A palladium-catalysed enolate alkylation cascade for the formation of adjacent quaternary and tertiary stereocentres

Abstract

The catalytic enantioselective synthesis of densely functionalised organic molecules containing all-carbon quaternary stereocentres is a challenge to modern chemical methodology research. The catalytically controlled asymmetric alpha-alkylation of ketones represents another difficult task and has been of major interest to our and other research groups in the past. We now report a palladium-catalyzed enantioselective process that addresses both problems at once and allows the installation of vicinal all-carbon quaternary and tertiary stereocentres at the alpha-carbon of a ketone in a single step. This multiple bond forming process is carried out on readily available beta-ketoester starting materials and proceeds via conjugate addition of an in situ-generated palladium enolate to activated Michael acceptors. In other words, the CO(2)-moiety of the substrate is displaced by a C-C fragment in an asymmetric cut-and-paste reaction. The products are obtained in high yield, diastereomeric ratio, and enantiomeric excess.

Figure 1. Concept for the enantioselective functionalisation of palladium-enolates

Three pathways for the palladium catalyzed generation α-functionalised ketones are shown. A palladium catalyst generated from [Pd₂(dba)₃] and ligand L undergoes oxidative addition to β-ketoester 1 following the loss of CO₂ to form an enolate intermediate A. This palladium enolate can either react following path a to yield enantioenriched α-alkylated products or following path b in the presence of a proton source to give α-protonated products. The envisioned path c would form miscellaneous enantioenriched α-substituted ketones depending on other electrophilic additives "E⁺" that intercept enolate A.

Figure 2. Absolute stereochemistry and limitations of the reported palladium catalysed enolate alkylation

a, The absolute configuration of the major diastereomer (4) matches the prouct from the previously reprted palladium-catalyzed decarboxylative protonation (6) and is opposite to the outcome of the regular decarboxylative allylic alkylation (5). b, Electrophiles 2i and 2j also lead to product formation but with diminished yields and stereoselectivities. Products 3,4q however have three continuous quaternary and tertiary stereocentres. c, An alkyl substituted electrophile does not yield any product. Instead olefin isomerisation and allylic alkylation of 2k are observed. d, A mechanism in form of a catalytic cycle is proposed starting with an oxidative addition to the substrate involving decarboxylation followed by conjugate addition and reductive alkylation.

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