One-pot synthesis of monodisperse dual-functionalized polyethylene glycols through macrocyclic sulfates

Article abstract of DOI:10.1039/C8OB02392A

Dual-functionalization of monodisperse oligoethylene glycols, especially hetero-functionalization, provides a series of highly valuable intermediates for life and materials sciences. However, the existing methods for the preparation of these compounds suffer excessive protecting and activating group manipulation as well as tedious purification. Here, a one-pot dual-substitution strategy with macrocyclic sulfates of polyethylene glycols as the key intermediates was developed for the convenient and scalable preparation of a series of homo-functionalized and hetero-functionalized oligoethylene glycols in just 1 step. A high synthetic efficacy was achieved by avoiding the protecting and activating group manipulation and the intermediate purification.

Full text of DOI:10.1039/C8OB02392A

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
One-pot synthesis of monodisperse dual-
functionalized polyethylene glycols through
macrocyclic sulfates†
Cite this: Org. Biomol. Chem., 2018,
16, 8537
a
Xiaoyan Lv,a Xing Zheng,b Zhigang Yang a and Zhong-Xing Jiang
*
Dual-functionalization of monodisperse oligoethylene glycols, especially hetero-functionalization, pro-
vides a series of highly valuable intermediates for life and materials sciences. However, the existing
methods for the preparation of these compounds suffer excessive protecting and activating group
manipulation as well as tedious purification. Here, a one-pot dual-substitution strategy with macrocyclic
sulfates of polyethylene glycols as the key intermediates was developed for the convenient and scalable
preparation of a series of homo-functionalized and hetero-functionalized oligoethylene glycols in just 1
step. A high synthetic efficacy was achieved by avoiding the protecting and activating group manipulation
and the intermediate purification.
Received 26th September 2018,
Accepted 19th October 2018
DOI: 10.1039/c8ob02392a
rsc.li/obc
purification, characterization, clinical application, and drug
regulatory approval.2 Therefore, although the synthesis of
Introduction
As the “gold standard” polymers in life and materials sciences, Monodisperse PEGs (M-PEGs) is challenging,3 it is highly ben-
polyethylene glycols (PEGs) have been extensively used to eficial to replace regular PEGs with M-PEGs for achieving the
improve solubility and stability, reduce immunogenicity and optimal physicochemical properties, drug efficacy and safety,
dosing frequency, and prolong blood circulation.1 For etc.4 Second, dual-functionalization of PEGs, especially hetero-
example, the high biocompatibility and “stealthy” effect of functionalization of PEGs, suffers the tedious protecting and
PEGs make them ideal modifiers and linkers for drugs. Since activating group manipulation, which dramatically prolongs
1991, the US FDA has approved 14 PEG-containing drugs, their synthetic route, degrades the synthetic efficacy, and compli-
including the blockbuster drug Pegasys®. PEGylation, conju- cates the purification process.3 In addition, for hetero-
gation of PEGs of certain molecular weights and functional functionalization of PEGs, a necessary mono-functionalization
groups with biomacromolecules or nanomaterials, has become step is very challenging because there is no steric or electronic
one of the most successful strategies in biopharmaceutics devel- effect to assist the mono-functionalization of linear PEGs and it
opment. Therefore, properly functionalized PEGs with high is very tedious to purify the resulting mono-, dual- and non-func-
purity are of great importance in many fields.
tionalized PEG mixture. For these reasons, dual-functionalized
During PEGylation, PEGs are usually pre-modified into PEGs, especially the monodisperse ones, are very expensive.
dual-functionalized forms X(CH2CH2O)n−1CH2CH2Y; X, Y = OH, Thus, novel strategies for the convenient and efficient synthesis
CH2CO2H, SH, NH2, N3, etc.), especially into hetero-functiona- of highly pure dual-functionalized PEGs are highly valuable.
lized forms (X ≠ Y). However, it is very challenging to prepare
Recently, a macrocyclic sulfate-based strategy for the highly
highly pure dual-functionalized PEGs because there are two efficient synthesis of monodisperse PEGs (M-PEGs) and their
major difficulties in their synthesis. First, as polymers of ethyl- derivatives was developed by this group (Scheme 1).5 In this
ene oxide, the heterogeneity in regular PEGs and their deriva- strategy, selective nucleophilic ring opening of the M-PEG
tives is inevitable, which leads to difficulties in PEGylation, macrocyclic sulfates conveniently provided a series of mono-
functionalized M-PEGs in just one step without protecting or
activating group manipulation. To transform these mono-func-
aHubei Province Engineering and Technology Research Center for Fluorinated
Pharmaceuticals, School of Pharmaceutical Sciences, Wuhan University,
Wuhan 430071, China. E-mail: zxjiang@whu.edu.cn
tionalized PEGs into hetero-functionalized PEGs for bio-
medical application, additional activating and substituting
steps are required.6 Herein, we expanded the macrocyclic
sulfate-based strategy to one-pot dual-functionalization of
oligoethylene glycols (Scheme 1). In organic synthesis, cyclic
sulfates are usually employed as highly active precursors for
bInstitute of Pharmacy & Pharmacology, University of South China,
Hengyang 421001, China
†Electronic supplementary information (ESI) available: Optimization of the reac-
tion conditions and the copies of spectra. See DOI: 10.1039/c8ob02392a
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 8537–8545 | 8537

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Preparation of macrocyclic sulfates 3a–3e
Scheme 1 Previous and current work on the functionalization of
M-PEGs.
the preparation of α-substituted alcohols through the nucleo-
philic ring-opening reaction, during which the sulfate salt
intermediates prevent further nucleophilic substitution and
selectively provide the mono-substituted products after acidic
hydrolysis.7 However, in some cases, traces of dual-substituted
products were isolated by us during the ring-opening reaction
of M-PEG macrocyclic sulfates. Therefore, we envision that the
a Yields of oxidation reactions with 2a–2e as the starting materials.
b Yields of one-pot macrocyclization and oxidation reactions with 1a–
M-PEG sulfate salt intermediates could be activated for further 1e as the starting materials.
nucleophilic substitution and provide the dual-functionalized
M-PEGs in just 1 step. In this way, dual-functionalized M-PEGs
could be conveniently prepared with minimum reaction steps.
tion and oxidation from M-PEGs 1a–1e with good yields. It is
noteworthy that the yields are comparable to those of our pre-
vious method. Finally, a 51-gram scale preparation of macro-
cyclic sulfate 3a was carried out with an 88% yield under the
reaction conditions.
Results and discussion
With these ideas in mind, the M-PEG macrocyclic sulfates
The homo-functionalization of M-PEGs was first explored
were prepared as the starting materials for dual-functionalized with tetraethylene glycol macrocyclic sulfate 3a and benzyl
M-PEGs. Our previous method involves the oxidation of M-PEG alcohol (Table 2). When 4.0 equiv. of benzyl alcohol were
macrocyclic sulfites to the corresponding macrocyclic sulfates treated with 4.0 equiv. of NaH followed by 1.0 equiv. of macro-
with expensive reagents such as NaIO4 and RuCl3·H2O. To reduce cyclic sulfate 3a in THF at 25 °C or 60 °C, no dual-benzylated
the cost of the M-PEG macrocyclic sulfates, many oxidation tetraethylene glycol 4a but mono-benzylated one was isolated.
systems were explored on tetraethylene glycol macrocyclic Then, the one-pot dual-functionalization reaction was split
sulfite 2a. However, due to the low stability of macrocyclic into two stages. First, under our previous nucleophilic ring
sulfite 2a and high reactivity of macrocyclic sulfate 3a, many opening conditions, macrocyclic sulfate 3a was treated with 1.1
widely used oxidation systems failed to provide macrocyclic equiv. of benzyl alcohol in the presence of 2.0 equiv. of NaH at
sulfate 3a, including H2O2, H2O2–RuCl3·3H2O, CrO3, CrO3– 25 °C to provide the sulfate salt intermediate. Second, the reac-
H2SO4, K2FeO4, tBuOOH, mCPBA, K2Cr2O7, KBrO3, and tri- tion mixture containing the sulfate salt intermediate was treated
chloroiso-cyanuric acid. Fortunately, macrocyclic sulfate 3a was with additional 2.9 equiv. of benzyl alcohol and 2.0 equiv.
isolated in a 30% yield when KMnO4 in the presence of H2SO4 of NaH and the resulting mixture was stirred at 60 °C for
was employed in the reaction. Further, macrocyclic sulfate 3a 12 hours. To our delight, dual-benzylated tetraethylene glycol
was obtained in high yield when NaOCl and RuCl3·3H2O were 4a was isolated in a 40% yield (entry 1). It was found that
used in the reaction. After a series of reaction condition optim- when all 4.0 equiv. of NaH were added to the first portion of
ization, 4.0 equiv. of NaOCl and 0.005 equiv. of RuCl3·3H2O in benzyl alcohol, dual-benzylated M-PEGs 4a was isolated with
a solvent mixture of CH2Cl2–CH3CN–H2O (1 : 1 : 2) at 0 °C to the same yield, which simplified the reaction procedures
room temperature were identified as the preferred oxidation (entry 1). Further optimization of the reaction conditions
reaction conditions (Table S1†). Compared to our previous showed that phase transfer catalysts could promote the reac-
method, this method is made more environmentally friendly tion, which is probably due to the formation of charged sulfate
by replacing the severe environmental pollutant CCl4 with salt intermediates (entries 2–6). Among the phase transfer cat-
CH2Cl2 and much less expensive by replacing expensive NaIO4 alysts tested, tetrabutylammonium hydrogen sulfate
with inexpensive NaOCl. Under the reaction conditions, a (TBAHSO4) effectively catalyzed the reaction with a 66% yield
series of macrocyclic sulfites 2a–2e, which were prepared with of 4a (entry 6). After a screening of the amount of TBAHSO4,
our previous method,5 were oxidized to the corresponding 0.1 equiv. of TBAHSO4 was identified as the appropriate
macrocyclic sulfates 3a–e in good yields (Table 1). Macrocyclic amount of catalyst loading. Solvent played an important role
sulfates 3a–e were also prepared through one-pot macrocycliza- in the reaction (entries 7–10). Toluene was chosen as the best
8538 | Org. Biomol. Chem., 2018, 16, 8537–8545
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Optimization of the reaction conditions
Entry
NaH (equiv.)
BnOHa (equiv.)
Catalyst
Solvent
Temp. (°C)
Yield (%)
1b
2
3
2.0 + 2.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
2.0
3.0
5.0
4.0
4.0
4.0
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 2.9
1.1 + 1.9
1.1 + 3.9
4.0
—
TBAC
TBAB
TBAI
THF
THF
THF
THF
THF
THF
DMF
CH3CN
Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
0–60
0–60
0–60
0–60
0–60
60
60
60
60
60
20
40
80
100
100
100
100
100
100
100
40
50
63
58
60
66
5
4
5
18-C-6
6c
7
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
TBAHSO4
8
9
6
7
10
11
12
13
14d
15
16
17
18
19
20
82
17
41
86
88
29
63
59
79
72
63
a BnOH was added in two portions as indicated. b When NaH was added in one portion, the yield was 40%. c When 0.05 equiv. and 0.2 equiv. of
TBAHSO4 were added to the reaction mixture, the yields were 63% and 48%, respectively. d When 4 mL and 6 mL toluene were used as the
solvent, the yields were 75% and 67%, respectively.
solvent for the following investigation. Other solvents were
found to be less effective for this reaction. 1,4-Dioxane and
acetonitrile couldn’t dissolve the intermediates well and DMF
resulted in side reactions. The yield was further improved by
elevating the reaction temperature (entries 11–14). Diluting the
concentration of the macrocyclic sulfate 3a lowered the yield of
4a. It was also found that benzyl alcohol with 1.1 equiv. of
benzyl alcohol in the presence of 4.0 equiv. of NaH for the first
nucleophilic substitution and 2.9 equiv. of benzyl alcohol for
the second one were essential for the reaction (entries 15–19).
When benzyl alcohol was added in one portion, the yield of 3a
was much lower. Finally, the reaction was carried out on an
8 mmol scale and dual-functionalized M-PEGs 4a was obtained
in an 84% yield.
Table 3 Dual-nucleophilic substitution on macrocyclic sulfates 3a and
3b with one nucleophile
Under the optimized reaction conditions, the scope of the
dual-nucleophilic substitution on macrocyclic sulfates 3a and
3b with the same nucleophile was first investigated (Table 3).
Through this reaction,
a series of homo-functionalized
M-PEGs were prepared with high efficacy. First, alcohols,
including benzyl, alkyl, fluorinated, and allyl alcohols, in the
presence of NaH were good nucleophiles and M-PEG di-ethers
were obtained with good yields (4a–4d, 5a–5d). Second, phenol
ethers 4e and 5e were obtained with high efficacy when the
macrocyclic sulfates 3a and 3b were treated with 4-methyl-
phenol, respectively. Third, thio-ethers 4f and 5f were con- tute the macrocyclic sulfates and provide M-PEG-containing
veniently prepared with this method, which could be further amines 4g, 5g and indoles 4h, 5h with high yields.
transformed into dithiolated M-PEGs under mild conditions.
Encouraged by these results, we investigated the dual-
Fourth, nucleophilic nitrogen atoms were able to dual-substi- nucleophilic substitution on macrocyclic sulfates with two
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 8537–8545 | 8539

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 4 Dual-nucleophilic substitution on macrocyclic sulfates 3a and
3b with two nucleophiles
6j and 7a–7j in good yields. It was found that the order of
adding the nucleophile had little effect on the yield of the
product (6e and 6g were synthesized in 2 different orders). The
dual-nucleophilic substitution reaction was expanded to the
macrocyclic sulfate of octaethylene glycol 3c. Both homo-func-
tionalized product 8a and hetero-functionalized product 8b
were obtained in good yields.
Conclusions
In this work, we developed a one-pot dual-nucleophilic substi-
tution method for the preparation of both homo-functiona-
lized and hetero-functionalized M-PEGs. Compared to the
existing methods, the macrocyclic sulfate-based method is
highly efficient and scalable which avoids the tedious protect-
ing and activating group manipulation. To facilitate the
method, a low cost and environmentally friendly process for
macrocyclic sulfates was also developed. Although cyclic sul-
fates are extensively used in organic synthesis, their appli-
cation is limited to the mono-nucleophilic substitution provid-
ing α-substituted alcohols. As far as we know, this is the first
example of dual-nucleophilic substitution providing dual-func-
tionalized products. Besides broadening the application of
cyclic sulfates, this study also provides quick access to a series
of highly valuable homo- and hetero-functionalized M-PEGs
which suffer limited availability due to their synthetic difficul-
ties. This process may promote the availability of functiona-
lized M-PEGs and therefore the wide applications of M-PEGs
in biomedicine and beyond.
Experimental section
General
1H and 13C NMR spectra were recorded on a Bruker 400 MHz
1
spectrometer. H NMR spectra were referenced to tetramethyl-
silane (s, 0.00 ppm) using CDCl3 as a solvent. 13C NMR spectra
were referenced to solvent carbons (77.16 ppm for CDCl3).
different nucleophiles to provide hetero-functionalized 19F NMR spectra were referenced to 2% perfluorobenzene (s,
M-PEGs (Table 4). Hetero-functionalized M-PEGs are the most −164.90 ppm) in CDCl3. The splitting patterns for 1H NMR
used forms in PEGylation and bioconjugation. Compared to spectra were denoted as follows: s = singlet, d = doublet, t =
homo-functionalized M-PEGs, hetero-functionalized M-PEGs triplet, q = quartet, m = multiplet. High resolution mass
are more valuable and their synthesis is more challenging. spectra were recorded on a 4.7 Tesla FT-MS using Electron
Under the optimized reaction conditions, 1.1 equiv. of the first Spray Ionization (ESI). Unless otherwise noted, solvents and
nucleophile, 1,1,1-trifuoroethanol, was treated with 4.0 equiv. reagents were purchased from commercial suppliers and used
of NaH followed by macrocyclic sulfate 3a at 25 °C. After com- as received. Flash chromatography was performed on silica gel
pletion of the nucleophilic ring opening reaction, 2.9 equiv. of (200–300 mesh) with EtOAc/petroleum ether (PE, 60–90 °C).
the second nucleophile, benzyl alcohol, were added to the reac- Macrocyclic sulfites 2a–2e were prepared according to reported
tion mixture and the resulting mixture was stirred at 100 °C procedures.5a
overnight. Fortunately, the hetero-functionalized product 6a was
isolated in a 53% yield. The scope the hetero-functionalization
reaction was then investigated on macrocyclic sulfates 3a and
General procedure for the preparation of macrocyclic sulfates
3a–3e (using the synthesis of 3a as an example)
3b. A series of O-, S-, N-containing nucleophiles could react Under an atmosphere of Ar, SOCl2 (95.2 mg, 0.8 mmol, in
effectively with macrocyclic sulfates 3a and 3b either in the first 2.0 mL of CH2Cl2) was added over 0.5 h to a stirring solution
nucleophile substitution or in the second nucleophilic substi- of tetraethylene glycol 1a (77.7 mg, 0.4 mmol), DIPEA
tution to provide a variety of hetero-functionalized M-PEGs 6a– (248.1 mg, 1.9 mmol) and DMAP (2.5 mg, 20.0 μmol) in
8540 | Org. Biomol. Chem., 2018, 16, 8537–8545
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
CH2Cl2 (8 mL) at 0 °C. After the addition, the mixture was organic layer was concentrated under vacuum and purified by
stirred at 0 °C for 1 h and quenched with cold brine (8 mL). flash chromatography on silica gel with EtOAc/PE (1/1) as the
1
The organic layer was collected and the aqueous layer was eluent to give 4a as a clear oil (131.7 mg, 88% yield). H NMR
extracted with CH2Cl2 (20 mL, twice). The combined organic (400 MHz, CDCl3) δ 7.45–7.29 (m, 8H), 7.29–7.23 (m, 2H), 4.55
layer was dried over anhydrous Na2SO4 and concentrated to (s, 4H), 3.85–3.45 (m, 16H).
give 78.7 mg of macrocyclic sulfites 2a as a brown oil in 82%
6,9,12,15,18-Pentaoxatricosane 4b was prepared from 1-pen-
yield. Macrocyclic sulfite 2a (78.7 mg, 0.3 mmol) was dissolved tanol by following the general procedure for the preparation of
in a mixture of CH3CN (1.6 mL), CH2Cl2 (1.6 mL) and water homo-substituted M-PEGs 4a as a clear oil (120.3 mg, 90%
(2.5 mL) at 0 °C. NaOCl (0.8 mL, 1.3 mmol, available chlorine yield). 1H NMR (400 MHz, CDCl3) δ 3.71–3.62 (m, 12H), 3.58
10%) and RuCl3·3H2O (0.5 mg, 1.7 μmol) were sequentially (m, 4H), 3.45 (t, J = 6.8 Hz, 4H), 1.64–1.52 (m, 4H), 1.37–1.26
added to the reaction mixture and the resulting mixture was (m, 8H), 0.89 (t, J = 6.9 Hz, 6H).
stirred at 0 °C for 1 h. The organic layer was collected and the
1,1,1,17,17,17-Hexafluoro-3,6,9,12,15-pentaoxaheptadecane
aqueous layer was extracted with CH2Cl2 (20 mL, twice). The 4c was prepared from 2,2,2-trifluoroethanol by following the
combined organic layer was dried over anhydrous Na2SO4, fil- general procedure for the preparation of homo-substituted
tered through a pad of Celite, concentrated under vacuum, M-PEGs 4a as a clear oil (111.7 mg, 78% yield). 1H NMR
and purified by flash chromatography on silica gel with EtOAc/ (400 MHz, CDCl3) δ 3.91 (q, J = 8.8 Hz, 4H), 3.82–3.77 (m, 4H),
PE (1/1) as the eluent to give the macrocyclic sulfate 3a as a 3.70–3.64 (m, 12H). 13C NMR (100 MHz, CDCl3) δ 124.1 (q, J =
1
white wax (77.3 mg, 92% yield). H NMR (400 MHz, CDCl3) δ 279.6 Hz), 72.0, 70.8, 70.7, 70.8, 68.8 (q, J = 33.9 Hz). 19F NMR
4.49 (t, J = 5.0 Hz, 4H), 3.88–3.82 (m, 4H), 3.73–3.62 (m, 8H).
(376 MHz, CDCl3) δ −77.33. HRMS (ESI) calcd for C12H20
Macrocyclic sulfate 3b was prepared from hexaethylene F6KO5+ ([M + K]+) 397.0847, found 397.0845.
glycol 1b by following the general procedure for the prepa-
2,20-Dimethyl-5,8,11,14,17-pentaoxahenicosa-2,19-diene 4d
ration of macrocyclic sulfate 3a as a clear oil (68.8 mg, 50% was prepared from isopentenyl alcohol by following the
yield). 1H NMR (400 MHz, CDCl3) δ 4.50–4.43 (m, 4H), general procedure for the preparation of homo-substituted
3.87–3.81 (m, 4H), 3.70–3.64 (m, 16H).
M-PEGs 4a as a clear oil (113.6 mg, 86% yield). 1H NMR
Macrocyclic sulfate 3c was prepared from octaethylene (400 MHz, CDCl3) δ 5.43–5.28 (m, 2H), 4.00 (d, J = 6.4 Hz, 4H),
glycol 1c by following the general procedure for the prepa- 3.62–3.67 (m, 12H), 3.60–3.56 (m, 4H), 1.74 (s, 6H), 1.67 (s,
ration of macrocyclic sulfate 3a as a clear oil (72.6 mg, 42% 6H). 13C NMR (100 MHz, CDCl3) δ 136.8, 121.1, 70.7,
+
yield). 1H NMR (400 MHz, CDCl3) δ 4.48–4.42 (m, 4H), 70.5, 69.1, 67.6, 25.8, 18.0. HRMS (ESI) calcd for C18H34NaO5
3.83–3.78 (m, 4H), 3.70–3.64 (m, 24H).
([M + Na]+) 353.2298, found 353.2294.
Macrocyclic sulfate 3d was prepared from decaethylene
4,4′-((((Oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))-
glycol 1d by following the general procedure for the prepa- bis(oxy))bis(methylbenzene) 4e was prepared from p-cresol by
ration of macrocyclic sulfate 3a as a clear oil (93.7 mg, 45% following the general procedure for the preparation of homo-
1
yield). 1H NMR (400 MHz, CDCl3) δ 4.51–4.38 (m, 4H), substituted M-PEGs 4a as a clear oil (122.1 mg, 82% yield). H
3.83–3.78 (m, 4H), 3.68–3.64 (m, 32H).
NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.2 Hz, 4H), 6.81 (d, J =
Macrocyclic sulfate 3e was prepared from dodecaethylene 8.3 Hz, 4H), 4.09 (t, J = 4.8 Hz, 4H), 3.84 (t, J = 4.8 Hz, 4H),
glycol 1e by following the general procedure for the prepa- 3.79–3.61 (m, 8H), 2.28 (s, 6H).
ration of macrocyclic sulfate 3a as a clear oil (102.2 mg, 42%
1,1,1,15,15,15-Hexaphenyl-5,8,11-trioxa-2,14-dithiapenta-
yield). 1H NMR (400 MHz, CDCl3) δ 4.47–4.37 (m, 4H), decane 4f was prepared from triphenylmethyl mercaptan by
3.82–3.76 (m, 4H), 3.72–3.57 (m, 40H).
following the general procedure for the preparation of
homo-substituted M-PEGs 4a as a yellow oil (250.0 mg, 88%
yield). 1H NMR (400 MHz, CDCl3) δ 7.44–7.39 (m, 12H),
7.23–7.26 (m, 12H), 7.19–7.14 (m, 6H), 3.49–3.52 (m, 4H),
3.38–3.42 (m, 4H), 3.27 (t, J = 6.9 Hz, 4H), 2.42 (t, J = 6.9 Hz,
General procedure for the preparation of homo-substituted
M-PEGs 4a–4h and 5a–5h (using the synthesis of 4a as an
example)
A stirring suspension of NaH (64.0 mg, 60% in mineral oil, 4H). 13C NMR (100 MHz, CDCl3) δ 144.9, 129.7, 128.0, 126.8,
1.6 mmol) in anhydrous toluene (0.5 mL) was cooled to 0 °C 70.6, 70.2, 69.7, 66.7, 31.7. HRMS (ESI) calcd for
and a solution of benzyl alcohol (47.5 mg, 0.4 mmol) in anhy-
drous toluene (0.5 mL) was added slowly. After 30 min, a solu-
C
46H46KO3S2+ ([M + K]+) 749.2520, found 749.2513.
N,N′-(((Oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))-
tion of macrocyclic sulfate 3a (102.4 mg, 0.4 mmol) in anhydrous bis(N-phenylaniline) 4g was prepared from diphenylamine by
toluene (0.5 mL) was slowly added. The reaction mixture was following the general procedure for the preparation of homo-
stirred for 4 h at room temperature. Then a solution of benzyl substituted M-PEGs 4a as a cyaneous oil (184.6 mg, 93% yield).
alcohol (125.3 mg, 1.2 mmol) and TBAHSO4 (13.6 mg, 1H NMR (400 MHz, CDCl3) δ 7.27–7.21 (m, 8H), 7.06–6.98 (m,
40.0 μmol) in anhydrous toluene (1.0 mL) was added at room 8H), 6.92 (t, J = 7.1 Hz, 4H), 3.93 (t, J = 7.7 Hz, 4H), 3.67 (t, J =
temperature. The reaction mixture was stirred for 12 h at 7.8 Hz, 4H), 3.57–3.59 (m, 8H). 13C NMR (100 MHz, CDCl3)
100 °C and the reaction was quenched with water. After the δ 147.9, 129.4, 121.4, 121.0, 70.8, 70.8, 68.2, 51.6. HRMS (ESI)
+
Na]+) 519.2618, found
+
removal of solvent under vacuum, the residue was dissolved in calcd for C32H36N2NaO3 ([M
EtOAc (20 mL) and washed with water (5 mL, three times). The 519.2615.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 8537–8545 | 8541

View Article Online
Paper
Organic & Biomolecular Chemistry
1,1′-(((Oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))- yield). 1H NMR (400 MHz, CDCl3) δ 7.46–7.39 (m, 12H),
bis(5-bromo-1H-indole) 4h was prepared from 5-bromine 7.30–7.25 (m, 12H), 7.23–7.17 (m, 6H), 3.63–3.53 (m, 12H),
indole by following the general procedure for the preparation 3.48–3.42 (m, 4H), 3.27 (t, J = 6.9 Hz, 4H), 2.42 (t, J = 6.9 Hz,
of homo-substituted M-PEGs 4a as a brown oil (160.0 mg, 4H). 13C NMR (100 MHz, CDCl3) δ 144.9, 129.7, 128.0, 126.7,
1
73% yield). H NMR (400 MHz, CDCl3) δ 7.69 (s, 2H), 7.21 (d, 70.6, 70.6, 70.5, 70.2, 69.7, 66.7, 31.7. HRMS (ESI) calcd for
J = 8.7 Hz, 2H)., 7.15 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 3.0 Hz, C50H54NaO5S2+ ([M + Na]+) 821.3305, found 821.3298.
2H), 6.36 (d, J = 2.8 Hz, 2H), 4.15 (t, J = 5.4 Hz, 4H), 3.66 (t, J =
N1,N1,N17,N17-Tetraphenyl-3,6,9,12,15-pentaoxaheptadecane-
5.4 Hz, 4H), 3.43–3.31 (m, 8H). 13C NMR (100 MHz, CDCl3) 1,17-diamine 5g was prepared from diphenylamine by follow-
δ 144.9, 129.7, 128.0, 126.7, 70.6, 70.6, 70.5, 70.2, 69.7, 66.7, ing the general procedure for the preparation of homo-substi-
+
31.7. HRMS (ESI) calcd for C24H26Br2KN2O3 ([M + K]+) tuted M-PEGs 4a as a cyaneous oil (184.6 mg, 79% yield).
586.9942, found 586.9938.
1H NMR (400 MHz, CDCl3) δ 7.27–7.22 (m, 8H), 7.05–6.99 (m,
1,21-Diphenyl-2,5,8,11,14,17,20-heptaoxahenicosane 5a was 8H), 6.93 (t, J = 7.1 Hz, 4H), 3.93 (t, J = 6.5 Hz, 4H), 3.67 (t, J =
prepared from benzyl alcohol by following the general pro- 6.5 Hz, 4H), 3.63–3.57 (m, 16H). 13C NMR (100 MHz, CDCl3)
cedure for the preparation of homo-substituted M-PEGs 4a as δ 147.9, 129.4, 121.4, 121.0, 70.8, 70.7, 70.7, 68.2, 51.6. HRMS
1
+
a clear oil (164.6 mg, 89% yield). H NMR (400 MHz, CDCl3) δ (ESI) calcd for C36H44N2NaO5 ([M + Na]+) 607.3142, found
7.37–7.29 (m, 8H), 7.29–7.26 (m, 2H), 4.57 (s, 4H), 3.69–3.61 607.3138.
(m, 24H).
1,17-Bis(5-bromo-1H-indol-1-yl)-3,6,9,12,15-pentaoxahepta-
6,9,12,15,18,21,24-Heptaoxanonacosane 5b was prepared decane 5h was prepared from 5-bromine indole by following
from 1-pentano by following the general procedure for the the general procedure for the preparation of homo-substi-
preparation of homo-substituted M-PEGs 4a as a clear oil tuted M-PEGs 4a as a brown oil (198.2 mg, 78% yield).
1
(121.6 mg, 72% yield). H NMR (400 MHz, CDCl3) δ 3.77–3.52 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 2H), 7.26–7.20 (m, 4H),
(m, 24H), 3.45 (t, J = 6.8 Hz, 4H), 1.64–1.55 (m, 4H), 1.35–1.27 7.16 (d, J = 3.1 Hz, 2H), 6.40 (d, J = 3.1 Hz, 2H), 4.24 (t, J =
(m, 8H), 0.89 (t, J = 6.9 Hz, 6H). 13C NMR (100 MHz, CDCl3) 5.5 Hz, 4H), 3.75 (t, J = 5.5 Hz, 4H), 3.56–3.49 (m, 16H).
δ 71.7, 70.7, 70.7, 70.7, 70.2, 29.4, 28.4, 22.7, 14.2. HRMS (ESI) 13C NMR (100 MHz, CDCl3) δ 134.9, 130.3, 129.8, 124.3, 123.4,
calcd for C22H46NaO7+ ([M + Na]+) 445.3136, found 445.3130.
112.7, 111.0, 100.9, 70.8, 70.6, 70.6, 70.6, 70.2, 46.5. HRMS
1,1,1,23,23,23-Hexafluoro-3,6,9,12,15,18,21-heptaoxatrico-sane (ESI) calcd for C28H34Br2KN2O5 ([M + K]+) 675.0466, found
5c was prepared from 2,2,2-trifluoroethanol by following the 675.0469.
+
general procedure for the preparation of homo-substituted
General procedure for the preparation of hetero-substituted
M-PEGs 4a as a clear oil (146.3 mg, 82% yield). 1H NMR
M-PEGs M-PEGs 6a–6j and 7a–7j (using the synthesis of 6a as
(400 MHz, CDCl3) δ 3.92 (q, J = 8.8 Hz, 4H), 3.82–3.77 (m, 4H),
an example)
3.72–3.62 (m, 20H). 13C NMR (100 MHz, CDCl3) δ 124.1 (q, J =
279.6 Hz), 72.0, 70.8, 70.7, 70.7, 70.6, 68.83 (q, J = 33.9 Hz). 19F A suspension of NaH (64.0 mg, 60% in mineral oil, 1.6 mmol)
NMR (376 MHz, CDCl3) δ −77.49. HRMS (ESI) calcd for in anhydrous toluene (0.5 mL) was cooled to 0 °C and a solu-
C16H28F6NaO7+ ([M + Na]+) 469.1631, found 469.1630.
tion of trifluoroethanol (44.0 mg, 0.4 mmol) in anhydrous
2,26-Dimethyl-5,8,11,14,17,20,23-heptaoxaheptacosa-2,25-diene toluene (0.5 mL) was added slowly at 0 °C. After 30 min of stir-
5d was prepared from isopentenyl alcohol by following the ring at 0 °C, a solution of macrocyclic sulfate 3a (102.4 mg,
general procedure for the preparation of homo-substituted 0.4 mmol) in anhydrous toluene (0.5 mL) was added slowly.
M-PEGs 4a as a clear oil (120.5 mg, 72% yield). 1H NMR The reaction mixture was stirred for 4 h at room temperature.
(400 MHz, CDCl3) δ 5.38–5.33 (m, 2H), 4.01 (d, J = 6.9 Hz, 4H), Then a solution of benzyl alcohol (125.3 mg, 1.2 mmol) and
3.68–3.64 (m, 20H), 3.61–3.56 (m, 4H), 1.76–1.72 (m, 6H), 1.67 (s, TBAHSO4 (13.6 mg, 40.0 μmol) in anhydrous toluene (1.0 mL)
6H). 13C NMR (100 MHz, CDCl3) δ 137.0, 121.2, 70.8, 70.7, 69.3, was added at room temperature. The reaction mixture was
+
67.8, 25.9, 18.2. HRMS (ESI) calcd for C22H42NaO7 ([M + Na]+) stirred for 12 h at 100 °C and the reaction was quenched with
441.2823, found 441.2818.
water. After the removal of solvent under vacuum, the residue
1,17-Bis(p-tolyloxy)-3,6,9,12,15-pentaoxaheptadecane 5e was was dissolved in EtOAc (20 mL) and washed with water (5 mL,
prepared from p-cresol by following the general procedure for three times). The organic layer was concentrated under
the preparation of homo-substituted M-PEGs 4a as a clear oil vacuum and purified by flash chromatography on silica gel
(173.8 mg, 94% yield). 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = with EtOAc/PE (1/1) as the eluent to give 6a as a clear oil
1
8.4 Hz, 4H), 6.81 (d, J = 8.5 Hz, 4H), 4.12–4.06 (m, 4H), (77.6 mg, 53% yield). H NMR (400 MHz, CDCl3) δ 7.38–7.32
3.86–3.81 (m, 4H), 3.74–3.70 (m, 4H), 3.69–3.62 (m, 12H), 2.27 (m, 4H), 7.30–7.25 (m, 1H), 4.56 (s, 2H), 3.89 (q, J = 8.8 Hz,
(s, 6H). 13C NMR (100 MHz, CDCl3) δ 156.7, 130.1, 130.0, 2H), 3.79–3.74 (m, 2H), 3.70–3.61 (m, 14H). 13C NMR
114.5, 70.9, 70.7, 70.6, 69.9, 67.5, 20.6. HRMS (ESI) calcd for (100 MHz, CDCl3) δ 138.3, 128.4, 127.71 (d, J = 15.2 Hz), 124.1
C26H38NaO7+ ([M + Na]+) 485.2510, found 485.2506.
(q, J = 279.6 Hz), 73.3, 71.9, 70.7, 70.7, 70.6, 69.5, 68.8 (q, J =
1,1,1,21,21,21-Hexaphenyl-5,8,11,14,17-pentaoxa-2,20-dithia- 33.9 Hz). 19F NMR (376 MHz, CDCl3) δ −77.40. HRMS (ESI)
henicosane 5f was prepared from triphenylmethyl mercaptan calcd for C17H25F3NaO5+ ([M + Na]+) 389.1546, found 389.1540.
by following the general procedure for the preparation of
17-Methyl-1-phenyl-2,5,8,11,14-pentaoxaoctadec-16-ene 6b
homo-substituted M-PEGs 4a as a yellow oil (252.3 mg, 79% was prepared from isopentenyl alcohol and benzyl alcohol by
8542 | Org. Biomol. Chem., 2018, 16, 8537–8545
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
+
following the general procedure for the preparation of hetero- 70.2, 68.3, 51.7, 46.6. HRMS (ESI) calcd for C28H31BrN2NaO3
substituted M-PEGs 6a as a clear oil (83.1 mg, 59% yield). ([M + Na]+) 545.1410, found 545.1406.
1H NMR (400 MHz, CDCl3) δ 7.36–7.30 (m, 4H), 7.29–7.26 (m,
N,N,1,1,1-Pentaphenyl-5,8,11-trioxa-2-thiatridecan-13-amine
1H), 5.35 (t, J = 6.9 Hz, 1H), 4.57 (s, 2H), 4.00 (d, J = 6.9 Hz, 6g was prepared from diphenylamine and triphenylmethyl
2H), 3.69–3.56 (m, 16H), 1.74 (s, 3H), 1.66 (s, 3H). 13C NMR mercaptan by following the general procedure for the prepa-
(100 MHz, CDCl3) δ 138.4, 137.0, 128.5, 127.9, 127.7, 121.2, ration of hetero-substituted M-PEGs 6a as a cyaneous oil
73.4, 70.8, 70.8, 70.7, 69.5, 69.3, 67.8, 25.9, 18.2. HRMS (ESI) (188.2 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J =
calcd for C20H32NaO5+ ([M + Na]+) 375.2141, found 375.2136.
7.8 Hz, 6H), 7.28–7.19 (m, 13H), 7.01 (dd, J = 8.6, 1.0 Hz, 4H),
17-Methyl-1,1,1-triphenyl-5,8,11,14-tetraoxa-2-thiaoctadec-16- 6.92 (dd, J = 10.5, 4.2 Hz, 2H), 3.92 (t, J = 6.5 Hz, 2H), 3.66
ene 6c was prepared from triphenylmethyl mercaptan and iso- (t, J = 6.5 Hz, 2H), 3.57–3.51 (m, 6H), 3.43–3.41 (m, 2H),
pentenyl alcohol by following the general procedure for the 3.30–3.26 (m, 2H), 2.42 (t, J = 7.0 Hz, 2H). 13C NMR (100 MHz,
preparation of hetero-substituted M-PEGs 6a as a yellow clear CDCl3) δ 147.9, 144.9, 129.7, 129.4, 128.0, 126.8, 121.4, 121.0,
oil (99.9 mg, 48% yield). 1H NMR (400 MHz, CDCl3) 70.8, 70.7, 70.6, 70.3, 69.7, 68.2, 66.7, 51.6, 31.7. HRMS (ESI)
δ 7.44–7.38 (m, 6H), 7.29–7.25 (m, 6H), 7.23–7.18 (m, 3H), 5.34 calcd for C39H41NNaO3S+ ([M
(t, J = 6.3 Hz, 1H), 3.99 (d, J = 6.8 Hz, 2H), 3.65–3.60 (m, 6H), 626.2693.
+
Na]+) 626.2699, found
3.59–3.53 (m, 4H), 3.47–3.42 (m, 2H), 3.29 (t, J = 6.9 Hz, 2H),
N,N,1-Triphenyl-2,5,8,11-tetraoxatridecan-13-amine 6h was
2.43 (t, J = 6.9 Hz, 2H), 1.73 (s, 3H), 1.66 (s, 3H). 13C NMR prepared from diphenylamine and benzyl alcohol by following
(100 MHz, CDCl3) δ 144.9, 137.0, 129.7, 128.0, 126.7, 121.2, the general procedure for the preparation of hetero-substituted
70.8, 70.7, 70.7, 70.5, 70.2, 69.7, 69.3, 67.7, 66.7, 31.7, 25.9, M-PEGs 6a as a brown oil (113.2 mg, 65% yield). 1H NMR
18.2. HRMS (ESI) calcd for C32H40NaO4S+ ([M + Na]+) 543.2540, (400 MHz, CDCl3) δ 7.34–7.22 (m, 9H), 7.05–7.00 (m, 4H), 6.93
found 543.2535.
(t, J = 7.3 Hz, 2H), 4.55 (s, 2H), 3.93 (t, J = 6.5 Hz, 2H),
16,16,16-Trifluoro-1,1,1-triphenyl-5,8,11,14-tetraoxa-2-thiahexa- 3.71–3.58 (m, 14H). 13C NMR (100 MHz, CDCl3) δ 147.9, 138.4,
decane 6d was prepared from triphenylmethyl mercaptan and 129.4, 128.5, 127.8, 127.7, 121.4, 121.0, 73.3, 70.8, 70.8,
+
2,2,2-trifluoroethanol by following the general procedure for the 70.7, 69.5, 68.2, 51.6. HRMS (ESI) calcd for C27H33NNaO4
preparation of hetero-substituted M-PEGs 6a as a yellow oil ([M + Na]+) 458.2302, found 458.2296.
(130.3 mg, 61% yield). 1H NMR (400 MHz, CDCl3) δ 7.45–7.39
5-Bromo-1-(1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)-1H-indole
(m, 6H), 7.30–7.24 (m, 6H), 7.22–7.17 (m, 3H), 3.88 (q, J = 8.8 Hz, 6i was prepared from 5-bromine indole and benzyl alcohol by
2H), 3.78–3.73 (m, 2H), 3.67–3.61 (m, 6H), 3.59–3.54 (m, 2H), following the general procedure for the preparation of hetero-
3.47–3.42 (m, 2H), 3.30 (t, J = 6.9 Hz, 2H), 2.43 (t, J = 6.9 Hz, 2H). substituted M-PEGs 6a as a brown oil (116.2 mg, 63% yield).
13C NMR (100 MHz, CDCl3) δ 144.9, 129.7, 128.0, 126.8, 124.1 (q, 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 1.5 Hz, 1H), 7.35–7.23
J = 279.6 Hz), 72.0, 70.8, 70.7, 70.7, 70.6 70.2, 69.7, 68.8 (q, J = (m, 7H), 7.17 (d, J = 3.1 Hz, 1H), 6.40 (d, J = 3.1 Hz, 1H), 4.55 (s,
33.9 Hz), 66.7, 31.7. 19F NMR (376 MHz, CDCl3) δ −77.31. HRMS 2H), 4.25 (t, J = 5.5 Hz, 2H), 3.77 (t, J = 5.5 Hz, 2H), 3.65–3.51 (m,
(ESI) calcd for C29H33F3NaO4S+ ([M + Na]+) 557.1944, found 12H). 13C NMR (100 MHz, CDCl3) δ 129.8, 128.5, 127.8, 124.3,
557.1939.
1,15,15,15-Tetraphenyl-2,5,8,11-tetraoxa-14-thiapentadecane calcd for C23H28BrNNaO4+ ([M + Na]+) 484.1094, found 484.1090.
6e was prepared from triphenyl-methyl mercaptan and benzyl 5-Bromo-1-(1,1,1-triphenyl-5,8,11-trioxa-2-thiatridecan-13-yl)-
123.4, 111.0, 100.9, 73.4, 70.9, 70.4, 70.2, 69.5, 46.6. HRMS (ESI)
alcohol by following the general procedure for the preparation 1H-indole 6j was prepared from 5-bromine indole and tri-
of hetero-substituted M-PEGs 6a as a yellow oil (173.5 mg, 80% phenylmethyl mercaptan by following the general procedure for
yield). 1H NMR (400 MHz, CDCl3) δ 7.44–7.39 (m, 6H), the preparation of hetero-substituted M-PEGs 6a as a brown oil
70.37–70.31 (m, 4H), 7.30–7.24 (m, 7H), 7.23–7.17 (m, 3H), (146.1 mg, 58% yield). 1H NMR (400 MHz, CDCl3) δ 7.70 (s,
4.55 (s, 2H), 3.68–3.55 (m, 10H), 3.47–3.42 (m, 2H), 3.33–3.27 1H), 7.47–7.39 (m, 6H), 7.29–7.15 (m, 12H), 6.37 (d, J = 2.9 Hz,
(m, 2H), 2.42 (t, J = 6.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.73 (t, J = 5.5 Hz, 2H), 3.51–3.25
δ 144.9, 138.4, 129.7, 128.5, 128.0, 127.9, 127.7, 126.8, 73.4, (m, 10H), 2.41 (t, J = 5.1 Hz, 2H). 13C NMR (100 MHz, CDCl3)
70.7, 70.6, 70.3, 69.7, 69.5, 66.7, 31.7. HRMS (ESI) calcd for δ 144.9, 134.9, 130.3, 130.2, 129.7, 128.0, 126.7, 124.2, 123.3,
C34H38NaO4S+ ([M + Na]+) 565.2383, found 565.2377.
112.7, 111.0, 100.9, 70.8, 70.6, 70.5, 70.2, 70.2, 69.6, 66.7, 46.5,
N-(2-(2-(2-(2-(5-Bromo-1H-indol-1-yl)ethoxy)ethoxy)ethoxy) 31.7. HRMS (ESI) calcd for C35H36BrNNaO3S+ ([M + Na]+)
ethyl)-N-phenylaniline 6f was prepared from diphenylamine 652.1491, found 652.1489.
and 5-bromine indole by following the general procedure for
22,22,22-Trifluoro-1-phenyl-2,5,8,11,14,17,20-heptaoxa-docosane
the preparation of hetero-substituted M-PEGs 6a as a brown oil 7a was prepared from 2,2,2-trifluoroethanol and benzyl alcohol
(121.1 mg, 58% yield). 1H NMR (400 MHz, CDCl3) δ 7.71 (s, by following the general procedure for the preparation of
1H), 7.27–7.21 (m, 6H), 7.15 (d, J = 3.1 Hz, 1H), 7.02 (d, J = hetero-substituted M-PEGs 6a as a clear oil (136.3 mg, 75%
8.1 Hz, 4H), 6.93 (t, J = 7.3 Hz, 2H), 6.39 (d, J = 3.0 Hz, 1H), yield). 1H NMR (400 MHz, CDCl3)
δ 7.38–7.32(m, 4H),
4.23 (t, J = 5.5 Hz, 2H), 3.92 (t, J = 6.5 Hz, 2H), 3.75 (t, J = 7.30–7.26 (m, 1H), 4.57 (s, 2H), 3.91 (d, J = 8.8 Hz, 2H),
5.5 Hz, 2H), 3.66 (t, J = 6.5 Hz, 2H), 3.54–3.47 (m, 8H). 3.80–3.77 (m, 2H), 3.67–3.63 (m, 22H). 13C NMR (100 MHz,
13C NMR (100 MHz, CDCl3) δ 147.9, 134.9, 130.4, 129.8, 129.4, CDCl3) δ 138.3, 128.4, 127.8, 127.7, 124.1 (q, J = 279.6 Hz),
124.3, 123.4, 121.4, 121.1, 112.7, 111.0, 100.9, 70.9, 70.8, 70.8, 73.3, 72.0, 70.7, 70.7, 70.6, 69.5, 68.8 (q, J = 33.9 Hz). 19F NMR
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 8537–8545 | 8543

View Article Online
Paper
Organic & Biomolecular Chemistry
(376 MHz, CDCl3)
δ
−77.48. HRMS (ESI) calcd for 1H), 4.25 (t, J = 5.5 Hz, 2H), 3.93 (t, J = 6.5 Hz, 2H), 3.76 (t, J =
C21H33F3NaO7+ ([M + Na]+) 477.2070, found 477.2063.
5.5 Hz, 2H), 3.67 (t, J = 6.5 Hz, 2H), 3.62–3.49 (m, 16H). 13C
23-Methyl-1-phenyl-2,5,8,11,14,17,20-heptaoxatetracos-22-ene NMR (100 MHz, CDCl3) δ 147.9, 134.9, 130.3, 129.8, 129.4,
7b was prepared from isopentenyl alcohol and benzyl alcohol 124.3, 123.4, 121.4, 121.0, 112.7, 111.0, 100.9, 70.9, 70.8, 70.7,
by following the general procedure for the preparation of 70.7, 70.7, 70.7, 70.6, 70.2, 68.2, 51.6, 46.6. HRMS (ESI) calcd
hetero-substituted M-PEGs 6a as a clear oil (118.0 mg, 67% for C32H39BrN2NaO5+ ([M + Na]+) 633.1935, found 633.1930.
1
yield). H NMR (400 MHz, CDCl3) δ 7.47–7.19 (m, 5H), 5.35 (t,
N,N,1,1,1-Pentaphenyl-5,8,11,14,17-pentaoxa-2-thianona-decan-
J = 6.3 Hz, 1H), 4.56 (s, 2H), 4.00 (d, J = 6.9 Hz, 2H), 3.70–3.55 19-amine 7g was prepared from diphenylamine and triphenyl-
(m, 24H), 1.74 (s, 3H), 1.66 (s, 3H). 13C NMR (100 MHz, CDCl3) methyl mercaptan by following the general procedure for the
δ 138.1, 136.7, 128.2, 127.6, 127.5, 121.0, 73.1, 70.6, 70.5, 70.5, preparation of hetero-substituted M-PEGs 6a as a cyaneous oil
70.4, 69.3, 69.0, 67.5, 25.7, 17.9. HRMS (ESI) calcd for (152.1 mg, 55% yield). 1H NMR (400 MHz, CDCl3) δ 7.43–7.38 (m,
C24H40KO7+ ([M + K]+) 479.2406, found 479.2400.
6H), 7.28–7.16 (m, 14H), 7.00–7.04 (m, 3H), 6.94–6.89 (m, 2H),
23-Methyl-1,1,1-triphenyl-5,8,11,14,17,20-hexaoxa-2-thiatetra- 3.93 (t, J = 6.5 Hz, 2H), 3.68 (d, J = 6.5 Hz, 2H), 3.61–3.54 (m,
cos-22-ene 7c was prepared from triphenylmethyl mercaptan 14H), 3.45–3.40 (m, 2H), 3.28 (t, J = 6.9 Hz, 2H), 2.42 (t, J = 6.9 Hz,
and isopentenyl alcohol by following the general procedure for 2H). 13C NMR (100 MHz, CDCl3) δ 147.8, 144.9, 129.7, 129.3,
the preparation of hetero-substituted M-PEGs 6a as a yellow oil 127.9, 126.7, 121.3, 121.0, 70.7, 70.7, 70.6, 70.6, 70.5, 70.2,
1
(177.6 mg, 73% yield). H NMR (400 MHz, CDCl3) δ 7.43–7.39 69.6, 68.2, 66.6, 51.6, 31.7. HRMS (ESI) calcd for C43H49NNaO5S+
(m, 6H), 7.27 (t, J = 7.5 Hz, 6H), 7.20 (t, J = 7.2 Hz, 3H), ([M + Na]+) 714.3224, found 714.3219.
5.43–5.26 (m, 1H), 4.00 (d, J = 6.9 Hz, 2H), 3.65–3.55 (m, 18H),
N,N,1-Triphenyl-2,5,8,11,14,17-hexaoxanonadecan-19-amine
3.46–3.42 (m, 2H), 3.29 (t, J = 7.0 Hz, 2H), 2.43 (t, J = 7.0 Hz, 7h was prepared from diphenylamine and benzyl alcohol by
2H), 1.74 (s, 3H), 1.66 (s, 3H). 13C NMR (100 MHz, CDCl3) following the general procedure for the preparation of hetero-
δ 144.9, 136.9, 129.7, 127.9, 126.7, 121.2, 70.7, 70.6, 70.5, 70.2, substituted M-PEGs 6a as a brown oil (110.9 mg, 53% yield).
69.6, 69.2, 67.7, 66.6, 31.7, 25.9, 18.1. HRMS (ESI) calcd for 1H NMR (400 MHz, CDCl3) δ 7.38–7.30 (m, 4H), 7.29–7.21 (m,
C36H48NaO6S+ ([M + Na]+) 631.3064, found 631.3060.
5H), 7.08–6.97 (m, 4H), 6.93 (t, J = 7.1 Hz, 2H), 4.56 (s, 2H),
22,22,22-Trifluoro-1,1,1-triphenyl-5,8,11,14,17,20-hexaoxa-2- 3.93 (t, J = 6.5 Hz, 2H), 3.73–3.53 (m, 22H). 13C NMR
thiadocosane 7d was prepared from triphenylmethyl mercap- (100 MHz, CDCl3) δ 147.9, 138.3, 129.3, 128.4, 127.8, 127.7,
tan and 2,2,2-trifluoroethanol by following the general pro- 121.4, 121.0, 73.3, 70.8, 70.7, 70.7, 70.6, 69.5, 68.2, 51.6. HRMS
+
cedure for the preparation of hetero-substituted M-PEGs 6a as (ESI) calcd for C31H41NNaO6 ([M + Na]+) 546.2826, found
1
a yellow oil (214.1 mg, 86% yield). H NMR (400 MHz, CDCl3) 546.2822.
δ 7.44–7.38 (m, 6H), 7.30–7.25 (m, 6H), 7.23–7.17 (m, 3H), 3.90
5-Bromo-1-(1-phenyl-2,5,8,11,14,17-hexaoxanonadecan-19-yl)-
(q, J = 8.8 Hz, 2H), 3.79–3.76 (m, 2H), 3.67–3.59 (m, 14H), 1H-indole 7i was prepared from 5-bromine indole and benzyl
3.58–3.54 (m, 2H), 3.47–3.42 (m, 2H), 3.29 (t, J = 6.9 Hz, 2H), alcohol by following the general procedure for the preparation
2.43 (t, J = 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 144.9, of hetero-substituted M-PEGs 6a as a brown oil (188.9 mg, 86%
129.7, 127.9, 126.7, 124.1 (q, J = 279.6 Hz), 72.0, 70.7, 70.7, yield). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 1.1 Hz, 1H),
70.6, 70.6, 70.5, 70.2, 69.6, 68.8 (q, J = 33.9 Hz), 66.6, 31.7. 7.35–7.23 (m, 7H), 7.17 (d, J = 3.1 Hz, 1H), 6.41 (d, J = 3.0 Hz,
19F NMR (376 MHz, CDCl3) δ −77.44. HRMS (ESI) calcd for 1H), 4.56 (s, 2H), 4.26 (t, J = 5.5 Hz, 2H), 3.77 (t, J = 5.5 Hz, 2H),
C33H41F3NaO6S+ ([M + Na]+) 645.2468, found 645.2465.
3.68–3.61 (m, 12H), 3.58–3.50 (m, 8H). 13C NMR (100 MHz,
1,21,21,21-Tetraphenyl-2,5,8,11,14,17-hexaoxa-20-thiahenico- CDCl3) δ 138.3, 134.9, 130.3, 129.8, 128.4, 127.8, 127.7, 124.2,
sane 7e was prepared from triphenylmethyl mercaptan and 123.3, 112.7, 111.0, 100.9, 73.3, 70.8, 70.7, 70.6, 70.6, 70.6, 70.2,
benzyl alcohol by following the general procedure for the 69.5, 46.5. HRMS (ESI) calcd for C27H36BrNNaO6 ([M + Na]+)
+
preparation of hetero-substituted M-PEGs 6a as a yellow oil 572.1618, found 572.1614.
1
(209.3 mg, 83% yield). H NMR (400 MHz, CDCl3) δ 7.46–7.36
5-Bromo-1-(1,1,1-triphenyl-5,8,11,14,17-pentaoxa-2-thianona-
(m, 6H), 7.35–7.30 (m, 4H), 7.30–7.24 (m, 7H), 7.23–7.17 (m, decan-19-yl)-1H-indole 7j was prepared from 5-bromine indole
3H), 4.56 (s, 2H), 3.68–3.60 (m, 16H), 3.55 (d, J = 3.5 Hz, 2H), and triphenylmethyl mercaptan by following the general pro-
3.44 (s, 2H), 3.29 (t, J = 6.8 Hz, 2H), 2.43 (t, J = 6.8 Hz, 2H). 13C cedure for the preparation of hetero-substituted M-PEGs 6a as a
1
NMR (100 MHz, CDCl3) δ 144.9, 138.3, 129.7, 128.4, 127.9, brown oil (180.7 mg, 63% yield). H NMR (400 MHz, CDCl3) δ
127.8, 127.7, 126.7, 73.3, 70.7, 70.6, 70.5, 70.2, 69.6, 69.5, 66.6, 7.72 (d, J = 1.3 Hz, 1H), 7.43–7.38 (m, 6H), 7.30–7.18 (m, 12H),
31.7. HRMS (ESI) calcd for C38H46NaO6S+ ([M + Na]+) 653.2907, 6.41 (d, J = 3.1 Hz, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.77 (t, J = 5.5
found 653.2901.
Hz, 2H), 3.60–3.50 (m, 14H), 3.45–3.42 (m, 2H), 3.29 (t, J = 6.9
17-(5-Bromo-1H-indol-1-yl)-N,N-diphenyl-3,6,9,12,15-penta- Hz, 2H), 2.42 (t, J = 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
oxaheptadecan-1-amine 7f was prepared from diphenylamine 144.9, 134.9, 130.3, 129.8, 129.7, 128.0, 126.7, 124.3, 123.4,
and 5-bromine indole by following the general procedure for 112.7, 111.0, 70.8, 70.7, 70.6, 70.6, 70.5, 70.2, 69.7, 66.7, 46.6,
the preparation of hetero-substituted M-PEGs 6a as a brown 31.7. HRMS (ESI) calcd for C39H44BrNNaO5S+ ([M + Na]+)
oil (178.2 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 7.72 740.2016, found 740.2012.
(d, J = 1.4 Hz, 1H), 7.27–7.21 (m, 6H), 7.16 (d, J = 3.1 Hz, 1H),
1,27-Diphenyl-2,5,8,11,14,17,20,23,26-nonaoxaheptacosane 8a
7.06–6.99 (m, 4H), 6.93 (t, J = 7.3 Hz, 2H), 6.40 (d, J = 3.0 Hz, was prepared from benzyl alcohol by following the general pro-
8544 | Org. Biomol. Chem., 2018, 16, 8537–8545
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
cedure for the preparation of homo-substituted M-PEGs 4a as a
clear oil (187.5 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ
7.37–7.29 (m, 8H), 7.29–7.25 (m, 2H), 4.56 (s, 4H), 3.70–3.59 (m,
Opin. Drug Delivery, 2008, 5, 593–614; (f) V. Gaberc-Porekar,
I. Zore, B. Podobnik and V. Menart, Curr. Opin. Drug
Discovery Dev., 2008, 11, 242–250.
32H). 13C NMR (100 MHz, CDCl3) δ 138.4, 128.4, 127.8, 127.7, 3 (a) E. M. D. Keegstra, J. W. Zwikker, M. R. Roest and
+
73.3, 70.7, 70.7, 70.6, 69.5. HRMS (ESI) calcd for C30H46NaO9
([M + Na]+) 573.3034, found 573.3036.
L. W. Jenneskens, J. Org. Chem., 1992, 57, 6678–6680;
(b) A. Harada, J. Li and M. Kamachi, J. Am. Chem. Soc., 1994,
11, 3192–3196; (c) F. A. Loiseau, K. K. Hii and A. M. Hill,
J. Org. Chem., 2004, 69, 639–647; (d) S. A. Ahmed and
M. Tanaka, J. Org. Chem., 2006, 71, 9884–9886;
(e) D. Niculesco-Duvaz, J. Getaz and C. J. Springer,
Bioconjugate Chem., 2008, 19, 973–981; (f) A. C. French,
A. L. Thompson and B. G. Davis, Angew. Chem., Int. Ed., 2009,
48, 1248–1252; (g) G. Székely, M. Schaepertoens,
P. R. J. Gaffney and A. G. Livingston, Polym. Chem., 2014, 5,
694–697; (h) Y. Li, Q. Guo, X. Li, H. Zhang, F. Yu, W. Yu,
G. Xia, M. Fu, Z. Yang and Z.-X. Jiang, Tetrahedron Lett., 2014,
55, 2110–2113; (i) G. Székely, M. Schaepertoens,
P. R. J. Gaffney and A. G. Livingston, Chem. – Eur. J., 2014, 20,
10038–10051; ( j) K. Maranski, Y. G. Andreev and P. G. Bruce,
Angew. Chem., Int. Ed., 2014, 53, 6411–6413; (k) A. M. Wawro,
T. Muraoka and K. Kinbara, Polym. Chem., 2016, 7, 2389–
2394.
1,27,27,27-Tetraphenyl-2,5,8,11,14,17,20,23-octaoxa-26-thia-
heptacosane 8b was prepared from benzyl alcohol and tri-
phenylmethyl mercaptan by following the general procedure
for the preparation of hetero-substituted M-PEGs 6a as a
brown oil (192.3 mg, 67% yield). 1H NMR (400 MHz, CDCl3)
δ 7.41 (d, J = 7.5 Hz, 6H), 7.36–7.30 (m, 4H), 7.29–7.24 (m, 7H),
7.22–7.17 (m, 3H), 4.56 (s, 2H), 3.68–3.59 (m, 24H), 3.57–3.53
(m, 2H), 3.46–3.42 (m, 2H), 3.29 (t, J = 7.0 Hz, 2H), 2.42 (t, J =
6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 144.9, 138.4, 129.7,
128.4, 128.0, 127.8, 127.7, 126.7, 73.3, 70.7, 70.7, 70.6, 70.5,
70.2, 69.7, 69.5, 66.7, 31.7. HRMS (ESI) calcd for
C
42H54NaO8S+ ([M + Na]+) 741.3432, found 741.3448.
Conflicts of interest
The authors declare no conflicts of interest.
4 (a) M. Berna, D. Dalzoppo, G. Pasut, M. Manunta, L. Izzo,
A. T. Jones, R. Duncan and F. M. Veronese,
Biomacromolecules, 2006, 7, 146–153; (b) A. Bach, C. N. Chi,
G. F. Pang, L. Olsen, A. S. Kristensen, P. Jemth and
K. Strϕmgaard, Angew. Chem., Int. Ed., 2009, 48, 9685–9689;
(c) T. Muraoka, K. Adachi, M. Ui, S. Kawasaki,
N. Sadhukhan, H. Obara, H. Tochio, M. Shirakawa and
K. Kinbara, Angew. Chem., Int. Ed., 2013, 52, 2430–2434;
(d) W. Yu, Y. Yang, S. Bo, Y. Li, S. Chen, Z. Yang, X. Zheng,
Z.-X. Jiang and X. Zhou, J. Org. Chem., 2015, 80, 4443–4449;
(e) S. Bo, C. Song, Y. Li, W. Yu, S. Chen, X. Zhou, Z. Yang,
X. Zheng and Z.-X. Jiang, J. Org. Chem., 2015, 80, 6360–6366;
(f) Z. Yu, S. Bo, H. Wang, Y. Li, Z. Yang, Y. Huang and
Z.-X. Jiang, Mol. Pharm., 2017, 14, 3473–3479.
Acknowledgements
We are thankful for financial support from the National Key
R&D Program of China (2016YFC1304704) and the National
Natural Science Foundation of China (21402144, 21572168,
and 81625011).
Notes and references
1 For recent reviews, see: (a) J. M. Harris and R. B. Chess, Nat.
Rev. Drug Discovery, 2003, 2, 214–221; (b) F. M. Veronese and
G. Pasut, Drug Discovery Today, 2005, 10, 1451–1458; 5 (a) H. Zhang, X. Li, Q. Shi, Y. Li, G. Xia, L. Chen, Z. Yang
(c) F. M. Veronese and A. Mero, BioDrugs, 2008, 22, 315–329;
(d) C. S. Fishburn, J. Pharm. Sci., 2008, 97, 4167–4183;
(e) K. Knop, R. Hoogenboom, D. Ficher and U. S. Schubert,
Angew. Chem., Int. Ed., 2010, 49, 6288–6308; (f) S. Jevševar,
M. Kunstelj and V. G. Porekar, Biotechnol. J., 2010, 5, 113–
128; (g) M. C. Parrott and J. M. DeSimone, Nat. Chem., 2012,
and Z.-X. Jiang, Angew. Chem., Int. Ed., 2015, 54, 3763–3767;
(b) Y. Li, X. Qiu and Z.-X. Jiang, Org. Process Res. Dev., 2015,
19, 800–805; (c) G. Xia, Y. Li, Z. Yang and Z.-X. Jiang, Org.
Process Res. Dev., 2015, 19, 1769–1773; (d) Z. Wan, Y. Li,
S. Bo, M. Gao, X. Wang, K. Zeng, X. Tao, X. Li, Z. Yang and
Z.-X. Jiang, Org. Biomol. Chem., 2016, 14, 7912–7919.
4, 13–14; (h) J. Herzberger, K. Niederer, H. Pohlit, J. Seiwert, 6 (a) X. Liu, Y. Yuan, S. Bo, Y. Li, Z. Yang, X. Zhou, S. Chen
M. Worm, F. R. Wurm and H. Frey, Chem. Rev., 2016, 116,
2170–2243.
2 (a) A. P. Chapman, P. Antoniw, M. Spitali, S. West,
S. Stephens and D. J. King, Nat. Biotechnol., 1999, 17, 780–
783; (b) J. E. Seely and C. W. Richey, J. Chromatogr. A, 2001,
908, 235–241; (c) R. Haag and F. Kratz, Angew. Chem., Int.
and Z.-X. Jiang, Eur. J. Org. Chem., 2017, 4461–4468;
(b) S. Bo, Y. Yuan, Y. Chen, Z. Yang, S. Chen, Z. Yang,
X. Zhou and Z.-X. Jiang, Chem. Commun., 2018, 54, 3875–
3878; (c) Q. Peng, Y. Li, S. Bo, Y. Yuan, Z. Yang, S. Chen,
X. Zhou and Z.-X. Jiang, Chem. Commun., 2018, 54, 6000–
6003.
Ed., 2006, 45, 1198–1215; (d) C. J. Fee and J. M. van Alstine, 7 (a) Z.-X. Jiang and F.-L. Qing, J. Org. Chem., 2003, 68, 7544–
Chem. Eng. Sci., 2006, 61, 924–939; (e) M. J. Vicent,
L. Dieudonne, R. J. Carbajo and A. Pineda-Lucena, Expert
7547; (b) Z.-X. Jiang, Y.-Y. Qin and F.-L. Qing, J. Org. Chem.,
2004, 69, 5486–5489.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 8537–8545 | 8545