Metabolic oxidation of pyrrolizidine alkaloids (PAs) from herbal and dietary supplements by cytochrome P450 produces dehydro‐PAs (DHPs), which leads to toxicities. A highly reactive cation species generated from the active pyrrole ring of DHPs readily reacts with various cellular components, causing hepatotoxicity and cytotoxicity. Inspired by PA‐induced hepatic damage, we developed a therapeutic approach based on a cyclization precursor that can be transformed into a synthetic DHP under physiological conditions through gold‐catalyzed 5‐endo‐dig cyclization using a gold‐based artificial metalloenzyme (ArM) instead of through metabolic oxidation by cytochrome P450. In cell‐based assays, the synthesis of the DHP by a cancer‐targeting glycosylated gold‐based ArM substantially suppressed cell growth of the targeted cancer cells without causing cytotoxicity to untargeted cells, highlighting the potential of the strategy to be used therapeutically in vivo.

A novel semipinacol rearrangement using dibromocyclopropanes as sources of carbocations was developed. Heating dibromocyclopropanes bearing a 1‐hydroxyalkyl group with silver perchlorate and 2,6‐lutidine induced cleavage of the cyclopropane ring to form allyl cations, which underwent 1,2‐shift of a substituent at the α‐position of the hydroxy group to give β,γ‐unsaturated carbonyl compounds having a quaternary carbon at the α‐position. Because the products have convertible functional groups such as bromo, vinyl, and formyl groups, the method is expected to be applicable to the synthesis of various molecules.

Metabolic oxidation of pyrrolizidine alkaloids (PAs) from herbal and dietary supplements by cytochrome P450 produces dehydro-PAs (DHPs), which leads to toxicities. A highly reactive cation species generated from the active pyrrole ring of DHPs readily reacts with various cellular components, causing hepatotoxicity and cytotoxicity. Inspired by PA-induced hepatic damage, we developed a therapeutic approach based on a cyclization precursor that can be transformed into a synthetic DHP under physiological conditions through gold-catalyzed 5-endo-dig cyclization using a gold-based artificial metalloenzyme (ArM) instead of through metabolic oxidation by cytochrome P450. In cell-based assays, the synthesis of the DHP by a cancertargeting glycosylated gold-based ArM substantially suppressed cell growth of the targeted cancer cells without causing cytotoxicity to untargeted cells, highlighting the potential of the strategy to be used therapeutically in vivo.

The Front Cover shows an integration of two features which makes a new aspect. Semipinacol rearrangement was combined with electrocyclic ring opening of dibromocyclopropanes, resulting in production of polyfunctional molecules containing a quaternary carbon. By being together, the two cats also showed new features. We acknowledge the two cats, Tenni and Terra. More information can be found in the Communication by S. Yokoshima et al.