As originally reported by Logothetis, alkenyl azides cyclize smoothly on warming, leading, depending on substitution, to cyclic imines or bicyclic aziridines. These intermediates can then be carried on to other products. This review summarizes the many ways the Logothetis reaction has been employed in target-directed synthesis.
 
The assembly of cyclic amines is fundamental to medicinal chemistry. While intramolecular azide–alkyne cycloaddition is widely practiced, intramolecular azide–alkene cycloaddition is much less used, even though it has been known since 1965. This review is an overview of the applications of intramolecular azide–alkene cycloaddition in target-directed synthesis since that time.

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Intramolecular Azide–Alkene Cycloaddition—The Logothetis Reaction

As originally reported by Logothetis, alkenyl azides cyclize smoothly on warming, leading, depending on substitution, to cyclic imines or bicyclic aziridines. These intermediates can then be carried on to other products. This review summarizes the many ways the Logothetis reaction has been employ...

To improve sensitivity toward H2O2, the boronic acid pinacol ester in known aminoferrocene-based anticancer prodrug 13b is replaced with an α-ketamide fragment to obtain prodrug 2a and some of its N-alkylated derivatives. 2a exhibits substantially improved cytotoxicity in vitro toward ovarian cancer A2780 and Burkitt's lymphoma BL-2 cells. Its mode of action relies on intracellular generation of reactive oxygen species.
 
Aminoferrocene (AF)-based prodrugs are activated in cancer cells through reactions with H2O2 and other reactive oxygen species (ROS), generating electron-rich AF's. These, in turn, induce the production of highly toxic O2
− and HO·, leading to cancer cell death. Effective activation of these prodrugs depends on their ability to target intracellular organelles rich in ROS, as nontargeted prodrugs are practically inactive. In this study, the boronic acid pinacol ester—previously used as a ROS-trigger—is replaced with an α-ketoamide fragment, which is more selective and sensitive to H2O2. This modification enhances the anticancer efficacy of untargeted AF prodrugs, reducing the IC50 from 23.9–35.5 μM (previously reported prodrug 13b) to 5–6.4 μM (new prodrug 2a) in human ovarian cancer A2780 and Burkitt's lymphoma BL-2 cells. Further analysis confirms that the anticancer effect of 2a is driven by its ability to markedly increase intracellular ROS levels in both the cytoplasm and mitochondria.

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Intramolecular Azide–Alkene Cycloaddition—The Logothetis Reaction

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