Cascade reactions of indigo with oxiranes and aziridines: efficient access to dihydropyrazinodiindoles and spiro-oxazocinodiindoles

Abstract

The base-initiated alkylation of the abundant natural dye indigo 1 with ring-strained electrophiles results in the unprecedented, one-pot synthesis of functionalised dihydropyrazino[1,2-a:4,3-a']diindoles, dihydroepoxy[1,5]oxazocino[5,4-a:3,2-b']diindoles, and dihydrodiazepino[1,2-a:4,3-a']diindoles, resulting from intramolecular ring opening-expansion cyclisation processes of their parent oxiranes and aziridines. Regiochemical and stereochemical aspects of the reactions are reported together with integrated mechanistic proposals. This new indigo cascade chemistry should have broad applicability in the synthesis of chemical architectures, not readily-accessible by other means. The three-step synthesis of the useful synthetic precursor (R)-2-(chloromethyl)-1-tosylaziridine 14 is also described. Initial biological activity investigations into these new 2,2'-dindolyl-based heterocyclic derivatives revealed potent, selective antiplasmodial activity in vitro for several isolated structures, with IC50 values as low as 76.6 nM for (±)-8, while demonstrating low human cell toxicity.

Synthesis and Density Functional Theory Studies of Azirinyl and Oxiranyl Functionalized Isoindigo and (3Z,3’Z)-3,3’-(ethane-1,2-diylidene)bis(indolin-2-one) Derivatives

“…The diverse array of 2-(bromomethyl)-1-(arylsulfonyl)aziridines, and 2-(bromomethyl)-1-(alkylsulfonyl)aziridines 6 constitute a unique subclass of N -activated aziridines due to the presence of three electrophilic sites; the exocyclic methylene group and the two carbon atoms of the aziridine moiety [36,37,38]. These valuable precursors, with extensive applications in the synthesis of organic or biological compounds such as β -lactams, amino acids, alkaloids, and antibiotics, were synthesized in high yields in two steps starting with allylsulfonamides [39].…”

Predicting phosphirane air stability using density functional theory

“…The ring opening of heterocyclic 3-membered rings is an established and versatile strategy in the synthetic chemists' toolbox for the generation of new stereogenic sites in complex molecules and has been applied in the nucleophilic ring opening of chiral oxiranes [1][2][3] and aziridines [4][5][6] (Scheme 1) in the syntheses of natural products, medicinal drugs and material structures. The evolution of this ring-opening methodology to incorporate other heterocycles, for example, phosphorus atoms to produce phosphiranes, is hampered by the apparent instability of these systems.…”

Novel base-initiated cascade reactions of hemiindigos to produce dipolar γ-carbolines and indole-fused pentacycles

“… 4 The base-initiated cascade reactions of indigo with oxiranes and aziridines offered efficient access to dihydropyrazinodiindoles and spiro-oxazocinodiindoles. 5 …”