Total Synthesis of Marformycins A and D.

We report the synthesis of the antimicrobial cyclodepsipeptides marformycin A () and marformycin D () using a solid-phase approach. A scalable solution-phase synthesis of the γ-hydroxypiperazic acid subunit in , starting from -hydroxyproline, is also described. Structural analysis of and its Leu- congener demonstrates conformational differences that may underlie their divergent antimicrobial activities.

Stabilizing Pseudouridimycin: Synthesis, RNA Polymerase Inhibitory Activity, and Antibacterial Activity of Dipeptide-Modified Analogues.

Pseudouridimycin (PUM) is a microbially produced C-nucleoside dipeptide that selectively targets the nucleotide addition site of bacterial RNA polymerase (RNAP) and that has a lower rate of spontaneous resistance emergence relative to current drugs that target RNAP. Despite its promising biological profile, PUM undergoes relatively rapid decomposition in buffered aqueous solutions. Here, we describe the synthesis, RNAP-inhibitory activity, and antibacterial activity of chemically stabilized analogues of PUM.

Total Synthesis of Pargamicin A.

We report the total synthesis and configurational assignment of pargamicin A, a highly oxidized nonribosomal peptide that potently inhibits the growth of drug-resistant bacteria. Our synthetic approach relies on late-stage piperazine ring formation and careful selection of condensation reagents to assemble the densely substituted hexapeptide backbone. This work enables the synthesis of pargamicin congeners for the development of structure-activity relationships and informs strategies for accessing other sterically congested piperazic acid-containing natural products.