Catalytic hydrolysis of ester or amide substrates in biochemical reactions are mediated through metalloenzymes. A zinc(II) ion is often found at the active site of these enzymes where the metal ion is coordinated to a combination of histidines and carboxylates with a water molecule completing the tetrahedral geometry. At physiological pH the zinc bound water deprotonates to act as a nucleophile for substrate hydrolysis. In this paper we present the synthesis of 1,5,9- triazacyclododecane (TACD) that is postulated to present three nitrogen donor ligands to coordinate with Zn (II) ions in an attempt to reproduce the coordination geometry in the active site of metalloenzymes. The synthesis was performed in two steps. In the first step, Hexahydropyrimidopyrimidine underwent a substitution nucleophilic bimolecular reaction (SN2) with 1,3-propane ditosylate reagent at room temperature resulting in a tricyclic salt of a carbocation intermediate at the most centered carbon in the molecule. This intermediate was subsequently reduced in situ by a mild reducing agent, sodium borohydride to form an orthoamide. In the second step, the orthoamide was hydrolyzed to form TACD in an overall 25-30% yield. The product was confirmed using nuclear magnetic resonance spectroscopy (1H NMR and 13C NMR) and infra-red spectroscopy (IR). The TACD ligand will be used to further synthesize pendant groups for binding substrates to study their hydrolysis in presence of Zn (II) ions.

Synthesis of a triazacyclic amine metalloenzyme mimic building block

2019 Spring National Meeting

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