Stereoselective synthesis of highly branched chiral cyclobutane-cored triamines and their conjugation to Gd-DOTA. Issue 42 (21st October 2015)

• Record Type: Journal Article
• Authors: Ospina, Jimena; Gutiérrez-Abad, Raquel; Lope-Piedrafita, Silvia; Illa, Ona; Branchadell, Vicenç; Ortuño, Rosa M.
• Is Part Of: Tetrahedron. Volume 71:Issue 42(2015)
• Page Start: 8085
• Page End: 8095
• Publication Date: 2015-10-21
• Subjects: Chiral chemical platforms -- Cyclobutane-cored triamines -- Macrocycle conjugates -- Gadolinium complexes; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2015.08.044
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: Several chiral cyclobutane-containing chemical platforms were synthesized in a stereoselective manner starting from (−)-verbenone as a suitable precursor. These compounds bear three orthogonally protected amine functions, two of them on side-chain and the other directly linked to the cyclobutane ring. Selective deprotection of the latter amine and subsequent coupling with the DOTA macrocycle followed by complexation with Gd(III) allowed the preparation of new GdDO3A monoamides whose potential ability as contrast agents (CAs) in magnetic resonance imaging (MRI) preliminary experiments was tested. Image contrast enhancement was shown to be dependent on the amine substitution and protecting groups (–NH–Cbz, –NH–CO–C6 H4 – p -NO2, –NH–Ac, and –NMe–Cbz), and in the case of acetamide the corresponding Gd complex manifested a better contrast enhancement than DOTAREM, a Gd-based commercial CA which was used as a reference. Computational studies suggest that water exchange rate in these complexes is associated to the ability of the amido-carbonyl groups in the cyclobutane side-chains to coordinate to Gd. Graphical abstract: