John B. Feltenberger

Enamide-benzyne-[2 + 2] cycloaddition: stereoselective tandem [2 + 2]-pericyclic ring-opening-intramolecular N-tethered [4 + 2] cycloadditions.

Benzyne-[2 + 2] cycloadditions with enamides are described. This effort led to the development of a highly stereoselective tandem [2 + 2] cycloaddition-pericyclic ring-opening-intramolecular-N-tethered-[4 + 2] cycloaddition for rapid assembly of nitrogen heterocycles.

Torquoselective Ring Closures of Chiral Amido Trienes Derived from Allenamides. A Tandem Allene Isomerization−Pericyclic Ring-Closure−Intramolecular Diels−Alder Cycloaddition

A new torquoselective ring-closure of chiral amide-substituted 1,3,5-hexatrienes and its application in tandem with [4 + 2] cycloaddition are described. The trienes were derived via either a 1,3-H or 1,3-H-1,7-H shift of alpha-substituted allenamides, and the entire sequence through the [4 + 2] cycloaddition could be in tandem from allenamides.

Regio- and stereoselective isomerizations of allenamides: synthesis of 2-amido-dienes and their tandem isomerization-electrocyclic ring-closure.

A regio- and stereoselective isomerization of allenamides is described, leading to preparations of de novo 2-amido-dienes and a tandem isomerization-6pi-electron electrocyclic ring-closure.

Total Syntheses of Chelidonine and Norchelidonine via an Enamide–Benzyne–[2 + 2] Cycloaddition Cascade

Total syntheses of chelidonine and norchelidonine featuring an enamide-benzyne-[2 + 2] cycloaddition initiated cascade is described. The cascade includes a pericyclic ring-opening and intramolecular Diels-Alder reaction.

Oppolzer-Type Intramolecular Diels–Alder Cycloadditions via Isomerizations of Allenamides

A new approach to Oppolzers intramolecular Diels-Alder cycloaddition (IMDA) through γ-isomerization of readily available N-tethered allenamides is described. These IMDA reactions are carried out in tandem with the allenamide isomerization or 1,3-H shift, leading to complex nitrogen heterocycles in a highly stereoselective manner.

Gassman’s Intramolecular [2 + 2] Cationic Cycloaddition. Formal Total Syntheses of Raikovenal and epi-Raikovenal

The first intramolecular version of Gassmans cationic [2 + 2] cycloaddition employing vinyl acetals tethered to an unactivated olefin and its application in the formal syntheses of raikovenal and epi-raikovenal are described.

An efficient and practical entry to 2-amido-dienes and 3-amido-trienes from allenamides through stereoselective 1,3-hydrogen shifts

Summary Preparations of de novo acyclic 2-amido-dienes and 3-amido-trienes through 1,3-hydrogen shifts from allenamides are described. These 1,3-hydrogen shifts could be achieved thermally or they could be promoted by the use of Brønsted acids. Under either condition, these processes are highly regioselective in favour of the α-position, and highly stereoselective in favour of the E-configuration. In addition, 6π-electron electrocyclic ring-closure could be carried out with 3-amido-trienes to afford cyclic 2-amido-dienes, and such electrocyclic ring-closure could be rendered in tandem with the 1,3-hydrogen shift.

Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR)

Cellular metabolites act as important signaling cues, but are subject to complex unknown chemistry. Kynurenine is a tryptophan metabolite that plays a crucial role in cancer and the immune system. Despite its atypical, non-ligand-like, highly polar structure, kynurenine activates the aryl hydrocarbon receptor (AHR), a PER, ARNT, SIM (PAS) family transcription factor that responds to diverse environmental and cellular ligands. The activity of kynurenine is increased 100–1000-fold by incubation or long-term storage and relies on the hydrophobic ligand-binding pocket of AHR, with identical structural signatures for AHR induction before and after activation. We purified trace-active derivatives of kynurenine and identified two novel, closely related condensation products, named trace-extended aromatic condensation products (TEACOPs), which are active at low picomolar levels. The synthesized compound for one of the predicted structures matched the purified compound in both chemical structure and AHR pharmacology. Our study provides evidence that kynurenine acts as an AHR pro-ligand, which requires novel chemical conversions to act as a receptor agonist.

Comparative analysis of PknB inhibitors for reactivity and toxicity

Bacterial serine/threonine kinases are increasingly sought after as drug targets for new antibiotics. PknB, an essential kinase in Mycobacteria tuberculosis, is intensely targeted, and many inhibitors are in the developmental pipeline. These inhibitors typically are derived from screens of known kinase inhibitors and most share similar chemical properties as their parent compounds were all designed for optimal pharmacokinetic properties in the human body. Here, we investigate the reactivity and toxicity of a proposed PknB inhibitor, YH-8, which does not follow traditional drug design rules. We found that the compound is highly reactive with thiolating agents and has appreciable toxicity in a zebrafish animal model. Furthermore, we find minimal anti-mycobacterial activity with non-tubercular mycobacteria strains. These data suggest that further investigation is needed into its efficacy and physiochemical properties if it is to be further developed as an effective antibiotic.

Facile Synthesis of 3-Amido-Dienynes via a Tandem α-Propargylation–Isomerization of Chiral Allenamides and their Applications in Diels–Alder Cycloadditions

A series of de novo 3-amido-dienynes was synthesized via tandem α-propargylation-isomerization of chiral allenamides with moderate E/Z ratio. Reactivities of E-and Z-isomers were examined.