A bold way to make guanidines

During a recent trip to the ISACS Conference in Irvine, CA (organized by my friend Vy Dong), I came across what I think is the craziest synthetic sequence I have had a pleasure of seeing in some time. This work is now more than a year old, yet it was still very invigorating to hear Seth Herzon describe it in detail. The reaction sequence depicted below is the pivotal cascade in Herzon’s synthesis of (+)-batzelladine B. In this process, deprotonation of the acetylene intermediate with n-butyllithium followed by the addition of lithium benzyl octanoate triggers 1,2-addition to the β-ketoester, retro-aldol ring-opening, and proton transfer to afford the enolyne intermediate. Subsequent to that, isomerization to the acylallene takes place, which is followed by Michael addition and neutralization of the resulting enolate. The role of DMPU is notable: this additive was found to be necessary to promote the retro-aldol ring- opening. This sequence takes the top prize in how chemoselectivity is achieved in an environment with multiple basic sites.