Divergent Strategy for Diastereocontrolled Synthesis of Small- and Medium-Ring Architectures.

Nitrogen and oxygen medium rings, in particular nine-membered rings, epitomize a unique area of chemical space that occurs in many natural products and biologically appealing compounds. The scarcity of 8- to 12-membered rings among clinically approved drugs is indicative of the difficulties associated with their synthesis, principally owing to the unfavorable entropy and transannular strain. We report here a scandium triflate-catalyzed reaction that allows for a modular access to a diverse collection of nine-membered ring heterocycles in a one-pot cascade and with complete diastereocontrol. This cascade features an intramolecular addition of an acyl group-derived enol to a α,ß-unsaturated carbonyl moiety, leading to N- and O-derived medium-ring systems. Computational studies using the density functional theory support the proposed mechanism. Additionally, a one-pot cascade leading to hexacyclic chromeno[3',4':2,3]indolizino[8,7-b]indole architectures, with six fused rings and four contiguous chiral centers, is reported. This novel cascade features many concerted events, including the formation of two azomethine ylides, [3 + 2]-cycloaddition, 1,3-sigmatropic rearrangement, Michael addition, and Pictet-Spengler reaction among others. Phenotypic screening of the resulting oxazonine collection identified chemical probes that regulate mitochondrial membrane potential, adenosine 5'-triphosphate contents, and reactive oxygen species levels in hepatoma cells (Hepa1-6), a promising approach for targeting cancer and metabolic disorders.

One-Pot Synthesis of Diverse Collections of Benzoxazepine and Indolopyrazine Fused to Heterocyclic Systems.

The development of efficient and modular synthetic methods for the synthesis of diverse collection of privileged substructures needed for a drug design and discovery campaign is highly desirable. Benzoxazepine and indolopyrazine ring systems form the core structures of distinct members of biologically significant molecules. Several members of these families have gained attention due to their broad biological activities, which depend on the type of ring-fusion and peripheral substitution patterns. Despite the potential applications of these privileged substructures in drug discovery, efficient, atom-economic, and modular strategies for their access are underdeveloped. Herein, a one-step build/couple/pair strategy that uniquely allows access to diversely functionalized benzoxazepine and indolopyrazine scaffolds is described. The methodology features a one-pot combination of condensation, Mannich, oxidation, and aza-Michael addition reactions, employing a variety of functionalized anilines and aldehydes suitably poised with Micheal acceptor. Scandium triflate (Sc(OTf)3) in acetonitrile (ACN) was found to promote the construction of benzoxazepines scaffolds, while sodium metabisulfite (Na2S2O5) in aqueous EtOH rapidly enhanced the cascade reaction that led to diverse collections of indolopyrazine frameworks. These protocols represent modular, efficient, and atom-economic access of constrained benzoxazepine and indolopyrazine systems with more than 10 points of diversity and large substrate tolerance.