t, J =
7.0 Hz, 2 H, CH2-9), 2.49 (t, J = 7.0 Hz, 2 H, CH2-10) ppm; COOH
signal not clearly observed. 13C NMR (CDCl3, 75 MHz): δ = 175.8
(C), 171.6 (C), 137.7 (2ϫC), 128.3 (4ϫCH), 127.6 (4ϫCH), 127.6
(2ϫCH), 73.1 (2ϫCH2), 68.3 (2ϫCH2), 48.7 (CH), 30.6 (CH2),
vacuo. The residue, a crude amine (1.85 g, 1.43 mmol, 100% yield),
was used in the next step without further purification. Succinic
anhydride (286 mg, 2.85 mmol) was added portionwise a solution
of the crude amine in Py (2.5 mL) and the mixture was stirred at
100 °C for 1.5 h. After being cooled to 0 °C, the resulting mixture
29.6 (CH2) ppm. EI-MS: m/z = 371 [M]+. EI-HRMS: calcd. for was poured into HCl (aq) (2 , 20 mL), extracted with CH2Cl2
C21H25NO5 371.1733; found 371.1744.
(3ϫ30 mL), washed with brine, dried with MgSO4, and concen-
Eur. J. Org. Chem. 2007, 3003–3011
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H. Nemoto, T. Araki, M. Kamiya, T. Kawamura, T. Hino
FULL PAPER
trated in vacuo. The residue was purified by silica gel column
chromatography (eluted with hexane/ethyl acetate, 1:3) to afford
13d as a pale yellow liquid (2.00 g, 1.43 mmol, 100% yield). FTIR
2,5-Dioxopyrrolidinyl 3-{N-[2-{2-(Phenylmethoxy)-1-[(phenylmeth-
oxy)methyl]ethoxy}-1-({2-(phenylmethoxy)-1-[(phenylmethoxy)-
methyl]ethoxy}methyl)ethyl]carbamoyl}propanoate (14c): Yield from
(neat): ν = 3220, 3030, 2866, 1729, 1664, 1544, 1454, 1366, 1098, 13c: 613.6 mg, 0.77 mmol, 77%. A colorless oil. FTIR (neat): ν =
˜
˜
739, 698 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.84 (d, J =
3337, 3062, 3030, 2919, 1815, 1784, 1739, 1673, 1528, 1454, 1366,
1
8.0 Hz, 1 H, one of NH-11), 7.31–7.19 (m, 40 H, 8ϫC6H5-15), 6.83
(d, J = 8.0 Hz, 1 H, one of NH-11), 4.46 (s, 16 H, 8ϫCH2-14),
4.21–4.09 (m, 2 H, 2ϫCH-12), 3.76–3.45 (m, 32 H, 4ϫCH2-13,
4ϫCH-16, 8ϫCH2-17, 2ϫCH2-18), 2.60–2.54 (m, 2 H, CH2-9),
1092, 742, 699 cm–1. H NMR (CDCl3, 400 MHz): δ = 7.35–7.27
(m, 20 H, 4ϫC6H5-15), 6.68 (d, J = 8.5 Hz, 1 H, NH-11), 4.51 (s,
4 H, 2ϫCH2-14), 4.50 (s, 4 H, 2ϫCH2-14), 4.17–4.09 (m, 1 H,
CH-12), 3.82–3.51 (m, 14 H, 2ϫCH2-13, 2ϫCH-16, 4ϫCH2-17),
2.41–2.35 (m, 2 H, CH2-10) ppm; COOH signal not clearly ob- 2.78 (t, J = 7.0 Hz, 2 H, CH2-9), 2.77 (s, 4 H, 2ϫCH2-19), 2.12 (t,
served. 13C NMR (CDCl3, 75 MHz): δ = 174.8 (C), 173.8 (C), 169.1
(C), 168.7 (C), 138.8 (2ϫC), 138.7 (4ϫC), 138.7 (2ϫC), 129.0,
129.0, 128.5, 128.4, 128.4, 128.3, 128.3, and 128.2 (40ϫCH), 79.5
(2 ϫ CH), 79.2 (2 ϫ CH), 74.1 (2 ϫ CH2), 73.9 (2 ϫ CH2), 73.9
(4ϫCH2), 71.0 (2 ϫCH2), 70.8 (2 ϫCH2), 70.5 (4 ϫCH2), 69.2
J = 7.0 Hz, 2 H, CH2-10) ppm. 13C NMR (CDCl3, 75 MHz): δ =
169.2 (C), 168.7 (2ϫC), 167.8 (C), 138.0 (2ϫC), 137.8 (2ϫC),
128.3 (4ϫCH), 128.2 (4ϫCH), 127.7 (4ϫCH), 127.6 (4ϫCH),
127.4 (4ϫCH), 79.0 (2ϫCH), 73.4 (2ϫCH2), 73.3 (2ϫCH2), 70.6
(2ϫCH2), 70.0 (2ϫCH2), 68.5 (2ϫCH2), 49.4 (CH), 29.8 (CH2),
(2ϫCH2), 69.0 (2ϫCH2), 54.0 (CH2), 52.7 (CH2), 50.5 (CH), 50.2 26.5 (CH2), 25.0 (2ϫCH2) ppm. FAB-MS: m/z = 797 [M – H]+.
(CH), 30.2 (CH2), 28.4 (CH2) ppm. FAB-MS: m/z = 1396 [M + FAB-HRMS: calcd. for C45H53N2O11 [M – H]+ 797.3649; found
H]+. FAB-HRMS: calcd. for C82H98N3O17 [M + H]+ 1396.7022; 797.3641.
found 1396.6886.
2,5-Dioxopyrrolidinyl 3-[N,N-Bis({N-[2-{2-(phenylmethoxy)-1-
[(phenylmethoxy)methyl]ethoxy}-1-({2-(phenylmethoxy)-1-[(phenyl-
methoxy)methyl]ethoxy}methyl)ethyl]carbamoyl}methyl)carbamoyl]-
propanoate (14d): Yield from 13d: 1150.2 mg, 0.79 mmol, 79%. A
General Procedure for the Preparation of Su Ester: HOSu
(126.6 mg, 1.1 mmol), EDC (412.7 mg, 2.0 mmol), and Et3N
(0.11 mL, 0.8 mmol) were added to a solution of acid 13
colorless oil. FTIR (neat): ν = 3258, 3030, 1740, 1657, 1544, 1454,
˜
(1.0 mmol) in anhydrous tetrahydrofuran (45 mL). The resulting
mixture was stirred for 1.5–3.5 h at reflux, cooled to room tempera-
ture, poured into an aqueous solution of potassium hydrogen sul-
fate [KHSO4 (aq)] (5 %, 30 mL), and extracted with CH2Cl2
(3 ϫ 30 mL). The combined organic layers were washed with
NaHCO3 (aq) and then brine, dried with MgSO4, and concentrated
in vacuo. The residue was purified by silica gel column chromatog-
raphy (eluted with hexane/ethyl acetate, 1:10) to afford N-hydroxy-
succinimide ester.
1
1366, 1096, 739, 698 cm–1. H NMR (CDCl3, 400 MHz): δ = 8.44
(d, J = 8.0 Hz, 1 H, one of NH-11), 7.31–7.19 (m, 40 H, 8ϫC6H5-
15), 6.95 (d, J = 8.0 Hz, 1 H, one of NH-11), 4.49 (s, 8 H, 4ϫCH2-
14), 4.48 (s, 8 H, 4ϫCH2-14), 4.22–4.11 (m, 2 H, 2ϫCH-12), 3.78–
3.40 (m, 32 H, 4ϫCH2-13, 4ϫCH-16, 8ϫCH2-17, 2ϫCH2-18),
2.78 (t, J = 7.0 Hz, 2 H, CH2-9), 2.67 (s, 4 H, 2ϫCH2-19), 2.48 (t,
J = 7.0 Hz, 2 H, CH2-10) ppm. 13C NMR (CDCl3, 75 MHz): δ =
171.8 (C), 169.5 (2 ϫ C), 169.3 (C), 168.9 (C), 168.6 (C), 139.0
(2ϫC), 138.9 (2ϫC), 138.9 (2ϫC), 138.8 (2ϫC), 129.0, 129.0,
128.7, 128.4, 128.3, 128.2, 128.2, and 128.2 (40 ϫ CH), 79.7
(2 ϫ CH), 79.3 (2 ϫ CH), 74.1 (2 ϫ CH), 74.0 (2 ϫ CH2), 73.9
(4ϫCH2), 71.1 (2 ϫCH2), 70.9 (2 ϫCH2), 70.7 (2 ϫCH2), 70.6
(2ϫCH2), 69.5 (2ϫCH2), 69.0 (2ϫCH2), 54.1 (CH2), 53.0 (CH2),
50.6 (CH), 50.1 (CH), 27.9 (CH2), 26.9 (CH2), 26.1 (2ϫCH2) ppm.
FAB-MS: m/z = 1493 [M + H]+. FAB-HRMS: calcd. for
C86H101N4O19 [M + H]+ 1493.7060; found 1493.7081.
2,5-Dioxopyrrolidinyl 3-{N-[2-(Phenylmethoxy)ethyl]-
carbamoyl}propanoate (14a): Yield from 13a: 216.0 mg, 0.62 mmol,
62%. A colorless oil. FTIR (neat): ν = 3583, 3390, 1814, 1783,
˜
1
1736, 1654, 1543, 1369, 1208, 1073, 747, 700, 665 cm–1. H NMR
(CDCl3, 400 MHz): δ = 7.42–7.31 (m, 5 H, C6H5-15), 6.25–6.13
(m, 1 H, NH-11), 4.55 (s, 2 H, CH2-14), 3.59 (t, J = 6.5 Hz, 2 H,
CH2-12), 3.49 (t, J = 6.5 Hz, 2 H, CH2-13), 3.19 (t, J = 9.5 Hz, 2
H, CH2-9), 2.87 (s, 4 H, 2ϫCH2-19), 2.61 (t, J = 9.5 Hz, 2 H, CH2-
10) ppm. 13C NMR (CDCl3, 75 MHz): δ = 170.1 (2ϫC), 169.1 (C),
168.2 (C), 137.8 (C), 128.5 (2ϫCH), 127.9 (2ϫCH), 127.9 (CH),
73.2 (CH2), 68.9 (CH2), 39.5 (CH2), 30.6 (CH2), 26.8 (CH2), 25.5
(2ϫCH2) ppm. EI-MS: m/z = 349 [M + H]+. EI-HRMS: calcd. for
C17H20N2O6 [M]+ 348.1321; found 348.1327.
General Procedure for Amide-Bond-Formation Reactions with 8:
Amine 8 (284.8 mg, 1.0 mmol) and Et3N (0.14 mL, 1.0 mmol) were
added to a solution of N-hydroxysuccinimide ester 14 (1.0 mmol)
in THF (20 mL). The mixture was stirred at room temperature for
3–6 h, poured into KHSO4 (aq) (5%, 30 mL), and extracted with
chloroform (3ϫ30 mL). The combined organic layers were washed
with NaHCO3 (aq) and then brine, dried with MgSO4, and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (eluted with chloroform/methanol, 20:1) to afford
N-benzoyl-NЈ-acylated 1,8-octamethylenediamine.
2,5-Dioxopyrrolidinyl 3-(N-{2-(Phenylmethoxy)-1-[(phenylmethoxy)-
methyl]ethyl}carbamoyl)propanoate (14b): Yield from 13b:
346.7 mg, 0.74 mmol, 74 %. A colorless crystal; m.p. 75–76 °C
(recrystallized from hexane/ethyl acetate). FTIR (KBr): ν = 3252,
˜
3079, 2945, 2909, 2868, 1818, 1784, 1732, 1651, 1557, 1384, 1211,
NЈ-[8-(Phenylcarbonylamino)octyl]-N-[2-(phenylmethoxy)ethyl]bu-
1104, 1075, 740, 698 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.39– tane-1,4-diamide (15a): Yield from 14a: 303.4 mg, 0.63 mmol, 63%.
7.25 (m, 10 H, 2ϫC6H5-15), 5.95 (d, J = 8.5 Hz, 1 H, NH-11),
4.51 (s, 4 H, 2ϫCH2-14), 4.34–4.27 (m, 1 H, CH-12), 3.64 (dd, J
= 9.5, 4.0 Hz, 2 H, 2ϫone of CH2-13), 3.54 (dd, J = 9.5, 6.0 Hz,
2 H, 2ϫone of CH2-13), 2.98 (t, J = 7.0 Hz, 2 H, CH2-9), 2.79 (s,
4 H, 2ϫCH2-19), 2.59 (t, J = 7.0 Hz, 2 H, CH2-10) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 169.3 (C), 168.7 (2ϫC), 167.9 (C), 137.9
(2 ϫ C), 128.2 (4 ϫ CH), 127.6 (4 ϫ CH), 127.5 (2 ϫ CH), 73.1
(2ϫCH2), 68.3 (2ϫCH2), 48.6 (CH), 30.7 (2ϫCH2), 26.7 (CH2),
25.5 (2ϫCH2) ppm. EI-MS: m/z = 467 [M – H]+. EI-HRMS: calcd.
for C25H28N2O7 [M]+ 468.1897; found 468.1918.
A colorless solid; m.p. 147–148 °C (recrystallized from hexane/
chloroform). FTIR (KBr): ν = 3313, 3060, 2922, 2854, 1627, 1539,
˜
1334, 1215, 1104, 1028, 997, 729, 694 cm–1 1H NMR (CDCl3/
.
CD3OD = 1:1, 400 MHz): δ = 8.07 (t, J = 5.5 Hz, 1 H, NH), 7.83–
7.26 (m, 10 H, CH-1, 2ϫCH-2, 2ϫCH-3, C6H5-15), 7.76 (t, J =
5.0 Hz, 1 H, NH), 7.69 (t, J = 5.0 Hz, 1 H, NH), 4.53 (s, 2 H, CH2-
14), 3.56 (t, J = 5.5 Hz, 2 H, CH2-12), 3.45–3.35 (m, 4 H, CH2-13,
CH2-5), 3.16 (dt, J = 7.0, 5.5 Hz, 2 H, CH2-7), 2.48 (t, J = 6.0 Hz,
2 H, CH2-10), 2.45 (t, J = 6.0 Hz, 2 H, CH2-9), 1.63 (quint, J =
7.0 Hz, 2 H, CH2-6), 1.49 (quint, J = 7.0 Hz, 2 H, CH2-6), 1.43–
3008
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3003–3011

Water-Solubilizing Properties of Branched Oligoglycerols
FULL PAPER
1.27 (m, 8 H, 4ϫCH2-6) ppm. 13C NMR (CDCl3/CD3OD, 10:1,
4.0 (m, 2 H, 2ϫCH-12), 3.80–3.40 (m, 34 H, CH2-5, 4ϫCH2-13,
75 MHz): δ = 172.9 (C), 172.7 (C), 168.1 (C), 137.8 (C), 134.7 (C), 4 ϫ CH-16, 8 ϫ CH2-17, 2 ϫ CH2-18), 3.10 (q, J = 6.5 Hz, 2 H,
131.5 (CH), 128.6 (2ϫCH), 128.5 (2ϫCH), 127.9 (2ϫCH), 127.9
(2ϫCH), 126.9 (CH), 73.2 (CH2), 68.7 (CH2), 40.0 (CH2), 39.5
CH2-7), 2.45 (t, J = 6.5 Hz, 2 H, CH2-9), 2.30 (t, J = 6.5 Hz, 2 H,
CH2-10), 1.68–1.23 (m, 12 H, 6ϫCH2-6) ppm. 13C NMR (CDCl3,
(CH2), 39.4 (CH2), 31.8 (CH2), 31.7 (CH2), 29.5 (CH2), 29.2 (CH2), 75 MHz): δ = 173.1 (C), 171.7 (C), 168.5 (C), 168.0 (C), 167.3 (C),
29.1 (CH2), 29.0 (CH2), 26.8 (CH2), 26.7 (CH2) ppm. EI-MS: m/z = 138.1 (2ϫC), 138.0 (4ϫC), 137.9 (2ϫC), 134.7 (C), 131.1 (CH),
481 [M]+. EI-HRMS: calcd. for C28H39N3O4 [M]+ 481.2941; found
481.2934.
128.3, 128.2, 128.2, 127.6, 127.6, 127.5, 127.5, 127.5, 127.4, 127.4,
and 126.7 (44ϫCH), 78.9 (2ϫCH), 78.8 (2ϫCH), 73.3 (2ϫCH2),
73.3 (2ϫCH2), 73.2 (4ϫCH2), 70.3 (2ϫCH2), 70.2 (2ϫCH2), 69.9
(2ϫCH2), 69.9 (2 ϫCH2), 68.8 (2 ϫCH2), 68.3 (2 ϫCH2), 53.4
(CH2), 52.3 (CH2), 49.9 (CH), 49.6 (CH), 40.0 (CH2), 39.4 (CH2),
31.1 (CH2), 29.5 (CH2), 29.4 (CH2), 29.1 (CH2), 29.0 (CH2), 28.2
(CH2), 26.8 (CH2), 26.7 (CH2) ppm. TOF-HRMS: calcd. for
C97H119N5NaO17 [M + Na]+ 1648.8493; found 1648.8534.
NЈ-[8-(Phenylcarbonylamino)octyl]-N-{2-(phenylmethoxy)-1-[(phen-
ylmethoxy)methyl]ethyl}butane-1,4-diamide (15b): Yield from 14b:
463.4 mg, 0.77 mmol, 77 %. A colorless solid; m.p. 110–112 °C
(recrystallized from hexane/chloroform). FTIR (KBr): ν = 3320,
˜
3060, 2931, 2860, 1643, 1542, 1475, 1453, 1204, 1104, 1028, 734,
696 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.78–7.27 (m, 15 H,
CH-1, 2ϫCH-2, 2ϫCH-3, 2ϫC6H5-15), 6.20–5.95 (m, 3 H, NH-
4, NH-8, NH-11), 4.50 (s, 4 H, 2ϫCH2-14), 4.32–4.24 (m, 1 H,
CH-12), 3.62 (dd, J = 9.8, 4.0 Hz, 2 H, 2ϫone of CH2-13), 3.51
(dd, J = 9.8, 6.0 Hz, 2 H, 2ϫone of CH2-13), 3.44 (q, J = 6.5 Hz,
2 H, CH2-5), 3.19 (q, J = 6.5 Hz, 2 H, CH2-7), 2.64–2.45 (m, 4 H,
CH2-9, CH2-10), 1.67–1.22 (m, 12 H, 6ϫCH2-6) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 172.1 (C), 172.0 (C), 167.6 (C), 137.8
(2ϫC), 134.6 (C), 131.2 (CH), 128.4 (2ϫ CH), 128.3 (6 ϫ CH),
127.6 (2ϫCH), 127.5 (2ϫCH), 126.7 (2ϫCH), 73.1 (2ϫCH2),
68.4 (2ϫCH2), 48.6 (CH), 40.0 (CH2), 39.5 (CH2), 31.9 (CH2),
31.8 (CH2), 29.5 (CH2), 29.3 (CH2), 29.0 (CH2), 29.0 (CH2), 26.8
(CH2), 26.6 (CH2) ppm. EI-MS: m/z = 601 [M]+. EI-HRMS: calcd.
for C36H47N3O5 [M]+ 601.3516; found 601.3497.
General Debenzylation Procedure: A solution of benzyl ether 15 (or
14d) (1.0 mmol) in ethanol (15 mL) in the presence of a catalytic
amount of palladium hydroxide/carbon (20 wt-% Pd, 30 mg) was
stirred at room temperature under hydrogen for 3–6 h. The re-
sulting suspension was filtered through Celite 535 and the filtrate
was concentrated in vacuo to give the desired debenzylated prod-
uct.
N-(2-Hydroxyethyl)-NЈ-[8-(phenylcarbonylamino)octyl]butane-1,4-di-
amide (16): Yield from 15a: 391.5 mg, 1.0 mmol, 100%. A colorless
solid; m.p. 161–163 °C (recrystallized from ethanol/diethyl ether).
FTIR (KBr): ν = 3317, 3056, 2937, 2849, 1623, 1539, 1462, 1315,
˜
1216, 1062, 715, 692 cm–1 1H NMR (CD3OD, 400 MHz): δ =
.
7.81–7.77 (m, 2 H, 2ϫCH-3), 7.53–7.41 (m, 3 H, 2ϫCH-2, CH-
1), 3.58 (t, J = 6.0 Hz, 2 H, CH2-12), 3.38 (t, J = 7.0 Hz, 2 H, CH2-
5), 3.30 (t, J = 6.0 Hz, 2 H, CH2-13), 3.16 (t, J = 7.0 Hz, 2 H, CH2-
7), 2.50–2.46 (m, 4 H, CH2-9, CH2-10), 1.62 (quint, J = 7.0 Hz, 2
H, CH2-6), 1.49 (quint, J = 7.0 Hz, 2 H, CH2-6), 1.41–1.28 (m, 8
H, 4ϫCH2-6) ppm. 13C NMR (CDCl3/CD3OD = 1:10, 75 MHz):
δ = 174.7 (C), 174.3 (C), 170.1 (C), 135.6 (C), 132.3 (CH), 129.3
(2ϫCH), 128.0 (2ϫCH), 61.4 (CH2), 42.8 (CH2), 40.9 (CH2), 40.3
(CH2), 32.2 (CH2), 32.1 (CH2), 30.3 (CH2), 30.2 (CH2), 30.2
(2ϫCH2), 27.8 (CH2), 27.7 (CH2) ppm. EI-MS: m/z = 391 [M]+.
EI-HRMS: calcd. for C21H33N3O4 [M]+ 391.2471; found 391.2449.
NЈ-[8-(Phenylcarbonylamino)octyl]-N-[2-{2-(phenylmethoxy)-1-
[(phenylmethoxy)methyl]ethoxy}-1-({2-(phenylmethoxy)-1-[(phenyl-
methoxy)methyl]ethoxy}methyl)ethyl]butane-1,4-diamide (15c):
Yield from 14c: 920.9 mg, 0.99 mmol, 99%. A colorless oil. FTIR
(neat): ν = 3312, 3062, 2927, 2858, 1644, 1542, 1453, 1099, 1028,
˜
1
738, 698 cm–1. H NMR (CDCl3, 400 MHz): δ = 7.79–7.28 (m, 25
H, CH-1, 2ϫCH-2, 2ϫCH-3, 4ϫC6H5-15), 6.73 (d, J = 8.0 Hz,
1 H, NH), 6.45–6.30 (m, 2 H, 2ϫNH), 4.50 (s, 4 H, 2ϫCH2-14),
4.45 (s, 4 H, 2ϫCH2-14), 4.15–4.07 (m, 1 H, CH-12), 3.84–3.65 (m,
4 H, 2ϫCH-16, 2ϫone of CH2-13), 3.65–3.52 (m, 10 H, 2ϫone of
CH2-13, 4ϫCH2-17), 3.42 (q, J = 6.5 Hz, 2 H, CH2-5), 3.15 (q, J
= 6.5 Hz, 2 H, CH2-7), 2.34 (t, J = 6.5 Hz, 2 H, CH2-10), 2.17 (t,
N-[2-Hydroxy-1-(hydroxymethyl)ethyl]-NЈ-[8-(phenylcarbonyl-
amino)octyl]butane-1,4-diamide (17): Yield from 15b: 421.5 mg,
1.0 mmol, 100%. A colorless solid; m.p. 170–171 °C (recrystallized
J = 6.5 Hz, 2 H, CH2-9), 1.68–1.23 (m, 12 H, 6ϫCH2-6) ppm. 13
C
NMR (CDCl3, 75 MHz): δ = 172.1 (C), 172.0 (C), 167.5 (C), 138.1
(2ϫC), 138.0 (2ϫC), 134.8 (C), 131.6 (CH), 128.4 (2ϫCH), 128.4
(4ϫCH), 128.3 (4ϫCH), 127.7 (4ϫCH), 127.7 (2ϫCH), 127.6
(2 ϫ CH), 127.6 (4 ϫ CH), 126.9 (2 ϫ CH), 79.0 (2 ϫ CH), 73.4
(2ϫCH2), 73.3 (2ϫCH2), 70.5 (CH2), 70.4 (CH2), 70.0 (CH2), 70.0
(CH2), 68.5 (2ϫCH2), 49.4 (CH), 40.0 (CH2), 39.4 (CH2), 31.7
(CH2), 31.4 (CH2), 29.5 (CH), 29.4 (CH2), 29.1 (CH2), 29.0 (CH2),
26.8 (CH2), 26.7 (CH2) ppm. FAB-MS: m/z = 931 [M + H]+. FAB-
HRMS: calcd. for C56H72N3O9 [M + H]+ 930.5269; found
930.5262.
from chloroform/diethyl ether). FTIR (KBr): ν = 3303, 3062, 2930,
˜
2852, 1631, 1543, 1469, 1220, 1073, 974, 668 cm–1 1H NMR
.
(CD3OD, 400 MHz): δ = 7.81–7.77 (m, 2 H, 2ϫCH-3), 7.53–7.41
(m, 3 H, CH-1, 2ϫCH-2), 3.90 (q, J = 5.5 Hz, 1 H, CH-12), 3.65–
3.55 (m, 4 H, 2ϫCH2-13), 3.38 (t, J = 7.0 Hz, 2 H, CH2-5), 3.16
(t, J = 7.0 Hz, 2 H, CH2-7), 2.52–2.46 (m, 4 H, CH2-9, CH2-10),
1.62 (quint, J = 7.0 Hz, 2 H, CH2-6), 1.49 (quint, J = 7.0 Hz, 2 H,
CH2-6), 1.41–1.28 (m, 8 H, 4ϫCH2-6) ppm. 13C NMR (CDCl3/
CD3OD = 3:7, 75 MHz): δ = 173.9 (C), 173.4 (C), 169.2 (C), 134.9
(C), 131.8 (CH), 128.8 (2ϫCH), 127.4 (2ϫCH), 61.6 (2ϫCH2),
53.3 (CH), 40.4 (CH2), 39.8 (CH2), 31.9 (CH2), 31.6 (CH2), 29.7
(CH2), 29.5 (3ϫCH2), 27.2 (CH2), 27.1 (CH2) ppm. EI-MS: m/z =
421 [M]+. EI-HRMS: calcd. for C22H35N3O5 [M]+ 421.2577; found
421.2573.
NЈ-[8-(Phenylcarbonylamino)octyl]-N,N-bis({N-[2-{2-(phenyl-
methoxy)-1-[(phenylmethoxy)methyl]ethoxy}-1-({2-(phenylmethoxy)-
1-[(phenylmethoxy)methyl]ethoxy}methyl)ethyl]carbamoyl}methyl)-
butane-1,4-diamide (15d): Yield from 14d: 1562 mg, 0.96 mmol,
96%. A colorless oil. FTIR (neat): ν = 3307, 3062, 3030, 2925,
N-(2-[2-Hydroxy-1-(hydroxymethyl)ethoxy]-1-{[2-hydroxy-1-(hy-
˜
1651, 1543, 1454, 1206, 1100, 1028, 739, 698 cm–1 1H NMR droxymethyl)ethoxy]methyl}ethyl)-NЈ-[8-(phenylcarbonylamino)oc-
.
(CDCl3, 400 MHz): δ = 8.29 (d, J = 8.0 Hz, 1 H, CONH), 7.77 (d,
J = 7.0 Hz, 2 H, 2ϫCH-3), 7.46 (t, J = 7.0 Hz, 1 H, CH-1), 7.40
(t, J = 7.0 Hz, 2 H, 2ϫCH-2), 7.41–7.35 (m, 40 H, 8ϫC6H5-15),
7.08 (d, J = 8.0 Hz, 1 H, NH), 6.36 (br., J = 5.0 Hz, 1 H, NH),
tyl]butane-1,4-diamide (18): Yield from 15c: 569.7 mg, 1.0 mmol,
100%. A colorless solid; m.p. 92–94 °C. FTIR (KBr): ν = 3321,
˜
2928, 2868, 1625, 1539, 1476, 1216, 1045, 926, 722, 693 cm–1. 1H
NMR (CD3OD, 400 MHz): δ = 7.84 (d, J = 7.0 Hz, 2 H, 2ϫCH-
5.97 (br. d, J = 5.0 Hz, 1 H, NH), 4.50 (s, 16 H, 8ϫCH2-14), 4.22– 3), 7.71 (t, J = 7.0 Hz, 1 H, CH-1), 7.62 (t, J = 7.0 Hz, 2 H, 2ϫCH-
Eur. J. Org. Chem. 2007, 3003–3011
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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H. Nemoto, T. Araki, M. Kamiya, T. Kawamura, T. Hino
FULL PAPER
2), 4.29–4.21 (m, 1 H, CH-12), 3.88–3.59 (m, 14 H, 2ϫCH-16,
2ϫCH2-13, 4ϫCH2-17), 3.49 (t, J = 6.0 Hz, 2 H, CH2-5), 3.23 (t,
J = 6.0 Hz, 2 H, CH2-7), 2.67–2.55 (m, 4 H, CH2-9, CH2-10), 1.72
(quint, J = 6.0 Hz, 2 H, CH2-6), 1.57 (quint, J = 6.0 Hz, 2 H,
CH2-6), 1.51–1.34 (m, 8 H, 4ϫCH2-6) ppm. 13C NMR (CD3OD,
75 MHz): δ = 174.5 (C), 174.3 (C), 169.9 (C), 135.7 (C), 132.4
(CH), 129.4 (2 ϫ CH), 128.1 (2 ϫ CH), 82.9 (2 ϫ CH), 69.5
(2ϫCH2), 62.4 (2ϫCH2), 62.3 (2ϫCH2), 51.0 (CH), 40.9 (CH2),
40.5 (CH2), 32.3 (CH2), 32.2 (CH2), 30.4 (2ϫCH2), 30.2 (2ϫCH2),
27.9 (CH2), 27.8 (CH2) ppm. FAB-MS: m/z = 570 [M + H]+. FAB-
HRMS: calcd. for C28H48N3O9 [M + H]+ 570.3391; found
570.3390.
[1]
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1360.
N,N-Bis{[N-(2-[2-hydroxy-1-(hydroxymethyl)ethoxy]-1-{[2-hydroxy-
1-(hydroxymethyl)ethoxy]methyl}ethyl)carbamoyl]methyl}-NЈ-[8-
(phenylcarbonylamino)octyl]butane-1,4-diamide (19): Yield from
15d: 1627.0 mg, 1.0 mmol, 100%. A pale yellow amorphous solid.
[2]
[3]
FTIR (neat): ν = 3307, 3086, 2930, 2878, 1644, 1554, 1468, 1216,
˜
1
1122, 1051, 697 cm–1. H NMR (CD3OD, 400 MHz): δ = 7.80 (d,
J = 7.0 Hz, 2 H, 2ϫCH-3), 7.52 (t, J = 7.0 Hz, 1 H, CH-1), 7.45
(t, J = 7.0 Hz, 2 H, 2ϫCH-2), 4.27 (s, 2 H, CH2-18), 4.22 (quint,
J = 5.0 Hz, 1 H, CH-12), 4.15 (quint, J = 5.0 Hz, 1 H, CH-12),
4.05 (s, 2 H, CH2-18), 3.82–3.52 (m, 28 H, 4ϫCH2-13, 4ϫCH-16,
8ϫCH2-17), 3.38 (t, J = 7.0 Hz, 2 H, CH2-5), 3.16 (t, J = 7.0 Hz,
2 H, CH2-7), 2.60 (t, J = 6.5 Hz, 2 H, CH2-9), 2.48 (t, J = 6.5 Hz,
2 H, CH2-10), 1.62 (quint, J = 6.5 Hz, 2 H, CH2-6), 1.49 (quint, J
= 6.5 Hz, 2 H, CH2-6), 1.41–1.28 (m, 8 H, 4ϫCH2-6) ppm. 13C
NMR (CD3OD, 75 MHz): δ = 175.6 (C), 174.2 (C), 171.65 (C),
171.37 (C), 170.0 (C), 135.7 (C), 132.4 (CH), 129.4 (2ϫCH), 128.1
(2 ϫ CH), 83.1 (2 ϫ CH), 82.9 (2 ϫ CH), 69.7 (2 ϫ CH2), 69.5
(2ϫCH2), 62.6 (2 ϫCH2), 62.5 (2 ϫCH2), 62.4 (4 ϫCH2), 54.5
(CH2), 54.0 (CH2), 51.6 (CH), 51.3 (CH), 41.0 (CH2), 40.5 (CH2),
31.7 (CH2), 30.5 (CH2), 30.3 (2ϫCH2), 30.3 (CH2), 29.2 (CH2),
28.0 (CH2), 27.9 (CH2) ppm. FAB-MS: m/z = 906 [M + H]+. FAB-
HRMS: calcd. for C41H72N5O17 [M + H]+ 906.4923; found
906.4971.
[4]
A. Battaglia, C. Bertucci, E. Bombardelli, S. Cimitan, A. Guer-
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[6]
R. B. Greenwald, C. W. Gilbert, A. Pendri, C. D. Conover, J.
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mura, Y. Tsuchiya, Heterocycles 2001, 54, 561–566.
Synthesis of various other oligomers of glycerol have been de-
scribed: S. Cassel, C. Debaig, T. Benvegnu, P. Chaimbault, M.
Lafosse, D. Plusquellec, P. Rollin, Eur. J. Org. Chem. 2001, 875–
896.
Although no evaluation of water solubilization has been per-
formed, the synthesis of dendrimers consisting of symmetri-
cally linked glycerols or serinols assembled via linkers has been
demonstrated: a) M. Jayaraman, J. M. J. Fréchet, J. Am. Chem.
Soc. 1998, 120, 12996–12997; b) M. A. Carnahan, M. W.
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2293–2298.
For our first papers on branched glycerols, see: a) H. Nemoto,
J. G. Wilson, H. Nakamura, Y. Yamamoto, J. Org. Chem. 1992,
57, 435; b) H. Nemoto, J. G. Wilson, H. Nakamura, Y. Yama-
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H. Nemoto, J. Cai, Y. Yamamoto, J. Chem. Soc., Chem. Com-
mun. 1994, 577–578.
Y. Yamamoto, N. Asao, M. Meguro, N. Tsukada, H. Nemoto,
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[7]
[8]
2,5-Dioxopyrrolidinyl 3-(N,N-Bis{[N-(2-[2-hydroxy-1-(hydroxy-
methyl)ethoxy]-1-{[2-hydroxy-1-(hydroxymethyl)ethoxy]-
methyl}ethyl)carbamoyl]methyl}carbamoyl)propanoate (24): Yield
from 14d: 906.0 mg, 1.0 mmol, 100%. A colorless oil. FTIR (neat):
ν = 3307, 3030, 2930, 2878, 1740, 1657, 1544, 1454, 1366, 1216,
˜
1122, 1096, 739, 697 cm–1 1H NMR (CD3OD, 300 MHz): δ =
.
4.22–4.05 (m, 6 H, 2ϫCH2-18, 2ϫCH-12), 3.80–3.43 (m, 28 H,
4ϫCH2-13, 4ϫCH-16, 8ϫCH2-17), 2.96 (t, J = 5.0 Hz, 2 H, CH2-
9), 2.82 (s, 4 H, 2ϫCH2-19), 2.74 (t, J = 5.0 Hz, 2 H, CH2-10)
ppm. 13C NMR (CD3OD, 75 MHz): δ = 174.1 (C), 171.8 (C), 171.7
(2ϫC), 171.5 (C), 169.9 (C), 83.0 (2ϫCH), 82.9 (2ϫCH), 69.7
(2ϫCH2), 69.4 (2 ϫCH2), 62.5 (4 ϫCH2), 62.4 (4 ϫCH2), 54.4
(CH2), 54.1 (CH2), 51.6 (CH), 51.3 (CH), 28.6 (CH2), 27.2 (CH2),
26.5 (2ϫCH2) ppm. FAB-MS: m/z = 773 [M + H]+. FAB-HRMS:
calcd. for C30H52O19N4 [M + H]+ 773.3304; found 773.3314.
[9]
[10]
[11]
[12]
Condensation Reaction between 8 and 24: BGL modification of 8
(28.5 mg, 0.1 mmol) with 24 (115.9 mg, 0.15 mmol) was performed
in water in the presence of Et3N (20.2 mg, 0.2 mmol). After concen-
tration to remove water and Et3N, 19 was obtained in quantitative
yield along with HOSu, any unreacted 24, and the carboxylic acid
obtained by hydrolysis of the CO2Su moiety of 24.
[13]
[14]
[15]
[16]
H. Nemoto, S. Iwamoto, H. Nakamura, Y. Yamamoto, Chem.
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For the preparation of p-boronophenylalanine, see: M. F. Haw-
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Acknowledgments
We thank Kyowa Hakko Kogyo Co. Ltd. for financial support.
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Eur. J. Org. Chem. 2007, 3003–3011

Water-Solubilizing Properties of Branched Oligoglycerols
FULL PAPER
[17]
in its synthesis. Therefore octabenzyl ether 14aЈ, which consists
of six glycerol units and one iminodiacetic acid unit, was syn-
thesized instead.
H. Nemoto, J. Kikuishi, S. Yanagida, T. Kawano, M. Yamada,
H. Harashima, H. Kiwada, M. Shibuya, Bioorg. Med. Chem.
Lett. 1999, 9, 205–208.
[18]
[19]
Linear-type oligo- and polyglycerols have a number of uncon-
trolled asymmetric centers.[7]
The use of an octaarginine moiety for both water solubility
and membrane permeation has been reported: L. R. Jones,
E. A. Goun, R. Shinde, J. B. Rothbard, C. H. Contag, P. A.
Wender, J. Am. Chem. Soc. 2006, 128, 6526–6527.
[20] When compounds more polar than 8 were modified with vari-
ous BGL-modified agents, a saturated aqueous solution of the
corresponding tetraol or octaol derivatives could not be pre-
pared (too water-soluble). When compounds less polar than 8
were modified similarly, the water solubility of the correspond-
ing monool or diol derivatives could not reproducibly be mea-
sured. This is the reason why 8 was chosen.
[21] F. Zaragoza-Dörwald, G. Von Kiedrowski, Synthesis 1988,
917–918.
[22] Although the preparation of an octabenzyl ether consisting of
seven glycerol units has been attempted, we have yet to succeed
Received: November 30, 2006
Published Online: April 23, 2007
Eur. J. Org. Chem. 2007, 3003–3011
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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