First Example of the Intermolecular Palladium‐Catalyzed Asymmetric Allylic Alkylation of Hydroxyacrylates: Synthesis of All‐Carbon α‐Aryl Quaternary Aldehydes

Abstract

A set of acyclic all‐carbon α‐aryl quaternary aldehydes was synthesized by intermolecular palladium‐catalyzed asymmetric allylic alkylation (Pd‐AAA). Hydroxyacrylates were used as unprecedented nucleophilic counterparts instead of widely used ketone substrates. This produced a very rare all‐carbon quaternary aldehyde. Chiral ligand (R,R)‐L3 was found to be optimal in this Pd‐AAA reaction and provided good to excellent yields (75–99 %) and enantioselectivities (75–94 %) with a range of analogs.

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications

“…Hossain’s group successfully employed hydroxyacrylates as nucleophiles instead of the commonly used ketoesters. , The reaction yielded a range of enantioenriched α-aryl quaternary carbonyl compounds in high ee values (up to 94%; Scheme ) using the Pd/( R , R )-DACH-naphthyl catalyst. The same group also developed an intramolecular version using the corresponding allyl enol ethers to yield α-aryl quaternary aldehydes in ee values of up to 90% …”

CuH-Catalyzed Regio- and Enantioselective Hydrocarboxylation of Allenes: Toward Carboxylic Acids with Acyclic Quaternary Centers

“…25−50 Nonetheless, catalytic access 51 to enantioenriched acyclic carboxylic acids or esters featuring an all-carbon α-quaternary stereocenter remains challenging. 5,6 In this regard, common synthetic methods include allylic alkylation of geometrically pure alkenes, 52−55 often with superstoichiometric organometallic reagents, and α-functionalization of carboxylic acid derivatives, [35][36][37][38][39][40][41][42][43][44]50 which typically necessitates a β-directing group or electron-withdrawing group (Figure 1B).…”

“…All-carbon quaternary stereocenters, a structural feature that can impart significant chemical and biological impact to a molecule, are critical to many synthetic and medicinal applications. − Consequently, catalytic and enantioselective approaches for constructing all-carbon quaternary centers, especially functionalized stereocenters, are highly desirable. − Carboxylic acids, a chemically versatile functional group, that can bear an α-stereogenic center often serve as useful synthetic intermediates. − More importantly, α-chiral carboxylic acid derivatives themselves constitute an essential class of compounds in pharmaceutical, agrochemical, and natural product arenas (Figure A). − Methods for generating enantioenriched α-chiral carboxylic acids have long been sought after . Prominent synthetic strategies targeting α-chiral carboxylic acids or esters via asymmetric catalysis include hydrogenation of α,β-unsaturated carboxylic acids, carbene-induced C–H insertion with diazoacetates, − enantioselective protonation , or hydrogen atom transfer processes, and α-functionalization of carboxylic acid derivatives. − Nonetheless, catalytic access to enantioenriched acyclic carboxylic acids or esters featuring an all-carbon α-quaternary stereocenter remains challenging. , In this regard, common synthetic methods include allylic alkylation of geometrically pure alkenes, − often with superstoichiometric organometallic reagents, and α-functionalization of carboxylic acid derivatives, − …”

Construction of Acyclic All-Carbon Quaternary Stereocenter Based on Asymmetric Michael Addition of Chiral Amine

“…Thus, extensive efforts have been made to develop a method for the formation of acyclic all-carbon quaternary stereocenters. 6,[23][24][25][26][27][28][29][30][31][32][33][34] The utilization of an enolate is one of the most powerful methods for the construction of acyclic all-carbon quaternary stereocenters. Effective methods that use the nucleophilicity of enolates have been reported.…”