Exploring the Chemistry of Spiroindolenines by Mechanistically-Driven Reaction Development: Asymmetric Pictet-Spengler-type Reactions and Beyond.

The Pictet-Spengler reaction is a fundamental named reaction in organic chemistry, and it is the most straightforward method for the synthesis of tetrahydro-β-carbolines, a core structure embedded in numerous alkaloids. Spiroindolenines are often proposed as possible intermediates in Pictet-Spengler reactions. However, whether the spiroindolenine species is an intermediate in the mechanism of the asymmetric Pictet-Spengler reaction remains unclear. Questions about the role of the spiroindolenine species regarding the mechanism include the following: Can the spiroindolenine species be formed effectively under Pictet-Spengler conditions? If so, what is its fate? Is the delivery of the enantioenriched tetrahydro-β-carboline product related to the spiroindolenine intermediate? Previous studies regarding these questions have not reached a consensus. Therefore, elucidating these questions will advance the field of synthetic organic chemistry.The first highly enantioselective synthesis of spiroindolenines that have the same molecular scaffold as the proposed key intermediate of the Pictet-Spengler reaction was accomplished by an Ir-catalyzed intramolecular asymmetric allylic substitution reaction of an indol-3-yl allylic carbonate. In this reaction, a piperidine, pyrrolidine, or cyclopentane ring can be introduced in conjunction with the indolenine structure.Spiroindolenines were found to undergo ring-expansive migration reactions when treated with a catalytic amount of an acid, leading to tetrahydro-β-carbolines or related tetrahydrocarbazoles. Comprehensive DFT calculations and Born-Oppenheimer molecular dynamics simulations have provided insight into the mechanism of the migration process. It has been found that the stereochemistry is strongly correlated with the electronic properties of the migratory group along with the acidity of the catalyst. Close interactions between the positively charged migratory group and the electron-rich indole ring favor the stereospecificity of the migration. Furthermore, a continuous mechanistic spectrum of the Pictet-Spengler reactions can be obtained on the basis of two readily accessible energetic parameters that are derived from computed energies for competing transition states relative to a key intermediate species. This theoretical model provides a unified mechanistic understanding of the asymmetric Pictet-Spengler reaction, which has been further supported by rationally designed prototype reactions. Chemically and stereochemically controllable migration can be achieved when multiple potential migratory groups are available.The reactivity of spiroindolenines has also been explored beyond Pictet-Spengler reactions. A one-pot Ir-catalyzed asymmetric allylic dearomatization/stereoconvergent migration allows the facile synthesis of enantioenriched tetrahydro-β-carbolines from racemic starting materials. An unprecedented six- to seven-membered ring-expansive migration can be achieved when a vinyliminium moiety is involved as a highly reactive migratory group. This reaction facilitates the stereoselective synthesis of thermodynamically challenging indole-annulated seven-membered rings. It has also been found that the migration process can be interrupted. The electrophilic migratory group released from the retro-Mannich reaction of a spiroindolenine can be captured by an inter- or intramolecular nucleophile, thus providing new entries into structurally diverse polycyclic indole derivatives.Therefore, the mechanism of the Pictet-Spengler reaction can be probed by manipulating the reactivity of the spiroindolenine species. In turn, the mechanistic insights gained herein will aid in chemical transformations toward various target molecules. This study serves as a vivid example of the positive interplay between experimental and theoretical investigations in synthetic organic chemistry.