Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates

Imidazoline I2 receptors (I2-IR) are untapped therapeutic targets lacking a structuraldescription. Although the levels of I2-IR are dysregulated in a plethora of illnesses,the arsenal of ligands that can modulate I2-IR is limited. In this framework, we havereported several new structural families embodying the iminophosphonate functionalgroup that have an excellent affinity and selectivity for I2-IR, and selected members havedemonstrated relevant pharmacological properties in murine models of neurodegenerationand Alzheimer’s disease. Starting with these iminophosphonates, we continued to exploittheir high degree of functionalization through a short and efficient synthesis to access unprecedented2,3-di, 2,2,3-tri, 2,3,4-tri, and 2,2,3,4-tetrasubstituted diethyl (pyrrolidine-2-yl)phosphonates. The stereochemistry of the new compounds was unequivocally characterizedby X-ray crystallographic analyses. Two selected compounds with structural featuresshared with the starting products were pharmacologically evaluated, allowing us to deducethe required key structural motifs for biologically active aminophosphonate derivatives.