Oxidative diversification of amino acids and peptides by small-molecule iron catalysis

Abstract

Secondary metabolites synthesized by nonribosomal peptide synthetases (NRPSs) display diverse and complex topologies and possess an impressive range of biological activities1,2 Much of this diversity derives from a synthetic strategy that entails the oxidation of both the chiral amino acid building blocks and the assembled peptide scaffolds pre-3 and post-assembly2. The vancomycin biosynthetic pathway is an excellent example of the range of oxidative transformations that can be performed by the iron-containing enzymes involved in its biosynthesis.4 However, because of the challenges associated with using such oxidative enzymes to carry out chemical transformations in vitro, chemical syntheses guided by these principles have not been fully realized outside of nature.5 In this manuscript, we report that two small-molecule iron catalysts are capable of facilitating the targeted C—H oxidative modification of amino acids and peptides with preservation of α-center chirality. Oxidation of proline to 5-hydroxyproline furnishes a versatile intermediate that can be transformed to rigid arylated derivatives or flexible linear carboxylic acids, alcohols, olefins, and amines in both monomer and peptide settings. The value of this C—H oxidation strategy is demonstrated in its capacity for generating diversity: four 'chiral pool' amino acids are transformed to twenty-one chiral unnatural amino acids (UAAs) representing seven distinct functional group arrays; late-stage C—H functionalizations of a single proline-containing tripeptide furnish eight tripeptides, each having different UAAs. Additionally, a macrocyclic peptide containing a proline turn element is transformed via late-stage C—H oxidation to one containing a linear UAA.

Ruthenium(II)-catalysed remote C–H alkylations as a versatile platform to meta-decorated arenes

“…Since the substrates of interest display a variety of C–H bonds with close dissociation energies, achieving positional selectivity in intermolecular C–H transformations is paramount1112131415. Thus, chelation assistance has proven particularly instrumental for proximity-induced ortho -C–H functionalizations16171819.…”

Remote, Late-Stage Oxidation of Aliphatic C–H Bonds in Amide-Containing Molecules

“…12 With the goal of elucidating whether the steric or electronic properties of the substituents flanking the peptide amide bond make it well suited toward remote C(sp 3 )—H oxidations, we systematically deconstructed dipeptide 3a to determine which of its features is important for maintaining selectivity for remote tertiary C—H bond oxidation over other deleterious oxidation pathways (Scheme 1). Removal of the methyl steric element on C -terminus slightly decreased the yield and selectivity ( 4b , 50% yield, 67% selectivity).…”

“…Interestingly, N -Ns protection in secondary amines furnishes α-oxidation products whereas for secondary amides remote oxidation is observed. 12 The remote oxidation strategies for 3° and 2° amides shown above could be also used for methylene C—H oxidation with Fe(CF 3 PDP) 2 (entries 9, 10). Significantly, the imidate salt strategy gave better site-selectivities for remote δ oxidation than Ns protection, suggesting that the cationic nature of the imidate salt provides stronger electronic deactivation than Ns protection.…”

Residue-Specific Peptide Modification: A Chemist’s Guide

“…114–117 In 2016, White and co-workers reported an iron-catalyzed oxidative functionalization inspired by known nonribosomal peptide synthetase (NRPS) pathways. 18 In an impressive display of versatility, the approach was used to synthesize 21 non-natural amino acids from four native residues, with no erosion of chirality observed. Notably, C–H oxidation of the tertiary carbon center of Leu and Val was also demonstrated.…”