CH-Diazomethane sulfonamides generated in situ for intramolecular [3+2] cycloaddition of alkynes: an entry into novel pyrazole-fused five-membered sultams

Previously reported CH-diazomethane sulfonamides carrying various propargylic groups were generated in situ from their acetyl precursors. Without purification, these compounds underwent a slow, albeit clean and efficient, intramolecular [3+2] cycloaddition to give pyrazole-fused five-membered sultams. The latter are the first analogs of medicinally important (hetero)arene-fused five-membered sultams which contain a five-membered nitrogenous heterocycle. The newly introduced scaffold can be further elaborated into N-arylated derivatives using the Chan-Evans-Lam protocol. The resulting compounds incorporate more than one privileged moiety and are highly suitable for interrogation of protein targets via biological screening.

Structural insights into enzymatic [4+2] aza-cycloaddition in thiopeptide antibiotic biosynthesis

The [4+2] cycloaddition reaction is an enabling transformation in modern synthetic organic chemistry, but there are only limited examples of dedicated natural enzymes that can catalyze this transformation. Thiopeptides (or more formally thiazolyl peptides) are a class of thiazole-containing, highly modified, macrocyclic secondary metabolites made from ribosomally synthesized precursor peptides. The characteristic feature of these natural products is a six-membered nitrogenous heterocycle that is assembled via a formal [4+2] cycloaddition between two dehydroalanine (Dha) residues. This heteroannulation is entirely contingent on enzyme activity, although the mechanism of the requisite pyridine/dehydropiperidine synthase remains to be elucidated. The unusual aza-cylic product is distinct from the more common carbocyclic products of synthetic and biosynthetic [4+2] cycloaddition reactions. To elucidate the mechanism of cycloaddition, we have determined atomic resolution structures of the pyridine synthases involved in the biosynthesis of the thiopeptides thiomuracin (TbtD) and GE2270A (PbtD), in complex with substrates and product analogs. Structure-guided biochemical, mutational, computational, and binding studies elucidate active-site features that explain how orthologs can generate rigid macrocyclic scaffolds of different sizes. Notably, the pyridine synthases show structural similarity to the elimination domain of lanthipeptide dehydratases, wherein insertions of secondary structural elements result in the formation of a distinct active site that catalyzes different chemistry. Comparative analysis identifies other catalysts that contain a shared core protein fold but whose active sites are located in entirely different regions, illustrating a principle predicted from efforts in de novo protein design.

Mechanism of degradation of a nitrogenous heterocycle induced by a reductive radical: decomposition of a sym-triazine ring

Cyanuric acid, a major component of many materials and chemicals, and also the most important intermediate in the degradation processes of sym-triazine compounds in the natural environment, as well as being used for water treatment, was selected to elucidate the mechanism of degradation of nitrogenous materials.