Total Synthesis and Determination of the Absolute Configuration of Guadinomines B and C2

This article describes the determination of the absolute configurations of the guadinomines, which are novel cyclic guanidyl natural products that are inhibitors of the type III secretion system (TTSS) of bacteria. Any compound that interrupts the TTSS of bacteria is potentially an ideal anti‐infectious drug. The reliable asymmetric synthesis of guadinomines has revealed their absolute configurations, which could not have been defined without this synthetic approach. Our report not only describes the asymmetric total synthesis of the title compounds, but also demonstrates the novel concise synthesis of tri‐substituted piperazinone cores as optically pure forms. The novel feature of our method is an intramolecular SN2 cyclization that uses PPh3 and I2 to construct the unique 5‐membered cyclic guanidine substructure. Clarification of indefinable configurations: Any compound that interrupts type III secretion systems (TTSS) of bacteria is a potentially ideal anti‐infectious drug. The reliable asymmetric synthesis of guadinomines (see scheme), which express a selective inhibition of TTSS, has revealed their absolute configurations, which could not have been defined without the synthetic approach chosen.