The synthesis of secondary 3-chloropiperidines and highly strained bicyclic aziridines is reported, including a new method for the selective mono-chlorination of unsaturated primary amines. The novel compounds, which closely resemble natural alkylating agents, proved to be more active than previously reported 3-chloropiperidines in a DNA cleavage assay, highlighting their potential as powerful alkylating agents.

Abstract

In previous works, we demonstrated that tertiary 3-chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3-chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N-chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3-chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3-chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart.