Regio‐ and Stereoselective Modification of Chiral α‐Amino Ketones by Pd‐Catalyzed Allylic Alkylation

Abstract

Chiral α-amino ketones are excellent nucleophiles for stereoselective palladium-catalyzed allylic alkylations. Both chiral as well as achiral allylic substrates can be applied, while the stereochemical outcome of the reaction is controlled by the chiral ketone enolate. The substituted amino ketones formed can be reduced stereoselectively, and up to five consecutive stereogenic centers can be obtained. This approach can be used for the synthesis of highly substituted piperidine derivatives.

Catalytic Enantioselective and Diastereoselective Allylic Alkylation with Fluoroenolates: Efficient Access to C3‐Fluorinated and All‐Carbon Quaternary Oxindoles

“…[17] The reaction between the fluorooxindole 1d and ( E )-1-(2-isopropylphenyl)-3-phenylallyl acetate, 2j , gave 3dj as the major regioisomer in 98% yield and with excellent enantio- and diastereoselectivity (Scheme 3). Ligand screening revealed that the regioselectivity increases from 2.5:1 to 9:1 and without compromising yield and asymmetric induction when L6 is replaced with L3 .…”

Stereoselective Allylic Alkylations of Amino Ketones and Their Application in the Synthesis of Highly Functionalized Piperidines

“…Allylic alkylations cannot only be used for the synthesis of γ,δ‐unsaturated amino acids, but also for the modifications of peptides in a highly stereoselective fashion . Recently, we could show that Pd‐catalyzed allylic alkylations can also be performed with chiral chelated α‐aminoketone enolates with excellent diastereoselectivity (Scheme b) . The stereochemical outcome of the reaction is mainly controlled by the enolate geometry and the sterical bulk of the side chain, which shields one face of the enolate in the allylation step.…”

Iridium‐Catalyzed Diastereoselective and Enantioselective Allylic Substitutions with Acyclic α‐Alkoxy Ketones

“…This structure has been exploited for the allylation of glycine derivatives. [6] However, these reactions occurred with low diastereoselectivity when forming products containing adjacent tetra -substituted and tertiary stereocenters. [6a] With the same strategy, Evans and co-workers achieved diastereoselective allylations of α-hydroxy, as well as α-alkoxy or α-siloxy acetophenone catalyzed by an achiral rhodium catalyst.…”

“…[6] However, these reactions occurred with low diastereoselectivity when forming products containing adjacent tetra -substituted and tertiary stereocenters. [6a] With the same strategy, Evans and co-workers achieved diastereoselective allylations of α-hydroxy, as well as α-alkoxy or α-siloxy acetophenone catalyzed by an achiral rhodium catalyst. [7] However, only products containing adjacent tertiary and tri -substituted stereocenters bearing oxygen were formed, and no enantioselective transformation was reported.…”

“…The reaction conducted after addition of LiCl [4o] to the lithium enolate gave the product with a lower dr of 1:1.1, slightly favoring the formation of the other diastereoisomer (entry 2). The reaction with added ZnCl 2 [6] afforded 4aa with excellent diastereoselectivity (16:1 dr , entry 3), albeit in a lower yield of 72%. In contrast, the reaction conducted with added CuI occurred with a higher diastereomeric ratio to 5.7:1 while maintaining excellent conversion to yield 4aa in 97% yield (entry 4).…”