Using the Ugi multicomponent condensation reaction to prepare families of chromophore appended azamacrocycles and their complexes

Article abstract of DOI:10.1039/b810083g

The Ugi reaction offers an effective method for preparing chromophore-appended DOTA-monoamide ligands, which can readily be elaborated to their lanthanide complexes. The Royal Society of Chemistry.

Full text of DOI:10.1039/b810083g

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Using the Ugi multicomponent condensation reaction to prepare families
of chromophore appended azamacrocycles and their complexeswz
Marcus Main,a John S. Snaith,*a Marco M. Meloni,b Maite Jauregui,a
Daniel Sykes,b Stephen Faulkner*b and Alan M. Kenwrightc
Received (in Cambridge, UK) 16th June 2008, Accepted 16th July 2008
First published as an Advance Article on the web 10th September 2008
DOI: 10.1039/b810083g
The Ugi reaction offers an effective method for preparing
chromophore-appended DOTA-monoamide ligands, which can
readily be elaborated to their lanthanide complexes.
lengthy and sometimes troublesome syntheses can limit the
range of complexes that can be accessed, as well as limiting
their potential application. New methods which simplify the
preparation of such systems and provide a ‘toolkit’ for the
biomedical sciences are desirable.
The paramagnetic and relaxometric properties of lanthanide
complexes have made them the subject of considerable current
interest, owing to their potential as agents for imaging1 and
assay2 in biological systems. For application in vivo, such
complexes need to be kinetically robust to avoid dissociation
in solution and to minimise the toxicity associated with
lanthanide ions.3 A wide variety of such complexes have been
prepared, and most of these are derived from polydentate
ligands such as DTPA, or from azamacrocycles such as
cyclen.1,3,4 Many such complexes have been attached to
monoclonal antibodies or low molecular weight targeting
vectors that are designed to deliver them to tissue associated
with specific disease states.5
The Ugi four-component condensation,11 in which an acid,
an aldehyde, an amine and an isocyanide react to afford an
acylaminoamide is a powerful tool to obtain peptide-like
sequences. This reaction has been extensively used, both in
solution and on the solid phase, to prepare large libraries of
compounds with interesting biological properties.12,13 We now
present the synthesis and study of a series of novel DOTA
monoamide derivatives and their complexes, using the Ugi
reaction as a key step. This approach potentially gives rapid
access to a variety of DOTA labelled compounds, while the
strategy can be varied to incorporate chromophores for
sensitised luminescence and/or targeting vectors as appropriate.
Scheme 1 shows our synthetic approach. Reaction of cyclen
1 with ethyl bromoacetate in the presence of sodium hydro-
gencarbonate yielded the ethyl triester 2, which was elaborated
further by reaction with tert-butylbromoacetate to give the
orthogonally protected tetraester 3. Subsequent exposure to
TFA to cleave the tert-butyl ester and purification by HPLC
gave the monoacid 4 in good overall yield.
Two techniques dominate the field. In MRI (magnetic
resonance imaging), the paramagnetic properties of gadolinium
ions are used to generate proton contrast in whole body
imaging;1a,b kinetically stable gadolinium complexes are widely
employed in this role, but are of limited utility in targeted
imaging due to the high concentrations required.6 By contrast,
luminescent complexes can be detected at the low concentra-
tions associated with cell-surface receptors (allowing targeted
imaging) as a result of the ease with which their long lived
emission can be separated from biological background,7 but
poor tissue penetration by light means that whole body
imaging is prohibitively difficult. Our own studies,8 and those
of others,9 have sought to overcome these difficulties by using
long wavelength excitation and emission to optimise tissue
penetration. We have also begun to prepare polymetallic
complexes that can be used to combine the advantages of
MRI with those of luminescence.10
We then investigated the suitability of 4 as a carboxylic acid
substrate for the Ugi reaction. Multi-component reaction with
Ph2CHNH2 (chosen as a representatively bulky amine),
benzaldehyde and benzylisocyanide yielded the protected
ligand 5 in good yield, while variation of the aldehyde
component yielded 6–8, showing that the procedure appears
generally applicable. Ester hydrolysis yielded the deprotected
ligands 9–12.
These ligands were reacted with one equivalent of the lantha-
nide triflate in methanol (Ln = Eu, Tb, Yb) to afford the
corresponding complexes in quantitative yield. 1H NMR
spectroscopy of the paramagnetic complexes gave rise to spectra
in which the protons close to the metal centre were shifted well
outside the 0–10 ppm region of the spectrum; Fig. 1 shows the
NMR spectrum of Tb.12. This spectrum shows groups of four
resonances spread over a broad chemical shift range. The
spectrum is much more complex than that of [Tb.DOTA]ꢀ,14
as loss of the fourfold symmetry in the monoamide complexes
making all the proton environments around the macrocycle ring
inequivalent and splitting each peak in the [Tb.DOTA]ꢀ into
four separate resonances. There is also another difference
between the spectra of Tb.12 and of [Tb.DOTA]ꢀ, in that the
NMR spectrum of the DOTA complex shows the presence of
two isomers, usually assigned to square antiprismatic (SAP) and
All the useful systems described above present considerable
synthetic challenges to the interested chemist. In particular,
a School of Chemistry, University of Birmingham, Edgbaston,
Birmingham, UK B15 2TT. E-mail: J.S.Snaith@bham.ac.uk;
Fax: +44 121 414 4403; Tel: +44 121 414 4363
b School of Chemistry, University of Manchester, Oxford Road,
Manchester, UK M13 9PL.
E-mail: Stephen.Faulkner@manchester.ac.uk;
Fax: +44 161 275 4616; Tel: +44 161 275 4659
c Department of Chemistry, University of Durham, South Road,
Durham, UK DH1 3LE
w Electronic supplementary information (ESI) available: Synthetic
procedures and spectroscopic data for the ligands and complexes.
See DOI: 10.1039/b810083g
z This paper is dedicated to Dr Josephine Peach on her retirement.
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Fig. 2 1H NMR spectrum of Eu.9.
additional complexity arises as a consequence of stereo-
isomerism on the NMR timescale. In DOTA complexes, both
the SAP and TSAP isomers exists as pairs of enantiomers.15
However, in the case of the complexes formed from Ugi
products, the stereogenic centre in the amide pendent arm means
that the major form will exist as two enantiomeric pairs of
diastereoisomers. In the case of Eu.9, these are clearly in slow
exchange on the NMR timescale. In fact HPLC suggests that
they are also in slow exchange under the conditions used for
purification. The HPLC traces for complexes showed two well
separated peaks, in ratios varying between 1 : 1 and 3 : 1; the
separated fractions gave identical mass spectra showing
Scheme 1 Synthesis of ligands and complexes. Reagents and conditions:
(a) BrCH2COOEt, NaHCO3, CHCl3, rt; (b) BrCH2COOtBu, Et3N,
THF, rt (c) TFA CH2Cl2 1 : 1, rt; (d) R1CHO, Ph2CHNH2, BnNC,
EtOH, 65 1C; (e) LiOH, THF/H2O (1 : 1), rt; (f) Ln(OTf)3, CH3OH,
40 1C, 3 days.
1
the expected molecular ion for the complex. H NMR of the
separated fractions revealed both to have identical spectra,
suggesting that the isomers re-equilibrate relatively rapidly in
aqueous solution. To confirm this, the two fractions were
separately injected onto the HPLC column at six minute inter-
vals over a four hour period. A slow equilibration between the
two species was observed, with a 1 : 1 ratio achieved after ca. 2 h.
Once the original equilibrium ratio had been reached, the sample
remained unchanged after 24 h.
The luminescence of the complexes was also studied, and the
luminescence lifetimes for a range of complexes are shown in
Table 1. Most of the data on these systems was collected in
aqueous solution, though we found that the increased lipo-
philicity conferred by the presence of the pyrene group alters
the solubility of Ln.11 to the point that studies could only be
carried out in alcoholic solvents.
A chromophore can act as a sensitiser to a lanthanide ion
only if the donor state (commonly the T1 state) is significantly
higher in energy than the lanthanide emissive state. This
relationship between triplet energy and sensitisation is illus-
trated by the behaviour of three ions in different complexes.
For the Tb3+ ion, the emissive state (5D4) is relatively high in
energy (B20 490 cmꢀ1) and can only be sensitised by chromo-
phores with high triplet energies;16 in the case of this study,
only Tb.9 and Tb.12 were found to be highly luminescent.
Tb.10 was weakly luminescent in aerated solution as a con-
sequence of facile thermal repopulation of the ligand triplet
state, while Tb.11 showed no metal-centred luminescence at
all. In the case of the europium complexes, the emissive state
Fig. 1 1H NMR spectrum of Tb.12.
twisted square antiprismatic (TSAP) geometry of donor atoms
around the metal centre,15 while the spectrum of Tb.12 indicates
the presence of a single isomer. These resonances are observed at
similar frequencies to those of the SAP isomer in [Tb.DOTA]ꢀ,
suggesting either that any minor isomer is present as an un-
detectably small percentage of the mixture, or that conversion
between the isomers is rapid on the NMR timescale (which is
unlikely). By contrast, the spectrum of the complex Eu.9 shows
the presence of resonances in groups of eight (Fig. 2), with
roughly equal intensities comparable to, and with shifts similar
to those of the SAP isomer in [Eu.DOTA]ꢀ. It is likely that this
(5D0, B17 250 cmꢀ1 1
) is significantly lower in energy and
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Table 1 Photophysical properties of emissive complexesa
R1
lex/nm
lem/nm
tH/ms
tD/ms
q
Tb.9b
Tb.12b
Eu.9b
Eu.10b
Eu.12b
Yb.10b
Yb.11c
a
Ph
250
280
250
280
280
337
337
545
545
617
617
617
980
980
1750
1740
550
640
500
2480
2150
2070
2340
1430
0.5
0.2
1.3
1.1
1.3
1.0
0.6
Indolyl
Ph
Np
Indolyl
Np
Pyrenyl
0.81
2.24
6.13
9.91
The terbium and europium complexes of the pyrenyl-bearing ligand were non-emissive owing to the mismatch between triplet and emissive states,
while the terbium complex with the naphthyl-bearing ligand exhibits weak emission as the result of efficient back energy transfer. The emission of
b
c
the Yb phenyl system was not studied in the absence of a suitable excitation source. Lifetimes are ꢂ10%. Measured in H2O–D2O. Measured in
CH3OH–CD3OD.
sensitised emission was observed for Eu.9, Eu.10 and Eu.12,
though not for Eu.11. The pyrene chromophore did, however,
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2
sensitise emission from the ytterbium F5/2 state at 980 nm
(B10 200 cmꢀ1).
The luminescence lifetimes of the emissive complexes were
used to probe the local environment and the solvation at the
metal centre. The number of inner sphere solvent molecules,
q, can be calculated using the equation
q = A(1/tH ꢀ 1/tD ꢀ B)
where A and B are constants for a given metal ion and solvent,
and tH and tD are the observed luminescence lifetimes in
protiated and deuteriated media respectively.17y Table 1 also
shows these calculated values for q, which illustrate that the metal
binding pocket changes little across the series. The lower values of
q obtained for Tb.9 and Tb.12 relative to their Eu analogues may
reflect the structure break commonly observed around
gadolinium as a consequence of the lanthanide contraction.
This study on a range of related complexes suggest that all
adopt very similar structures in solution, in which a single
isomer predominates around the metal centre.
The approach described above illustrates how luminescent
complexes can be prepared from simple building blocks by using
a multi-component synthesis approach. We are currently investi-
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and other substrates to allow the use of a flexible molecular toolkit
in ‘‘smart’’ bioassay and imaging applications.
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exchangeable amide N–H oscillators; for Yb3+ in water, A = 1 ms,
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5214 | Chem. Commun., 2008, 5212–5214