Synthesis of polyglycerol, porphyrin-cored dendrimers using click chemistry

Article abstract of DOI:10.1002/ejoc.200800401

Polyglycerol, porphyrin-cored dendrimers were synthesized by the click reaction of azide-cored polyglycerol dendrons and octa-alkynylporphyrin 19. The dendrons were synthesized divergently starting with TBDPS-protected allyl alcohol 2. Two, three and four

Full text of DOI:10.1002/ejoc.200800401

FULL PAPER
DOI: 10.1002/ejoc.200800401
Synthesis of Polyglycerol, Porphyrin-Cored Dendrimers Using Click Chemistry
Stephanie L. Elmer,[a] Sonny Man,[a] and Steven C. Zimmerman*[a]
Keywords: Azide / Dendrimers / Click chemistry / Biocompatibility / 1,3-Dipolar cycloaddition
Polyglycerol, porphyrin-cored dendrimers were synthesized
by the click reaction of azide-cored polyglycerol dendrons
and octa-alkynylporphyrin 19. The dendrons were synthe-
sized divergently starting with TBDPS-protected allyl alcohol
2. Two, three and four cycles of dihydroxylation-allyl etherifi-
cation gave dendrons [G-2.5] 6, [G-3.5] 8, [G-4.5] 11, with
four, eight, and sixteen alkene groups, respectively. Dendron
11 was readily prepared on large scale with an overall yield
of 45%. Dendron 8 was deprotected and converted into the
corresponding alkyne – and azide-cored dendron 13 and 15
in 89% and 75% yield, respectively. Dendron 11 was depro-
tected and converted into the corresponding alkyne – and
azide-cored dendron 16 and 18 in 68% and 24% yield,
respectively. Both the [G-3.5]-azide 15 and [G-4.5]-azide 18
were separately “clicked” to polyalkyne core 19 via the
Huisgen 1,3-dipolar cycloaddition to afford 20 and 21 in 65%
and 66% yield, respectively. Dendrimer 21 has a MW of ca.
16000 and 128 peripheral alkene groups.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Given the high yields reported in the preparation of
dendrimers using the Huisgen 1,3-dipolar cycloaddition
(“click”) reaction,[16–19] we sought to synthesize polygly-
cerol dendrons with either azide or alkyne focal points. The
goal was to enable attachment of biocompatible polygly-
cerol dendrons to a wide variety of materials, surfaces, or
molecular core units. In preparing the dendrons, it was nec-
essary to find a protecting group sufficiently robust to with-
stand the highly basic and oxidative conditions required for
divergent growth. A number of protecting groups were con-
sidered and the most promising based on ease of synthesis
and overall yield was the tert-butyldiphenylsilyl (TBDPS)
group.[20]
Herein we report the scalable synthesis of polyglycerol
dendrons [G-3.5]-8 and [G-4.5]-11, with eight and sixteen
peripheral alkene groups, respectively, and a single TBDPS-
protected alcohol group at the core. Both 8 and 11 were
deprotected and converted into the corresponding alkyne-
and azide-cored polyether dendrons. The azide-cored den-
drons readily underwent copper-catalyzed 1,3-dipolar cy-
cloaddition reaction with an octa-alkynyl tetraaryl-porphy-
rin. Using this approach, dendritic porphyrins with molecu-
lar weights close to 16000 were synthesized.
Introduction
Polyethylene glycol and materials derived from it con-
tinue to attract attention because of their applicability in
the fields of biotechnology and pharmacology.[1,2] The
properties of polyethylene glycol that make it among the
most useful polymers for biomedical applications include:
reactive chain ends, excellent water solubility, and a high
level of biocompatibility.
A wide range of polyethylene glycol-derived materials
and their analogs have been developed with considerable
interest in new architectures that may afford new and useful
properties. Particularly interesting in this regard are the po-
lyglycerol dendrimers, which have been explored as poten-
tial drug delivery agents,[3–6] as pH-responsive molecular
nanocarriers[7] and as soluble polymeric supports.[8,9]
The synthesis of these dendrimers was developed by
Haag and co-workers using an iterative two-step process
consisting of allylation using sodium hydroxide and allyl
chloride followed by catalytic dihydroxylation.[10] The den-
drimer was efficiently constructed in a divergent strategy
that started with a triol core. To the best of our knowledge
the synthesis had not been reported using core structures
that would leave functionality at the focal point.[11] We were
attracted to the possibility of using reactive groups at the
focal point to directly link polyglycerol dendrons to func-
tional cores. Although several other promising syntheses of
aliphatic polyether dendrimers have appeared in the litera-
ture,[12–14] our favourable experience with the Haag synthe-
sis led us to pursue this general approach.[15]
Results and Discussion
The synthesis of TBDPS-protected dendrons [G-2.5] 6,
[G-3.5] 8, and [G-4.5] 11 and their deprotection is outlined
in Scheme 1. The synthesis began with allyl alcohol, a com-
mercially available and inexpensive starting material which
underwent TBDPS protection to provide 2 in high yield as
described by Carreira.[21] The dihydroxylation step em-
ployed catalytic osmium tetroxide and N-methylmorpholine
[a] Department of Chemistry, University of Illinois at Urbana-
Champaign,
600 S. Mathews Avenue, Urbana, IL 61801, USA
Fax: +1-217-244-9919
E-mail: sczimmer@uiuc.edu
Eur. J. Org. Chem. 2008, 3845–3851
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3845

S. L. Elmer, S. Man, S. C. Zimmerman
FULL PAPER
Scheme 1. a) TBDPS-Cl, imidazole, DMF; b) OsO4, NMO, acetone, water, tert-butyl alcohol; c) allyl bromide, NaH, TBAI, DMF; d)
TBAF, THF.
oxide (NMO) as cooxidant.[22] However, it was found that ing with allyl alcohol, 12 grams of dendron 8 were readily
traces of DMF remaining in 2 were problematic, so a silica prepared in about one week with a yield of 58% over seven
gel plug was used to remove all traces of DMF. Using mate- steps. Additionally, it was observed that the dihydroxylation
rial purified in this manner, 3 was obtained in 96% yield. steps could be performed using K2OsO4·2H2O instead of
Because of the lipophilic TBDPS group, it was readily sepa- OsO4, and the crude products obtained could be used in
rated from unreacted NMO and N-methylmorpholine the next reaction without purification with no change in
(NMM) byproduct by ethyl acetate extraction.
yield. The K2OsO4·2H2O was less volatile and had a longer
The allylation of 3 employed classical Williamson etheri- shelf-life.
fication conditions and was best effected using allyl bro-
Subsequent dihydroxylation of 8 afforded the [G-4]-
mide, sodium hydride, and tetrabutylammonium iodide as dendron 10 in 91% yield. Dendron 10 contained a small
a phase-transfer catalyst. Because of the close proximity of amount of NMO impurity even after repeated extractions
the alcohol groups to the silyl group, reaction conditions using a 9:1 ratio of chloroform to 2-propanol. The [G-4]-
were chosen to discourage silyl migration.[23] To ensure that dendron 10 was found to be insoluble in tetrahydrofuran
silyl migration did not occur, 8 equivalents of allyl bromide therefore, it was necessary to run the allylation reaction in
per hydroxy group were added to the dendron in a minimal DMF. Allylation followed by purification by silica gel
amount of THF prior to the addition of the sodium hy- chromatography provided product 11 with 16 allyl groups
dride. In this manner a high concentration of allyl bromide in 66% yield. The material so isolated was shown to be pure
1
was present and product 4 could be obtained in 91% yield. by MALDI-TOF-MS, H NMR, 13C NMR and analytical
There was no evidence for any silyl migration in either the SEC.
1H or 13C NMR spectroscopy.
It was found that the allylated dendrons were not stable
Dihydroxylation of 4 with catalytic OsO4 proceeded in in air at room temperature. The decomposition mechanism
92% yield to produce alcohol 5. After this second cycle di- or product was not firmly established but the observation
hydroxylation, the product could still readily be purified by of an insoluble gel formation after a few days suggests a
extraction into ethyl acetate. Alcohol 5 was allylated to pro- free-radical polymerization. Even the [G-1.5]-dendron 4 po-
duce dendron 6 in 96% yield followed by dihydroxylation lymerized after storage open to air at room temperature for
to afford alcohol 7 in 98% yield. The polyhydroxy [G-3]-
dendron could not be extracted into ethyl acetate however,
repeated extractions using a 9:1 mixture of chloroform to
2-propanol provided a product containing only a small
1
amount of the NMO/NMM impurity by H NMR spec-
troscopy. Allylation of 7 to afford the [G-3.5]-dendron 8
proceeded in 99% yield. The [G-3.5]-protected dendron 8
was shown to be pure by MALDI-TOF-MS, 1H NMR and
the analytical SEC.
Using the TBDPS protecting group, this scheme has been
shown to be amenable to large-scale synthesis. Thus, start- Scheme 2. Synthesis of 13 and 15.
3846
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3845–3851

Porphyrin-Cored Dendrimers
several months. As observed by Haag and co-workers,[10]
the perallylated dendrons tend to cross-link within several
days. Therefore, it was necessary to store these materials in
the freezer after backfilling the containers with nitrogen.
Using these precautions, it was possible to store the den-
drons for up to six months with no observed polymeriza-
tion.
The focal point of [G-3.5]-ol 9 and [G-4.5]-ol 12 was pro-
pargylated by treatment with sodium hydride and propargyl
bromide, affording the [G-3.5]-alkyne 13 and [G-4.5]-alkyne
16 in 91% yield and 69%, respectively (Scheme 2 and
Scheme 3. Synthesis of 16 and 18.
Figure 1. MALDI-TOF-MS spectra of dendron a) 13, b) 15, c) 16, and d) 18.
Scheme 4. Synthesis of dendrimers 20 and 21 using click chemistry and porphyrin core 19.
Eur. J. Org. Chem. 2008, 3845–3851
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3847

S. L. Elmer, S. Man, S. C. Zimmerman
FULL PAPER
Scheme 3). Dendrons 9 and 12 could also be converted into cal SEC. As seen in Figure 2 (a), dendrimer 20 appears to
the [G-3.5]-azide 15 and the [G-4.5]-azide 18 using a two- be homogeneous with a full eight attachments present. Typ-
step approach with tosylation followed by sodium azide dis- ical for highly branched macromolecules the SEC deter-
placement, the desired products obtained in an overall yield mined molecular weight underestimates the actual value.
of 70% and 27%, respectively. Identification of the focal The SEC does show the presence of dimer, which reflects
group functionality by 1H and 13C NMR as well as by ESI- the beginning of the oligomerization observed with all of
MS and MALDI-TOF-MS facilitated the characterization the polyallyl polyglycerol dendrimers unless care is taken
of these compounds. In CDCl3 the carbon adjacent to the to exclude oxygen. Alternatively, the alkene groups may be
alcohol group was readily distinguished from the carbon dihydroxylated to provide stable material, something that
peak adjacent to the azide or the alkyne groups by 13C was observed with the dendrons, but not yet examined with
NMR spectroscopy. In the 13C NMR spectrum the carbon the dendrimers. Dendrimer 21 was observed by MALDI-
adjacent to the alcohol exhibited a peak at δ = 62.6 ppm as TOF-MS to contain a mixture of 6, 7, and 8 attachments,
compared to the peaks at δ = 58.8 and 52.1 ppm for the with the latter predominating. (Figure 2, c). Nonetheless,
carbons adjacent to the alkyne and azide, respectively. The the measured PDI was quite low (Figure 2, d).
molecular weight determinations for the 3rd and 4th gener-
ation azide and alkyne dendrons were confirmed by
MALDI-TOF-MS. Thus, shown in Figure 1 are the spectra
with peaks corresponding primarily to the sodium and po-
tassium adducts of 13, 15, 16 and 18.
A copper-catalyzed 1,3-dipolar cycloaddition was in-
duced between porphyrin core 19 containing eight alkyne
groups and azides [G-3.5]-15 and [G-4.5]-18 (Scheme 4).
The porphyrin was chosen as a conveniently prepared,
multivalent core with a strong UV/Vis signal. Additionally,
there has been considerable interest in dendritic por-
phyrins.[24]
The crude products were purified by silica gel
chromatography followed by preparative SEC chromatog-
raphy, affording the desired dendrimers 20 and 21 in 65%
and 66% yield, respectively. The 1H NMR spectra were
consistent with the assigned structures, but the dendrimers
were best characterized by MALDI-TOF-MS and analyti-
Conclusions
Polyether dendrons containing a TBDPS protecting
group have been synthesized in high yield and high purity.
The synthesis proceeds very rapidly and purification by col-
umn chromatography is only necessary after the allylation
steps. After deprotection of the TBDPS group, the focal
point of the polyether dendrons can be readily converted to
a wide variety of functional groups including the azide and
alkyne group. Dendrons containing azide focal points have
been shown to attach to polyalkynyl cores in good yields
using the copper-catalyzed 1,3-dipolar cycloaddition
(“click”) reaction. Even highly congested, high molecular
weight dendrimers such as 21 with 128 allyl ether groups
on their periphery can be made in this manner. Overall, the
chemistry is likely to be particularly useful both for making
biocompatible nanostructures and for mono-molecular im-
printing.[25]
Experimental Section
General Dihydroxylation Procedure: The allyl compound was vigor-
ously stirred in a 5:3:1 acetone/water/tert-butyl alcohol mixture at
a concentration of 0.6  at room temperature under ambient atmo-
sphere. To this was added a 50 wt.-% solution of N-methylmorph-
oline N-oxide (NMO) in water (1.10 mmol per alkene) followed
by OsO4 (0.25 mol-% per alkene). When the starting material had
disappeared according to TLC analysis, the solvents were removed
in vacuo at 50 °C. The residue was evaporated twice at 40 °C with
toluene in vacuo to give the crude product as a brown viscous oil.
General NaH Allylation Procedure: To the crude diol was added
allyl bromide, tetrabutylammonium iodide (TBAI) and THF. The
reaction vessel was cooled to 0 °C and NaH (60% in mineral oil)
was added slowly with vigorous stirring. The reaction vessel was
warmed to room temperature. After 20 h water was added and the
dendrimer extracted with EtOAc.
3-(tert-Butyl-diphenyl-silyloxy)propane-1,2-diol (3): To 5.6 g of 2,
was added 2.3 g (14 mmol) NMO, 9 mL acetone, 9 mL H2O,
1.8 mL tert-butyl alcohol and 0.3 mL OsO4 (4 wt.-% in H2O).
Using the general dihydroxylation procedure, a brown oil was ob-
tained that could be used in the next step without purification.
Extracted with EtOAc (3ϫ100 mL), dried with sodium sulfate, fil-
tered and evaporated to obtain 6.0 g (96%) of a beige solid. 1H
Figure 2. MALDI-TOF-MS spectra of dendrimers (a) 20 and (c)
21 and analytical SEC chromatograms of (b) 20 and (d) 21.
3848
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3845–3851

Porphyrin-Cored Dendrimers
NMR (CDCl3, 400 MHz): δ = 7.67 (m, 4 H), 7.42 (m, 6 H), 3.81 lylation procedure, obtained a crude brown oil. Purified using col-
(m, 1 H), 3.69 (m, 4 H), 2.71 (d, J = 4.8 Hz, 1 H), 2.20 (t, J = umn chromatography (silica gel, 9:1 PE/EtOAc to 4:1 PE/EtOAc)
4.8 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 135.8, 133.1,
130.2, 128.1, 72.1, 65.5, 64.1, 27.1, 19.5 ppm. MS (ESI): m/z =
331.5 [MH+].
to afford 1.4 g (99 %) of a light yellow oil. 1H NMR (CDCl3,
500 MHz): δ = 7.66 (m, 4 H), 7.38 (m, 6 H), 5.87 (m, 8 H), 5.24
(m, 8 H), 5.12 (m, 8 H), 4.12 (m, 8 H), 3.97 (m, 8 H), 3.57 (m, 35
H), 1.04 (s, 9 H) ppm. 13C NMR (CDCl3, 126 MHz): δ = 135.8,
135.5, 135.1, 135.0, 129.9, 127.9, 117.1, 117.0, 116.9, 116.8, 79.1,
77.6, 77.5, 77.3, 77.2, 72.5, 72.0, 71.8, 71.5, 71.4, 70.6, 70.5, 70.4,
27.0, 19.4 ppm. MS (MALDI-TOF-MS): m/z = 1117.8 [M + Na+],
1134.2 [M + K+].
[2,3-Bis(allyloxy)propoxy]-tert-butyl-diphenylsilane (4): To 2.8 g
(8.3 mmol) of the crude diol 3 in 20 mL THF was added 12 mL
(0.14 mol) allyl bromide and 14 mg (0.039 mmol) TBAI. Using the
general NaH allylation procedure, obtained a crude brown oil.
Purified using column chromatography (silica gel, 9:1 PE/EtOAc)
to obtain 3.1 g (91%) of 4 as a white solid. 1H NMR (CDCl3,
400 MHz): δ = 7.71 (m, 4 H), 7.42 (m, 6 H), 5.92 (ddt, J = 17.2,
14.4, 10.4, 4.8 Hz, 2 H), 5.28 (ddt, J = 17.2, 6.6, 1.6 Hz, 2 H), 5.17
(ddt, J = 14.4, 10.4, 1.6 Hz, 2 H), 4.11 (m, 2 H), 4.03 (m, 2 H),
2,3-Bis{2,3-bis[2,3-bis(allyloxy)propoxy]propoxy}propan-1-ol (9): To
0.55 g (0.50 mmol) of 8 in 6 mL THF was added 2.0 mL (2.0 mmol)
of TBAF (1.0  in THF). After 20 h evaporated to remove residual
solvent. Extracted with EtOAc (3ϫ50 mL), washed with 50 mL
H2O, dried with sodium sulfate, filtered and the solvents evapo-
rated. Purified using column chromatography [silica gel, 9:1 PE/
EtOAc (0.5 L), 1:1 PE/EtOAc (0.5 L)] to obtain 0.42 g (98%) of a
3.77 (m, 2 H), 3.67 (m, 2 H), 3.58 (m, 1 H), 1.08 (s, 9 H) ppm. 13
C
NMR (CDCl3, 100 MHz): δ = 135.9, 135.5, 135.1, 133.9, 129.9,
127.9, 117.1, 117.0, 78.9, 72.6, 71.6, 70.4, 63.6, 27.1, 19.5 ppm. MS
(ESI): m/z = 433.3 [M + Na+].
1
light yellow oil. H NMR (CDCl3, 500 MHz): δ = 5.90 (m, 8 H),
5.27 (m, 8 H), 5.16 (m, 8 H), 4.13 (m, 8 H), 3.99 (m, 8 H), 3.65
(m, 12 H), 3.53 (m, 23 H) ppm. 13C NMR (CDCl3, 126 MHz): δ
= 135.3, 135.4, 135.0, 134.9, 117.1, 117.0, 77.5, 77.3, 77.2, 72.6,
72.5, 71.9, 71.6, 71.5, 70.7, 70.4, 70.3, 70.0, 53.5 ppm. MS (ESI):
m/z = 857.7 [MH+].
3-{2-(tert-Butyl-diphenylsilyloxy)-1-[(2,3-dihydroxypropoxy)methyl]-
ethoxy}propane-1,2-diol (5): To 6.5 g (0.016 mol) of 4 was added
5.6 g (0.048 mol) NMO, 0.3 mL OsO4 (4 wt.-% in H2O), 9 mL ace-
tone, 9 mL H2O and 1.8 mL tert-butyl alcohol. Using the general
dihydroxylation procedure, obtained a white solid that could be
used in the next step without purification. Extracted with EtOAc
(3ϫ100 mL), dried with sodium sulfate, filtered and evaporated to
obtain 7.0 g (92%) of a yellow oil. 1H NMR (CDCl3, 400 MHz): δ
= 7.65 (m, 4 H), 7.40 (m, 6 H), 4.20 (m, 2 H), 3.82 (m, 2 H), 3.58
(m, 15 H), 1.05 (s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
135.8, 133.3, 130.1, 128.0, 80.6, 80.3, 78.0, 73.4, 73.1, 72.8, 72.3,
71.6, 71.1, 70.9, 70.8, 64.3, 64.2, 64.0, 63.5, 27.0, 19.4 ppm. MS
(ESI): m/z = 501.3 [M + Na+].
3-{3-[3-(2-{2,3-Bis[2,3-bis(2,3-dihydroxypropoxy)propoxy]propoxy}-
3-(tert-butyl-diphenylsilyloxy)propoxy)-2-[2,3-bis(2,3-dihydroxy)-
propoxy]propoxy]propoxy}-2-(2,3-dihydroxypropoxy)propoxy]-
propane-1,2-diol (10): To 2.2 g (2.0 mmol) of 8 was added 2.9 g
(25 mmol) NMO, 0.5 mL OsO4 (4 wt.-% in H2O), 9 mL acetone,
9 mL H2O and 3.0 mL tert-butyl alcohol. After 20 h evaporated
off solvents leaving a minimal amount of H2O. Extracted with 9:1
CHCl3/2-propanol (3ϫ200 mL), dried with sodium sulfate, filtered
and evaporated to afford 3.1 g (91%) of a yellow oil. 1H NMR
(DMSO, 500 MHz): δ = 7.64 (m, 4 H), 7.45 (m, 6 H), 4.60 (m, 16
H), 3.50 (m, 75 H), 0.99 (s, 9 H) ppm. 13C NMR (DMSO,
126 MHz): δ = 140.7, 140.5, 135.3, 133.3, 78.3, 77.1, 77.0, 76.3,
76.2, 75.9, 68.5, 32.0, 24.2 ppm. MS (MALDI-TOF-MS): m/z =
1390.3 [M + Na+].
2,3-Bis{[2,3-bis(allyloxy)propoxy]propoxy}-tert-butyl-diphenylsilane
(6): To 5.5 g (12 mmol) of the crude diol 5 was added 45 mL (0.49
mol) allyl bromide and 24 mg (0.06 mmol) TBAI in 50 mL THF.
Using the general allyation procedure, obtained a brown oil that
was purified using column chromatography (silica gel, 9:1 PE/
EtOAc) to afford 7.1 g (96 %) of a light yellow oil. 1H NMR
(CDCl3, 400 MHz): δ = 7.67 (m, 4 H), 7.39 (m, 6 H), 5.88 (m, 4
H), 5.24 (m, 4 H), 5.14 (m, 4 H), 4.11 (m, 4 H), 3.98 (m, 4 H), 3.70
(m, 2 H), 3.55 (m, 13 H), 1.05 (s, 9 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 135.8, 135.5, 135.4, 135.1, 135.0, 133.6, 129.9, 127.9,
118.2, 117.1, 117.0, 116.9, 80.4, 72.5, 71.9, 71.7, 71.6, 71.5, 70.6,
29.9, 27.0, 19.5 ppm. MS (ESI): m/z = 661.4 [M + Na+].
[2,3-Bis{2,3-bis(2,3-bis[2,3-bis(allyloxy)propoxy]propoxy)propoxy}-
propoxy]-tert-butyl-diphenylsilane (11): To 3.1 g (2.2 mmol) of 10
was added 26 mL (0.29 mmol) allyl bromide and 9.1 mg
(0.025 mmol) TBAI in 30 mL DMF. Using the general allylation
procedure, obtained a brown oil that was purified using column
chromatography [silica gel, 9:1 PE/EtOAc (1.0 L), 4:1 PE/EtOAc
(1.0 L), 1:1 PE/EtOAc (1.0 L)] to afford 2.7 g (66%) of a light yel-
3-[2-{2-[2,3-Bis(2,3-dihydroxypropoxy)propoxy]-3-(tert-butyl-di-
phenylsilyloxy)propoxy}-1-(2,3-dihydroxypropoxymethyl)ethoxy]-
propane-1,2-diol (7): To 3.3 g (5.1 mmol) of 6 was added 3.6 g
(30.7 mmol) NMO, 0.2 mL OsO4 (4 wt.-% in H2O), 7 mL acetone,
7 mL H2O and 4 mL tert-butyl alcohol. Using the general dihy-
droxylation procedure, obtained a crude brown oil that could be
used in the next step without purification. Extracted with 9:1
CHCl3/2-propanol (3ϫ200 mL), dried with sodium sulfate, filtered
and evaporated to obtain 3.9 g (98%) of a yellow oil. 1H NMR
(CDCl3, 400 MHz): δ = 7.66 (m, 4 H), 7.41 (m, 6 H), 4.66 (br. s, 3
H), 4.22 (br. s, 3 H), 3.85 (m, 2 H), 3.56 (m, 35 H), 1.05 (s, 9 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 135.8, 133.4, 130.1, 128.0,
80.6, 78.9, 78.7, 73.0, 72.2, 72.1, 71.9, 71.8, 71.7, 71.4, 71.3, 71.2,
71.1, 70.9, 63.9, 63.7, 63.4, 63.3, 27.1, 19.4 ppm. MS (ESI): m/z =
797.6 [M + Na+].
1
low oil. H NMR (CDCl3, 500 MHz): δ = 7.65 (m, 4 H), 7.38 (m,
6 H), 5.88 (m, 16 H), 5.25 (m, 16 H), 5.14 (m, 16 H), 4.11 (m, 16
H), 3.98 (m, 16 H), 3.54 (m, 75 H), 1.04 (s, 9 H) ppm. 13C NMR
(CDCl3, 126 MHz): δ = 135.8, 135.6, 135.5, 135.1, 135.0, 129.9,
128.0, 117.1, 117.0, 116.9, 116.8, 79.1, 78.9, 72.5, 72.0, 71.9, 71.7,
71.5, 70.7, 70.6, 70.5, 27.1, 19.5 ppm. MS (MALDI-TOF): m/z =
2031.7 [M + Na+], 2047.9 [M + K+].
3-[2-Allyloxy-3-(2-[2,3-bis(allyloxy)propoxy]-3-{2-(2,3-bis[2,3-bis-
(allyloxy)propoxy]propoxy)-3-prop-2-ynyloxypropoxy}propoxy)-
propoxy]propan-1-ol (12): To 2.02 g (1.0 mmol) of 11 in 5.0 mL
THF was added 4.0 mL of TBAF (1.0  in THF). After 20 h evap-
orated to remove residual solvent. Extracted with EtOAc
(3ϫ50 mL), washed with 50 mL H2O, dried with sodium sulfate,
filtered and the solvents evaporated. Purified using column
chromatography [silica gel, 9:1 PE/EtOAc (0.5 L), 1:1 PE/EtOAc
(0.5 L)] to obtain 1.64 (92 %) of a light yellow oil. 1H NMR
(CDCl3, 500 MHz): δ = 5.88 (m, 16 H), 5.25 (m, 16 H), 5.14 (m,
16 H), 4.11 (m, 16 H), 3.98 (m, 16 H), 3.54 (m, 75 H), 2.96 (s, 1
{2,3-Bis(2,3-bis[2,3-bis(allyloxy)propoxy]propoxy)propoxy}-tert-
butyl-diphenylsilane (8): To 1.0 g (1.3 mmol) of the crude brown
oil 7 was added 8.0 mL (88 mmol) allyl bromide and 5.0 mg
(0.014 mmol) TBAI in 9 mL THF. Using the general NaH al-
Eur. J. Org. Chem. 2008, 3845–3851
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3849

S. L. Elmer, S. Man, S. C. Zimmerman
FULL PAPER
H) ppm. 13C NMR (CDCl3, 126 MHz): δ = 135.8, 135.6, 135.5,
135.1, 135.0, 117.1, 117.0, 116.9, 116.8, 79.1, 78.9, 72.5, 72.0, 71.9,
71.7, 71.5, 70.7, 70.6, 70.5 ppm. MS (MALDI-TOF): m/z = 1792.3
[M + Na+], 2047.9 [M + K+].
EtOAc to 1:1 PE/EtOAc) to afford 0.15 g (69%) of a light yellow
oil. H NMR (CDCl3, 500 MHz): δ = 5.89 (m, 16 H), 5.26 (m, 16
1
H), 5.14 (m, 16 H), 4.15 (d, J = 1.5 Hz, 2 H), 4.11 (m, 16 H), 3.99
(m, 16 H), 3.54 (m, 75 H), 2.43 (t, J = 1.5 Hz, 1 H) ppm. 13C NMR
(CDCl3, 126 MHz): δ = 135.8, 135.6, 135.5, 135.1, 135.0, 117.1,
117.0, 116.9, 116.8, 79.1, 78.9, 72.5, 72.0, 71.9, 71.7, 71.5, 70.7,
70.6, 70.5, 58.8 ppm. MS (MALDI-TOF): m/z = 1807.2 [M + Na+],
1823.3 [M + K+].
3-[2-Allyloxy-3-(2-[2,3-bis(allyloxy)propoxy]-3-{2-(2,3-bis[2,3-bis-
(allyloxy)propoxy]propoxy)-3-prop-2-ynyloxypropoxy}propoxy)-
propoxy]propene (13): To 0.51 g (0.59 mmol) of 9 was added
0.53 mL (4.8 mmol) propargyl bromide (80 wt.-% in toluene) and
24 mg (0.065 mmol) TBAI in 5 mL THF. The reaction vessel was
cooled to 0 °C and 78 mg (2.0 mmol) of sodium hydride (60 wt.-%
in mineral oil) was added slowly. The reaction vessel was warmed
to room temperature. After 16 h added 20 mL H2O and evaporated
off solvent. Extracted with EtOAc (3ϫ50 mL), washed with 50 mL
H2O, dried with sodium sulfate, filtered and the solvents evapo-
rated. Purified using column chromatography (silica gel, 9:1 PE/
3-(2-Allyloxy-3-[2-(2,3-bis(allyloxy)propoxy]-3-{2-[2,3-bis[2,3-bis-
(allyloxy)propoxy]propoxy)-3-prop-2-ynyloxypropoxy}propoxy)-
propoxy]propyl Toluene-4-sulfonate (17): To 4.2 g (2.35 mmol) of 12
was added 2.325 g (12 mmol) tosyl chloride and 2 mL (14 mmol)
triethylamine in 20 mL CH2Cl2. The mixture was stirred at room
temperature overnight. The mixture was diluted with H2O (50 mL)
and extracted with CH2Cl2 (3ϫ100 mL). The organic layer was
EtOAc to 1:1 PE/EtOAc) to afford 0.48 g (91%) of a light yellow dried with MgSO4, filtered, and concentrated under vacuum. The
oil. 1H NMR (CDCl3, 400 MHz): δ = 5.90 (m, 8 H), 5.26 (m, 8 H), crude material was purified by column chromatography (silica gel,
5.15 (m, 8 H), 4.15 (d, J = 1.6 Hz, 2 H), 4.13 (m, 8 H), 3.99 (m, 8
H), 3.65 (m, 11 H), 3.53 (m, 24 H), 2.43 (t, J = 1.6 Hz, 1 H) ppm.
2:1 PE/EtOAc to EtOAc) to afford a 4.198 g (93%) of yellow oil
1H NMR (CDCl3, 500 MHz): δ = 7.78 (d, J = 8.0 Hz, 2 H), 7.34
13C NMR (CDCl3, 100 MHz): δ = 135.6, 135.5, 135.1, 135.0, 117.1, (d, J = 8.0 Hz, 2 H), 5.89 (m, 16 H), 5.26 (m, 16 H), 5.14 (m, 16
117.0, 116.9, 116.8, 116.7, 79.9, 79.0, 78.8, 78.6, 77.2, 74.8, 72.5,
72.0, 71.9, 71.8, 71.7, 71.5, 71.3, 71.2, 70.7, 70.6, 70.5, 70.0, 58.8
ppm. MS (ESI): m/z = 917.7 [M + Na+].
H), 4.13 (d, J = 4.8 Hz, 16 H), 3.99 (d, J = 4.8 Hz, 16 H), 3.73–
3.33 (m, 75 H), 2.44 (s, 3 H) ppm. 13C NMR (CDCl3, 126 MHz):
δ = 144.8, 135.4, 135.3, 134.9, 134.8, 129.9, 128.0, 116.9, 116.8,
116.7, 116.6, 78.9, 78.6, 78.4, 72.3, 71.8, 71.7, 71.6, 71.4, 71.3, 70.5,
70.4, 70.3, 70.2, 69.6, 69.5 ppm. MS (MALDI-TOF): m/z = 1946.21
[M + Na+], 1962.3 [M + K+].
2,3-Bis{2,3-bis[2,3-bis(allyloxy)propoxy]propoxy}propyl Toluene-4-
sulfonate (14): To 0.70 g (0.82 mmol) of 9 in 5 mL CH2Cl2 was
added 0.32 g (1.7 mmol) of tosyl chloride and 0.46 mL (3.3 mmol)
triethylamine. After 20 h added 20 mL H2O and evaporated off
solvents. Extracted with EtOAc (3ϫ75 mL), washed with 75 mL
H2O, dried with sodium sulfate, filtered and the solvents evapo-
rated. Purified using column chromatography [silica gel, 9:1 PE/
Dendron 18: To 4.2 g (2.2 mmol) of 17 in 30 mL DMF was added
0.73 g (11.23 mmol) of sodium azide. The reaction was heated to
40 °C. After 23 h added 2  NaOH (50 mL) and extracted with
EtOAc (3ϫ75 mL). The organic layer was washed with H2O
EtOAc (0.5 L), 4:1 PE/EtOAc (0.5 L) and 7:3 PE/EtOAc (0.5 L)] to (75 mL), washed with brine (75 mL), dried with MgSO4, filtered,
obtain 0.70 g (84 %) of a light yellow oil. 1H NMR (CDCl3, and concentration under vacuum. The crude material was purified
400 MHz): δ = 7.77 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H),
by column chromatography (silica gel, 2:1 PE/EtOAc to 1:2 PE/
5.89 (m, 8 H), 5.25 (m, 8 H), 5.14 (m, 8 H), 4.12 (m, 9 H), 3.98 EtOAc) to afford 1.136 g (29%) viscous yellow oil. 1H NMR
(m, 9 H), 3.63 (m, 9 H), 3.50 (m, 24 H), 2.43 (s, 3 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 145.0, 135.5, 135.4, 135.0, 133.2,
130.1, 128.2, 117.2, 117.1, 117.0, 78.9, 78.7, 77.5, 77.2, 77.1, 77.0,
72.6, 72.5, 71.9, 71.8, 71.5, 71.4, 70.7, 70.6, 70.4, 70.3, 70.1,
21.9 ppm. MS (MALDI-TOF): m/z = 1034.4 [M + Na+], 1050.2
[M + K+].
(CDCl3, 500 MHz): δ = 5.91 (m, 16 H), 5.28 (m, 16 H), 5.17 (m,
16 H), 4.15 (d, J = 5.3 Hz, 16 H), 4.01 (d, J = 2.3 Hz, 16 H), 3.73–
3.39 (m, 75 H) ppm. 13C NMR (CDCl3, 126 MHz): δ = 135.5,
135.4, 135.0, 117.1, 117.0, 116.9, 79.1, 78.8, 72.6, 72.5, 71.9, 71.6,
71.5, 70.5, 70.4 ppm. MS (MALDI-TOF): m/z = m/z 1816.5 [M +
Na+].
3-(2-Allyloxy-3-[3-{3-azido-2-(2,3-bis[2,3-bis(allyloxy)propoxy]-
Porphyrin Click Dendron Core 19: To 0.27 g (0.37 mmol) of
propoxy)propoxy}-2-(2,3-bis(allyloxypropoxy)propoxy]propoxy)- 5,10,15,20-tetrakis(3Ј,5Ј-dihydroxyphenyl)porphyrin and 1.32 g
propene (15): To 1.1 g of 14 in 12 mL DMF was added 0.29 g
(4.5 mmol) of sodium azide. The reaction was heated to 80 °C.
After 20 h added 100 mL H2O, extracted with EtOAc (3ϫ50 mL),
washed with H2O (2ϫ100 mL), dried with sodium sulfate, filtered
(9.5 mmol) of K2CO3 in 5 mL DMF was added. To the DMF solu-
tion, propargyl bromide (80 wt.-%) in toluene solution (0.7 mL)
was added. The mixture was stirred at room temperature overnight.
The resulting crude solid was diluted with 2  NaOH (25 mL) and
extracted with CH2Cl2 (2ϫ100 mL). The organic layer was washed
and the solvents evaporated. Obtained 0.89 g (91%) of a light yel-
1
low oil. H NMR (CDCl3, 400 MHz): δ = 5.88 (m, 8 H), 5.25 (m, with water (50 mL) and brine (50 mL), dried with Na2SO4, filtered,
8 H), 5.14 (m, 8 H), 4.12 (m, 8 H), 3.98 (m, 8 H), 3.56 (m, 34 H), and concentrated under vacuum. The crude material was purified
3.35 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 135.5, 135.4, by column chromatography (silica gel, CH2Cl2) to afford 0.21 g
1
135.0, 134.9, 117.0, 116.9, 116.8, 78.9, 78.6, 77.5, 72.5, 72.4, 71.9,
71.8, 71.5, 71.4, 70.7, 70.6, 70.5, 70.4, 70.3, 52.1 ppm. MS (ESI):
m/z = 904.5 [M + Na+].
(54%) of purple solid. H NMR (CDCl3, 500 MHz): δ = 8.95 (s, 8
H), 7.51 (d, J = 2.3 Hz, 8 H), 7.07 (t, J = 2.3 Hz, 4 H), 4.88 (d, J
= 2.3 Hz, 16 H), 2.60 (t, J = 2.3 Hz, 8 H), –2.88 (s, 2 H) ppm. 13C
NMR (CDCl3, 126 MHz): δ = 157.0, 144.2, 119.6, 115.5, 102.4,
78.6, 76.2, 56.4 ppm. HRMS (ESI): m/z = 1047.3 [MH+].
C68H46N4O8 (1047.13): calcd. C 78.00, H 4.43, N 5.35; found C
77.63, H 4.23, N 5.38.
Dendron (16): To 0.20 g (0.12 mmol) of 12 was added 0.10 mL
(1.1 mmol) propargyl bromide (80 wt.-% in toluene) and 5.5 mg
(0.015 mmol) TBAI in 3 mL THF. The reaction vessel was cooled
to 0 °C and 24 mg (0.59 mmol) of sodium hydride (60 wt.-% in
mineral oil) was added slowly. The reaction vessel was warmed to
room temperature. After 16 h added 20 mL H2O and evaporated
off solvent. Extracted with EtOAc (3ϫ50 mL), washed with 50 mL
H2O, dried with sodium sulfate, filtered and the solvents evapo-
rated. Purified using column chromatography (silica gel, 9:1 PE/
Porphyrin Dendrimer 20: To 0.53 g (0.601 mmol) of 15 and 0.062 g
(0.059 mmol) of 19 in 10 mL CH2Cl2/H2O (1:1, v/v), 0.074 g
(0.30 mmol) CuSO4·2H2O and 0.094 g (0.473 mmol) sodium--as-
corbate were added. After 6 d, the mixture was diluted with H2O
(50 mL) and extracted with CH2Cl2 (3ϫ50 mL). The organic layer
3850
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3845–3851

Porphyrin-Cored Dendrimers
[8]
[9]
[10]
H. Frey, R. Haag, Rev. Mol. Biotechnol. 2002, 90, 257–267.
R. Haag, Chem. Eur. J. 2001, 7, 327–335.
R. Haag, A. Sunder, J. F. Stumbé, J. Am. Chem. Soc. 2000, 122,
2954–2955.
was dried with MgSO4, filtered, and concentrated under vacuum.
The crude was purified by column chromatography (silica gel, 1:1
PE/EtOAc to EtOAc to 4:1 EtOAc/MeOH) and by preparative
SEC [Bio-Beads S-X1 200–400 mesh beads (Bio-Rad), toluene] to
afford a viscous dark purple oil. 1H NMR (CDCl3, 500 MHz): δ =
7.89 (s, 8 H), 5.84 (m, 64 H), 5.36–4.87 (m, 128 H), 4.59 (s, 16 H),
4.24–3.77 (m, 128 H), 3.75–3.22 (m, 266 H) ppm. 13C NMR
(CDCl3, 126 MHz): δ = 135.4, 134.9, 117.1, 117.0, 116.9, 78.7, 72.5,
72.3, 71.9, 71.4, 70.8, 70.7, 70.5, 70.3, 70.8, 70.2, 70.1 ppm. MS
(MALDI-TOF): m/z = 8126.7 [M + Na+].
[11]
During the course of this investigation, the synthesis of poly-
glycerol dendrons with amine cores was described: a) M.
Wyszogrodzka, K. Möws, S. Kamlage, J. Wodzin´ska, B. Pli-
etker, R. Haag, Eur. J. Chem. Org. 2008, 53–63; b) M. Wyszog-
rodzka, R. Haag, Polym. Mater. Sci. Eng. 2007, 48, 760–761.
M. Jayaraman, J. M. J. Fréchet, J. Am. Chem. Soc. 1998, 120,
12996–12997.
S. M. Grayson, M. Jayaraman, J. M. J. Fréchet, Chem. Com-
mun. 1999, 1329–1330.
A. B. Padias, H. K. Hall, D. A. Tomalia, J. R. McConnell, J.
Org. Chem. 1987, 52, 5305–5312.
S. C. Zimmerman, J. R. Quinn, E. Burakowska, R. Haag, An-
gew. Chem. Int. Ed. 2007, 46, 8164–8167.
M. Malkoch, K. Schleicher, E. Drockenmuller, C. J. Hawker,
T. P. Russell, P. Wu, V. V. Fokin, Macromolecules 2005, 38,
3663–3678.
J. W. Lee, J. H. Kim, B. K. Kim, W. S. Shin, S. H. Jin, Tetrahe-
dron 2006, 62, 894–900.
E. Fernandez-Megia, J. Correa, I. Rodriguez-Meizoso, R. Rig-
uera, Macromolecules 2006, 39, 2113–2120.
[12]
[13]
[14]
[15]
[16]
Porphyrin Dendrimer 21: To 0.487 g (0.271 mmol) of 18 and 0.033 g
(0.031 mmol) of 19 in 18 mL CH2Cl2/H2O (1:1, v/v), 0.14 g
(0.58 mmol) CuSO4·2H2O and 0.114 g (0.575 mmol) sodium--as-
corbate were added. After 5 d, the mixture was diluted with H2O
(50 mL) and extracted with CH2Cl2 (5ϫ50 mL). The organic layer
was dried with MgSO4, filtered, and concentrated under vacuum.
The crude was purified by column chromatography (silica gel,
CH2Cl2 to 95:5 CH2Cl2/MeOH) and preparative SEC [Bio-Beads
S-X1 200–400 mesh beads (Bio-Rad), toluene] to afford a viscous
dark purple oil. Although 21 is a mixture, the NMR spectrum
showed peaks consistent with product, presumably as a result of
[17]
[18]
[19]
1
similar chemical shifts for the various products. H NMR (CDCl3,
D. T. S. Rijkers, G. Wilma van Esse, R. Merkx, A. J. Brouwer,
H. J. F. Jacobs, R. J. Pieters, R. M. J. Liskamp, Chem. Com-
mun. 2005, 4581–4583.
S. Hanessian, P. Lavallee, Can. J. Chem. 1975, 53, 2975–2977.
J. Waser, B. Gaspar, H. Nambu, E. M. Carreira, J. Am. Chem.
Soc. 2006, 128, 11693–11712.
500 MHz): δ = 7.89 (s, 8 H), 5.87 (m, 128 H), 5.44–4.94 (m, 256
H), 4.58 (s, 16 H), 4.27–3.82 (m, 256 H), 3.78–3.20 (m, 586 H)
ppm. 13C NMR (CDCl3, 126 MHz): δ = 135.5, 135.0, 134.9, 117.1,
116.9, 116.8, 77.9, 76.7, 72.4, 71.8, 71.7, 71.4, 71.3, 70.6, 70.4 ppm.
MS (MALDI-TOF): m/z = 15600.1 [M + Na+].
[20]
[21]
[22]
[23]
V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett. 1976,
23, 1973–1976.
Acknowledgments
a) R. W. Friesen, A. K. Daljeet, Tetrahedron Lett. 1990, 31,
6133–6136; b) M. Delgado, J. D. Martin, J. Org. Chem. 1999,
64, 4798–4816.
This work was funded by the National Institutes of Health (NIH)
(GM61067).
[24]
[25]
a) P. Bhyrappa, J. K. Young, J. S. Moore, K. S. Suslick, J. Am.
Chem. Soc. 1996, 118, 5708–5711; b) P. J. Dandliker, F. Dieder-
ich, J.-P. Gisselbrecht, A. Louati, M. Gross, Angew. Chem. Int.
Ed. Engl. 1995, 34, 2725–2728; c) R. Sadamoto, N. Tomioka,
T. Aida, J. Am. Chem. Soc. 1996, 118, 3978–3979; d) E. M.
Harth, S. Hecht, B. Helms, E. E. Malmstrom, J. M. J. Fréchet,
C. J. Hawker, J. Am. Chem. Soc. 2002, 124, 3926–3938; e) S. C.
Zimmerman, I. Zharov, M. S. Wendland, N. A. Rakow, K. S.
Suslick, J. Am. Chem. Soc. 2003, 125, 13504–13518.
a) S. C. Zimmerman, N. G. Lemcoff, Chem. Commun. 2004, 5–
14; b) E. Mertz, S. C. Zimmerman, J. Am. Chem. Soc. 2003,
125, 3424–3425; c) S. C. Zimmerman, M. S. Wendland, N. A.
Rakow, I. Zharov, K. S. Suslick, Nature 2002, 418, 399–403; d)
E. Mertz, S. L. Elmer, A. M. Balija, S. C. Zimmerman, Tetra-
hedron 2004, 60, 11191–11204.
[1] J. M. Harris, Poly(ethylene glycol) Chemistry. Biotechnical and
Biomedical Applications, Plenum Press, New York, 1992.
[2] J. M. Harris, S. Zalipsky, Poly(ethylene glycol): Chemistry and
Biological Applications, Am. Chem. Soc., Washington D. C.,
1997.
[3] T. Ooya, J. Lee, K. Park, J. Controlled Release 2003, 93, 121–
127.
[4] T. Ooya, K. M. Huh, M. Saitoh, E. Tamiya, K. Park, Sci. Tech-
nol. Adv. Mater. 2005, 6, 452–456.
[5] T. Ooya, J. Lee, K. Park, Bioconj. Chem. 2004, 15, 1221–1229.
[6] L. T. Tziveleka, C. Kontoyianni, Z. Sideratou, D. Tsiourvas,
C. M. Paleos, Macromol. Biosci. 2006, 6, 161–169.
[7] M. Krämer, J. F. Stumbé, H. Türk, S. Krause, A. Komp, L.
Delineau, S. Prokhorova, H. Kautz, R. Haag, Angew. Chem.
Int. Ed. 2002, 41, 4252–4256.
Received: April 23, 2008
Published Online: June 13, 2008
Eur. J. Org. Chem. 2008, 3845–3851
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3851