Efficient synthesis of glycoporphyrins by microwave-mediated click reactions

Article abstract of DOI:10.1002/ejoc.200901292

The Cu^I-catalysed Huisgen cycloaddition click reaction, has been applied to the synthesis of a range of triazole-linked glycoporphyrins. The click reaction under microwaveheating conditions has been shown to provide a general and robust methodology for the synthesis of mono-, di-, tri- and tetra-modified glycoporphyrins. A sequential double-click process was employed to access a new class of bis-modified 5,10-diglycoporphyrins displaying heterogeneous carbohydrates.

Full text of DOI:10.1002/ejoc.200901292

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901292
Efficient Synthesis of Glycoporphyrins by Microwave-Mediated “Click”
Reactions
Oliver B. Locos,[a] Claudia C. Heindl,[a] Ariadna Corral,[a] Mathias O. Senge,[b] and
Eoin M. Scanlan*[a]
Keywords: Porphyrinoids / Glycoporphyrin / Carbohydrates / Click chemistry / Microwave chemistry
The CuI-catalysed Huisgen cycloaddition “click” reaction
has been applied to the synthesis of a range of triazole-linked
glycoporphyrins. The “click” reaction under microwave-
heating conditions has been shown to provide a general and
robust methodology for the synthesis of mono-, di-, tri- and
tetra-modified glycoporphyrins. A sequential “double-click”
process was employed to access a new class of bis-modified
5,10-diglycoporphyrins displaying heterogeneous carbo-
hydrates.
Introduction
Results and Discussion
For this study we chose to investigate if the CuI-catalysed
1,3-dipolar “click” reaction[8] could be employed as a ro-
bust methodology to access a highly defined, multifunction-
alised glycoporphyrin system.
Glycoporphyrins offer fascinating prospects for medici-
nal chemistry and glycobiology.[1a–1d] Carbohydrates not
only improve the solubility of porphyrins in an aqueous en-
vironment, but also offer improved targeting of porphyrin
therapeutics.[2] For photodynamic therapy (PDT),[3] carbo-
hydrates can bind to tumour-associated lectins displayed on
the surface of cancer cells therefore offering the potential
for enhanced efficiency and improved selectivity in cancer
treatment. Because lectin–carbohydrate interactions are rel-
atively weak it would be advantageous to have access to a
PDT photosensitiser with a defined cluster displaying more
than one carbohydrate unit. Even more advantageous
would be a defined system that displays more than one
“type” of carbohydrate. The synthesis of selectively modi-
fied, heterogeneous glycoporphyrins has not previously
been reported. To date, the synthesis of glycoporphyrins has
relied predominantly on the condensation reaction between
a glycosylated aldehyde and a glycosylated aldehyde and
a pyrrole.[4a–4c] This reaction is often low yielding and is
unsuitable for systems where small quantities of a carbo-
hydrate are available. A more general strategy involves the
introduction of carbohydrates at specific sites predefined by
a regioselective chemical modification.[5] A number of
methodologies for the functionalisation of porphyrins with
carbohydrates have been investigated including the use of
Sonogashira[6] and olefin metathesis[7] cross coupling.
Click chemistry has previously been applied to the func-
tionalisation of porphyrins,[9a–9b] but to date there are few
literature examples describing a “click” reaction between a
carbohydrate and a porphyrin or chlorin.[10] Recently, Vicente
and co-workers have employed a “click” methodology for the
preparation of glycoporphyrins displaying either one or four
galactose or lactose moieties, carbohydrate functionalised tet-
abenzoporphyrin (TBP) was found to be efficiently uptaken
by human carcinoma Hep2 cells.[11] Hasegawa and co-
workers have applied “click” chemistry to the preparation of
octaglycosylated porphyrins.[12] 5,10,15,20-Tetraphenylpor-
phyrin was chosen as a common starting material for all
modifications. This symmetrical porphyrin can be readily ac-
cessed in good yield via a condensation reaction of benzalde-
hyde and pyrrole. Porphyrin derivative 1, displaying a single
azide was prepared according to the literature procedure.[12]
The coupling reaction with commercially available β-propar-
gyl glucose 2 (Scheme 1) was investigated under both conven-
tional and microwave-mediated heating. The use of MW
heating conditions reduced the reaction time from 3 d to
20 min. A range of reaction conditions were screened. The
results of this initial study are outlined in Table 1.
It was found that copper chloride in toluene/water (4:1)
at 120 °C for 20 min furnished the desired mono-glycopor-
phyrin 5 in excellent yield (93%). THF/water (4:1) also gave
a very good yield of 81% at a lower temperature but longer
times (40 min) were required for complete consumption of
the starting material. It was found that zinc porphyrin was
required for “click” conditions in order to avoid complex
formation with the copper catalyst.
[a] School of Chemistry, Centre for Synthesis and Chemical Bio-
logy (CSCB), University of Dublin,
Trinity College, Dublin 2, Ireland
Fax: +353-1-671-2826
E-mail: eoin.scanlan@tcd.ie
[b] Institute of Molecular Medicine, Medicinal Chemistry, Trinity
Centre for Health Sciences,
St. James’s Hospital, Dublin 8, Ireland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901292.
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1026–1028

Glycoporphyrins by Microwave-Mediated “Click” Reactions
These compounds were easily separated by column
chromatography. They were both subsequently converted
into the corresponding (azidophenyl)porphyrins after re-
duction of the nitro groups were achieved. The click reac-
tion using two equivalents of the propargyl glucose worked
efficiently and the 5,10-diglycoporphyrin 8 was isolated in
80% yield and the 5,15 compound 9 in 75% yield. This
ability to control the relative position of carbohydrate side
chains on the porphyrin may have very important conse-
quences for lectin binding.
Scheme 1. Synthesis of mono-glycoporphyrin by microwave-medi-
ated “click” reaction.
Table 1. Optimisation of conditions for Cu-catalysed click reaction.
Entry
Sugar catalyst[a]
Solvent[b]
Temp.[c] Yield (%)[d]
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
2
CuCl
CuCl
CuCl
CuBr
CuI
toluene
toluene
90–140
140
140
140
140
140
140
160
160
80
47
85
93
78
44
89
67
63
52
81
74
toluene/H2O
toluene/H2O
toluene/H2O
CuSO4, Na+ ascorbate toluene/H2O
CuCl
CuCl
CuCl
CuCl
CuCl
DMSO/H2O
DMSO/H2O
DMSO/H2O
THF/H2O
9
10
11
Scheme 2. Synthesis of 5,10-bis-modified heterogeneous glycopor-
phyrin via stepwise “double click” reaction.
DMF/H2O
140
[a] Catalyst loading was 30%. [b] Where two solvents were used
ratio was (4:1). [c] Temperatures were obtained under microwave
heating for 20 min. [d] Isolated yield.
Efficient, regioselective synthesis of bis-modified glyco-
porphyrins has not previously been described. It was deter-
mined that a sequential “double click” reaction where one
The reaction was repeated with α-propargyl mannose, carbohydrate moiety was introduced followed by addition
prepared according to the literature procedure,[13] and the of a second onto the “latent” azide could be achieved.
desired mannosylated glycoporphyrin 6 was isolated in 91%
Reaction of propargyl glucoside 2 with three equivalents
yield. A fully deprotected mannosyl residue 4 was also in- of diazaporphyrin 10 furnished the glycoporphyrin 11 as
troduced via the “click” reaction to furnish 7 in good yield the sole product isolated in very good yield 87%. The pro-
61%. This reaction highlights the potential for the introduc- pargyl mannoside 3 was then introduced via a second se-
tion of unprotected oligosaccharides isolated from natural quential click reaction to furnish the bis-modified glycopor-
sources using this methodology. It also means that depro- phyrin 12 in 53% yield.
tection reactions, which can be low yielding for oligosaccha-
In order to avoid reduction of the “latent” azide and al-
rides can be carried out prior to functionalisation of the low the stepwise process to occur, the amount of copper
porphyrin. The fact that the glycoporphyrin was easily vis- catalyst had to be carefully controlled. It was found that
ible on the chromatography column facilitated the rapid 30% catalyst loading was optimum for each step of the
and simple purification of the glycoconjugate displaying the “double click” reaction. The excess porphyrin required for
fully deprotected sugar.
the first click reaction was recovered almost quantitatively
The next step was to investigate if the methodology could by column chromatography making this an efficient pro-
be applied to diazidoporphyrins. Nitration of 5,10,15,20- cess. The scope of this reaction is not just limited to carbo-
tetraphenylporphyrin furnished the 5,10 and 5,15 regioiso- hydrates and studies are currently underway to prepare
mers in a 2:1 ratio and offers an alternative entry to the mixed porphyrins functionalised with carbohydrates, lipids
5,10-disubstitution pattern in porphyrins (Scheme 2).[14a,14b] and amino acids.
Eur. J. Org. Chem. 2010, 1026–1028
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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O. B. Locos, C. C. Heindl, A. Corral, M. O. Senge, E. M. Scanlan
SHORT COMMUNICATION
Following the successful preparation of the bis-modified Studies are currently underway to explore additional, or-
product, the tri- (13) and tetraazido (14) porphyrins were thogonal modification strategies including cross metathesis
synthesised. The conditions employed for the mono- and and organometallic coupling reactions for the construction
dimodification were repeated, using three and four equiva- of highly diverse glycoporphyrins and analogues. Carbo-
lents of the propargyl glycoside, respectively. The tri- (15) hydrate sequences suitable for binding tumour associated
and tetraglycosylated porphyrins (16) were both isolated in lectins will be introduced using this methodology. Bio-
good to moderate yields, respectively (Scheme 3). This dem- logical assays to study the therapeutic applications of these
onstrated that the same general conditions could be used to systems are also under investigation.
prepare the mono-, di-, tri- and tetra-functionalised glyco-
porphyrins. This suggests that the methodology could even
be applied to the synthesis of dendritic glycoporphyrins dis-
playing a large number of carbohydrate side chains. It
should be noted that while the conditions for 15 and 16 are
unoptimised, the yield of 16 is considerably lower, most
likely due to solubility issues with the azaporphyrin 14.
Supporting Information (see also the footnote on the first page of
this article): General experimental procedures and complete char-
1
acterisation data of all products, H and 13C NMR spectra.
Acknowledgments
This work was supported by grants from Science Foundation Ire-
land (SFI 04/RP1/B482) and the Health Research Board (HRB
TRA2007/11).
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Received: November 10, 2009
Conclusions
The “click” reaction under microwave-heating conditions
represents an efficient and robust methodology for the syn-
thesis of defined glycoporphyrins amenable for further elab-
orations. General conditions were determined for the intro-
duction of homogeneous carbohydrates and conditions for
the stepwise bis-modification with heterogeneous carbo-
hydrates were also determined. The methodology has been
optimised to allow functionalistion of the tetrapyrrole core
with both protected and fully deprotected carbohydrates.
Published Online: January 12, 2010
1028
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Eur. J. Org. Chem. 2010, 1026–1028