Diastereoselective synthesis of substituted macrocyclic complexes from achiral starting materials

Substituted derivatives of the DOTA framework are of general interest to alter chelate properties and facilitate conjugation of chelates to other molecular structures. However, the scope of substituents that can be introduced into the alpha-position has traditionally been limited by the availability of a suitable enantiopure starting materials to facilitate a stereoselective synthesis. Tetra-substituted DOTA derivatives with phenyl and benzoate substituents in the -position were prepared. Initial syntheses used enantiopure starting materials but did not afford enantiopure products. This indicates that integrity of the stereocentres was not preserved during synthesis, despite the homo-chiral diastereoisomer being the major reaction product. The homochiral diastereoisomer could be produced as the major or sole reaction product when starting from racemic or even achiral materials. Stereochemical resolution was found to occur during chelation through formation of an enolate stabilized by the aryl substituent. This general ability of aryl groups to enable stereoisomeric resolution greatly increases the range of substituents that can be introduced into DOTA-type ligands with diastereochemical selectivity.