Syntheses of azamacrocycles such as triazacyclonane (TACN) and tetrazadodcane (cyclen) still generally utilize the approach described by Richman and Atkins forty years ago to generate highly symmetric ligands with little opportunity for multiple functional groups or chiral centers. Thus, azamacrocycles are being systematically outclassed by other ligand classes for a whole range of applications. In contrast, we have used the significant advances in the science of protecting groups to develop alternative synthetic strategies that enable synthesis of azamacrocycles with multiple functional groups under greener and safer synthetic conditions. Specifically, instead of the standard difficult-to-remove toluenesulfonate esters we have used readily available and inexpensive nitrated and trifluoromethylated sulfonate ester derivatives for activation of hydroxyl functions utilized in the cyclization step as opposed to the use of alkyl halides. We also used trifluoroamide and butoxycarbonyl protecting groups to yield orthogonally functionalized versatile components for azamacrocycles with as many as four different functional groups on the ring nitrogens with mild and green deprotection conditions.

Versatile synthesis of orthogonally protected azamacrocyclic ligands

247th National Meeting (2014)

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