Synthesis of Heptagon-Containing Polyarenes by Catalytic C-H Activation.

Nanocarbons incorporating non-hexagonal aromatic rings - such as five-, seven-, and eight-membered rings - have various intriguing physical properties such as curved structures, unique one-dimensional packing, and promising magnetic, optical, and conductivity properties. Herein, we report an efficient synthetic approach to polycyclic aromatics containing seven-membered rings via a palladium-catalyzed intramolecular Ar-H/Ar-Br coupling. In addition to all-hydrocarbon scaffolds, heteroatom-embedded heptagon-containing polyarenes can be efficiently constructed with this method. Rhodium- and palladium-catalyzed sequential six- and seven-membered ring formations also afford complex heptagon-containing molecular nanocarbons from readily available arylacetylenes and biphenyl boronic acids. Detailed mechanistic analysis by DFT calculations showed the feasibility of seven-membered ring formation by a concerted metalation-deprotonation mechanism. This reaction can serve as a template for the synthesis of a wide range of seven-membered ring-containing molecular nanocarbons.

Construction of Heptagon-Containing Molecular Nanocarbons.

Molecular nanocarbons containing heptagonal rings have attracted increasing interest due to their dynamic behavior, electronic properties, aromaticity, and solid-state packing. Heptagon incorporation can not only induce negative curvature within nanocarbon scaffolds, but also confer significantly altered properties through interaction with adjacent non-hexagonal rings. Despite the disclosure of several beautiful examples in recent years, synthetic strategies toward heptagon-embedded molecular nanocarbons remain relatively limited due to the intrinsic challenges of heptagon formation and incorporation into polyarene frameworks. In this Review, recent advances in solution-mediated and surface-assisted synthesis of heptagon-containing molecular nanocarbons, as well as the intriguing properties of these frameworks, will be discussed.

Palladium-Catalyzed Ring Expansion of Spirocyclopropanes to Form Caprolactams and Azepanes.

A palladium(0)-catalyzed rearrangement of piperidones and piperidines bearing a spirocyclopropane ring was developed. The ring expansion reaction led to a variety of functionalized caprolactam and azepane products in good to excellent yields. Experimental and computational mechanistic studies revealed an initial oxidative addition of the distal carbon-carbon bond of a cyclopropane ring to the palladium(0) catalyst and the relief of ring strain as a driving force for product formation.

Antibiotic Discovery with Synthetic Fermentation: Library Assembly, Phenotypic Screening, and Mechanism of Action of ß-Peptides Targeting Penicillin-Binding Proteins.

In analogy to biosynthetic pathways leading to bioactive natural products, synthetic fermentation generates mixtures of molecules from simple building blocks under aqueous, biocompatible conditions, allowing the resulting cultures to be directly screened for biological activity. In this work, a novel ß-peptide antibiotic was successfully identified using the synthetic fermentation platform. Phenotypic screening was carried out in an initially random fashion, allowing simple identification of active cultures. Subsequent deconvolution, focused screening, and structure-activity relationship studies led to the identification of a potent antimicrobial peptide, showing strong selectivity for our model system Bacillus subtilis over human HEK293 cells. To determine the antibacterial mechanism of action, a peptide probe bearing a photoaffinity tag was readily synthesized through the use of appropriate synthetic fermentation building blocks and utilized for target identification using a quantitative mass spectrometry-based strategy. The chemoproteomic approach led to the identification of a number of bacterial membrane proteins as prospective targets. These findings were validated through binding affinity studies with penicillin-binding protein 4 using microscale thermophoresis, with the bioactive peptide showing a dissociation constant ( Kd) in the nanomolar range. Through these efforts, we provide a proof of concept for the synthetic fermentation approach presented here as a new strategy for the phenotypic discovery of novel bioactive compounds.

Synthetic fermentation of bioactive molecules.

The concept of synthetic fermentation is to 'grow' complex organic molecules in a controlled and predictable manner by combining small molecule building blocks in water-without the need for reagents, enzymes, or organisms. This approach mimics the production of small mixtures of structurally related natural products by living organisms, particularly microbes, under conditions compatible with direct screening of the cultures for biological activity. This review discusses the development and implementation of this concept, its use for the discovery of protease inhibitors, its basis as a chemistry outreach program allowing non-specialists to make and discover new antibiotics, and highlights of related approaches.

Synthetic fermentation of ß-peptide macrocycles by thiadiazole-forming ring-closing reactions.

Macrocyclic ß-peptides were efficiently prepared using a thiadiazole-forming cyclization reaction between an α-ketoacid and a thiohydrazide. The linear ß-peptide precursors were assembled from isoxazolidine monomers by α-ketoacid-hydroxylamine (KAHA) ligations with a bifunctional initiator - a process we have termed 'synthetic fermentation' due to the analogy of producing natural product-like molecules from simpler building blocks. The linear synthetic fermentation products underwent Boc-deprotection/thiadiazole-forming macrocyclization under aqueous, acidic conditions to provide the cyclic products in a one-pot process. This reaction sequence proceeds from easily accessed initiator and monomer building blocks without the need for additional catalysts or reagents, enabling facile production of macrocyclic ß-peptides, a relatively underexplored structural class.

Regioselective magnesiation of N-heterocyclic molecules: securing insecure cyclic anions by a ß-diketiminate-magnesium clamp.

Using a specially designed magnesium metallating manifold, combining kinetically activated TMP amide base with a sterically amplified ß-diketiminate ligand, this study has established a new regioselective strategy for magnesiation of challenging N-heterocyclic molecules. The broad scope of the approach is illustrated through reactions of pyrazine, triazoles and substituted pyridines by isolation and structural elucidation of their magnesiated intermediates.