The Power of Automation in Polymer Chemistry: Precision Synthesis of Multiblock Copolymers with Block Sequence Control.

Machines can revolutionize the field of chemistry and material science, driving the development of new chemistries, increasing productivity, and facilitating reaction scale up. The incorporation of automated systems in the field of polymer chemistry has however proven challenging owing to the demanding reaction conditions, rendering the automation setup complex and costly. There is an imminent need for an automation platform which uses fast and simple polymerization protocols, while providing a high level of control on the structure of macromolecules via precision synthesis. This work combines an oxygen tolerant, room temperature polymerization method with a simple liquid handling robot to automatically prepare precise and high order multiblock copolymers with unprecedented livingness even after many chain extensions. The highest number of blocks synthesized in such a system is reported, demonstrating the capabilities of this automated platform for the rapid synthesis and complex polymer structure formation.

Star-Peptide Polymers are Multi-Drug-Resistant Gram-Positive Bacteria Killers.

Antibiotic resistance in bacteria, especially Gram-positive bacteria like Staphylococcus aureus, is gaining considerable momentum worldwide and unless checked will pose a global health crisis. With few new antibiotics coming on the market, there is a need for novel antimicrobial materials that target and kill multi-drug-resistant (MDR) Gram-positive pathogens like methicillin-resistant Staphylococcus aureus (MRSA). In this study, using a novel mixed-bacteria antimicrobial assay, we show that the star-peptide polymers preferentially target and kill Gram-positive pathogens including MRSA. A major effect on the activity of the star-peptide polymer was structure, with an eight-armed structure inducing the greatest bactericidal activity. The different star-peptide polymer structures were found to induce different mechanisms of bacterial death both in vitro and in vivo. These results highlight the potential utility of peptide/polymers to fabricate materials for therapeutic development against MDR Gram-positive bacterial infections.

Progress and perspectives on directing group-assisted palladium-catalysed C-H functionalisation of amino acids and peptides.

Peptide modifications can unlock a variety of compounds with structural diversity and abundant biological activity. In nature, peptide modifications, such as functionalisation at the side-chain position of amino acids, are performed using post-translational modification enzymes or incorporation of unnatural amino acids. However, accessing these modifications remains a challenge for organic chemists. During the past decades, selective C-H activation/functionalisation has attracted considerable attention in synthetic organic chemistry as a pathway to peptide modification. Various directing group strategies have been discovered that assist selective C-H activation. In particular, bidentate directing groups that enable tuneable and reversible coordination are now recognised as one of the most efficient methods for the site-selective C-H activation and functionalisation of numerous families of organic compounds. Synthetic peptide chemists have harnessed bidentate directing group strategies for selective functionalisation of the ß- and γ-positions of amino acids. This method has been expanded and recognised as an effective device for the late stage macrocyclisation and total synthesis of complex peptide natural products. In this review, we discuss various ß-, γ-, and δ-C(sp3)-H bond functionalisation reactions of amino acids for the formation of C-X bonds with the aid of directing groups and their application in late-stage macrocyclisation and the total synthesis of complex peptide natural products.

Depsipeptide synthesis using a late-stage Ag(i)-promoted macrolactonisation of peptide thioamides.

Macrolactonisation of peptides to generate cyclic depsipeptides is often challenging due to the low nucleophilicity of hydroxyl groups, epimerisation, cyclodimerisation, and potential acyl transfer reactions of the ester. Herein, we report a novel macrolactonisation strategy employing a Ag(i)-promoted conversion of peptide thioamides to isoimide intermediates, which undergo site-selective intramolecular acyl transfer to serine/threonine side chains to generate the macrolactone.

Total Synthesis of the Putative Structure of Asperipin-2a and Stereochemical Reassignment.

The total synthesis of the putative structure of asperipin-2a is described. The synthesis features ether cross-links between the phenolic oxygen of Tyr6 and the ß position of Tyr3 and the phenolic oxygen of Tyr3 and the ß position of Hpp1 in the unique 17- and 14-membered bicyclic structure of asperipin-2a, respectively. The synthesized putative structure does not match the natural product, and a stereochemical reassignment is postulated.

Total Synthesis of Seongsanamide B.

The first total synthesis of the bicyclic depsipeptide natural product seongsanamide B is described. The successful approach employed solid-phase peptide synthesis of a core heptapeptide, incorporating on-resin esterification, followed by solution-phase macrolactamization and a late stage intramolecular Evans-Chan-Lam coupling to generate the biaryl ether of the isodityrosine unit.

Synthesis of the C-Terminal Macrocycle of Asperipin-2a.

A synthetic approach to the C-terminal macrocycle of asperipin-2a is presented. Two epimers were prepared, possessing R- and S-configurations at the ß-position of Tyr3. Comparison of NMR data of the natural product with these isomers and X-ray crystallographic data for one macrocycle support assignment of the 2 S,3 S -configuration of Tyr3. Key steps in the synthesis include a stereoselective benzylic oxidation of the tyrosine residue and Lewis-acid-catalyzed ring opening of the subsequently generated aziridine.