Pyrroloindoles as Therapeutically Invaluable Agents: A Review on their Diverse Synthetic Methodologies

Abstract

In the realm of medicinal chemistry, heterocyclic compounds play a vital role due to their diverse pharmacological properties, especially, pyrroloindoles standing out as crucial motifs in drug development. Pyrroloindoles, which are formed by combining indole and pyrrole rings, exhibit unique characteristics and serve as integral components in numerous drugs and natural compounds. The synthesis of pyrroloindoles is challenging due to their complex ring structures and diverse substitution patterns. This comprehensive review compiles various synthetic strategies for obtaining pyrroloindole derivatives via metal‐catalyzed reactions; cyclopropanation/ ring opening/ iminium cyclization (CRI reaction); organocatalytic cascade addition‐cyclization; 1,3‐dipolar cycloaddition; Brønsted acid‐catalyzed [3+2] cyclodimerization; ring closure mechanisms; thermally‐induced ring‐opening and cyclization reactions; condensation reactions; and visible‐light photocatalytic asymmetric reactions providing a valuable resource for synthetic organic chemists and researchers interested in the synthesis of pyrroloindoles and their derivatives. These compounds play a pivotal role in drug discovery thus, making this review an indispensable reference.

Iron-Catalyzed Oxidative Rearrangement of Cyclopropanone Hemiaminals: General Access to Pyrroloindolones from Indoles

“…In fact, the indole unit represents the fourth most prevalent heteroaromatic ring system found in FDA-approved drugs . Specifically, pyrroloindolones and related 1,2-fused indole natural products have recently emerged as promising therapeutic agents for a variety of diseases . While a number of synthetic approaches exist for their formation, most rely on the multistep prefunctionalization of substrates prior to cyclization, − the use of expensive and/or elaborate metal complexes as catalysts, − or only give access to specific substitution patterns on the resulting pyrroloindolone. − Therefore, the development of alternative sustainable strategies leading to a general access to the pyrroloindolone scaffold from simple starting materials is highly desirable.…”

“…The resulting bench-stable hemiaminals are shown to smoothly rearrange to the corresponding pyrroloindolones in mild conditions via an iron­(III)-catalyzed oxidative fragmentation to β-carboxylic radical intermediates with complete regiocontrol. Considering the relevance of 1,2-fused indole derivatives in natural product and medicinal chemistry research, this approach should find utility in the streamlined production of complex biologically active molecules. Notably, this method constitutes the first example of the use of cyclopropanone equivalents as three-carbon annulative reactants via a ring opening/ring closing transform of cyclopropanone hemiaminals.…”