Enantioselective Access to γ-All-Carbon Quaternary Center-Containing Cyclohexanones by Palladium-Catalyzed Desymmetrization

Abstract

An efficient desymmetrization of γ-quaternary carbon-containing cyclohexanones using readily available Pd/ (S)-t BuPhox and benzylamine as dual catalysts is reported. We describe herein the development of the reaction, exploration of the substrate scope, and studies on the reaction mechanism. The intramolecular coupling reaction leads to the formation of bicyclo[3.3.1]nonanones with a quaternary carbon bridgehead in synthetically useful yields (up to 98%) with high enantioselectivities (up to 98:2 er) and good functional group tolerance (>30 examples). Significantly, aryl and alkenyl bromides as well as less reactive triflates are all compatible substrates for this process. The synthetic versatility of this strategy is demonstrated by scale-up synthesis and diverse transformations of the products into valuable building blocks, including quaternary center-containing dihydronaphthalenes, ring-fused indoles and lactones, tetralones, and 6,6,5-tricycles. Mechanistic studies by computational calculations provide insights into the role of benzylamine in accelerating the reaction rate and enhancing the enantioselectivities.

Crystal structure of tert-butyl 4-[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate

“…1. The challenge of synthesizing quaternary carbons (Wei et al, 2020;Liu et al, 2015;Volla et al, 2014;Fuji, 1993;Martin, 1980), particularly amine-bearing quaternary carbons (Zhu et al, 2019;Yeung et al, 2019;Xu et al, 2019;Velasco-Rubio et al, 2019;Vasu et al, ISSN 2056-9890 Figure 1…”

“…1. The challenge of synthesizing quaternary carbons (Wei et al, 2020;Liu et al, 2015;Volla et al, 2014;Fuji, 1993;Martin, 1980), particularly amine-bearing quaternary carbons (Zhu et al, 2019;Yeung et al, 2019;Xu et al, 2019;Velasco-Rubio et al, 2019;Vasu et al, ISSN 2056-9890 Figure 1 Synthesis of tert-butyl 4-[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate (1) via Bruylants reaction (Firth et al, 2016). 2019; Trost et al, 2019;Ling & Rivas, 2016;Hager et al, 2016;Clayden et al, 2011;Fu et al, 2008;Riant & Hannedouche, 2007), is well established.…”

Catalytic Asymmetric Synthesis of Tröger’s Base Analogues with Nitrogen Stereocenter

“…Since the pioneering work by Miura, Buchwald, Hartwig, and others, α-arylation of carbonyls has become one of powerful and useful method in organic synthesis. − Recently, Jia, Shi, Zhou, Liu and Gong did seminal contribution in the asymmtric intramolecular α-arylation of ketones, leading various types of bridged bicyclic skeletons. − Very recently, our group also disclosed the asymmetric intermolecular α-arylation of acyclic aldehydes and γ-arylation of β,γ-unsaturated butenolides. , Along this research line, we wonder whether the rigid cheft-like scaffold could be accessed by the arylation of carbonyl compounds using N -benzyl substituted dihydroquinolinone derivatives as starting materials. This approach demonstrates the following advantages: (1) in comparison to Tröger’s base, this designed scaffold is configurationally stable under either acidic or basic conditions; (2) the nitrogen stereocenter, as well as the neighboring carbon stereocenter, is established simultaneously.…”

Enantioselective Arylation of Tetrasubstituted Enamines: Access to Enantioenriched Indolenine and 1H-Indole Derivatives

“…This is probably due to the increased steric hindrance and the lack of efficient catalyst. Previously, we and others have developed the palladium-catalyzed enantioselective β-arylation of in situ generated enamines as an efficient approach to α-arylated optically active ketones . We envisaged that enantioenriched indolenines might be achieved through an intramolecular arylation of the preformed β,β -disubstituted enamines.…”