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.

PCTA[12] is a 12‐membered tetraaza‐macrocyclic ligand that incorporates a pyridine unit within the macrocyclic ring and three acetate pendant arms. Unlike DOTA and NOTA chelators, PCTA is a recent entry to the field of macrocyclic polyaminocarboxylate ligands available to complex a variety of M2+/M3+ ions for biomedical applications such as diagnostic and radiotherapeutic. Despite the promising properties of its chelates, only a few of bifunctional chelating agents (BFCAs) derived from PCTA have been described so far. Based on our very recent methodology for the preparation of PCTA[12] itself, we report here the efficient synthesis of several BFCAs derived from PCTA bearing a free reactive function group, mainly devoted to conjugation purposes: ester, carboxylic acid, alcohol, aliphatic amine, aromatic amine, maleimide, bromo or azide functions. These functions were introduced either on the 4‐position of the pyridine ring or on the methylene carbon atom of the central acetate chelating arm, while keeping the three carboxylate groups available for metal chelation. Moreover, two of these BFCAs‐PCTA were used for conjugation with a tetrapeptide (cholecystokinin analogue), a bioactive molecule (biotin), or a solid support (silica gel).

The first total synthesis of transalpinecine, a pyrrolizidine alkaloid extracted from Heliotropium transalpinum is reported. The concise synthetic route developed towards these unusual iminosugar‐like natural compounds relies on an intramolecular Morita–Baylis–Hillman reaction. The four diastereoisomers of transalpinecine, as well as the two diastereoisomers of the parent epoxide subulacine, were prepared. 1H NMR‐based stereochemical assignment of these different diastereoisomers was substantiated by quantum calculations of NMR shifts and coupling constants, allowing revision of the initially reported transalpinecine structure. One of these synthetic compounds significantly potentiates the activity of the F508del‐CFTR corrector VX‐809.