Facile Access to the 12‐Membered Macrocyclic Ligand PCTA and Its Derivatives with Carboxylate, Amide, and Phosphinate Ligating Functionalities

Abstract

We describe a convenient synthetic pathway to access the 12‐membered PCTA macrocycle, a polyaminocarboxylate ligand for which its M2+ and M3+ complexes are commonly associated with applications in biomedical diagnostics and radiotherapy. The synthetic pathway is based on the use of a linear tri‐N‐alkylated triamine synthon incorporating masked acetate arms and an efficient sodium template ion effect for the crucial macrocyclization step (87 % macrocyclization yield). This approach was then successfully applied to access three new PCTA[12] derivatives containing either a 4‐pyridol unit, an amide or a phosphinate coordinating function in the central arm. In all cases, the macrocyclization reactions were controlled by a sodium template ion effect, and the macrocyclization yields were in the range of 60 to 75 %. The luminescence and relaxometric properties of EuIII, TbIII, and GdIII complexes derived from PCTA derivatives with mixed coordinating arms were also investigated, making these complexes possible alternatives to PCTA[12]–LnIII complexes.

Bimodal Probe for Magnetic Resonance Imaging and Photoacoustic Imaging Based on a PCTA‐Derived Gadolinium(III) Complex and ZW800–1

“…i) a NaBr adduct as evidenced by the elemental analysis, and in accordance with Na + species reported for such derivatives . This NaBr adduct is characterized by a 1 H NMR trace with sharp signals where the methylenic protons in the 3–5 ppm region are split into AB patterns which indicates a stable form in solution without fluxional behavior at the NMR timescale (Figure (a)).…”

“…For that protocol, successive monitoring (mass spectroscopy) of the conversion of the intermediates 5a–b into 5c , then from 5c and 6a into the desired compound 6b were performed to avoid extending reaction times, particularly that for the second step, thus limiting the formation of the more polar lactamized side‐product as reported before . Our pathway constitutes an interesting alternative to that recently reported by C. Picard et al that involves benzylic protections whose cleavage required pressure of dihydrogen that may be limiting for scaling‐up.…”

“…We previously reported the synthesis of PCTA(CO 2 t Bu) 3 ‐COOH,, , as a precursor of a bifunctional derivative of PCTA‐[12] bearing an additional carboxylic acid function anchored to the pyridine subunit that led to the corresponding Gd‐PCTA‐COOH chelate for application to the synthesis of targeted Gd‐based CA (Figure ). As previously discussed by us and other,, , the preferred synthetic route to PCTA(CO 2 t Bu) 3 ‐COOH was based on the assembly of two units bearing the final desired functionalities as it allows easier modulation of the nature and number of coordinating sites while avoiding post‐macrocyclization functionalization steps with boring selectivity control. Herein, we described optimized protocols to produce higher quantities of this key synthon that is precursor of a variety of PCTA‐based bifunctional chelators (BFC).…”

“…The two previously prepared units 3 and 6b were then assembled on the basis of a recent published macroring process conducted in a diluted medium (reactants concentration 0.002 M) in rather “hard” conditions (refluxing acetonitrile for 2 days with a large excess of sodium carbonate) that gave access to small batches of only a few hundred milligrams . The protocol was revised in the perspective of larger scales.…”

Síntese de oxamacrolida

“…O fato dessa definição ser vaga, faz com que não exista um consenso sobre qual o número mínimo de membros que uma molécula cíclica deve ter para que ela seja considerada "macro". Encontram-se na literatura autores que designam anéis de 8 2-4 , 9 2,5-7 , 10 8,9 , 11 10 ou 12 [11][12][13] membros como macrociclos, enquanto outros os denominam como anéis medianos [14][15][16] e classificam como macrociclos anéis contendo mais do que 12 constituintes.…”