Indole-based chiral heterocycles constitute a class of important heterocyclic compounds that are found in numerous pharmaceuticals, functional materials, and chiral catalysts or ligands. Catalytic asymmetric synthesis, for which the 2001 Nobel Prize in Chemistry was awarded, has been demonstrated to be the most efficient method for accessing chiral compounds. Therefore, the catalytic asymmetric synthesis of indole-based chiral heterocycles has attracted great interest from the scientific community. However, the strategies toward this goal are rather limited, and great challenges remain in this field, such as metal contamination in the products, the limited number of platform molecules with versatile reactivity, and the limited number of catalytic asymmetric reactions that offer high step economy, atom economy, and excellent enantiocontrol. Therefore, novel strategies for the catalytic asymmetric synthesis of indole-based chiral heterocycles are urgently needed. To achieve this goal, our group has developed a series of unique strategies, such as designing and developing versatile platform molecules and their corresponding organocatalytic asymmetric reactions to access indole-based chiral heterocycles. In this Account, we describe our efforts to address the remaining challenges in this research field. Namely, we have designed and developed vinylindoles, indolylmethanols, arylindoles and indole derivatives as versatile platform molecules for the construction of indole-based chiral heterocyclic scaffolds with structural diversity and complexity. Based on the reactivities of these platform molecules, we have designed and accomplished a series of organocatalytic asymmetric cycloaddition, cyclization, addition and dearomatization reactions with a high step economy, atom economy and excellent enantiocontrol. Using these strategies, a wide range of indole-based chiral heterocycles, including five-membered to seven-membered heterocycles, axially chiral heterocycles and tetrasubstituted heterocycles, have been synthesized with high efficiency and excellent enantioselectivity. In addition, we have investigated the properties of some indole-based chiral heterocycles, including their bioactivities and catalytic activities, and showed that these chiral heterocycles have potent anticancer activities and promising catalytic activities in asymmetric catalysis. These results help elucidate the potential applications of indole-based chiral heterocycles in drug development and chiral catalysts. The organocatalytic asymmetric synthesis of indole-based chiral heterocycles has undoubtedly become and will continue to be a hot topic in the field of asymmetric catalysis and synthesis. Our efforts, summarized in this Account, will not only open a window for the future development of innovative strategies toward organocatalytic asymmetric synthesis of indole-based chiral heterocycles but also inspire chemists worldwide to confront the remaining challenges in this field and prompt further advances.

Organocatalytic Asymmetric Synthesis of Indole-Based Chiral Heterocycles: Strategies, Reactions, and Outreach.

The first catalytic asymmetric inverse-electron-demand (IED) oxa-Diels–Alder reaction of ortho-quinone methides, generated in situ from ortho-hydroxybenzyl alcohols, has been established. By selecting 3-methyl-2-vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho-hydroxybenzyl alcohols as precursors of dienes and 3-methyl-2-vinylindoles as dienophiles, as well as the hydrogen-bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa-Diels–Alder reaction.

Catalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction of In Situ Generated ortho‐Quinone Methides with 3‐Methyl‐2‐Vinylindoles

Quinone methides (QMs) are highly reactive compounds that have been defined as "elusive" intermediates, or even as a "synthetic enigma" in organic chemistry. Indeed, there were just a handful of examples of their utilization in catalytic asymmetric settings until some years ago. This review collects organocatalytic asymmetric reactions that employ QMs as substrates and intermediates, from the early examples, mostly based on stabilized QMs bearing specific substitution patterns, to more recent contributions, which have dramatically expanded the scope of QM chemistry. In fact, it was only very recently that the generation of QMs in situ through strategies compatible with organocatalytic methodologies has been realized. This tactic has finally opened the gate to the full exploitation of these unstable intermediates, leading to a series of remarkable disclosures. Several types of synthetically powerful asymmetric addition and cycloaddition reactions, applicable to a broad range of QMs, are now available.

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The Emergence of Quinone Methides in Asymmetric Organocatalysis

In recent decades, transient and highly reactive ortho-quinodimethanes (o-QDMs), ortho-quinone methides (o-QMs) and aza-ortho-quinone methides (aza-o-QMs) have attracted much attention and have been extensively studied and applied in organic synthesis, especially natural product total synthesis. This review summarizes recent advances in Diels–Alder reactions involving in situ-generated o-QDMs, o-QMs and aza-o-QMs, highlighting the power and potential of this strategy in organic synthesis and natural product total synthesis. An overview of the methods for generating these intermediates is also available.

Recent advances in the application of Diels-Alder reactions involving o-quinodimethanes, aza-o-quinone methides and o-quinone methides in natural product total synthesis.

The first enantioselective construction of a new class of axially chiral naphthyl-indole skeletons has been established by organocatalytic asymmetric coupling reactions of 2-naphthols with 2-indolylmethanols (up to 99 % yield, 97:3 e.r.). This approach not only affords a new type of axially chiral heterobiaryl backbone, but also provides a new catalytic enantioselective strategy for constructing axially chiral biaryl scaffolds by making use of the C3-electrophilicity of 2-indolylmethanols.

Design and Enantioselective Construction of Axially Chiral Naphthyl‐Indole Skeletons

The organocatalytic asymmetric arylative dearomatization of indoles was achieved through two tandem approaches involving 2,3-disubstituted indoles and quinone imine ketals. One approach utilized the enantioselective cascade 1,4 addition/alcohol elimination reaction, the other employed the one-pot tandem arylative dearomatization/transfer hydrogenation sequence. In both cases, enantiomerically pure indole derivatives that bear an all-carbon quaternary stereogenic center were generated in high yields and excellent stereoselectivities (all d.r.>95:5, up to 99 % ee).

Organocatalytic Asymmetric Arylative Dearomatization of 2,3‐Disubstituted Indoles Enabled by Tandem Reactions

Brønsted acid-catalyzed stereoselective [4+3] cycloadditions of ortho-hydroxybenzyl alcohols with N,N′-cyclic azomethine imines

A catalytic chemo-, E/Z-, and enantioselective cyclization of o-hydroxybenzyl alcohols with dimedone-derived enaminones has been established, which not only realized a chemoselective C1,2 cyclization of enaminones but also achieved the catalytic asymmetric construction of the biologically important tetrahydroxanthene framework with high E/Z- and enantioselectivities (all >95:5 E/Z, up to 98% yield, 97:3 er). This approach not only represents the first catalytic asymmetric C1,2 cyclization of enaminones with o-hydroxybenzyl alcohols but also provides an efficient strategy for constructing oxygenous heterocyclic frameworks with optical purity.

Catalytic Chemo-, E/Z-, and Enantioselective Cyclizations of o-Hydroxybenzyl Alcohols with Dimedone-Derived Enaminones.

An organocatalytic arylation of 3-indolylmethanols has been established via chemo- and regiospecific C6-functionalization of 2,3-disubstituted indoles, leading to the production of bisindolyloxindoles containing an all-carbon quaternary stereocenter in high yields (up to 99% yield). This reaction not only represents the first catalytic arylation of 3-indolylmethanols using 2,3-disubstituted indoles as aromatic nucleophiles but also serves as a good example of direct catalytic C6-functionalization of indoles, which have been scarcely investigated. Besides, this approach also provides an efficient method to access a biologically important 3,3′-disubstituted oxindole framework and a 3′,6-linked bisindole skeleton. Furthermore, the investigation of the activation mode suggested that the dual activation of an ion pair and H-bond between the substrates and the catalyst cooperatively contributed to the success of the reaction.

Jia-Jia Zhao

Papers

Catalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction of In Situ Generated ortho‐Quinone Methides with 3‐Methyl‐2‐Vinylindoles

Organocatalytic Asymmetric Arylative Dearomatization of 2,3‐Disubstituted Indoles Enabled by Tandem Reactions

Brønsted acid-catalyzed stereoselective [4+3] cycloadditions of ortho-hydroxybenzyl alcohols with N,N′-cyclic azomethine imines

Catalytic Chemo-, E/Z-, and Enantioselective Cyclizations of o-Hydroxybenzyl Alcohols with Dimedone-Derived Enaminones.

Organocatalytic arylation of 3-indolylmethanols via chemo- and regiospecific C6-functionalization of indoles.