Iridium-Catalyzed Diastereo- and Enantioselective [4 + 3] Cycloaddition of 4-Indolyl Allylic Alcohols with Azomethine Ylides

Abstract

An unprecedented iridium-catalyzed asymmetric [4 + 3] cycloaddition of racemic 4-indolyl allylic alcohols with azomethine ylides is reported. The ability of acid promoter zinc triflate to perform multiple roles is the key factor for the success of this strategy. This method provides scalable and efficient access to biologically important azepino [3,4,5-cd] indoles in good yields with generally excellent diastereo-and enantioselectivities (up to >20:1 dr and >99% ee). Mild reaction conditions, easily accessible substrates and chiral catalyst, and broad substrate scope highlight the practicality of this methodology.

Enantioselective Allylation of Alkenyl Boronates Promotes a 1,2-Metalate Rearrangement with 1,3-Diastereocontrol

“…The best results were obtained with Carreira’s phosphoramidite ligand, ( S )- L1 . − Our initial attempt with 1.1 equiv of (±)- 2a in the presence of [Ir­(COD)­Cl] 2 and ( S )- L1 provided alcohol 3 in 68% yield and 4:1 dr, with the major diastereomer displaying 82:18 er (entry 1). We speculated that (±)- 2a might be undergoing a kinetic resolution under the reaction conditions. − Accordingly, upon increasing the carbonate loading to 2.1 equiv, we obtained product 3 in improved yields and enantioselectivity (entry 2). Addition of LiCl further improved the yield and dr, with the major diastereomer now displaying excellent er (entry 3).…”

Regioselectivity of the SEAr-based cyclizations and SEAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

“…In 2021, Deng et al showcased an unprecedented iridium-catalyzed asymmetric [4 + 3] cycloaddition of racemic 4-indolyl allylic alcohols 22 with α-imino esters 23 as azomethine ylide precursors to afford azepino[3,4,5- cd ]indoles 24 in good yields and with complete regioselectivity and generally excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee) ( Scheme 8 ) [ 18 ]. The optimized reaction conditions for the annulation reaction were as follows: [Ir(cod)Cl] 2 (4 mol %), Carreira’s P/olefin ligand ( S )- L3 (16 mol %), Zn(OTf) 2 (100 mol %), and 4 Å MS in CH 2 Cl 2 at rt.…”

Stereoselective Synthesis of Azacycles Induced by Group 8–11 Late Transition Metals

“…In another study, they used the same catalyst/ligand combination and reacted 4-indolyl allylic alcohols with azomethine ylides to afford highly substituted azepino[3,4,5-cd]indoles up to 95 % yields with excellent enantio-and diastereoselectivities in a [4 + 3] cycloaddition process. [24] The group of Jiang and Nie carried out intramolecular asymmetric reductive aminations applied in combination with tBu-ax-Josiphos ligand 12 with a ferrocenyl scaffold and an axial binaphthalene moiety. [25] 2-Substituted N-Boc-protected phenethylcarbamates underwent acid-catalyzed deprotection followed by cyclization and asymmetric hydrogenation to provide tetrahydroisoquinolines in high product yields with good to excellent enantioselectivities (Scheme 17).…”