Click chemistry inspired synthesis of glycoporphyrin dendrimers

Article abstract of DOI:10.1021/jo4012392

A series of porphyrin-cored glycodendrimers containing 8, 12, 16, and 24 β-d-glucopyranose units at the periphery, have been synthesized by convergent methodology using click chemistry. The structure of developed dendrimers is established by ¹H

Full text of DOI:10.1021/jo4012392

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Click Chemistry inspired Synthesis of Glycoporphyrin Dendrimers
Divya Kushwaha, and Vinod K. Tiwari
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4012392 • Publication Date (Web): 17 Jul 2013
Downloaded from http://pubs.acs.org on July 24, 2013
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Click Chemistry Inspired Synthesis of Glycoporphyrin Dendrimers
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Divya Kushwaha and Vinod K Tiwari*
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Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasiꢀ221005, India
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*Eꢀmail: tiwari_chem@yahoo.co.in, vtiwari@ucdavis.edu
Graphical Abstract:
A series of porphyrinꢀcored glycodendrimers containing 8, 12, 16, and 24 βꢀDꢀglucopyranose units at
the periphery, have been synthesized by convergent methodology using click chemistry. The structure of
1
developed dendrimers is established by H, 13C NMR, IR, MALDIꢀTOF MS and SEC analysis.
Absorptionꢀemission behavior of dendrimers and its modulation under the influence of dendritic
environment is also investigated.
Keywords: Dendrimer, Click Chemistry, Porphyrin, Glycoconjugate.
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Porphyrins are essential component of various biological representatives such as hemoglobin,
cytochromes and vitamin B12 that play crucial roles in several biologically relevant processes on
account of their distinct physical and chemical properties including gas binding and releasing
ability.1 Several porphyrin derivatives possessing interesting photochemical, photophysical and
electrochemical properties have been obtained by suitable substitution of this macrocycle.2 In this
context, large dendrimeric architectures containing porphyrin moiety surrounded with a variety of
peripheral functional units have been developed and explored for various applications.3
Photodynamic therapy (PDT) is one such interesting application of the porphyrin variants, which is
of paramount importance in cancer treatment and have been particularly exploited in porphyrin
glycoconjugates.2b,4 Porphyrin upon exposure to a particular wavelength of light generates lethal
singlet oxygen that kills tumor cell whereas, sugars installed over this hydrophobic core provides
water solubility and increased tumor cell specificity. Therefore, the whole glycoconjugated
porphyrin system acts as a promising PDT sensitizer.5 Apart from this, multiple copies of saccharide
with a specific spatial arrangement in glycodendrimers allow their potential application in the study
of carbohydrateꢀprotein and carbohydrateꢀlectin interactions, which enriches the field of
nanomedicine.6 Consequently, with these perspectives synthesis of glycoporphyrin dendrimers is
valuable, which can be brought about either by condensation of carbohydrateꢀcontaining
benzaldehydes with pyrrole7 or by the insertion of sugars onto the porphyrin framework.8 The former
method suffers limitation of lower yields, however, success of the latter depends on the efficacy of
coupling methodology.7,8
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Cu(I)ꢀcatalyzed click reaction of terminal alkyne and azide presents an attractive strategy in this
regard, as it gives highly regioselective 1,4ꢀdisubstituted triazole product in excellent yield under
mild reaction condition.9 This highly expeditious protocol has been widely applied in carbohydrate
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chemistry for generating glycoconjugates such as glycopeptides, glycoꢀmacrocycles, glycoꢀarrays,
glycoꢀdendrimers, glycoꢀclusters and glycopolymers etc.10 In last few years, with the aid of click
reaction a number of glycodendrimers comprising of different peripheral sugars like; mannose,11aꢀd
lactose,11bꢀd fucose,11c,d xylose,11e and glucose11f adorned over various core units have been
developed. Numerous porphyrin dendrimers possessing different peripheral functionalizations have
also been successfully constructed using click chemistry.12 However, reports on porphyrin
glycodendrimer is scarce and yet to be explored. Herein, we report the synthesis of glycodendrimers
built on porphyrin core by convergent synthetic strategy using click reaction.
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A variety of first and secondꢀgeneration azideꢀfunctionalized glycosylated dendrimeric wedges were
prepared and coupled with alkyneꢀfunctionalized mesoꢀpositions of porphyrin core using click
reaction to obtain glycodendrimers. Glycosylated azides 13, 14, 16, and 18 were obtained in a
multistep synthetic strategy starting from methyl 3,5 dihydroxy benzoate 5 and methyl 3,4,5
trihydroxy benzoate 6 (Scheme 1) 11f,13
Free hydroxyl groups of each of compound 5 and 6 were
.
propargylated with propargyl bromide to obtain 7 and 8, which on further reduction with LAH
followed by chlorination with thionyl chloride furnished 3,5ꢀbis(propargyloxy)benzyl chloride 9 and
3,4,5ꢀtris(propargyloxy)benzyl chloride 10, respectively. The reaction of 9 and 10 with 2,3,4,6ꢀtetraꢀ
OꢀacetylꢀβꢀDꢀglucopyranosyl azide in presence of CuSO4/Lꢀsodium ascorbate (NaAsc) in
THF/water afforded first generation dendritic chloride 11 and 12 respectively, in good yields. Their
formation was examined by 1H NMR spectrum which showed characteristic triazole proton singlet at
δ 7.92 for 11, whereas for 12 more down field signals were observed at δ 8.45 and δ 8.33 in 2:1 ratio.
Two distinct triazolyl singlets and anomeric doublets identified in 12 corresponded to two
chemically nonꢀequivalent triazolyl glycosides in 2:1 ratio. In 13C NMR, the peaks appeared at δ
121.3 and δ 144.6 for 11 and δ 122.0, 122.6, and 144.8 for 12 confirmed the presence of triazolyl
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carbons. In the next step, azidation of 11 and 12 was brought about by their reaction (at 70oC) with
NaN3 in acetone/water to generate dendritic azides 13 and 14 in quantitative yields. This
transformation was established by IR spectra of 13 and 14, where an intense peak characteristic to
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azide functionality appeared at around 2105 cmꢀ1. In H NMR, this is further followed by the upꢀ
field shifting of ꢀCH2Cl singlet upon ꢀCH2N3 conversion.
Scheme 1: Synthesis of first generation azide functionalized dendrons
After synthesizing first generation azides, utilizing them we next attempted the synthesis of secondꢀ
generation dendritic azides. The azide functionalized dendrons 13 and 14 (two equivalents) were
clicked with 3,5ꢀbis(propargyloxy)benzyl chloride 9 to afford respective dendritic chloride 15 and 17
(Scheme 2). The appearance of new triazolyl peak at δ 7.63 for 15 and δ 7.67 for 17 with integrals
corresponding to two protons confirmed this click transformation. Subsequently, these two chlorides
were quantitatively converted into their respective azides 16 and 18, and characterized on the basis
IR and NMR spectroscopy.
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Scheme 2: Synthesis of second generation dendritic azide
We next prepared click counterpart of dendritic azides i.e. compound 19, for which porphyrin core
obtained by Lindsey type condensation14 was primarily functionalized with propargyl group to obtain
tetraꢀalkyne armed porphyrin macrocycle and then metalated with Zn via refluxing in presence of
zinc acetate in chloroform/methanol. Protection of porphyrin by Zn(II) complexation is essential
prior to Cu(I) catalyzed click reaction, since Zn insertion sufficiently stabilizes the system against
any replacement by Cu(II) ions.15
Finally, the tetrasubstituted porphyrin 19 was utilized as starting material for the coupling of azidic
wedges 13, 14, 16 and 18 each, using CuSO4/NaAsc in THF/water to derive their respective
glycoporphyrin dendrimers 1a, 2a, 3a and 4a (Scheme 3). The column chromatographic purification
afforded a good to satisfactory yield of 1a-4a (40ꢀ64%) without any significant involvement of steric
congestion imposed by large azidic wedges.
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RO
RO
RO
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OR
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RO
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O
RO
OR
N
OR
OR
OR
OR
RO
O
RO RO
RO
O
RO
RO
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RO
O
RO
N
N
O
N
N
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RO
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N
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N
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N
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O
O
OR
OR
O
RO
RO
O
N
N
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RO
O
RO
RO
OR
O
O
O
O
OR
N
OR
N
N
O
N
O
O
N
N
OR
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
N
O
O
O
O
14
, CuSO4, NaAsc
THF/water, 18h, rt
sc
rt
, NaA
, 18h,
13, CuSO4
/water
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N
Zn
N
THF
N
Zn
N
N
N
N
Zn
N
N
N
54%
40%
N
N
O
O
19
O
O
N
N
N
O
O
N
N
N
N
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RO
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RO
O
OR
N
N
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O
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RO
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N
N
O
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OR
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O
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O
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OR
OR
N
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O
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RO
RO
1a: R = Ac
1b: R = H
2a: R = Ac
N
N
NaOMe,
MeOH
NaOMe,
MeOH
OR
O
N
N
O
N
OR
OR
N
N
RO
O
N
N
OR
2b:
O
R = H
RO
RO OR
N
92%
N
OR
OR
94%
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OR
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O
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OR
RO OR
OR
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RO
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OR
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OR
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N
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Zn
N
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O
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OR
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OR
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OR
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O OR
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OR OR
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OR
3a: R = Ac
3b: R = H
4a:
R = Ac
NaOMe,
MeOH
NaOMe,
MeOH
4b: R = H
92%
89%
Scheme 3: Synthesis of first and second generation Glycoporphyrin dendrimers
The symmetrical structures of 1a-4a and their extensive spectral studies (NMR, IR, MALDIꢀTOF
MS and size exclusion chromatography (SEC) techniques) led to unambiguous structural
determination. Synthesis of 1aꢀ4a was evidenced by appearance of newly formed triazolyl protons at
1
δ 7.43, 7.69, 7.58, and 7.89, respectively in their H NMR spectrum. IR spectral analysis confirmed
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the completion of reaction since characteristic peaks corresponding to alkynyl and azide
functionality were no longer seen in the spectrum. SEC analysis of the dendrimers ascertained a well
defined molecular structure for all the four glycodendrimers with low polydispersity ranging
between 1.01ꢀ1.03 and implicated dendrimer size growth from 1a-4a having retention time of 29.88,
29.63, 28.78, and 28.57 for 1a to 4a, respectively (Fig. 1).
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Fig. 1. SEC diagrams of glycoporphyrin dendrimers
The structure of developed glycodendrimers and their purity was also elucidated by MALDIꢀTOF
MS. In all the cases, most intense peak was observed for [M+HꢀZn]+ species along with [M+H]+
peak that suggested the loss of Zn metal under ionization conditions. Also, with increasing
generations of dendrimer, a poor quality of baseline, broadened peaks, and fragmentation in
compounds was noticed due to requirement of higher laser power in MALDI analysis.11c In this way,
after complete characterization of 1a-4a, the acetyl protection of sugar moieties residing over
dendrimers were quantitatively removed under slightly modified Zemplen’s transesterification
conditions16 to obtain waterꢀsoluble final products (1bꢀ4b). The structure of these compounds was
determined by MALDIꢀTOF MS analysis only.
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Fig. 2. Absorption and emission spectra of dendrimers 1aꢀ4a in dichloromethane
Absorption and emission study of protected dendrimers were performed in order to investigate the
effect of dendritic environments over the photophysical properties of porphyrin core. UVꢀvisible
spectra of 1a-4a recorded in dichloromethane showed typical metalloporphyrin behaviour.17 All the
dendrimers displayed characteristic soret band in 426ꢀ428 nm range along with two Q bands in 557ꢀ
561 and 599ꢀ603 nm range (Fig 2). On going from first generation to second generation, a small red
shift (2ꢀ3 nm) along with insignificant decrease in extinction coꢀefficient was noticed in absorption
maxima. However, in comparison to reference compound 19, a remarkable red shift of almost 10 nm
in Q absorption bands was observed. Absorption study of deprotected dendrimers (1bꢀ4b) was done
in DMSO, water and DMSO/water mixed systems of various compositions. All of them showed
intense soret band in DMSO and no significant change in spectra was observed upon successively
increasing percentage of water in DMSO. This result implicated a single molecular dispersion of
dendrimers in solvents. However, a gradual decrease in peak intensity and peak broadening was
found when water content goes beyond 50%. UVꢀvis spectra studied in water still exhibited original
soret band that suggested a good water solubility of 1b-4b arising due to effective shielding of
hydrophobic porphyrin and aromatic systems by hydrophilic peripheral sugars. Also, a little red shift
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along with strict peak broadening attributable to strong aggregations via hydrophobic interactions
was observed in water. Fluorescence study of the dendrimers 1a-4a was also carried out which
showed slightly higher fluorescence intensity in comparison to reference 19, but in all a neglegible
difference in emission behavior of dendrimers was observed under dendritic influences (Fig. 2) (see
supporting information, Table 1; S55).
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In conclusion, the click reaction coupling of tetrafurcated propargylated porphyrin with azide
functionalized glycosylated wedges allowed the efficient synthesis of G(1) and G(2)
1
glycodendrimers. Synthesized dendrimers were characterized by H, 13C NMR, MALDIꢀTOF MS
and SEC analysis. The specific topology attained by sugar moieties over porphyrin core and good
water solubility of 1bꢀ4b makes them promising for lectin binding study. In absorption study of
dendrimers 1aꢀ4a, a significant red shifting in Q bands was observed that is encouraging towards
evaluation of their behaviour as photosensitizer in PDT.
EXPERIMENTAL SECTION
General Methods: All reagents and solvents used were of pure analytical grade. Thinꢀlayer
chromatography (TLC) was performed on 60 F254 silica gel, precoated on aluminum plates and
visualized either by a UV lamp or by spraying with methanolic H2SO4 solution and subsequent
charring by heating at 100°C. Flash column chromatography was performed using silica gel 60
1
13
(230−400 mesh). H and C spectra were recorded at 300 and 75 MHz spectrometers respectively,
using internal standard tetramethylsilane (TMS). Chemical shifts are given in ppm and J values are
in Hertz. Matrixꢀassisted laser desorption ionization timeꢀofꢀflight mass spectrometry
(MALDITOFMS) was performed with 2,5ꢀ dihydroxy benzoic acid (DHB) matrix. The numberꢀ
average molecular weight (Mn) and polydispersity index (Mw/Mn) were determined in DMF at 40oC
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with flow rate 0.5 mL/ min on two polystyrene gel columns. The columns were calibrated against
seven poly(methyl methacrylate) (PMMA) standard samples. Electronic absorption and emission
spectra were obtained in airꢀequilibrated solvents at room temperature.
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Experimental procedure for Cu(I) catalyzed Azide-Alkyne Cycloaddition (A)
Polypropargylated moieties (1.0 eq) and azide functionalized compounds (1.2 eq per azide
functionalization), CuSO4 (0.3 eq per propargyl group) and sodium Lꢀascorbate (0.3 eq per propargyl
group) were stirred at room temperature for 18 hrs in THF/water. After confirming the completion of
reaction on TLC; ethyl acetate was added to reaction mixture and washed with saturated aqueous
NH4Cl (2 x 10 ml), water (10 ml) and brine (10 ml). The separated organic layer was dried over
Na2SO4 and evaporated to obtain crude product. Purification was done by flash chromatography.
Experimental procedure for azidation of dendritic chlorides (B)
Dendritic chloride (1.0 eq) and NaN3 (1.5 eq) were heated at 70oC in acetone/water (10mL/10 mL)
for 4 hours. After completion of reaction, acetone was evaporated and dichloromethane was added in
reaction mixture. The organic layer was washed with water (10 ml) and brine (10 ml), dried over
Na2SO4 and evaporated to obtain azideꢀfunctionalized product with good purity.
Glycoconjugate dendron 11:
Compound 9 (0.4 g, 1.70 mmol, 1.0 eq) was reacted with 2,3,4,6ꢀtetraꢀOꢀacetylꢀβꢀDꢀglucopyranosyl
azide (1.53 g, 4.1 mmol, 2.4 eq), CuSO4.5H2O ( 0.26 g, 1.0 mmol, 0.6 eq) and sodium Lꢀascorbate
(0.20 g, 1.0 mmol, 0.6 eq) in THF/water (10 mL/10 mL) using procedure A. Pure compound 11 was
obtained by silica gel column chromatography (hexane/ethyl acetate) as white solid; Yield 1.44 g,
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86%; Rf = 0.52 Hexane/EtOAc (1:1); IR (υ, cmꢀ1): 3483, 3094, 2925, 1753; H NMR (CDCl3, 300
MHz): δ 7.92 (s, 2 H), 6.64 (s, 3 H), 5.91 (d, 2 H, J = 8.7 Hz), 5.46ꢀ5.42 (m, 4 H), 5.30ꢀ5.20 (m, 6
H), 4.51 (s, 2 H), 4.31 (dd, 2 H, J = 12.6, 4.8 Hz), 4.17ꢀ4.13 (m, 2 H), 4.04ꢀ4.01 (m, 2 H), 2.08, 2.04
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(each s, 18 H), 1.86 (s, 6 H); 13C NMR (CDCl3, 75 MHz): δ 170.5, 169.9, 169.4, 168.9, 159.4, 144.6,
139.8, 121.3, 108.2, 101.7, 85.8, 75.1, 72.6, 70.3, 67.7, 61.9, 61.5, 46.0, 20.7, 20.5, and 20.1 ppm.
Glycoconjugate dendron 12:
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Compound 10 (0.4 g, 1.39 mmol, 1.0 eq) was reacted with 2,3,4,6ꢀtetraꢀOꢀacetylꢀβꢀDꢀ
glucopyranosyl azide (1.86 g, 4.98 mmol, 3.6 eq), CuSO4.5H2O ( 0.31 g, 1.25 mmol, 0.9 eq) and
sodium Lꢀascorbate (0.24 g, 1.25 mmol, 0.9 eq) in THF/water (10 mL/10 mL) using procedure A.
The compound 12 was purified by silica gel column chromatography (hexane/ethyl acetate) as white
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solid; Yield 1.64 g, 84%; Rf = 0.42 Hexane/EtOAc (3:7); H NMR (CDCl3, 300 MHz): δ 8.45 (s, 2
H), 8.33 (s, 1 H), 6.71 (s, 2 H), 6.23 (d, 1 H, J = 9.6 Hz), 5.97 (d, 2 H, J = 9.3 Hz), 5.65ꢀ5.38 (m, 9
H), 5.28ꢀ5.20 (m, 6 H), 4.53 (s, 2 H), 4.31 (dd, 3 H, J = 12.3, 4.5 Hz), 4.18ꢀ4.15 (m, 4 H), 4.05 (m, 2
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H), 2.09, 2.05, 2.04, 2.01 (each s, 27 H), 1.86, 1.80 (each s, 9 H); C NMR (CDCl3, 75 MHz): δ
170.5 170.0, 169.5, 169.0, 168.9, 152.1, 144.8, 137.4, 133.6, 122.6, 122.0, 107.8, 85.7, 85.4, 75.0,
74.7, 73.0, 72.7, 70.4, 70.1, 67.8, 66.0, 63.1, 61.6, 60.4, 46.3, 21.0, 20.6, 20.5, 20.2, and 20.1 ppm.
Glycoconjugate dendron 13:
Compound 11 (1.44 g, 1.47 mmol, 1.0 eq) and NaN3 (0.14 g, 2.2 mmol, 1.5 eq) was reacted in
acetone/water (10mL/10 mL) according to method B to afford compound 13 as white solid; Yield
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1.41 g, 97%; Rf = 0.52 Hexane/EtOAc (1:1); IR (υ, cmꢀ1): 3482, 3153, 2925, 2104, 1756; H NMR
(CDCl3, 300 MHz): δ 7.93 (s, 2 H), 6.65ꢀ6.57 (m, 3 H), 5.92 (d, 2 H, J = 8.4 Hz), 5.50ꢀ5.40 (m, 4 H),
5.29ꢀ5.21 (m, 6 H), 4.34ꢀ4.28 (m, 4 H), 4.17ꢀ4.13 (m, 2 H), 4.05ꢀ4.02 (m, 2 H), 2.08, 2.04 (each s,
18 H), 1.86 (s, 6 H); 13C NMR (CDCl3, 75 MHz): δ 170.5, 169.9, 169.3, 168.9, 159.5, 144.6, 138.0,
121.3, 107.7, 101.5, 85.8, 75.1, 72.6, 70.3, 67.7, 61.9, 61.5, 54.6, 20.6, 20.5, and 20.1 ppm.
Glycoconjugate dendron 14:
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Compound 12 (1.64 g, 1.16 mmol, 1.0 eq) was heated with NaN3 (0.11 g, 1.75 mmol, 1.5 eq) in
acetone/water (10mL/10 mL) according to method B to afford compound 14 as white solid; Yield
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(CDCl3, 300 MHz): δ 8.46 (s, 2 H), 8.32 (s, 1 H), 6.64 (s, 2 H), 6.23 (d, 1 H, J = 9.6 Hz), 5.97 (d, 2
H, J = 9.3 Hz), 5.67ꢀ5.38 (m, 9 H), 5.28ꢀ5.20 (m, 6 H), 4.29 (m, 5 H), 4.18ꢀ4.05 (m, 6 H), 2.09, 2.05,
2.04, 2.00 (each s, 27 H), 1.86, 1.81 (each s, 9 H); 13C NMR (CDCl3, 75 MHz): δ 170.5, 170.0,
169.5, 168.9, 152.4, 144.9, 137.3, 131.7, 122.0, 107.4, 85.8, 85.4, 75.1, 74.8, 72.8, 70.5, 70.1, 67.8,
66.0, 63.1, 61.6, 54.7, 20.6, 20.5, and 20.1 ppm.
Glycoconjugate dendron 15:
Compound 9 (0.1 g, 0.43 mmol, 1.0 eq) was stirred at room temperature with 13 (1.0 g, 1.02 mmol,
2.4 eq), CuSO4.5H2O (0.06 g, 0.26 mmol, 0.6 eq) and sodium Lꢀascorbate (0.05 g, 0.26 mmol, 0.6
eq) in THF/water (10 mL/10 mL) using procedure A. The compound was purified by silica gel
column chromatography (CHCl3/MeOH) as white solid; Yield 0.75 g, 80%; Rf = 0.56 CHCl3/MeOH
(97:3); IR (υ, cmꢀ1): 3488, 3145, 2942, 1755; 1H NMR (CDCl3, 300 MHz): δ 7.94 (s, 4 H), 7.63 (s, 2
H), 6.63ꢀ6.51 (m, 9 H), 5.91 (d, 4 H, J = 8.7 Hz), 5.49ꢀ5.39 (m, 12 H), 5.30ꢀ5.15 (m, 16 H), 4.47 (s,
2 H), 4.30 (dd, 4 H, J = 12.6, 4.8 Hz), 4.16ꢀ4.13 (m, 4 H), 4.04ꢀ4.00 (m, 4 H), 2.07, 2.05, 2.02 (each
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s, 36 H), 1.82 (s, 12 H); C NMR (CDCl3, 75 MHz): δ 170.5, 169.9, 169.4, 168.9, 159.7, 159.5,
150.4, 144.3, 136.9, 123.0, 121.5, 108.1, 107.8, 101.8, 100.3, 85.8, 75.1, 72.6, 70.3, 67.7, 61.8, 61.5,
44.6, 20.7, 20.6, and 20.1 ppm.
Glycoconjugate dendron 16:
Compound 15 (0.75 g, 0.34 mmol, 1.0 eq) was heated with NaN3 (0.03 g, 0.58 mmol, 1.5 eq) in
acetone/water (6 mL/6 mL) according to method B to afford compound 16 as white solid; Yield 0.73
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g, 98%; Rf = 0.56 CHCl3/MeOH (97:3); IR (υ, cmꢀ1): 3476, 3143, 2926, 2104, 1754; H NMR
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(CDCl3, 300 MHz): δ 7.94 (s, 4 H), 7.62 (s, 2 H), 6.64ꢀ6.51 (m, 9 H), 5.91 (d, 4 H, J = 8.4 Hz), 5.50ꢀ
5.39 (m, 12 H), 5.30ꢀ5.15 (m, 16 H), 4.33ꢀ4.13 (m, 10 H) 4.04ꢀ4.01 (m, 4 H), 2.07, 2.05, 2.02 (each
s, 36 H), 1.83 (s, 12 H); 13C NMR (CDCl3, 75 MHz): δ 170.5, 169.9, 169.4, 168.9, 159.7, 159.6,
152.2, 144.2, 137.8, 136.9, 123.0, 121.5, 107.7, 107.6, 101.8, 85.7, 75.1, 72.6, 70.3, 67.6, 62.1, 61.7,
61.5, 54.6, 54.0, 20.5, and 20.1 ppm.
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Glycoconjugate dendron 17:
Compound 9 (0.1 g, 0.43 mmol, 1.0 eq) was reacted with compound 14 (1.45 g, 1.02 mmol, 2.4 eq),
CuSO4.5H2O (0.06 g, 0.26 mmol, 0.6 eq) and sodium Lꢀascorbate (0.05 g, 0.26 mmol, 0.6 eq) in
THF/water (10 mL/10 mL) using procedure A. Pure compound 17 was obtained by silica gel column
chromatography (CHCl3/MeOH) as white solid; Yield 1.11 g, 85%; Rf = 0.64 CHCl3/MeOH (95:5);
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7.67 (s, 2 H), 6.64ꢀ6.61 (m, 7 H), 6.23 (d, 2 H, J = 9.6 Hz), 5.97 (d, 4 H, J = 9.3 Hz), 5.67ꢀ5.40 (m,
18 H), 5.46ꢀ5.17 (m, 20 H), 4.49 (s, 2 H), 4.34ꢀ4.28 (m, 6 H), 4.18ꢀ4.04 (m, 12 H), 2.09, 2.04, 2.02,
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1.99 (each s, 54 H), 1.81, 1.79 (each s, 18 H); C NMR (CDCl3, 75 MHz): δ 170.5, 170.0, 169.5,
169.0, 168.9, 159.4, 152.4, 144.8, 144.5, 144.1, 139.7, 137.6, 130.7, 123.1, 122.7, 122.2, 108.1,
107.4, 101.8, 85.7, 85.4, 75.0, 74.7, 72.9, 72.7, 70.4, 70.1, 67.7, 66.0, 62.9, 62.0, 61.6, 54.1, 46.1,
20.6, 20.5, and 20.1 ppm.
Glycoconjugate dendron 18:
Compound 15 (1.11 g, 0.36 mmol, 1.0 eq) was heated with NaN3 (0.04 g, 0.54 mmol, 1.5 eq) in
acetone/water (6 mL/6 mL) according to method B to afford 18 as white solid; Yield 1.07 g, 96%; Rf
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= 0.64 CHCl3/MeOH (95:5); IR (υ, cmꢀ1): 3484, 3144, 2941, 2105, 1755; H NMR (CDCl3, 300
MHz): δ 8.47 (s, 4 H), 8.35 (s, 2 H), 7.67 (s, 2 H), 6.62, 6.58 (each s, 7 H), 6.23 (d, 2 H, J = 9.6 Hz),
5.97 (d, 4 H, J = 9.0 Hz), 5.67ꢀ5.36 (m, 18 H), 5.30ꢀ5.17 (m, 20 H), 4.34ꢀ4.26 (m, 8 H), 4.18ꢀ4.05
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(m, 12 H), 2.13, 2.09, 2.04, 2.02, 1.99, 1.96 (each s, 54 H) 1.82, 1.79 (each s, 18 H); 13C NMR
(CDCl3, 75 MHz); δ 170.5, 170.0, 169.5, 169.0, 168.9, 159.6, 152.4, 144.8, 144.5, 144.1, 137.8,
137.6, 130.6, 123.0, 122.7, 122.2, 107.6, 107.4, 101.6, 85.7, 85.3, 75.0, 74.7, 72.9, 72.7, 70.4, 70.0,
67.7, 66.0, 62.9, 62.0, 61.6, 54.6, 54.1, 20.6, and 20.1 ppm.
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Glycoconjugate dendron 19:
5, 10, 15, 20ꢀTetrakis(4ꢀhydroxyphenyl)ꢀporphyrin (0.5 g, 0.737 mmol, 1.0 equiv) was dissolved in
anhydrous DMF under argon atmosphere and then K2CO3 (1.0 g, 7.374 mmol, 10 equiv) and
propargyl bromide (0.39 ml, 4.42 mmol, 6 equiv) were added. The reaction was allowed to stir at
room temperature for overnight. After completion of reaction, DMF was evaporated under reduced
pressure and extracted with CH2Cl2/H2O system at least 3 times to remove excess of K2CO3. Organic
layer was dried over Na2SO4, filtered and concentrated to obtain purple solid. The crude mixture was
further purified by flash chromatography over SiO2 (hexane/ethyl acetate) to give 5, 10, 15, 20ꢀ
Tetrakis(4ꢀpropargyloxyphenyl)ꢀporphyrin; Yield 0.58 g, 95%; UVꢀvis abs (CH2Cl2): λmax (nm) =
420, 517, 554, 592, 647; 1H NMR (CDCl3, 300 MHz): δ 8.85 (s, 8 H), 8.11 (d, 8 H, J = 8.4 Hz), 7.32
(d, 8 H, J = 8.4 Hz), 4.94 (s, 8 H), 2.67 (s, 4 H), ꢀ2.76 (s, 2 H); 13C NMR (CDCl3, 75 MHz): δ 157.4,
135.5, 119.6, 113.1, 78.7, 75.9, and 56.1 ppm. A solution of this tetrapropargyl functionalized
porphyrin (0.58 g, 0.702 mmol, 1.0 equiv) in CHCl3 (7 ml) and solution of zinc acetate (0.77 g,
3.514 mmol, 5 equiv) in methanol (7 ml) were mixed and refluxed under N2 for 2ꢀ3 h. The reaction
mixture was concentrated by vacuum evaporation and CH2Cl2 was added. The organic layer was
washed with water (3 x 20 ml), dried over Na2SO4, filtered and concentrated. The crude mixture was
further purified by flash chromatography over SiO2 (hexane/ethyl acetate) to give pure compound 19
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as purple solid; Yield 0.61 g, 98%; UVꢀvis abs (CH2Cl2): λmax (nm) = 422, 550, 590; H NMR
(CDCl3, 300 MHz): δ 8.86 (s, 8 H), 8.13 (d, 8 H, J = 8.4 Hz), 7.36 (d, 8 H, J = 8.4 Hz), 4.99 (m, 8
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H), 2.70 (s, 4 H); 13C NMR (CDCl3, 75 MHz): δ 157.3, 150.4, 136.1, 135.4, 131.9, 120.6, 113.0,
78.7, 75.8, and 56.2 ppm.
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Experimental procedure for deprotection of glycodendrimers
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Acetyl protected glycodendrimer was dissolved in dry MeOH (if needed, a few drops of CH2Cl2
added) and a solution of sodium methoxide (1 M in MeOH, 5 ꢁL per 30 min period) was added (till
pH 9) and stirred for overnight. Further, reaction mixture was neutralized by ionꢀexchange resin
(Amberlite IR 120 H+), filtered and evaporated. This way, completely deprotected waterꢀsoluble
glycodendrimers 1b-4b was obtained and characterized by MALDIꢀTOF MS spectra.
Glycoporphyrin dendrimer 1a: Compound 19 (0.1 g, 0.11 mmol, 1.0 eq) was reacted with 13 (0.53
g, 0.54 mmol, 4.8 eq), CuSO4.5H2O (0.03 g, 0.13 mmol, 1.2 eq) and sodium Lꢀascorbate (0.03 g,
0.13 mmol, 1.2 eq) in THF/water (5 mL/5 mL) according to procedure A. Pure compound 1a was
isolated by silica gel column chromatography as purple solid with hexane/ethyl acetate followed by
CHCl3; Yield 0.22g, 40%; MW 4845.80 g.molꢀ1; Rf = 0.64 CHCl3/MeOH (95:5); IR (υ, cmꢀ1): 3454,
3146, 2924, 1755; 1H NMR (CDCl3, 300 MHz): δ 8.90 (s, 8 H), 8.03 (d, 8 H, J = 7.2 Hz), 7.71 (s, 8
H), 7.43 (s, 4 H), 7.18 (d, 8 H, J = 7.5 Hz), 6.61ꢀ6.36 (m, 12 H), 5.60 (d, 8 H, J = 8.7 Hz), 5.43ꢀ5.18
(m, 44 H), 5.01ꢀ4.81 (m, 12 H) 4.17ꢀ4.14 (m, 8 H), 3.96ꢀ3.92 (m, 8 H), 3.75 (m, 8 H), 2.02, 1.99
(each s, 72 H), 1.76 (s, 24 H); 13C NMR (CDCl3, 75 MHz): δ 170.4, 169.8, 169.3, 168.8, 159.6,
157.5, 150.3, 144.0, 136.8, 136.1, 135.6, 131.8, 122.6, 121.7, 120.4, 112.9, 107.5, 101.7, 85.4, 74.8,
72.5, 70.1, 67.5, 61.6, 61.3, 60.3, 53.9, 53.4, 21.0, 20.6, 20.5, 20.4, and 20.0 ppm; SEC shows
polydispersity 1.01; m/z MALDI TOF MS calcd for C220H232N40O84Zn 4846.493: found 4843.447
[M+H]+. Deprotected dendrimer 1b: Yield 0.11 g, 92%; MW 3500.62 g.molꢀ1; m/z MALDI TOF
MS calcd for C156H168N40O52Zn 3498.11: found 3490.298 [M+H]+.
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Glycoporphyrin dendrimer 2a: Compound 19 (0.05 g, 0.056 mmol, 1.0 eq) was reacted with 14
(0.38 g, 0.27 mmol, 4.8 eq), CuSO4.5H2O (0.016 g, 0.067 mmol, 1.2 eq) and sodium Lꢀascorbate
(0.013 g, 0.067 mmol, 1.2 eq) in THF/water (6 mL/6 mL) using procedure A. Pure compound 2a
was obtained by silica gel column chromatography using CHCl3/MeOH as purple solid; Yield 0.19
g, 54%; MW 6555.25 g.molꢀ1; Rf = 0.56 CHCl3/MeOH (95:5); IR (υ, cmꢀ1): 3472, 3146, 2924, 1755;
1H NMR (CDCl3, 300 MHz): δ 8.93 (s, 8 H), 8.25 (s, 12 H), 8.10 (d, 8 H, J = 7.8 Hz), 7.70 (s, 4 H),
7.32 (d, 8 H, J = 7.5 Hz), 6.56 (s, 8 H), 6.20 (d, 6 H, J = 9.6 Hz), 5.94 (d, 3 H, J = 9.3 Hz), 5.66ꢀ5.55
(m, 12 H), 5.45ꢀ5.31 (m, 48 H), 5.20ꢀ5.18 (m, 5 H), 5.07 (m, 4 H), 4.90 (m, 10 H), 4.28ꢀ4.09 (m, 24
H), 4.01ꢀ3.97 (m, 6 H), 3.82 (m, 6 H), 2.05, 2.01 (broad s, 126 H), 1.93 (s, 18 H); 13C NMR (CDCl3,
75 MHz): 170.5, 169.9, 169.5, 169.0, 168.7, 157.7, 152.3, 150.3, 144.6, 144.4, 144.1, 137.4, 136.3,
135.7, 131.8, 130.6, 123.0, 122.6, 122.1, 120.3, 113.3, 107.3, 85.5, 85.3, 74.8, 74.6, 72.9, 72.6, 70.3,
70.0, 67.7, 67.6, 65.6, 62.5, 61.7, 61.4, 54.2, 20.6, 20.5, 20.1, and 20.0 ppm; SEC shows
polydispersity 1.01; m/z MALDI TOF MS calcd for C288H316N52O124Zn 6553.94: found 6556.78
[M+H]+ and 6493.67 [M+HꢀZn]+. Deprotected dendrimer 2b: Yield 0.12 g, 94%; MW 4537.48
g.molꢀ1; m/z MALDI TOF MS calcd for C194H222N52O77Zn 4535.431: found 4470.583 [M+HꢀZn]+.
Glycoporphyrin dendrimer 3a: Compound 19 (0.05 g, 0.056 mmol, 1.0 eq) was reacted with 16
(0.59 g, 0.27 mmol, 4.8 eq), CuSO4.5H2O (0.016 g, 0.067 mmol, 1.2 eq) and sodium Lꢀascorbate
(0.013 g, 0.067 mmol, 1.2 eq) in THF/water (6 mL/6 mL) using procedure A. Pure compound 3a
was obtained by silica gel column chromatography with CHCl3/MeOH as purple solid; Yield 0.37 g,
57%; MW 9762.29 g.molꢀ1; Rf = 0.40 CHCl3/MeOH (95:5); IR (υ, cmꢀ1): 3437, 3153, 2924, 1755; 1H
NMR (CDCl3, 300 MHz); δ 8.84 (s, 8 H), 7.99, 7.83, 7.55 (m, 36 H), 7.27 (m, 8 H), 6.56ꢀ6.34 (m, 36
H), 5.73 (10 H), 5.93ꢀ4.96 (m, 134 H), 4.16ꢀ3.87 (m, 48 H), 2.02, 1.98, 1.76 (192 H) ppm; 13C NMR
(CDCl3, 75 MHz); δ 170.4, 169.9, 169.4, 168.8, 159.6, 157.5, 150.2, 144.0, 143.7, 139.2, 137.0,
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136.0, 135.6, 131.8, 123.3, 121.7, 114.0, 107.5, 101.7, 85.5, 72.6, 70.2, 67.5, 61.5, 61.4, 60.4, 53.8,
20.6, 20.5, and 20.0 ppm; SEC shows polydispersity 1.03; m/z MALDI TOF MS calcd for
C436H472N88O172Zn 9759.031, found 9758.225 [M+H]+, 9696.891 [M+HꢀZn]+. Deprotected
dendrimer 3b: Yield 0.25 g, 92%; MW 7071.93 g.molꢀ1; m/z MALDI TOF MS calcd for
C308H342N88O108Zn 7069.352, found 7007.376 [M+HꢀZn]+.
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Glycoporphyrin dendrimer 4a: Compound 19 (0.025 g, 0.028 mmol, 1.0 eq) was reacted with 18
(0.41 g, 0.13 mmol, 4.8 eq), CuSO4.5H2O (0.008 g, 0.034 mmol, 1.2 eq) and sodium Lꢀascorbate
(0.007 g, 0.034 mmol, 1.2 eq) in THF/water (6 mL/6 mL) using procedure A. Pure compound 4a
was obtained by silica gel column chromatography (CHCl3/MeOH) as purple solid; Yield 0.24 g,
64%; MW 13181.19 g.molꢀ1; Rf = 0.37 CHCl3/MeOH (95:5); IR (υ, cmꢀ1): 3480, 3145, 2927, 1756;
1H NMR (CDCl3, 300 MHz): δ 8.86 (s, 8 H), 8.39, 8.28 (each s, 24 H), 8.08 (d, 8 H, J = 7.2 Hz),
7.87 (s, 4 H), 7.64 (s, 8 H), 7.33 (d, 8 H, J = 7.8 Hz), 6.64, 6.53 (each s, 28 H), 6.20 (d, 8 H, J = 9.0
Hz), 5.82 (d, 15 H, J = 8.4 Hz), 5.59ꢀ5.30 (m, 123 H), 5.16ꢀ4.92 (m, 46 H), 4.24ꢀ3.96 (m, 96 H),
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2.05, 2.01, 1.99, 1.93 (each s, 228 H), 1.74 (m, 60 H) ppm; C NMR (CDCl3, 75 MHz): δ 170.5,
169.9, 169.5, 169.0, 168.8, 159.7, 157.7, 152.3, 150.2, 144.6, 144.3, 143.7, 137.3, 137.0, 136.2,
135.7, 131.7, 130.8, 123.4, 122.6, 122.2, 107.6, 107.2, 102.0, 85.5, 85.2, 74.8, 74.6, 72.9, 72.6, 70.3,
70.0, 67.6, 65.8, 65.6, 62.6, 61.5, 53.9, 20.6, 20.5, and 20.0 ppm; SEC shows polydispersity 1.02;
m/z MALDI TOF MS calcd for C572H640N112O252Zn 13177.01671, found 13111.248 [M+HꢀZn]+.
Deprotected dendrimer 4b: Yield 0.15 g, 89%; MW 9145.66 g.molꢀ1; m/z MALDI TOF MS calcd
for C380H448N112O156Zn 9142.999, found 9078.450 [M+HꢀZn]+.
ACKNOWLEDGEMENTS
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We sincerely thank CSIR, India for the funding and CISC, BHU for spectroscopic studies. We
gratefully acknowledge Prof. D. S. Pandey and Prof. B. Ray, BHU for their help in fluorescence and
SEC studies of dendrimers and Prof. M. J. Crossley, University of Sydney for his useful suggestion.
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SUPPORTING INFORMATION AVAILABLE Spectroscopic data H, C NMR, MALDIꢀTOF
MS, SEC, and absorptionꢀemission spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
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