Variation of water exchange dynamics with ligand structure and stereochemistry in lanthanide complexes based on 1,4-diazepine derivatives

Article abstract of DOI:10.1039/b818445c

Complexes of Gd, Eu and Yb(iii) have been prepared with a series of heptadentate ligands related to the parent complex AAZTA, based on the 6-methyl-6-aminoperhydrodiazepine moiety. For (RR) and (RS)-diastereoisomers of a di-glutarate ligand, solution NMR

Full text of DOI:10.1039/b818445c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Variation of water exchange dynamics with ligand structure and
stereochemistry in lanthanide complexes based on 1,4-diazepine derivatives†
Elisa M. Elemento,a David Parker,*a Silvio Aime,b Eliana Gianoliob and Luciano Lattuadac
Received 17th October 2008, Accepted 11th December 2008
First published as an Advance Article on the web 30th January 2009
DOI: 10.1039/b818445c
Complexes of Gd, Eu and Yb(III) have been prepared with a series of heptadentate ligands related to
the parent complex AAZTA, based on the 6-methyl-6-aminoperhydrodiazepine moiety. For (RR) and
(RS)-diastereoisomers of a di-glutarate ligand, solution NMR studies revealed the presence of two
major species that undergo water exchange rates at Gd differing by a factor of six. Comparison of
solution hydration states for Eu(III) complexes reveals that each complex possesses two bound water
molecules. The absence of a good correlation of 1H NMR pseudo-contact shifts for Eu and Yb
analogues is suggested to arise from a change in hydration state between Eu and Yb.
Coordination complexes of gadolinium(III) have been the subject
of intense research activity over the past 25 years. Since 1988,
they have been used as contrast agents for magnetic resonance
imaging (MRI) and millions of scans are carried out at clinical
centres each year following injection of a gadolinium complex to
aid image contrast.1,2 The factors that determine the efficacy of the
contrast agent for this purpose are well understood.3–6 Thus, the
relaxivity (r1P: units mM-1 s-1) of a given complex is determined by
the number of coordinated and second sphere water molecules,3,4
the water exchange rate at the metal ion centre4,5 and the rotational
dynamics that define the extent of motional coupling between local
water molecules and the tumbling motion of the overall complex
or conjugate.1,6,7
7.1 mM-1 s-1 (298 K, 20 MHz), that does not vary significantly
in the presence of added anions or protein.
With this background in mind, we set out to explore the
behaviour of the lanthanide(III) complexes of the mono and di-
glutarate analogues of H4L2 (AAZTA). Such systems offer the
opportunity to allow conjugation of selected hydrophilic moieties,
based on primary amines, leading to complexes of defined
molecular volume. The extent to which the modulation of the
ligand structure and stereochemistry affect exchange dynamics—
and hence relaxivity—is analysed for complexes of L2–L5.
Ligand and complex synthesis and NMR characterisation
The gadolinium(III) complexes are most often based on
poly(aza-carboxylate) or poly(phenolic) ligands that exist in
solution as nine or occasionally eight coordinate complexes. These
complexes exist as coordination diastereoisomers, typically they
are in slow exchange with respect to the water exchange rate. As
each diastereoisomer usually possesses a different water exchange
rate,3,5 it is important to study this aspect in solution. Recently,
there has been an upsurge of interest in di-aqua complexes of
gadolinium, owing to the desire to maximise relaxivity.8,9 Provided
that displacement of the bound waters by endogenous anions10
or protein11 is suppressed and that sufficient kinetic stability
with respect to premature loss of Gd(III) is retained, then di-
aqua systems may offer distinct advantages. A recent example
of such a system was introduced in 2004, with a heptadentate
ligand based on the 6-alkyl-6-aminoperhydro-1,4-diazepine ring
system, L1. Thus, Gd(III) complexes of L2 have been studied4a
and [Gd.L1(H2O)2] or [Gd-AAZTA]-1 exhibits a relaxivity of
The synthesis of the 6-amino-1,4-perhydrodiazepine intermedi-
ate, L1, and the ligand L2 (or AAZTA), was carried out according
to a literature method.4a Alkylation of L1 occurs preferentially at
the endocyclic ring nitrogen atoms, even with reactive electrophiles
such as the a-bromo esters 1 and 2, owing to the high steric demand
at the 6-amino position. Reaction of L1 with one equivalent of the
orthogonally protected a-bromo ester, (S)-1, (K2CO3, MeCN),
gave rise to the diastereoisomers, 3a and 4a, which were sepa-
rated by fractional crystallisation from ethanol. The dialkylation
product, 5a, was also isolated from this procedure and could be
obtained in a separate procedure in 70% yield by stoichiometric
1
alkylation. Compounds 3a and 4a were distinguished by the H
NMR chemical shift non-equivalence of the benzylic CH2 singlet
(Dd = 0.008 ppm, CDCl3, 295 K, 700 MHz), but their absolute
configuration was not assigned. Subsequent reaction of 3a or 5a
with tert-butylbromoacetate (K2CO3, Na2SO4, MeCN) afforded
the esters 3b and 5b, which were purified by chromatography on
neutral alumina. Stepwise reaction with trifluoroacetic acid and
hydrogenolysis of the benzylic ester yielded the ligands H6L3 and
H5L5. In a separate reaction pathway, Scheme 1, the two (meso)-
diastereoisomers of H6L4 were obtained, possessing a pseudo-
asymmetric centre at the quaternary C, involving a sequence of
three alkylation reactions, using (R) and (S)-1.
aDepartment of Chemistry, Durham University, South Road, Durham, UK
DH1 3LE
bDipartimento di Chimica IFM, Universita degli Studi di Torino, via P. Giuria
7, 10125 Turin, Italy
cBracco Imaging s.p.a., Via E. Folli 50, 20134 Milano, Italy. E-mail: david.
parker@durham.ac.uk
For purposes of comparison, a statistical mixture of (RR)-
L3, (SS)-L3 and (meso)-L4 was also prepared. Reaction of L1
with racemic a-bromodimethylglutarate afforded the ester 6a
† Electronic supplementary information (ESI) available: 1H NMR spectra
of complexes, NMRD profiles of [Gd.L5]2- and HPLC methods of analysis.
See DOI: 10.1039/b818445c
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Scheme 1
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1
and subsequent treatment with tert-butylbromoacetate afforded
the intermediate hexa-ester, 6b. Stepwise ester hydrolysis (90%
TFA–CH2CH2CL2 then aq. KOH) afforded the mixture of (RR)–
(SS)H6L3 and the two meso diastereoisomers of H6L4, following
treatment with ion-exchange resin. Complexes of ligands L2–L5
with lanthanide(III) ions (Ln = Eu, Gd, Yb) were prepared at
pH 5.5, using LnCl3·6H2O salts.
Comparison of the H NMR spectra of Eu and Yb(III) com-
plexes of a common ligand, e.g. (RS)-L4, suggested that the two
isomers observed had different solution coordination structures.
The sense and sequence of NMR dipolar shifts differed in each case
and most markedly for the complexes of (RS)-L4. Previous work
has established that the dipolar shifts of Eu/Yb(III) complexes of
a common ligand, in which a constant coordination number and
geometry are conserved, are strictly related.5,12 In this case, given
the rigidity of the ligand, the absence of a good correlation may be
due to a change in complex hydration, reducing the coordination
number from 9 (earlier Ln(III) ions) to 8 for the smaller ions, e.g.
Yb(III). This may be manifested in a reduction in the number of
coordinated waters from two (Eu) to one (Yb). Examples of this
change in hydration state across the lanthanide(III) series have been
frequently reported.1,5,13–15 For example, in Ln(III) complexes based
on DOTA (DOTA is 1,4,7,10-tetraazacyclododecane-tetracetate)
and related phosphinate complexes, there is a reduction from
mono-hydrated systems in the early and central Ln(III) ions, to
species with no directly bound water molecules towards the end of
the series.14
Information about the number of diastereoisomers present in
solution was obtained by comparing 1H NMR spectral data for the
Eu(III) and Yb(III) complexes at 200, 500 and 700 MHz. First, the
case of the Yb(III) complexes of (RR)-L3, (SS)-L3 (n.b. gives rise
to identical NMR spectra for the enantiomeric series) and (meso)-
L4, present in the stereoisomeric mixture of ligands prepared
from ( )-2 was considered. Two diastereoisomeric complexes were
observed in approximately a 9 : 4 ratio, (Fig. 1); each isomer
was characterised by a separate set of dipolar shifts, exemplified
by the resonance for the 6-methyl group at +10 and +14 ppm.
The corresponding Eu(III) complex, derived from the same ligand
1
mixture, gave a H NMR spectrum of similar but not identical
overall form, with two species in a ratio of ~2 : 1, with reduced
dipolar shifts, in one of which the 6-Me group resonated at
+6.6 ppm.
Complex hydration and structure
The assignment of these NMR spectra was aided by separate
examination of 1H NMR spectra from the enantiopure complexes,
(RR)-[Yb.L3]3- and (RS)-[Yb.L4]3-, (Fig. 2). In this case, the major
species were observed in a ratio of 10 : 1, in which the 6-Me
group resonated at +14 ppm. For (RS)-[Yb.L4]3- the same sets
of resonances were apparent, but in a ratio of 1 : 4, with the
6-Me group resonating at +10 ppm. Examination of the analogous
Eu(III) complexes was also undertaken. In this case, the major
isomer observed for the (RR)-[Eu.L3]3- complex (in an 8 : 1 ratio)
corresponded in chemical shift to the minor isomer for (RS)-
[Eu.L4]3- (ratio 1 : 3) and vice versa, (Fig. 3).
The solution hydration state of each europium complex was
measured using a luminescence method15 in which the radiative
rate constant characterising depopulation of the Eu(III) excited
was measured in water and D2O. In each case (Table 1), data were
consistent with the europium ion binding to two water molecules.
Measurements of the paramagnetic relaxivity r1p of the Gd(III)
complexes at 298 K and 20 MHz gave values of about 8.0 mM-1 s-1
(Table 1), consistent with the expected value for a di-aqua complex
of such a molecular volume.2 It is evident that the ‘mono-glutarate’
complexes, (R)-[Eu.L5]2- and (R)-[Gd.L5]2-, also form di-aqua
Fig. 1 1H NMR spectrum of the mixture of Yb(III) complexes derived from (RR)-L3, (SS)-L3 and (meso)-L4, revealing a mixture of two major
diastereoisomers in a ratio of 9 : 4 (295 K, pD 5.4, 200 MHz; major species—circles, minor species—squares).
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Table 1 Radiative rate constants (ms-1, 10%) for europium(III) com-
plexes in water and deuterium oxide (296 K, 1 mM complex, lexc 397 nm)a
Analysis of water exchange rates at gadolinium
Previous studies have shown that in diastereoisomeric complexes
of lanthanide(III) ions, the rate of water exchange may differ
by up to two orders of magnitude.3,5,15 Rates of water exchange
at a gadolinium centre may be determined by analysing the
temperature dependence of the transverse relaxation rate of the
17-O nucleus in water.1,2,16,17 This data may then be used to enhance
the fitting of NMRD profiles (r1p as f (Bo)), in order to deduce
appropriate relaxation terms. Details of such analyses have been
extensively and thoroughly discussed.1,2,5,15–17 Analysis of the data
obtained, (Table 2), highlights the differing water exchange rates of
the stereoisomeric Gd(III) complexes (Fig. 4), allowing the analysis
of the variable temperature 1-H NMRD profiles (Fig. 5 and ESI†).
Plausible representations of the structures of the diastereoiso-
meric complexes of (RR)-[Ln.L3]3- are given in Scheme 2; for
(RS)-[Ln.L4]3-, analogous structures may be considered, differing
only in configuration at one of the stereogenic centres in the
glutarate arm. As was observed for the (RRRR), (RRRS), (RSRS)
and (RRSS)-lanthanide(III) complexes of gDOTA,3 each ligand
stereoisomer gives rise to two common types of metal complex
diastereoisomer, the relative proportion of which determines
the overall water exchange dynamics. The 1H NMR analysis
kHEu2
/ms-1
kDEu2
O
/ms-1
O
Complex
qb ( 20%)
2.1
(RR/SS)-[EuL3]3- + (meso)-[EuL3]3-
(statistical mixture)
(RR)-[Eu.L3]3-
3.20
1.20
3.40
2.94
3.00
2.90
1.15
1.27
1.16
1.20
2.4
1.7
1.9
2.0
(RS)-[Eu.L4]3-
(R)-[Eu.L5]2-
[Eu.L2]-
a [EuL2]- was obtained from Bracco s.a. and was prepared as described in
reference 4a. b q represents the metal ion hydration number.15
complexes in aqueous solution. The 1H NMR spectra of the Eu(III)
and Yb(III) complexes (see ESI†) suggested the presence of one
dominant solution species (8 : 1 for Yb; 6 : 1 for Eu) in each
case. Again, the dipolar NMR shifts for the Eu/Yb(III) complexes
of L5 did not correspond (sequence/relative shift), consistent with
a change in the local coordination number and ligand field, as you
pass from Eu(III) to the smaller, more sterically demanding Yb(III)
complex.
Fig. 2 1H NMR spectrum of (RR)-[Yb.L3]3- (pD 5.4, 700 MHz, 295 K) showing selected assignments of the major (circles) and minor (squares)
diastereoisomeric complexes in a ratio of ~10 : 1.
Table 2 Water exchange ratesa ( 298 , s-1), relaxivity valuesb and selected relaxation parameters obtained by analysis of variable temperature 17O R2
kex
measurements17 and by fitting of NMRD profiles4a
Complex
r1p/mM-1 s-1
kex (298 K) ¥ 106 s-1
D2/s-2
tv/ps
(R)-[Gd.L5]2-
7.3
7.5
8.0
8.6
7.1
8.70
4.12
2.42
1.39
11.1
3.4 ¥ 1019
1.6 ¥ 1019
2.7 ¥ 1019
2.2 ¥ 1019
2.1 ¥ 1019
21
28
28
63
31
(RS)-[Gd.L4]3-
(RR)/(SS) + (meso)-[Gd.L3/L4]3- (mix of stereoisomers)
(RR)-[Gd.L3]3-
[Gd.L2]-
a
17O NMR data was measured at pH 7.4 at 14.1 T. b Relaxivity values are quoted at 298 K and 20 MHz. c tr values (298K) were estimated to be: [GdL2]-
74 ps; [GdL3]3- 111ps (83 ps at 310 K) and [GdL5]2- 93 ps (75 ps at 310 K).
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Fig. 3 1H NMR spectra for (RR)-[Eu.L3]3- (upper) and (RS)-[Eu.L4]3- (lower) revealing the 1 : 9 and 3 : 1 ratio of corresponding diastereoisomers
(295 K, pD 5.4, 700 MHz; major species—circles, minor species—squares).
not change significantly between europium and gadolinium; only
small changes are expected based on earlier analyses of gDOTA
complexes.3
Using these mole fractions to define the weighting of the
contributions of each Gd(III) complex diastereoisomer to the
observed rate, the rates of water exchange may be estimated by
solving the simultaneous eqn (1) and (2), where x and y represent
the unknowns:
koRbRs 1.39 ¥ 106 = 0.88x + 0.11y
(1)
Scheme 2
RS
obs
4.12 ¥ 106 = 0.25x + 0.75y
(2)
k
of the corresponding Eu(III) complexes had suggested that for
complexes of the (RR)-isomeric ligand, L3, the ratio of solution
diastereoisomers was 8 : 1; this ratio was 1 : 3 for the complexes
of (RS)-L5. It is an implicit assumption that this isomer ratio does
hence: x = 9.2 ¥ 105 s-1; y = 5.4 ¥ 106 s-1.
The values obtained reveal a difference in water exchange
rate of a factor of six and the data is consistent ( 10%) with
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Conclusions
The measured water exchange rates for Gd(III) complexes of the
mono and di-glutarate derivatives of AAZTA are less than 107 s-1
(298 K), and are lower than the value of 1.1 ¥ 107 s-1 recorded
for [Gd·AAZTA]- itself,4a and for related anionic di-aqua Gd(III)
complexes of comparable molecular volume.8,9 Faster exchange
dynamics (¥3) were observed for (RS)-[Gd.L4]3- compared to
(RR)-[Gd.L3]3-, reflecting the greater proportion of a diastereoiso-
mer in solution that exchanges with a rate of 5.4 ¥ 106 s-1,
compared to 9.2 ¥ 105 s-1 for the other isomer. The introduction
of substituents at each ring N increases the steric demand at the
metal centre, and this increased steric crowding may be inhibiting
the approach of water molecules, slowing the water interchange
process.
Such behaviour suggests that MRI contrast agents, based
on these glutarate derivatives, are unlikely to give rise to high
relaxivity values in amide conjugates of greater molecular volume.
Fig. 4 Comparison of 17O NMR R2p vs. T profiles for the stated complexes
(14.1 T, pH 7.4; see Table 2 for analysis), showing the fit (line) to the
experimental data.
Experimental
All reagents were used as supplied by commercial sources unless
otherwise stated. Solvents were dried over the appropriate drying
agents when required. Water and H2O refer to high purity water
with conductivity ≤0.04 mScm-1, obtained from the “PuriteSTILL
Plus” purification system. Reactions requiring anhydrous condi-
tions were carried out using Schlenk-line techniques under an
atmosphere of dry argon. Anhydrous solvents when required were
freshly distilled over the appropriate drying agent. Thin-layer
chromatography was carried out on silica plates (Merck 5554)
and visualised under UV light (254 nm) or by washing in a bath
of ethanol–sulfuric acid 5% or permanganate or by staining with
iodine. Preparative column chromatography was performed using
neutral aluminium oxide (Merck Aluminium Oxide 90, activity
II–III, 70–230 mesh) washed in ethyl acetate, or silica (Merck
Silica Gel 60, 230–400 mesh). The HPLC analysis and separation
were carried out on a Perkin Elmer system comprising a Perkin
Elmer Series 200 Pump, Perkin Elmer Series 200 Autosampler
and a Perkin Elmer Series 200 Fluorescence detector. A Gilson-
FC203B fraction collector was used in separation procedures. The
stationary phase was a Phenomenex Synergi 4 m Fusion-RP 80,
and the size of the column used was 150 ¥ 4.6 mm (flow rate
1mL min-1). Details of the HPLC methods used are given in the
ESI.†
Fig. 5 Proton NMRD profile for (RR)-[GdL3]3- at 298 K and 310 K
(lower), showing the fit (line) to the experimental data; (profile for [GdL5]2-
is in the ESI†).
Electrospray mass spectra were recorded on a VG Platform
II (Fisons Instruments), operating in positive or negative ion
mode, with methanol as the carrier solvent. Accurate masses were
recorded on a Thermo Finnigan LTQ instrument. Measurements
of [Gd] using ICP-mass spectrometry were performed by Dr C
Ottley (Durham University, Earth Sciences) following sample
digestion in conc. HCl at 120 ◦C for 18 h.
1H and 13C NMR spectra were recorded on a Varian Unity-300
spectrometer (1H at 299.908 MHz, 13C at 75.412 MHz), Varian
VXR 400 (1H at 399.968 MHz, 13C at 100.572 MHz), Bruker
AMX 500 spectrometer or Varian Unity-700 spectrometer (1H at
699.73 MHz). Spectra were referenced internally to the residual
proton-solvent resonances and are reported in ppm relative to
TMS, with coupling constants in Hz (typically 0.4 Hz). Solution
pD values stated are given as pH (meter reading) + 0.4.
values measured for the stereoisomeric mixture of complexes
(L3–L4). In (RS)-[Gd.L4]3-, the more abundant solution isomer
possesses the faster water exchange rate and for (RR)-[Gd.L3]3-, the
opposite is true. Examples of water exchange rates that differ for
diastereoisomeric complexes of a given ligand have been defined
previously.2,3,5,15 In certain cases, these observations may reflect
the differing activation energies to water exchange that arise from
changes in local hydration.
The magnitude of these individual exchange rates is lower than
required for most MRI applications. Faster rates—of the order
of ten to one hundred times faster—are needed in derivatives of
such systems, in order to avoid the ‘quenching’ of relaxivity gains
in more slowly rotating conjugates, in the magnetic field range
0.5 to 3 T.
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Variable temperature 17O NMR experiments were recorded
at 14.1 T and 298 K and were performed and analysed as
described in the recent literature; see ref. 4a and references therein.
Measurements of 1-H NMRD profiles at 298 and 310 K in the
range 0.001 to 20 MHz were made using a Stelar Spinmaster
relaxometer. Profiles were fitted with standard iterative methods
reported in ref. 4a, using the tau-m values derived from the 17-O
analysis.
Luminescence spectra of the EuIII complexes were recorded
using a direct excitation of the EuIII ion at 397 nm. Lifetime
measurements of the EuIII complex were recorded on a Perkin
Elmer LS55 luminescence spectrometer using FL Winlab software.
The EuIII ion was excited directly at 397 nm, with an excitation
slit width of 10 nm. Lifetime values were measured following
excitation of the sample by a short pulse of light, monitoring
the integrated intensity of light (613 nm for europium) emitted
during a fixed gate time, tg, a delay time, td, later. A gate time of
0.1 ms was used.
(Note: this compound reacts readily with carbon dioxide and
should be stored as the hydrochloride salt and handled under dry
argon or nitrogen.)
6-Amino-6-methylperhydro-1,4-bis(1¢-methoxycarbonyl 3¢me-
thoxycarbonylpropyl)diazepine, 6a: (mixture of diastereoisomers).
The racemic a-bromoglutarate ester, 2 (1 g, 4.18 mmol) dissolved
in CH3CN (10 mL) was added over a period of 10 min to
a suspension of L1 (0.257 g, 1.99 mmol) and K2CO3 (0.55 g,
◦
3.98 mmol) in MeCN (10 mL). After stirring at 75 C for 24 h,
the solvent was removed under reduced pressure and the residue
dissolved in EtOAc (15 mL), washed with water–brine (80 : 20
v/v, 3 ¥ 15 mL) and dried over Na2SO4. Evaporation of the
solvent to dryness gave a dark yellow oil (0.74 g, 1.66 mmol,
84%). Rf (CHCl3–MeOH–conc. aq. NH3 9 : 1 : 0.1, SiO2) = 0.2
(UV, KMnO4).
d
H (CDCl3, 399.96 MHz): 0.91 (3H, s, CH3), 1.73–1.88 (2H, m,
2 ¥ CHaCH2CO2CH3), 1.89–2.04 (2H, m, 2 ¥ CHbCH2CO2CH3),
2.37–2.42 (4H, m, 2 ¥ CH2CO2CH3), 2.42–2.80 (8H, br. m, 4 ¥
CH2ring), 3.15–3.23 (1H, br. dd, CHX N), 3.23–3.30 (1H, br. dd,
CHY N), 3.58–3.60 (12H, m, 4 ¥ OCH3). dC (CDCl3, 75 MHz):
24.42 (CH3), 25.0–25.5 (CH2CH2CO2CH3), 30.8 (CH2CO2CH3),
Ligand and complex synthesis
Racemic dimethyl-a-bromoglutarate was prepared as described in
ref. 3; samples of L2 and [Eu.L2(H2O)2] H3O+ were obtained from
Bracco s.a. and were prepared according to methods defined in
ref. 4a.
=
51.8 (OCH3), 49.9–55.4 (CH2ring), 67.41 (CHN), 173.0 (C O),
+
+
=
173.6 (C O). m/z (ES+): 446.3 [M + H] , 468.3 [M + Na] .
(Found: [M + H]+, 446.2493 C20H36N3O8 requires [M + H]+,
446.2497).
6-Amino-bis(tert-butoxycarbonylmethyl)-6-methyl-1,4-bis(1¢-
1,4-Dibenzyl-6-methyl-6-nitroperhydro-1,4-diazepine.
A sus-
methoxycarbonyl-3¢methoxycarbonylpropyl)-diazepine,
6b.
A
pension of N,N¢-dibenzylethylenediamine (5.0 mL, 0.02 mol) and
para-formaldehyde (1.91 g, 0.06 mmol) in EtOH (50 mL) was
boiled under reflux for 4 h. Nitroethane (1.52 mL, 0.02 mol)
was added dropwise, and the reaction mixture was boiled under
reflux overnight, under an argon atmosphere. The progress of
the reaction was monitored by TLC, and after 16 h, solvent
was removed under reduced pressure and the residue partitioned
between CH2Cl2 and saturated aqueous Na2CO3 solution. The
organic extracts were washed with water, dried, filtered, evaporated
and purified by column chromatography (SiO2, CH2Cl2) to afford
a light brown waxy solid (6.50 g, 96%). Rf (CH2Cl2, SiO2) =
0.4 (UV). Mp 49.5–51 ◦C. dH (CDCl3, 300 MHz): 1.34 (3H, s,
CH3C(quat)), 2.59 (4H, m, 2 ¥ CH2N), 2.95 (2H, d, 14.1), 3.60 (2H,
d, J = 14.1), 3.65 (2H, d, J = 13.2), 3.78 (2H, d, J = 13.2), 7.26–
7.33 (10H, m, 2 ¥ Ph-H). ES-MS: m/z 339.3 [M]+, 340.3 [M + H]+,
361.4 [M + Na]+. Found: C, 70.6; H, 7.51; N, 12.2%. C20H25N3O2
requires: C, 70.8; H, 7.38; N, 12.4%.
suspension of 6a (0.7 g, 1.57 mmol), tert-butylbromoacetate
(0.66 g, 3.4 mmol) and K2CO3 (0.86 g, 6.20 mmol) in CH3CN
(15 mL) was cooled to 0 ◦C. The reaction mixture was allowed
to warm to room temperature, Na2SO4 (0.20 g, 1.41 mmol) was
added and the suspension boiled under reflux overnight. After
cooling to room temperature, salts were filtered off and the mother
liquor evaporated to give the crude product (0.85 g, 1.26 mmol).
Purification by flash chromatography (SiO2, 20% EtOAc in
hexane → 50% EtOAc in hexane) gave a pale yellow oil (0.37 g,
0.55 mmol, 35%). Rf (hexane–EtOAc 7 : 3, SiO2) = 0.2 (UV,
iodine). dH (CDCl3, 399.95 MHz): 0.95 (3H, s, CH3), 1.34–1.35
(18H, s, C(CH3)3), 1.73–1.85 (2H, m, 2 ¥ CH2aCH2CO2CH3),
1.86–1.98 (2H, m, 2 ¥ CH2bCH2CO2CH3), 2.31–2.36 (4H, m, 2 ¥
CH2CO2CH3), 2.36–3.05 (8H, br. m, 4 ¥ CH2ring), 3.17–3.23 (1H,
br. dd, CHX N), 3.26–3.31 (1H, br. dd, CHY N), 3.51 (2H, d, J =
12.4, CH2COOtBu), 3.56 (2H, d, J = 12.4, CH2COOtBu), 3.56–
3.60 (12H, m, 4 ¥ OCH3). dC (CDCl3, 125.66 MHz): 23.9 (CH3),
24.20 (CH2CH2CO2CH3), 28.3 (CH2CO2CH3), 51.8 (OCH3),
51.40–51.87 (CH2ring), 54.03 (CquatCH3), 68.42 (CH2COOtBu),
6-Amino-6-methylperhydro-1,4-diazepine, L1
. A suspension
4a
of the nitro compound (2.27 g, 6.69 mmol) in MeOH (10 mL) and
20% Pd(OH)2/C (1.88 g, 13.4 mmol) was hydrogenated overnight
using a Parr hydrogenator (10 psi H2). The reaction mixture was
filtered over Celite, the solvent was evaporated under reduced
pressure and a pale yellow oil (0.850 g, 98%) was obtained. Rf
(CH2Cl2–MeOH 19%–conc. aq. NH3 1%, SiO2) = 0.10 (iodine).
dH (CDCl3, 400 MHz): 0.85 (3H, s, CH3C(quat)), 1.86 (br. s, 4H, exch.
with D2O), 2.50 (4H, m, 2 ¥ CH2(ring) H-5a, 5b and H-7a, 7b), 2.63–
2.69 (2H, m, CH2(ring) H-2a, 3a), 2.74–2.80 (2H, m, CH2(ring) H-2b,
3b). dC (CDCl3, 100.6 MHz): 26.81 (CH3C(quat)), 52.06 (C-2 and
C-3), 54.15 (C(quat)), 62.42 (C-5 and C-7). ES-MS: m/z 130 [M +
H]+. Found: 130.1343; C6H16N3 requires: 130.1344.
=
68.5 (CHN), 80.71 (Cquat(CH3)3), 172.6–172.9 (C O), 173.19
+
=
=
(C O), 173.75 (C O). m/z (ES-): 674.2 [M + H] , 696.3 [M +
Na]+. (Found: [M + H]+, 674.3858. C32H56O12N3 requires [M +
H]+, 674.3856; found: [M + Na]+, 696.3678. C32H55O12N3Na
requires [M + Na]+, 696.3676).
6-Amino-bis(carboxymethyl)-6-methyl-1,4-bis(1¢-methoxycar-
bonyl-3¢methoxycarbonylpropyl)-diazepine. A solution of the
tert-butyl ester 6b (0.2 g, 0.29 mmol) in TFA–CH2Cl2 (1 : 1,
3.0 mL) was stirred at room temperature for 24 h. The solvent
was removed under reduced pressure, the residue was dissolved
in CH2Cl2 (3 mL) and the solution evaporated. This procedure
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was repeated twice. The residue was washed twice with diethyl
ether (2 ¥ 2 mL) and the trifluoroacetate salt was obtained as a
rather hygroscopic white precipitate (0.146 g, 0.26 mmol, 90%).
dH (CDCl3, 399.96 MHz): 1.2 (3H, br. s, CH3), 1.96–2.11 (4H, m,
2 ¥ CH2CH2CO2CH3), 2.38–2.55 (4H, m, 2 ¥ CH2CO2CH3), 2.80–
3.35 (8H, br. m, 4 ¥ CH2ring), 3.46 (1H, br. dd, CHX N), 3.48 (1H,
br. dd, CHY N), 3.6 (2H, br. d, 2 ¥ CH2COOH), 3.69–3.72 (12H,
m, 4 ¥ OCH3). This was used directly in the next step (methyl ester
hydrolysis, below) without further characterisation.
suspension of (S)-1 (2.25 g, 6.32 mmol), L1 (0.54 g, 4.2 mmol) and
K2CO3 (0.87 g, 6.3 mmol) in MeCN (80 mL) was stirred at room
temperature for 18 h. The solvent was removed under reduced
pressure and the residue dissolved in EtOAc (80 mL), washed
with brine (20%, 2 ¥ 70 mL), dried over Na2SO4 and evaporated
to dryness. The residue was dissolved in EtOAc (50 mL), washed
with hydrobromic acid solution (1 M) (3 ¥ 40 mL), dried over
Na2SO4 and evaporated to dryness, to give 5a, a pale brown oil
(1.19 g, 1.76 mmol, 28%).
Concentrated aqueous ammonia (5.2 mL) was added dropwise
to the aqueous phase (until pH ~ 9), which was then extracted with
EtOAc (4 ¥ 40 mL). The organic phase was washed with H2O–
brine (4 : 1 v/v, 3 ¥ 50 mL), dried over Na2SO4 and evaporated to
dryness to give an oil (1.5 g, 3.7 mmol). Crystallization from EtOH
and washing of the precipitated solid with CH3CN gave 3a as a
yellow oil (1.02 g, 2.52 mmol, 40%) and 4a as a semi-crystalline
white solid (0.25 g, 0.61 mmol, 10%).
6-Amino-bis(carboxymethyl)-6-methyl-1,4-bis(1¢-carboxy-3¢-
carboxypropyl)-diazepine: L3–L4 as a statistical mixture of RR/SS
and the RS and SR isomers. KOD (1 M solution in D2O, 1 mL)
was added to the methyl ester (0.15 g, 0.27 mmol) and the
solution stirred at 40 ◦C. The reaction progress was checked by 1H
NMR. After 7 days, the measured pH was adjusted to 7 and solvent
removed under reduced pressure. The residue was treated with
freshly activated Dowex H+ resin, and the acid eluted following
addition of 20% acetic acid solution. The white glassy solid that
was obtained was used directly for complexation.
dH (D2O, 399.96 MHz): 1.1 (3H, s, CH3), 1.6–1.88 (4H, m, 2 ¥
CH2CH2CO2H), 2.03–2.15 (4H, m, 2 ¥ CH2CH2CO2H), 2.45–3.32
(8H, br. m, 4 ¥ CH2ring), 3.55 (1H, br. dd, CHX N), 3.67 (1H, br.
dd, CHY N), 3.7 (4H, br. d, 2 ¥ CH2COOH). m/z (ES): 504.2 [M -
H]-. Found: [M - H]-, 504.1834. C20H30N3O12 requires [M - H]-,
504.1836.
(R,R)-1,4-Bis(1¢-tert-butoxycarbonyl-3¢-benzyloxycarbonylpro-
pyl)-6-amino-6-methylperhydro-1,4-diazepine, 5a. This com-
pound could be obtained directly in 70% yield using 2.2
equivalents of (S)-1 using the reaction conditions and work-up
described above, where it was isolated as a pale yellow oil from
the ethyl acetate extraction of the residue.
Rf (CHCl3–EtOH–NH3 95 : 5 : 0.1, SiO2) = 0.2 (UV, KMnO4).
HPLC (Chromatographic method A2): tr: 14 min. dH (CDCl3,
399.9 MHz): 0.91 (3H, s, CH3), 1.40 (9H, s, C(CH3)3), 1.42
(9H, s, C(CH3)3), 1.82–2.19 (4H, br. m, 2 ¥ CH2CHN), 2.35–
2.72 (8H, m, CH2ring), 2.88–3.0 (4H, m, 2 ¥ CH2COOBn), 3.44–3.5
(2H, m, 2 ¥ CHN), 5.10 (4H, d, J = 7.2, 2 ¥ CH2Ph), 7.29–
7.35 (10 H, m, 2 ¥ Ph–H). dC (CDCl3, 75 MHz): 25.10 (CH3),
26.08 (CH2CHN), 28.56 (C(CH3)3), 32.11 (CH2COOBn), 49.10
(CH2(ring)N), 51.75 (CH2(ring)Cquat), 66.54 (CH2Ph), 68.33 (CHN),
128.5–129.08 (Carom), 136.33 (Cquat arom), 171.98 (CquatNH2), 173.21
[LnIII(Glu)2Racemic-AAZTA]3- (i.e. a mixture of (RR/SS)-
L3 and (RS/SR)-L4). An aqueous solution of LnCl3·6H2O
(0.1 mmol, 0.95 eq.) was added dropwise to a solution of H6L3–L4
(0.1 mmol, 1 eq,) dissolved in the minimum volume of H2O. The
pH was adjusted to ~5.5 with aqueous KOH solution (1 M) and
the mixture was left to stir at 50 ◦C. After 48 h, the reaction
mixture was cooled to room temperature and the pH of the
solution raised to ~10 (using aqueous KOH, 1 M). The white
powder that precipitated was isolated by centrifugation and the
pH of the supernatant readjusted to ~5.5. Freeze drying of the
liquid gave the complex as a colourless crystalline solid, together
with residual salts. The properties of the complex were examined
in the presence of the salts.
(C OBn), 174.00 (C OtBu). m/z (ES+): 682.4 [M + H]+, 704.3 [M +
Na]+, 626.33 [M - tBu]+. (Found: C, 64.3; H, 8.15; N, 5.90%;
C38H55N3O8·3/2 H2O requires: C, 64.4; H, 8.19; N, 5.93%).
=
=
(1¢R,6S)-(1¢-tert-Butoxycarbonyl-3¢-benzyloxycarbonylpropyl)-
6-amino-6-methylperhydro-1,4-diazepine, 3a diastereoisomer solu-
ble in EtOH (arbitrary assignment of configuration). Rf (CHCl3–
MeOH–NH3 86 : 12 : 1, SiO2) = 0.35 (UV, KMnO4). HPLC (Chro-
matographic method A2): tr: 5 min. dH (CDCl3, 699.73 MHz):
0.94 (3H, s, CH3), 1.42 (9H, s, C(CH3)3), 1.81–1.91 (1H, m,
CH2aCHN), 1.96–2.03 (1H, m, CH2bCHN), 2.45–2.54 (2H, m,
CH2COOBn), 2.61–2.91 (8H, m, Hring), 3.14–3.19 (1H, m, CHN),
5.09 (2H, s, CH2Ph), 7.31–7.33 (5H, m, Ph–H). dC (CDCl3,
125.67 MHz): 25.42 (CH2CHN), 25.7 (CH3), 28.44 (C(CH3)3),
31.26 (CH2COOBn), 49.42 (CH2N), 54.3 (CH2N), 56.8 (Cquat),
56.9 (CH2Cquat), 60.0 (CH2Cquat), 66.73 (CH2Ph), 68.7 (CHN), 82.6
[YbIIIL3/4]3-. m/z (TOF MS ES-): 672.5 [M]-. (Found: [M]-,
668.4998. C20H27N3O12170Yb1 requires [M]-, 668.4998.
[GdIIIL3/4]3-. m/z (TOF MS ES-): 659.0 [M]-. (Found: [M]-,
659.0304 C20H27N3O12158Gd1 requires [M - H]-, 659.0309; [M]-,
655.0465 C20H27N3O12154Gd1 requires [M - H]-, 655.0470; [M]-,
656.0506 C20H27N3O12155Gd1 requires [M - H]-, 656.0510). r1p
=
8.02 mM-1s-1 (20 MHz, 298 K). The [Gd3+]◦ was determined
following mineralization with 37% HCl at 120 C overnight and
then ICP-MS analysis was used to determine [Gd].
[EuIIIL3/4]3-. m/z (TOF MS ES-): 652.2 [M]-. (Found:
[M]-, 652.0795 C20H27O12N3151Eu requires [M]-, 652.0798; [M]-,
654.0808 C20H27O12N3153Eu requires [M]-, 654.0813).
=
(C(CH3)3), 128.4–128.84 (Carom), 136.0 (Cquat arom), 171.01 (C OBn),
173.0 (C OtBu). m/z (ES+): 406.2 [M + H]+, 428.3 [M + Na]+.
=
(1¢R,6R)-(1¢-tert-Butoxycarbonyl-3¢-benzyloxycarbonylpropyl)-
6-amino-6-methylperhydro-1,4-diazepine, 4a crystalline solid in-
soluble in EtOH (arbitrary assignment of configuration at the
quaternary centre). Rf (CHCl3–MeOH–NH3 86 : 12 : 1, SiO2) =
0.35 (UV, KMnO4). HPLC (Chromatographic method A2): tr:
5 min. Mp 119–121 ◦C. dH (CDCl3, 699.73 MHz): 0.98 (3H, s,
CH3), 1.44 (9H, s, C(CH3)3), 1.82–1.89 (1H, m, CH2aCHN),
(1¢R,6S)-(1¢-tert-Butoxycarbonyl-3¢-benzyloxycarbonylpropyl)-
6-amino-6-methylperhydro-1,4-diazepine, 3a; (1¢R,6R)-1¢-tert-
butoxycarbonyl-3¢-benzyloxycarbonylpropyl)-6-amino-6-methyl-
perhydro-1,4-diazepine, 4a; (R,R)-1,4-bis(1¢-tert-butoxycarbonyl-
3¢-benzyloxycarbonylpropyl)-6-amino-6-methylperhydro-1,4-diaze-
pine, 5a: (arbitrary assignment of configuration for 3a).
A
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2.0–2.07 (1H, m, CH2bCHN), 2.49–2.52 (2H, td, 3J = 2.8,
CH2COOBn), 2.62–2.68 (m, 5H, Hring), 2.71–2.75 (m, 1H, Hring),
2.79–2.83 (m, 1H, Hring), 2.91–2.95 (m, 1H, Hring), 3.17 (1H, dd,
EtOAc 8 : 2, SiO2) = 0.5 (UV, KMnO4). HPLC (Chromatographic
method A2): tr: 21 min. dH (CDCl3, 699.74 MHz): 0.99 (3H, s,
CH3), 1.40–1.43 (36H, m, 4 ¥ C(CH3)3), 1.82–1.87 (1H, m,
CH2aCHXN), 1.88–1.94 (1H, m, CH2bCHXN), 1.98–2.05 (2H, m,
CH2a,bCHYN), 2.35–2.59 (8H, m, CH2ring), 2.71 (1H, d, J = 14.7,
CH2aCOOBn), 2.74 (1H, d, J = 12.6, CH2bCOOBn), 2.90 (1H, d,
J = 12.6, CH2bCOOBn), 3.00 (1H, d, J = 14.7, CH2aCOOBn),
3.14 (1H, dd, J = 5.6, J = 10, CHX N), 3.25 (1H, dd, J =
5.6, J = 10, CHY N), 3.57 (2H, d, J = 17.5, CH2bCOOtBu),
3.67 (2H, d, J = 17.5, CH2aCOOtBu), 5.10 (4H, m, JHaHb =
15, CH2(a,b)Ph + CH2(a¢,b¢)Ph), 7.31–7.35 (10H, m, 2 ¥ Ph–H). dC
(CDCl3, 125.67 MHz): 25.23 (CH3), 26.14 (CH2CHN), 28.32–
28.53 (C(CH3)3), 31.13 (CH2COOBn), 51.7–54.2 (CH2ring), 61.74
(CquatCH3), 66.6 (CH2Ph), 68.13 (CH2COOtBu), 69.23 (CHN),
80.58 (C(CH3)3), 81.26 (C(CH3)3), 81.33 (C(CH3)3), 128.44–128.79
3
3J = 6.3, J = 9.1, CHN), 5.11 (2H, s, CH2Ph), 7.33–7.35 (5H,
m, Ph–H). dC (CDCl3, 175.95 MHz): 25.73 (CH2CHN), 26.41
(CH3), 28.51 (C(CH3)3), 31.19 (CH2COOBn), 51.84 (CH2N),
53.62 (CH2N), 55.5 (Cquat), 62.46 (CH2Cquat), 66.54 (CH2Cquat),
66.87 (CH2Ph), 68.91 (CHN), 81.46 (C(CH3)3), 128.48–128.8
=
=
(Carom), 136.13 (Cquat arom), 171.95 (C OBn), 173.32 (C OtBu). m/z
(ES+): 406.2 [M + H]+, 428.3 [M + Na]+.
(1¢R,6S)-(1¢-tert-Butoxycarbonyl-3¢-benzyloxycarbonylpropyl)-
4–6-tris(tert-butoxycarbonylmethyl)-6-amino-6-methylperhydro-
1,4-diazepine, 3b. tert-Butyl bromoacetate (0.26 mL, 1.75 mmol)
was added dropwise to a stirred solution of 3a (0.20 g, 0.5 mmol),
K2CO3 (0.27 g, 1.95 mmol) and Na2SO4 (0.064 g, 0.45 mmol)
in CH3CN (10 mL) cooled at 0 ◦C. The reaction mixture was
allowed to warm to room temperature, boiled under reflux for
6 h and then left stirring overnight at room temperature. The
mixture was evaporated under reduced pressure and the residue
treated with petroleum ether–EtOAc 8 : 2 (20 mL). Salts were
filtered off and the mother liquor evaporated to give the crude
product (0.6 g). Purification by flash chromatography (SiO2,
10% EtOAc in petroleum ether to 20% EtOAc in petroleum
ether) gave the product as a yellow oil (0.22 g, 0.3 mmol, 60%).
Rf (petroleum ether–EtOAc 8 : 2, SiO2) = 0.3 (UV, KMnO4).
HPLC (Chromatographic method A2): tr: 19 min. dH (CDCl3,
699.73 MHz): 0.99 (3H, s, CH3), 1.42–1.47 (36H, m, C(CH3)3),
1.81–1.91 (1H, m, CH2aCHN), 1.94–2.04 (1H, m, CH2bCHN),
2.45–2.76 (8H, m, 4 ¥ CH2ring), 3.0–3.07 (2H, m, CH2COOBn),
3.13 (1H, dd, J = 5.6, J = 10.5, CHN), 3.26 (1H, d, J =
14, CH2aNring), 3.33 (1H, d, J = 14, CH2bNring), 3.67 (2H, s,
CH2COOtBu), 3.68 (2H, s, CH2COOtBu), 5.11 (2H, s, CH2Ph),
7.31–7.35 (5H, m, Ph–H). dC (CDCl3, 125.67 MHz): 24.38 (CH3),
25.11 (CH2CHN), 28.4 (C(CH3)3), 31.15 (CH2COOBn), 51.84
(CringH2N), 52.56 (CringH2N), 60.1 (CH2Cquat), 61.24 (Cquat), 62.07
(NCH2COOtBu), 66.52 (CH2Ph), 67.33 (CH2COOtBu), 69.33
(CHN), 80.46 (C(CH3)3), 80.94 (C(CH3)3), 81.21 (C(CH3)3),
=
=
(Carom), 136.15 (Cquat Ph), 172.0 (C OBn), 172.21 (C OBn), 172.64
(C OtBu), 173.38 (C OtBu). m/z (ES+): 910.5 [M + H]+, 932.5
[M + Na]+. (Found: C, 62.2; H, 8.10; N, 4.11%; C50H75N3O12·3H2O
requires: C, 62.3; H, 8.41; N, 4.36%).
=
=
(R,S)-1,4-Bis(1¢-tert-butoxycarbonyl-3¢-benzyloxycarbonylpro-
pyl)-6-amino-6-methylperhydro-1,4-diazepine, 7a. (R)-1 (0.73 g,
2.05 mmol) dissolved in CH3CN (10mL) was added dropwise
to a stirred solution of 3a (0.83 g, 2.05 mmol), K2CO3 (0.28 g,
2.05 mmol) and Na2SO4 (0.064 g, 0.45 mmol) in CH3CN (10 mL)
cooled at 0 ◦C. The reaction mixture was allowed to warm to
room temperature and left stirring for 18 h. The solvent was
removed under reduced pressure and the residue dissolved in
EtOAc (30 mL), washed with water–brine (80 : 20, v/v, 2 ¥ 30 mL),
dried over Na2SO4 and evaporated to dryness. The residue was
dissolved in EtOAc (20 mL), washed with H2O–HBr (1 M) (10 : 1
v/v, 3 ¥ 20 mL), dried over Na2SO4 and evaporated to dryness,
to give 7a as a yellow oil (0.97 g, 1.42 mmol, 70%). Rf (CHCl3–
EtOH–NH3 95 : 5 : 0.1, SiO2) = 0.2 (UV, KMnO4). dH (CDCl3,
400.13 MHz): 1.40–1.46 (21H, br. s, 2 ¥ C(CH3)3 + CH3), 1.83–
2.03 (2H, m, CH2aCHN), 2.08–2.17 (2H, m, CH2bCHN), 2.33–
3.10 (12H, m, 2 ¥ CH2COOBn + Hring), 3.46 (2H, dd, J = 6,
J = 8.8, 2 ¥ CHN), 5.10–5.12 (2H, s + s, 2 ¥ CH2Ph), 7.28–
7.34 (10 H, m, 2 ¥ Ph–H). dC (CDCl3, 100 MHz): 24.72 (CH3),
27.72 (C(CH3)3), 29.71 (CH2CHN), 31.63 (CH2COOBn), 48.8
(CH2(ring)N), 52.61 (CH2(ring)Cquat), 66.54 (CH2Ph), 68.21 (CHN),
=
128.44–128.77 (Carom), 136.18 (Cquat Ph), 171.24 (C OBn), 172.07
=
=
=
(C OBn), 172.88 (C OtBu), 173.47 (C OtBu). m/z (ES+): 748.4 [M +
H]+, 770.4 [M + Na]+.
=
127.0–128.75 (Carom), 136.0 (Cquat arom), 168.29 (C OBn), 173.01
=
(R,R)-1,4-Bis(1¢-tert-butoxycarbonyl-3¢-benzyloxycarbonylpro-
pyl)-6-bis(tert-butoxycarbonlymethyl)-amino-6-methylperhydro-
1,4-diazepine, 5b. tert-Butyl bromoacetate (0.13 mL, 0.88 mmol)
was added to a stirred solution of 5a (0.24 g, 0.35 mmol) and
(C OtBu), 173.13 (CquatNH2). m/z (ES+): 682.4 [M + H]+, 704.3
[M + Na]+, 626.33 [M - tBu]+. Found: 682.4069; C38H56N3O8
requires: 682.4067.
◦
K2CO3 (0.1 g, 0.7 mmol) in CH3CN (5 mL) cooled to 0 C. The
(RS)-1,4-Bis(1¢-tert-butoxycarbonyl-3¢-benzyloxycarbonylpro-
pyl)-6-bis(tert-butoxycarbonylmethyl)-amino-6-methylperhydro-
1,4-diazepine, (RS)-7b. tert-Butyl bromoacetate (0.53 mL,
3.56 mmol) was added to a stirred solution of 7a (0.97 g,
1.42 mmol) and K2CO3 (0.57 g, 4.12 mmol) in CH3CN (10 mL)
cooled to 0 ◦C. The reaction mixture was allowed to warm to
room temperature, Na2SO4 (0.025 g, 0.17 mmol) was added and
then boiled under reflux overnight and stirred for a further 6 h
at 60 ◦C. The solvent was removed under reduced pressure and
the residue treated with petroleum ether–EtOAc 8 : 2 (15 mL).
Salts were filtered off and the mother liquor evaporated to give
the crude product (1.05 g). Purification by flash chromatography
(SiO2, 5% EtOAc in petroleum ether to 20% EtOAc in petroleum
ether) gave 7b as a yellow oil (0.52 g, 0.57 mmol, 40%). Rf
reaction mixture was allowed to warm to room temperature
and Na2SO4 (0.025 g, 0.17 mmol) was added. The suspension
was boiled under reflux overnight and stirred at 60 ◦C for a
further 8 h. After addition of more tert-butyl bromoacetate
(0.13 mL, 0.88 mmol), the reaction mixture was boiled under
reflux again overnight, then cooled to room temperature and
left to stir for 5 h. The suspension was filtered, the solvent
removed under reduced pressure and the residue was treated with
petroleum ether–EtOAc 8 : 2 (10 mL). Salts were filtered off and
the mother liquor evaporated to give a crude product (0.37 g)
that was purified by flash chromatography (SiO2, 5% EtOAc in
petroleum ether → 15% EtOAc in petroleum ether) to give 5b
as a yellow oil (0.2 g, 0.23 mmol, 65%). Rf (petroleum ether–
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(petroleum ether–EtOAc 8 : 2, SiO2) = 0.4 (UV, KMnO4). dH
(CDCl3, 400.13 MHz): 1.01 (3H, s, CH3), 1.43–1.46 (36H, s + s,
4 ¥ C(CH3)3), 1.89–1.95 (2H, m, CH2CHN), 1.98–2.10 (2H, m,
CH2CHN), 2.36–2.57 (8H, m, CH2ring), 2.62–2.87 (1H, m, 2 ¥
CH2COOBn), 3.01–3.12 (2H, m, 2 ¥ CHN), 3.63 (2H, d, J = 17.6,
CH2COOtBu), 3.69 (2H, d, J = 17.6, CH2COOtBu), 5.13 (4H, d,
J = 2.4, CH2(a,b)Ph + CH2(a¢,b¢)Ph), 7.30–7.37 (10H, m, 2 ¥ Ph–H).
dC (CDCl3, 125.67 MHz): 25.22 (CH3), 25.8 (CH2CHN), 28.31–
28.52 (C(CH3)3), 31.40 (CH2COOBn), 31.52 (CH2COOBn), 51.1–
54.1 (CH2ring), 61.74 (CquatCH3), 66.51 (CH2Ph), 66.73 (CH2Ph),
68.13 (CH2COOtBu), 68.38 (CH2COOtBu), 69.23 (CHN), 69.3
(CHN), 80.44 (C(CH3)3), 80.57 (C(CH3)3), 81.26 (C(CH3)3), 81.33
(C(CH3)3), 128.43–128.78 (Carom), 136.15 (CquatPh), 136.20 (CquatPh),
J = 14, CH2bCOOH), 3.25–3.28 (2H, m, 2 ¥ CHN), 3.50 (2H, d,
J = 17.5, CH2COOtBu), 3.61 (2H, d, J = 17.5, CH2COOtBu).
dC (CD3OD, 125.67 MHz): 25.8 (CH3), 26.9 (CH2CHN), 27.04–
27.31 (C(CH3)3), 29.92 (CH2COOH), 30.17 (CH2COOH), 50.68
(CH2ring), 65.40 (CquatCH3), 67.41–67.61 (CH2COOtBu), 82.23
=
=
(C(CH3)3), 82.54 (C(CH3)3), 167.45 (C OtBu), 170.8 (C OtBu),
+
=
=
174.7 (C OOH), 174.9 (C OOH). m/z (ES+): 730.3 [M + H] .
m/z (ES-): 728.5 [M - H]-. (Found: MH+, 730.4493. C36H64N3O12
requires MH+, 730.4485).
Alternate route. A solution of compound 5b (0.07 g,
0.077 mmol) in TFA and CH2Cl2 (1 : 1, 2 mL) was stirred at
room temperature for 24 h. The mixture was then evaporated, the
residue taken up with CH2Cl2 (2 mL) and the solution evaporated
under reduced pressure. This operation was repeated three times,
then the residue was washed twice with diethyl ether (2 ¥ 2 mL) to
yield a white solid (0.06 g, 0.087 mmol). dH (D2O, 399.96 MHz):
1.05 (3H, s, CH3), 1.98–2.06 (4H, m, 2 ¥ CH2CHN), 2.50–2.80
(4H, m, 2 ¥ CH2COOBn), 3.0–3.75 (10H, br. m, 4 ¥ CH2ring + 2 ¥
CHN), 3.80–3.90 (4H, m, NCH2COOH), 5.14 (4H, d, J = 4, 2 ¥
CH2Ph), 7.33–7.36 (10H, m, 2 ¥ Ph–H). This trifluoroacetate salt
was used directly without further characterisation.
Pearlman’s catalyst (0.006 g) was added to a solution of the
acid obtained above (0.06 g, 0.087 mmol) in EtOH (3 mL) and
H2O (0.4 mL). The reaction mixture was stirred under a hydrogen
atmosphere for 24 h (30 psi H2). The catalyst was filtered over
Celite and the solvent evaporated under reduced pressure, to afford
the bis-trifluoroacetate salt of H6L3 as a white glassy solid (0.044 g,
0.08 mmol). dH (D2O, 399.96 MHz): 1.06 (3H, s, CH3), 1.8–2.05
(4H, m, 2 ¥ CH2CHN), 2.40–2.55 (4H, m, 2 ¥ CH2COOH), 2.95–
3.40 (10H, br. m, 4 ¥ CH2ring + 2 ¥ CHN), 3.62–3.75 (4H, m,
2 ¥ NCH2COOH). m/z (ES): 504.2 [M - H]-. Found: [M - H]-,
504.1838. C20H30N3O12 requires [M - H]-, 504.1836.
=
=
=
=
171.73 (C OBn), 172.0 (C OBn), 172.64 (C OtBu), 173.38 (C OtBu).
m/z (ES+): 910.3 [M + H]+, 932.4 [M + Na]+. (Found: MH+,
910.5427. C50H76N3O12 requires MH+, 910.5423; Found: [M +
Na]+, 932.5250. C50H75N3O12Na requires [M + Na]+, 932.5243).
(1¢R,6S)-6-[Bis(carboxymethyl)]-4-(carboxymethyl)-1-(1¢-car-
boxy-3¢-carboxypropyl)-tetrahydro-6-amino-6-methyl-1H-1,4-dia-
zepine, Glu-AAZTA, L5. 10% Pd/C (0.005 g) was added to a
solution of compound 3b (0.05 g, 0.067 mmol) in EtOH (4 mL)
and H2O (0.5 mL). The reaction mixture was stirred under a
hydrogen atmosphere for 48 h (30 psi H2). The catalyst was filtered
over Celite and the solvent evaporated under reduced pressure,
to afford a white glassy solid (0.047 g, 0.07 mmol, 96%). dH
(D2O, 199.99 MHz): 1.05 (3H, br. s, CH3), 1.45 (9H, s C(CH3)3),
1.92–2.01 (2H, m, CH2CHN), 2.42–2.49 (2H, br. m, CH2COOH),
3.06–3.57 (9 H, br. m, CHN + 4 ¥ CH2ring), 3.67 (4H, br. s, 2 ¥
CH2COOH), 3.7 (2H, br. s, CH2COOH). m/z (ES-MS): 703 [M +
Na]-.
The acid prepared above (0.047 g, 0.07 mmol) was treated with
TFA–CH2Cl2 (1 : 1, 2.5 mL) and stirred at room temperature
for 24 h. The solvent was removed under reduced pressure and
the residue taken up with CH2Cl2 (3 ¥ 4 mL) and the solution
evaporated under reduced pressure each time. The residue was
washed twice with diethyl ether (2 ¥ 2 mL) and a colourless
precipitate was obtained of the bis-trifluoroacetate salt of H5L5
(0.03 g, 0.06 mmol). dH (D2O, 399.96 MHz): 1.04 (3H, br. s,
CH3), 1.91–1.93 (2H, m, CH2CHN), 2.41 (2H, br. m, CH2COOH),
3.0–3.49 (9 H, br. m, CHN + 4 ¥ CH2ring), 3.62 (4H, br. s, 2 ¥
CH2COOH), 3.82 (2H, br. s, CH2COOH). m/z (ES+): 456.4 [M +
Na]+. Found: 456.1596; C17H27O10N3Na requires: 456.1594.
(RS)-6-[Bis(tert-butoxycarbonylmethyl)]-1,4-bis(1¢-tert-butoxy-
carbonyl-3¢-carboxypropyl)-tetrahydro-6-amino-6-methyl-1H-1,4-
diazepine. 10% Pd/C (0.03 g) was added to a solution of
compound 7b (0.30 g, 0.33 mmol) in EtOH (8 mL) and H2O (1 mL).
The reaction mixture was stirred under a hydrogen atmosphere for
48 h using a hydrogenator (30 psi H2). The catalyst was filtered
over Celite and the solvent evaporated under reduced pressure, to
afford the tetra-tert-butyl ester as a colourless glassy solid (0.48 g,
0.35 mmol, 94%). dH (CD3OD, 499.77 MHz): 1.09 (3H, s, CH3),
1.48–1.50 (36H, m, 4 ¥ C(CH3)3), 1.85–1.89 (2H, m, CH2CHN),
1.95–2.0 (2H, m, CH2CHN), 2.36–2.48 (4H, m, 2 ¥ CH2ring), 2.66–
2.77 (4H, m, CH2ring), 3.0 (2H, d, J = 14, CH2COOH), 3.16
(2H, d, J = 14, CH2COOH), 3.26–3.36 (2H, m, 2 ¥ CHN),
3.6 (2H, d, J = 17.5, CH2COOtBu), 3.75 (2H, d, J = 17.5,
CH2COOtBu). dC (CD3OD, 125.67 MHz): 25.7 (CH3), 26.04
(CH2CHN), 27.26–27.43 (C(CH3)3), 31.0 (CH2COOH), 51.5–
53.68 (CH2ring), 64.55 (CquatCH3), 68.8–69.3 (CH2COOtBu), 67.9
(CHN), 80.73 (C(CH3)3), 80.9 (C(CH3)3), 81.13 (C(CH3)3), 81.37
(RR)-6-[Bis(carboxymethyl)]-1,4-bis(1¢-carboxy-3¢-carboxypro-
pyl)-tetrahydro-6-amino-6-methyl-1H-1,4-diazepine,
L3. This
compound could be obtained by stepwise de-benzylation followed
by TFA removal of the tert-butyl groups or vice versa. Only the
first step is shown for the first of these routes.
Pearlman’s catalyst (0.008 g) was added to a solution of
compound 5b (0.08 g, 0.12 mmol) in EtOH (10 mL) and H2O
(1 mL). The reaction mixture was stirred under a hydrogen
atmosphere for 48 h (30 psi H2). The catalyst was filtered over
Celite and the solvent evaporated under reduced pressure, to
afford the de-benzylated product as a white glassy solid (0.08 g,
0.11 mmol, 92%). dH (CD3OD, 699.73 MHz): 1.18 (3H, br. s,
CH3), 1.48 (18H, s, C(CH3)3), 1.56 (18H, m, C(CH3)3), 1.96–1.99
(2H, m, CH2CHN), 2.07–2.1 (2H, m, CH2CHN), 2.1–2.18 (4H,
m, 2 ¥ CH2ring), 2.47–2.58 (4H, m, 2 ¥ CH2ring), 2.65 (2H, dd, J =
14, CH2COOH), 2.96 (1H, d, J = 14, CH2aCOOH), 3.10 (1H, d,
=
=
=
(C(CH3)3), 171.73 (C OtBu), 171.95 (C OtBu), 173.10 (C OOH).
m/z (ES+): 730.3 [M + H]+, 752.4 [M + Na]+. (Found: MH+,
730.4475. C36H64N3O12 requires MH+, 730.4484; Found: MNa+,
752.4303. C36H63N3O12Na requires MNa+, 752.4304).
(RS)-6-[Bis(carboxymethyl)]-1,4-(bis-1¢-carboxy-3¢-carboxy-
propyl)-tetrahydro-6-amino-6-methyl-1H-1,4-diazepine:
(RS)-
Glu2AAZTA, L4. A solution of the tert-butyl ester (0.24 g,
0.33 mmol) in TFA–CH2Cl2 (1 : 1, 4.0 mL) was stirred at
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room temperature for 24 h. The solvent was removed under
reduced pressure, the residue taken up with CH2Cl2 (4 mL)
and the solution evaporated under reduced pressure. This
procedure was repeated three times, then the residue was washed
twice with diethyl ether (2 ¥ 2 mL) and a colourless solid was
obtained of the bis-trifluoroacetate salt (0.18 g, 0.34 mmol).
dH (D2O, 499.77 MHz): 1.05 (3H, s, CH3), 1.92–2.06 (4H, m,
2 ¥ CH2CHN), 2.36–2.50 (4H, m, 2 ¥ CH2COOH), 3.02–3.32
(8H, m, CH2ring), 3.54–3.58 (2H, m, 2 ¥ CHN), 3.59 (2H, d,
J = 11.5, NCH2COOH), 3.65 (2H, d, J = 11.5, NCH2COOH).
dC (D2O, 125.67 MHz): 22.01 (CH3), 24.37 (CH2CHN), 30.65
(CH2COOH), 50.65–51.61 (CH2ring), 61.61 (CquatCH3), 66.17
[M]-, 654.0806 C17H27O10N3153Eu requires [M - H]-, 654.0813).
t(H
= 0.28, t(D
= 0.87. dH (Major isomer) (D2O, 699.73 MHz):
O)
O)
2
2
-14.65, -5.19, -2.21, -1.59, -1.03, -1.59, -1.03, -0.62, 0.09, 0.43,
0.69, 1.86, 1.96, 4.90, 6.63, 7.29, 7.79, 10.29, 11.77. dH (Minor isomer)
(D2O, 499.79 MHz): -10.27, -8.39, -5.89, -4.64, 0.09, 0.89, 2.32,
2.46, 3.84, 5.52, 9.23, 13.76.
[Gd.L3]3-. The Gd complex was prepared in an analogous
manner; m/z (ES+): 658.9 [M - H]- (Found: [M - H]-, 659.0831.
C20H27N3O12158Gd1 requires [M - H]-, 659.0841; [M - H]-,
655.0801. C17H27N3O10154Gd requires [M - H]-, 655.0809; [M -
H]-, 656.0817. C17H27N3O12155Gd requires [M - H]-, 584.0826).
r1p = 8.65 mM-1 s-1 (20 MHz, 298 K). Th◦e [Gd3+] was determined
by mineralization with 37% HCl at 120 C overnight. Fitting of
the 17O NMR R2p vs. T (K) profile gave tM = 720 ns.
[YbIIIL3]3-. dH (Major isomer) (D2O, 699.73 MHz): -50.83, -26.87,
-18.45, -17.30, -9.92, -8.53, -8.08, -7.41, -5.43, -4.29, -1.62,
-0.79, 10.41, 14.03, 28.65, 30.38, 32.69, 40.18, 42.95, 48.55.
dH (Minor isomer) (D2O, 499.79 MHz): -36.32, -33.80, -22.23, -14.76,
-13.55, -9.22, 9.64, 16.31, 22.93, 24.27, 33.87, 36.58.
=
(NCH2COOH), 67.81 (CHN), 173.08 (CHC OOH), 176.1
=
=
(NCH2C OOH), 177.0 ((CH2)2C OOH). m/z (ES-): 504.3 [M -
H]-. (Found: [M - H]-, 504.1835. C20H30N3O12 requires [M - H]-,
504.1836).
[LnIIIL5]2-. An aqueous solution of LnCl3·6H2O (0.1 mmol,
0.95 eq.) was added dropwise to a solution of H5L5.(CF3CO2)2 in
H2O–MeOH 5% solution (0.1 mmol), dissolved in the minimum
volume of solvent. The pH was adjusted to ~5.5 with aqueous
KOH solution (1 M) and the mixture was left to stir at 50 ◦C,
maintaining the pH at about 5.5 by additional additions of base.
After 48 h, the reaction mixture was cooled to room temperature
and the pH of the solution raised to ~10 (using aqueous KOH
solution, 1 M). Any white solid that precipitated was isolated by
centrifugation and the pH of the supernatant readjusted to ~5.0.
Freeze drying of the liquid gave a white crystalline solid, together
with potassium salts. The properties of the complex were examined
in the presence of the salts.
[Gd.L4]3-. Crude yield: 50%. m/z (ES-): 659.2 [M - H]-.
(Found: [M - H]-, 659.0845. C20H27N3O12158Gd requires [M - H]-,
659.0841). r1p = 7.5 mM-1 s-1 (20 MHz, 298 K).
Fitting of the 17O NMR R2p vs. T (K) profile gave tM = 246 ns.
[YbIIIL4]3-. Crude yield: 60%. m/z (ES-): 675.3 [M]-. (Found:
[M]-, 675.0996. C20H27N3O12174Yb requires [M - H]-, 675.0989).
dH (Major isomer) (D2O, 699.73 MHz): -51.48, -37.01, -35.99, -26.08,
-19.10, -16.28, -11.24, -9.67, -9.27, -7.18, -4.77, -2.69, -1.48,
0.23, 0.64, 0.82, 1.88, 3.56, 7.25, 10.10, 10.98, 14.85, 24.39,
28.16, 33.13, 35.07, 37.44, 43.18, 47.42, 50.24. dH (Minor isomer) (D2O,
699.73 MHz): -55.84, -49.92, -43.70, -38.62, -34.93, -32.15,
-21.73, -19.96, -17.60, -12.45, -10.03, -7.99, -5.87, -4.4, -0.53,
6.14, 9.00, 10.32, 14.56, 17.59, 25.82, 29.22, 31.49, 38.50, 41.43,
44.32, 52.14.
[Yb.GluAAZTA]2- or [Yb.L5]2-. m/z (ES-): 603.07 [M - H]-
(Found: [M - H]-, 599.0737. C17H23N3O10170Yb requires [M - H]-,
599.0737 and [M - H]-, 603.0777. C17H23N3O10174Yb requires [M -
H]-, 603.0777). dH (Major isomer) (D2O, 499.79 MHz): -36.05, -28.62,
-8.72, -5.69, -5.47, -3.84, -3.38, -2.21, -1.07, -1.17, 5.65, 6.01,
8.88, 10.66, 27.26, 29.54, 30.92, 32.51, 36.09, 42.33. dH (Minor isomer)
(D2O, 499.79 MHz): -41.85, -25.32, -8.14, -6.31, -3.82, -3.81,
-3.62, -2.50, -1.11, -0.89, 0.70, 7.62, 9.1, 12.03, 28.43, 33.85,
34.25, 36.23.
[EuIIIL4]3-. Crude yield: 45%. t(H
= 0.38, t(D
= 1.27.
O)
O)
2
2
dH (Major isomer) (D2O, 699.73 MHz): -10.32, -8.37, -6.03, -5.86,
-4.54, -1.46, -1.38, -0.85, -0.51, 0.11, 1.75, 2.07, 3.21, 3.95, 5.31,
6.38, 6.84, 7.23, 8.29, 9.17, 10.14, 10.57, 11.45, 13.64. dH (Minor isomer)
(D2O, 699.73 MHz): -14.66, -5.16, -2.16, -1.09, -1.04, 5.56, 8.29,
11.83.
[Gd.GluAAZTA]2- or [GdL5]2-. m/z (ES-): 587.1 [M - H]-
(Found: [M - H]-, 587.0618. C17H23N3O10158Gd requires [M - H]-,
587.0630; [M - H]-, 583.0590. C17H23N3O10154Gd requires [M -
H]-, 583.0597); [M - H]-, 584.0607. C17H23N3O10155Gd requires
[M - H]-, 584.0615).
Acknowledgements
Relaxivity value found by NMRD analysis: r1p = 7.3 mM-1s-1
(20 MHz, 298 K). The [Gd3+]◦have been determined by mineral-
ization with 37% HCl at 120 C overnight, followed by ICP-MS
analysis of [Gd]. Fitting of the 17O NMR R2p vs. T (K) profile gave
tM = 115 ns.
We thank EPSRC, the Royal Society, the EC-networks, EMIL and
DIMI and the ESF-COST Action D-38 for support.
References
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Org. Biomol. Chem., 2009, 7, 1120–1131 | 1131
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