Americium separation from high level nuclear waste can provide certain benefits such as reducing the long-term heat generation or the possibility of re-use as fuel in innovative reactors. The separation is carried out through solvent extraction. Among commonly used ligands, diglycolamide (DGA) derivatives have shown high distribution ratios for trivalent lanthanides (Ln(III)) and actinides (An(III)). Recently, different diastereomers of DGAs with substitutions in the backbone have shown an inverse selectivity for Am over Cm, in comparison with commonly used DGAs. Hence, we synthesised, characterized, and tested novel syn- and anti-diastereomers of tetra-n-octyl and tetra-n-decyl DGAs with two propyl and ethyl-methyl substituents at the backbone methylene carbon atoms. The distribution ratios for An(III) and Ln(III) were found to be generally lower than for the unsubstituted parent molecules due to steric hindrance. On the other hand, ²³⁹Pu was much better extracted. All tested ligands showed the inverse selectivity for Am with an Am/Cm separation factor (SF_Am/Cm) around 1.5. Finally, slope analysis confirmed a 1 : 3 metal : ligand ratio for the DGA complexes.