Cobalt(III)‐Catalyzed C−H Amidation of Dehydroalanine for the Site‐Selective Structural Diversification of Thiostrepton

Abstract

Thiostrepton is a potent antibiotic against a broad range of Gram‐positive bacteria, but its medical applications have been limited by its poor aqueous solubility. In this work, the first C(sp2)−H amidation of dehydroalanine (Dha) residues was applied to the site selective modification of thiostrepton to prepare a variety of derivatives. Unlike all prior methods for the modification of thiostrepton, the alkene framework of the Dha residue is preserved and with complete selectivity for the Z‐stereoisomer. Additionally, an aldehyde group was introduced by C−H amidation, enabling oxime ligation for the installation of an even greater range of functionality. The thiostrepton derivatives generally maintain antimicrobial activity, and importantly, eight of the derivatives displayed improved aqueous solubility (up to 28‐fold), thereby addressing a key shortcoming of this antibiotic. The exceptional functional group compatibility and site selectivity of CoIII‐catalyzed C(sp2)−H Dha amidation suggests that this approach could be generalized to other natural products and biopolymers containing Dha residues.

Introduction to Thiopeptides: Biological Activity, Biosynthesis, and Strategies for Functional Reprogramming

“…Unfortunately, thiostrepton tail makes contacts with L11 protein when bound to the 50S ribosome (Harms et al, 2008) and thus, Dha functionalization often (Key and Miller, 2017), although not always (Aminake et al, 2011), compromises potency of such derivatives. A recent work reports an interesting site-specific cobalt(III)-catalyzed C-H amidation of C-terminal Dha in thiostrepton, a method that preserves the structure of the dehydroamino acid (Scamp et al, 2020). Many of the derivatives prepared in this way retained antibiotic activity against contemporary drug-resistant pathogens while having higher solubility than the parent compound.…”

Bioorthogonal Aza-Michael Addition to Dehydrated Amino Acids in Antimicrobial Peptides

“…6,7,8 They are carbon electrophiles because of their unsaturated side chain, which permit siteselective chemical modification. In recent years several bioorthogonal modifications of dehydroamino acids in RiPPs have been established, including: conjugate phospa-Michael additions, 9 β-silylation, 10 radical carbon-carbon bond formation, 11,12 cross-coupling reactions, 13,14 amidations, 15,16 cyclopropanations 17 and cycloadditions. 18,19 Recently, we reported the Cu(II) catalysed β-borylation of RiPPs (Scheme 1A), 20 with a particular focus on the thiopeptide Thiostrepton.…”

Late-stage stitching enabled by manganese-catalyzed C─H activation: Peptide ligation and access to cyclopeptides

“…Thus, manganese-catalyzed C─H activation has proved instrumental for efficient and selective C─H functionalization (35,36). In sharp contrast, base metal catalysis for peptide diversification and macrocyclization continues to be scarce (37)(38)(39)(40). As part of our program on sustainable C─H activation (41,42), we now report on the first manganese(I)-catalyzed C─H activation for hydroarylations of structurally complex peptides with easily accessible propiolates.…”