The current P411-AzetS lineage performs poorly with other substrate classes. Aziridine substrates with substituents on the carbon backbone of the ring were unable to undergo ring expansion due to their pronounced capacity for ring opening by hydrolysis relative to unsubstituted aziridine rings: this limitation also prevented N-alkyl or N-aryl aziridines from serving as viable substrates. Other classes of nitrogen protecting groups (e.g., amides and sulfonamides) demonstrated poor activity; one explanation is that the decreased N-nucleophilicity of these species hinders their ability to form aziridinium ylides. Finally, other carbamate-protecting groups (e.g., -Boc, -Alloc, and -CO2Me) did not form the desired products, suggesting that the arene may be necessary for proper substrate binding with this lineage of enzymes. With respect to the diazo coupling partner, diazoacetates were uniquely effective: when other diazo coupling partners were subjected to the reaction conditions, only unreacted diazo starting materials or dimerization products were recovered. Efforts to expand the observed, unprecedented reactivity and selectivity to the synthesis of other classes of azetidines are ongoing.