Synthesis of Spirocyclic Indolenines

Abstract

This Review provides an in-depth account of the synthesis of spirocyclic indolenines. Over the last 77 years, a wide array of diverse synthetic methods has been developed in order to generate these synthetically useful and biologically important spirocyclic scaffolds. The main synthetic strategies discussed are grouped into three main categories, namely interrupted Fischer indolisations, dearomatisation reactions of indoles and condensation reactions. The historical background, common synthetic challenges, current state-of-the-art and future perspectives of this field are examined.

Catalyst‐Driven Scaffold Diversity: Selective Synthesis of Spirocycles, Carbazoles and Quinolines from Indolyl Ynones

“…Herein, we report the successful realisation of this approach. Notably, by judicious choice of catalyst, simple, inexpensive ynone starting materials 1 can be converted into spirocyclic indolenines 3 using Ag I , carbazoles 5 using Au I and quinolines 7 using Ag I /Al III in high yield, each by a simple, catalytic and atom‐economical process. Furthermore, in suitable cases, tetracyclic scaffolds 8 can be formed with complete diastereoselectivity, by a telescoped spirocyclisation/nucleophilic addition sequence, which was performed using a chiral Ag I salt to furnish an enantiopure product.…”

“…[5] Ak ey design feature of our strategy was the idea that varyingt he catalystw ould alter the nature and reactivity of the vinyl-metal intermediate 2 in ap rogrammablew ay,s uch that alternative products could be formed by different rearrangementr eactions.H erein, we report the successful realisation of this approach. Notably,b yj udiciousc hoice of catalyst, simple, inexpensive ynone startingm aterials 1 can be converted into spirocyclic indolenines [6] 3 using Ag I ,c arbazoles 5 using Au I and quinolines 7 using Ag I /Al III in high yield, each by as imple, catalytic and atom-economical process. Furthermore, in suitable cases, tetracyclic scaffolds 8 can be formed with complete diastereoselectivity,b yatelescoped spirocyclisation/ nucleophilic addition sequence, which was performed using ac hiral Ag I salt to furnish an enantiopure product.…”

A Simple and Broadly Applicable C−N Bond Forming Dearomatization Protocol Enabled by Bifunctional Amino Reagents

“…Satisfactory results were achieved for Alloc‐protected system 4 f using Conditions B. The results in Table 1 are significant as they show that the method tolerates a wide range of synthetically useful N ‐protecting groups and that it is also mild enough for efficient dearomatization of the oxidatively sensitive indole core; C−N bond forming dearomatizations of this unit to provide spirocyclic pyrrolidine products have not been reported previously 4, 10, 11, 12…”

Metal‐Free Dearomatization: Direct Access to Spiroindol(en)ines in Batch and Continuous‐Flow

“…This nucleophilic catalysis enables the formation of aw ide scope of five-a nd six-membered spiroindol(en)ines in moderate to excellent yields in batch as well as under continuous-flow conditions. Triphenylphosphine-catalyzedn ucleophilic activationo fa lkynes allows the exclusive formation of exo-productu nder mild reactionc onditions.Dearomatization [1] is ar obust strategy to synthesize three-dimensional rigid moleculars caffolds from simple planar aromatic molecules. The synthesis of spiroindol(en)ines and related spirocarbocycles through dearomatization of indole and substituted phenols has captured the close attention of chemist due to their widespread presence in various naturalp roducts and biologically relevant molecules.…”