How the Lewis Base F– Catalyzes the 1,3-Dipolar Cycloaddition between Carbon Dioxide and Nitrilimines

Bio-organic Synthesi

Phosphine-catalyzed activation of cyclopropenones: a versatile C3 synthon for (3+2) annulations with unsaturated electrophiles

We herein report a phosphine-catalyzed (3 + 2) annulation of cyclopropenones with a wide variety of electrophilic π systems, including aldehydes, ketoesters, imines, isocyanates, and carbodiimides, offering products of butenolides, butyrolactams, maleimides, and iminomaleimides, respectively, in high yields with broad substrate scope. An α-ketenyl phosphorous ylide is validated as the key intermediate, which undergoes preferential catalytic cyclization with aldehydes rather than stoichiometric Wittig olefinations. This phosphine-catalyzed activation of cyclopropenones thus supplies a versatile C3 synthon for formal cycloadditon reactions

Interception of the Bycroft-Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides

Thiopeptides are a broad class of macrocyclic, heavily modified peptide natural products that are unified by the presence of a substituted, nitrogen-containing heterocycle core. Early work indicated that this core might be fashioned from two dehydroalanines by an enzyme-catalyzed aza-[4 + 2] cycloaddition to give a cyclic-hemiaminal intermediate. This common intermediate could then follow a reductive path toward a dehydropiperidine, as in the thiopeptide thiostrepton, or an aromatization path to yield the pyridine groups observed in many other thiopeptides. Although several of the enzymes proposed to perform this cycloaddition have been reconstituted, only pyridine products have been isolated and any hemiaminal intermediates have yet to be observed. Here, we identify the conditions and substrates that decouple the cycloaddition from subsequent steps and allow interception and characterization of this long hypothesized intermediate. Transition state modeling indicates that the key amide-iminol tautomerization is the major hurdle in an otherwise energetically favorable cycloaddition. An anionic model suggests that deprotonation and polarization of this amide bond by TbtD removes this barrier and provides a sufficient driving force for facile (stepwise) cycloaddition. This work provides evidence for a mechanistic link between disparate cyclases in thiopeptide biosynthesis

Analyzing reaction rates with the distortion/interaction-activation strain model

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Theoretical Studies of Conformational Preferences of NAD+ and NADH Analogs: Protonated nicotinamide and 1,4-dihydro-nicotinamide

The conformations of nicotinamide (N+) and 1,4-dihydronicotinamide (NH) have been studied by ab initio calculations at the MP2/6-31G{*}//6-31G{*} level. The amide group favors a cis conformation by about 1 kcal/mol for both N+ and NH. The rotational barrier for cis to trans interconversion is about 4 and 7 kcal/mol for N+ and NH, respectively. The amide group in the trans conformation is out of plane by about 20-degrees. The 1,4-dihydronicotinamide ring is slightly puckered and adopts a boat conformation. The calculated N-15 equilibrium isotope effect for hydride transfer is small, in agreement with experimental observations