Mechanistic Origins of Stereodivergence in Asymmetric Cascade Allylation and Cyclization Reactions Enabled by Synergistic Cu/Ir Catalysis

Abstract

Stereodivergent syntheses of bioactive tetrahydro-γcarbolines have been achieved via synergistic chiral Cu/Ir catalysis [Nat. Commun. 2019, 10, 5553], in which three stereogenic centers were generated via two consecutive C−C formation procedures in one-pot conditions. Herein, density functional theory (DFT) calculations were applied to reveal the mechanism and origins of stereochemistry of the catalytic asymmetric cascade allylation and the iso-Pictet−Spengler cyclization reaction. For copper-based chiral catalysis, nucleophilic (S,S p )-L1/Cu(I)-azomethine ylide (IM3-Si) with Si-face orientation was formed as the major active species through deprotonation, in which the reactive site of (S,S p )-L1/Cu(I)ylide cis to the −PPh 2 Cp′ moiety has more space for reaction, while the site cis to the oxazoline ring was blocked due to steric repulsions. For iridium-based chiral catalysis, the electrophilic (R,R a )-L2/Ir(III)-π-allyl species (IM7-Si) with Si-face orientation was formed kinetically favorable via decarboxylation and takes on the main active catalyst, wherein the internal carbon of the allyl moiety has stronger electrophilicity than the terminal one. Then, the two active species converge via a facile C−C bond-forming process, in which the two distinct chiral metal catalysts control the absolute stereoselectivity (TS5-Si-Si-cis), delivering the branched allylated compound (2S,3R)-Int-I and regenerating the two catalysts. TS5-Si-Si-cis is also stabilized by the π−π dispersion interaction between the aryl group of azomethine and the indolyl allyl moiety, thanks to their cis and parallel configurations. The rest of the C− C bonding events with different substrate orientations or arising from the other sets of chiral catalysts are disfavored, which is ascribed to bearing large steric repulsions and lacking π−π interaction. Finally, the intramolecular C−C formation of indole C3 to Siface protonated imine followed by deprotonation completes the iso-Pictet−Spengler cyclization and produces final (1R,3S,4R)tetrahydro-γ-carboline. Overall, the mechanistic insights are useful for the further advancement of stereodivergent synthesis via cooperative bimetallic catalysis.

Dispersion and Steric Effects on Enantio-/Diastereoselectivities in Synergistic Dual Transition-Metal Catalysis

“…While synergistic catalysis triggered much computational effort, − theoretical studies on stereodivergent dual TM catalysis remain limited. , Sunoj et al recently investigated a related synergistic Cu/Ir system, highlighting the role of noncovalent interactions in absolute and relative stereocontrol . Notwithstanding the expanding scope of reported reactions, ,− little is known about how differences in TM-stabilized chiral partners influence the mechanism and nature of stereorecognition.…”

Stereodivergent synthesis of enantioenriched azepino[3,4,5-cd]-indoles via cooperative Cu/Ir-catalyzed asymmetric allylic alkylation and intramolecular Friedel–Crafts reaction

“…This dual-catalytic process will be studied first. 27,28 The ensuing steps feature achiral reagent promoted cyclization and epimerization with effective delivery of chirality, which will be explored later.…”

“…With an understanding of the generation of allyl-iridium, we investigated the coupling of the electrophilic allyl-iridium IM3a with the nucleophilic Cu-AMY complex IM4 to rationalize the stereoselectivity for the C7 center. 27,28 The mechanistic origin of the C7-stereoselection lies in a diastereofacial preference of the AMY unit ( Fig. 3A ).…”

Arylsulfonylation-Triggered Cyclization of 3-Alkenyl Indoles Enabling Synthesis of Tetrahydro-γ-carboline

“…10 Recently, Wang's group 11 developed a cascade allylation and iso-Pictet−Spengler cyclization reaction of 2-indolyl allylic methyl carbonates with aldimine esters, which afforded functionalized tetrahydro-γ-carbolines in good yields (Scheme 1a). 12 On the other hand, 2-indolylnitroethylenes have been developed by Deng's group as substrates for the construction of tetrahydro-γ-carboline skeletons via chemoselective [3 + 3] cycloaddition with azomethine ylides. 13 The same group also reported a strategy via Sc-catalyzed [3 + 3] cycloaddition with β-(indol-2-yl)-α,β-unsaturated ketones and aziridines as substrates.…”

“…As tetrahydro-γ-carbolines are widely used in organic synthesis and medicinal chemistry, much research attention has been devoted to the construction of functionalized tetrahydro-γ-carbolines. , In particular, an iso -Pictet–Spengler reaction of indole derivatives represents an efficient strategy . Recently, Wang’s group developed a cascade allylation and iso -Pictet–Spengler cyclization reaction of 2-indolyl allylic methyl carbonates with aldimine esters, which afforded functionalized tetrahydro-γ-carbolines in good yields (Scheme a) . On the other hand, 2-indolylnitroethylenes have been developed by Deng’s group as substrates for the construction of tetrahydro-γ-carboline skeletons via chemoselective [3 + 3] cycloaddition with azomethine ylides .…”