Mechanically interlocked molecules that change their conformation in response to stimuli have been developed by synthetic chemists as building blocks for molecular machines. Here we describe a natural product, the lasso peptide benenodin-1, which exhibits conformational switching between two distinct threaded conformers upon actuation by heat. We have determined the structures of both conformers and have characterized the kinetics and energetics of the conformational switch. Single amino acid substitutions to benenodin-1 generate peptides that are biased to a single conformer, showing that the switching behavior is potentially an evolvable trait in these peptides. Lasso peptides such as benenodin-1 can be recognized and cleaved by enzymes called lasso peptide isopeptidases. We show that only the native conformer of benenodin-1 is cleaved by its cognate isopeptidase. Thus thermally-induced conformational switching of benenodin-1 may also be relevant to the biological function of these molecules.

General strategies for the chemical synthesis of organic compounds, especially of architecturally complex natural products, are not easily identified. Here, we present a method to establish a strategy for such syntheses, which begins with a process termed ‘network analysis’. This exercise, along with other considerations, has been used to identify a versatile synthetic intermediate that facilitated syntheses of the diterpenoid alkaloids weisaconitine D and liljestrandinine, as well as the core of gomandonine. The diterpenoid alkaloids comprise some of the most architecturally complex and functional group dense secondary metabolites ever isolated. For these reasons, they present a significant challenge for chemical synthesis. The synthesis approach described herein is a notable departure from other strategies adopted for the syntheses of related structures and affords not only the targeted natural products, but also intermediates and derivatives in the three subfamilies of diterpenoid alkaloids (i.e., C-18, C-19, and C-20), providing the first unified synthetic strategy to these natural products. This work validates the utility of network analysis as a starting point for identifying strategies for the syntheses of architecturally complex secondary metabolites. An easily accessible web-based graphing program has been developed for this purpose.