The concise and efficient total synthesis of (+)-bionectins A and C is described. Our approach to these natural products features a new and scalable method for erythro-β-hydroxytryptophan amino acid synthesis, an intramolecular Friedel–Crafts reaction of a silyl-tethered indole, and a new mercaptan reagent for epipolythiodiketopiperazine (ETP) synthesis that can be unravelled under very mild conditions. In evaluating the impact of C12-hydroxylation, we have identified a unique need for an intramolecular variant of our Friedel–Crafts indolylation chemistry. Several key discoveries including the first example of permanganate-mediated stereoinvertive hydroxylation of the α-stereocenters of diketopiperazines as well as the first example of a direct triketopiperazine synthesis from a parent cyclo-dipeptide are discussed. Finally, the synthesis of (+)-bionectin A and its unambiguous structural assignment through X-ray analysis provides motivation for the reevaluation of its original characterization data and assignment.National Institute of General Medical Sciences (U.S.) (Grant GM089732)American Society for Engineering Education. National Defense Science and Engineering Graduate FellowshipNational Science Foundation (U.S.). Graduate Research Fellowship ProgramNational Science Foundation (U.S.) (CHE-0946721
