Efficient route to pre-organized and linear polyaminopolycarboxylates: Cy-TTHA, Cy-DTPA and mono/di- reactive, tert-butyl protected TTHA/Cy-TTHA

Article abstract of DOI:10.1016/j.tetlet.2017.02.056

Pre-organized polyaminopolycarboxylate chelators Cy-TTHA and Cy-DTPA were synthesized via modular five-step syntheses from commercially available starting materials in ～62% and 47% overall yields, respectively. Furthermore, strategies are reported for the efficient preparation of mono- and di-reactive, tert-butyl-protected TTHA/Cy-TTHA to selectively functionalize central chelators’ carboxylic acids.

Full text of DOI:10.1016/j.tetlet.2017.02.056

Accepted Manuscript
Efficient route to pre-organized and linear polyaminopolycarboxylates: Cy-
TTHA, Cy-DTPA and mono/di- reactive, tert-butyl protected TTHA/Cy-TTHA
Ali Mohamadi, Lawrence W. Miller
PII:
S0040-4039(17)30233-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.056
TETL 48667
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 December 2016
10 February 2017
15 February 2017
Please cite this article as: Mohamadi, A., Miller, L.W., Efficient route to pre-organized and linear
polyaminopolycarboxylates: Cy-TTHA, Cy-DTPA and mono/di- reactive, tert-butyl protected TTHA/Cy-TTHA,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.056
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Efficient route to pre-organized and linear
polyaminopolycarboxylates: Cy-TTHA, Cy-
DTPA and mono/di- reactive, tert-butyl
protected TTHA/Cy-TTHA
Leave this area blank for abstract info.
Ali Mohamadi, Lawrence W. Miller*
Department of Chemistry,
845 W. Taylor Street, MC 111,
Chicago, IL 60607.
Phone: 312-996-8542; Fax: 312-996-0431

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Efficient route to pre-organized and linear polyaminopolycarboxylates: Cy-TTHA,
Cy-DTPA and mono/di- reactive, tert-butyl protected TTHA/Cy-TTHA
Ali Mohamadi and Lawrence W. Miller∗
University of Illinois at Chicago, Department of Chemistry, 845 W. Taylor Street, MC 111, Chicago, IL 60607.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Pre-organized polyaminopolycarboxylate chelators Cy-TTHA and Cy-DTPA were synthesized
via modular five-step syntheses from commercially available starting materials in ∼ 62% and
47% overall yields, respectively. Furthermore, strategies are reported for the efficient
preparation of mono- and di-reactive, tert-butyl-protected TTHA/Cy-TTHA to selectively
functionalize central chelators’ carboxylic acids.
Available online
Keywords:
Chelators
2009 Elsevier Ltd. All rights reserved.
Lanthanides
Ligand Design
———
∗Corresponding author. Tel.: +1-312-996-8542; e-mail: lwm2007@uic.edu

2
Tetrahedron
Diethylenetriamine pentaacetic acid (DTPA) and
an amidation reaction with an amino group on the appropriate
biomolecules. However, dianhydrides can cross-link to form
undesired dimers.21,49 Alternatively, mono-anhydride analogues
can be prepared by treatment of DTPA with isobutyl
chloroformate/trimethylamine, but this approach gives a mixture
of terminal/central activated-carboxylic acids as well as small
triethylenetetraamine hexaacetic acid (TTHA) are among the
most widely employed acyclic chelators for the coordination of
metal ions (Fig. 1).1-3 Due to their ability to provide high
denticities via a hard base binding core (carboxylate ions and
tertiary amines), their corresponding lanthanide complexes have
been heavily studied.4-20 While linear polyaminopolycarboxylates
form thermodynamically stable complexes, their relative kinetic
instability with respect to many metals such as Gd(III) can limit
their utility in biological or clinical environments.21-25 In contrast,
the widely used macrocyclic polyaminocarboxylates DOTA and
TETA (Fig. 1) form exceptionally stable complexes with a
variety of clinically important radiometals used in diagnostic
imaging and therapy.26,27 However, macrocycles often require
elevated temperature (60-95 °C) and extended reaction times (30-
90 minutes) for efficient metal chelation.26,27 These labeling
conditions can limit macrocycles’ applications in heat sensitive
experiments, such as antibody labeling, or when utilizing short
amounts of linear dianhydride analogue.50,51 Various approaches
52-58
have been developed both in solution
and in solid phase59
that exploit differential protection of carboxylic acids followed
by orthogonal deprotection so as to conjugate mono-reactive pro-
ligands under standard amide coupling conditions.
Spurred by our interest in developing luminescent lanthanide
complexes for bioanalytical and imaging applications,10,11,60-63 we
sought to develop more efficient strategies for preparing Cy-
TTHA (6) and Cy-DTPA (11) derivatives. Herein, we report a
modular, five-step syntheses of Cy-TTHA (6) and Cy-DTPA (11)
with good overall yields. Moreover, our approach makes it
possible to prepare novel mono- and di-reactive TTHA and Cy-
TTHA analogues that may be selectively functionalized at their
central pendant carboxylic acids.
half-life isotopes (e.g. 44Sc, 62Cu, 68Ga, and 212 213Bi).26,27 In order
/
to improve the kinetic inertness of DTPA, Brechbiel incorporated
a pre-organized cyclohexyl moiety into the chelator backbone.3,28-
30
The structurally reinforced Cy-DTPA effectively formed
Previously reported syntheses required purification of Cy-
TTHA (6), Cy-DTPA (11) and their derivatives by reversed-
phase HPLC and ion-exchange.3,28,45 In order to avoid these
methods, we prepared tert-butyl-protected pro-ligands by
leveraging the oft-employed,64,57 orthogonal benzyl and tert-butyl
protecting groups. Cy-TTHA (6) was synthesized with a general
reaction scheme that follows reductive amination of
benzaldehyde, dialkylation of the corresponding secondary amine
thermodynamically stable and kinetically inert complexes with
111In, 90Y and 177Lu.31-44 Similarly, Gestin reported elevated in
vivo kinetic inertness for a bioconjugate of Cy-TTHA(111In) with
mouse immunoglobulin G (IgG) over 96 h.45 This group
subsequently reported exceptional in vitro stability for
dimethanephosphonic Cy-TTHA(153Sm) when challenging it
against high excess of optimal 153Sm chelator EDTMP.46,17
with
di-tert-butyl
2,2'-((2-bromoethyl)azanediyl)diacetate,
second
catalytic debenzylation by Pd/C followed by
a
dialkylation with tert-butyl bromoacetate. The tert-butyl
deprotection of the pro-ligand 5 afforded Cy-TTHA (6) in high
overall yield of 62% (Scheme 1).
Fig 1. Structures of chelators discussed in this work
Recently, we prepared a series of luminescent Tb(III) and
Eu(III) complexes based on Cy-TTHA (6) that exhibited
exceptional quantum yields of emission in aqueous solution.20
We also demonstrated that Cy-TTHA analogues were
substantially more kinetically inert than their linear counterparts,
as evidenced by an EDTA challenge assay. In order to prepare
brightly emissive complexes, we needed an efficient synthetic
approach that permitted selective mono-substitution of
chromophoric sensitizer moieties at designated pendant positions.
Previously reported syntheses of Cy-TTHA (6) and Cy-DTPA
(11) suffer from low overall yields ( 18% for Cy-DTPA and
29% for Cy-TTHA).28,45 Furthermore, with the installation of all
pendant carboxylic groups in one step, there is no easy way to
further electronically or coordinatively modify the chelator
scaffolds.12,13 Frequently, selective conjugation of DTPA or
TTHA terminal carboxylic acids to biomolecules has been
performed by preparing a dianhydride analogue,47,48 followed by
Scheme 1. Synthesis of Cy-TTHA
Taking advantage of an established synthetic method for
Py3CA by Caravan65 we prepared the key intermediate 9 with
few modifications (Scheme 2). Subsequent alkylation with di-
tert-butyl 2,2'-((2-bromoethyl)azanediyl)diacetate followed by
tert-butyl deprotection afforded Cy-DTPA (11) in a good
cumulative yield of 47%. Most notably, our strategy permits
using modified alkylating groups in order to develop carbon-
functionalized derivatives hence precluding concomitant
reduction of the aryl nitro group in the original synthesis of
CHX-AĻ-DTPA and its derivatives.3

3
t
CO Bu
2
Ph
X
t
CO Bu
2
n
N
t
a
N
N
BuO C
2
2
a
Ph
b
t
N
Ph
N
N
BuO C
2
12
H N
2
NH
2
tBuO C
2
H N
2
N
CO tBu
2
Ph
H
t
BuO C
2
c
8
7
X , 21
1
b
X , 3
2
t
t
CO Bu
CO tBu
2
BuO C
2
2
tBuO C
2
d
N
N
N
N
NH
X
tBuO C
2
t
CO Bu
t
CO Bu
2
n
N
2
tBuO C
2
tBuO C
2
CO tBu
2
HN
N
t
H
10
N
BuO C
2
e
9
t
BuO C
2
X , 22
1
c
HO C
2
CO H
2
X , 4
2
N
N
N
t
CO Bu
HO C
2
CO H
2
2
HO C
2
11
BnO C
2
X
t
CO Bu
2
n
N
N
N
Reagents and conditions: (a) benzyl bromide (0.1 equiv), MeCN, rt. (b) tert-butyl
bromoacetate (3.1 equiv), Na CO (3.1 equiv), MeCN, rt. (c) Pd/C (10 wt %), H ,
t
N
BuO C
2
2
3
2
CO Bn
2
MeOH, rt. (d) di-tert-butyl 2,2'-((2-bromoethyl)azanediyl)diacetate (1.1 equiv), Na CO
2
3
t
BuO C
2
(1.1 equiv), MeCN, 60 °C. (e) TFA/CH Cl / iPr SiH, 5:5:1.8, v/v, rt.
2
b
2
3
Scheme 2. Synthesis of Cy-DTPA
X , 23
1
X , 24
2
t
CO Bu
2
Selective incorporation of a chromophore or conjugation
handle at a single pendant arm position may be required when
preparing, for example, emissive lanthanide complexes or bio-
reactive chelators. Synthesis of monocarboxylate-functionalized
analogues 19 and 20 began with mono-alkylation of secondary
amines 2 and 12 by tert-butyl bromoacetate followed by a second
alkylation with benzyl bromoacetate that provided differently
alkylated compounds 15 and 16, which were subsequently
debenzylated with Pd/C to afford key intermediates 17 and 18,
respectively (Scheme 3). The target molecules 19 and 20 were
readily obtained by a dialkylation reaction with di-tert-butyl 2,2'-
((2-bromoethyl)azanediyl)diacetate in 43% and 46% overall
yields respectively.
HO C
2
X
t
CO Bu
2
n
N
N
N
t
N
BuO C
2
CO H
2
t
BuO C
2
X , 25
1
X , 26
2
X
=
1
X
=
2
Reagents and conditions: (a) di-tert-butyl 2,2'-((2-bromoethyl)
azanediyl)diacetate (2.1 equiv), Na CO (3.0 equiv), MeCN, 60
2
3
°C. (b) Pd/C (10 wt %), H , MeOH, rt. (c) benzyl bromoacetate
2
(2.1 equiv), Na CO (3.0 equiv), MeCN, 60 °C.
2 3
t
BuO C
2
X
n
X
n
t
CO Bn
2
BuO C
2
X
a
n
NH
HN
b
NH
N
N
N
Scheme 4. Modular synthesis of di reactive tert-butyl
protected TTHA and Cy-TTHA
Ph
Ph
Ph
Ph
Ph
Ph
X , 15
1
X , 13
1
X , 12
1
X , 14
2
X , 2
2
X , 16
2
c
In summary, the five-step synthesis of Cy-TTHA (6) and Cy-
DTPA (11) are reported. Both synthesis are straightforward and
provide the desired products in an overall yield of 62% and 47%,
respectively. A stepwise alkylation-based strategy allows control
over the choice of chelator scaffolds as well as coordination
groups. Using analogous conditions, we prepared mono- and di-
reactive tert-butyl protected TTHA and Cy-TTHA so as to
selectively functionalize central carboxylic arms.
t
CO Bu
2
t
BuO C
2
X
n
t
d
t
CO Bu
2
BuO C
2
X
n
N
N
N
t
NH
N
BuO C
2
N
H
COOH
t
CO H
2
BuO C
2
X , 19
1
X , 17
1
X , 20
2
X , 18
2
X
=
1
X
=
2
Reagents and conditions: (a) tert-butyl bromoacetate (0.25 equiv), Na CO (1.0 equiv),
2 3
MeCN, rt. (b) benzyl bromoacetate (1.0 equiv) Na CO (1.0 equiv), MeCN, 60 °C. (c)
2 3
Pd/C (10 wt %), H , MeOH, rt. (d) di-tert-butyl 2,2'-((2-bromoethyl)azanediyl)diacetate
2
(2.1 equiv), Na CO (3.0 equiv), MeCN, 60 °C.
2 3
Acknowledgments
Scheme 3. Modular synthesis of mono reactive tert-butyl
protected TTHA and Cy-TTHA
This work was supported by the National Institutes of Health
(R01GM081030).
Di-reactive analogues were accessed by an initial dialkylation
of precursors
2
and 12 with di-tert-butyl 2,2'-((2-
References and notes
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bromoacetate followed by catalytic debenzylation to afford di-
reactive, tert-butyl protected TTHA (27) and Cy-TTHA (28) in
54% and 45% overall yields (Scheme 4).
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5
Highlights
•
•
•
Efficient syntheses of cyclohexyl DTPA and
TTHA are reported.
Stepwise alkylation permits variation of
coordination groups.
Mono-reactive analogs may be selectively
functionalized at central pendant arms.