Development of an Enantioselective Allylic Alkylation of Acyclic α‐Fluoro‐β‐ketoesters for Asymmetric Synthesis of 3‐Fluoropiperidines

Abstract

The first useful enantioselective Pd-catalyzed asymmetric allylic alkylation of α-fluoro-β-ketoesters has been achieved using the Trost family of chiral ligands yielding products in up to 92 % ee. This work provides new insights regarding the typically modest selectivities associated with acyclic α-fluoroenolates and shows experimental evidence that the typically poor levels of enantiocontrol associated with these systems are not necessarily due to the presence of E/Z enolate mixtures. Finally, this methodology allows the easy preparation of useful 3-fluoropiperidine intermediates, and it is demonstrated that these systems are applicable to a range of functionalization reactions leading to new building blocks for the discovery of bioactive products.

Catalytic Enantioselective α-Allylation of Deconjugated Butenolides with Aza-π-allylpalladium 1,4-Dipoles: Access to Optically Pure 2-Piperidones Bearing an All-Carbon Quaternary Stereocenter

“…As a continuation of our research on the construction of chiral heterocycles, we have realized a catalytic enantioselective α-allylation of deconjugated butenolides with aza-π-allylpalladium 1,4-diploes, in situ generated from cyclic carbamates 1 and amide-substituted acyclic carbonates 4 , followed by an intramolecular aminolysis to access an array of chiral 2-piperidones bearing an all-carbon quaternary stereocenter (Scheme , bottom). Importantly, it is obviously different from the precedents (Scheme a–d) that triggered the reaction with nucleophilic attack from the anion moiety of the π-allylpalladium 1,4-diploes. ,− In this work, similar to Harrity’s work (Scheme e), the reaction is triggered by the nucleophilic attack to the π-allylpalladium cation unit of the 1,4-diploes (Scheme , bottom). Herein, we report our results on this subject.…”

“…Trost and co-workers designed diverse 1,4-dipole precursors and successfully employed them in enantioselective cycloaddition (Scheme d) . Despite these well-designed 1,4-dipole precursors, a cyclic carbamate, tert -butyl 5-methylene-1,3-oxazinan-2-one, which could generate an aza-π-allylpalladium 1,4-dipole, was synthesized from the Harrity group and preliminarily applied in the catalytic enantioselective piperidine synthesis (Scheme e) . It is imaginable that there is great research potential in the application of structurally diverse aza-π-allylpalladium 1,4-diploe precursors for the synthesis of optically active heterocyclic compounds.…”

A Pd‐Catalyzed Annulation Strategy to Linearly Fused Functionalized N‐Heterocycles

“…Having established the scope of the general transformation, we next explored the potential for these products to be accessed with high enantiocontrol. We have recently found that the Trost ligand series is effective in promoting enantioselective additions to the Pd π‐allyl intermediate derived from 1 [5c,d] and opted to investigate the enantioselective allylation with this catalyst system. Employing optimal conditions previously developed by us on a related system, [5c] we screened Trost ligands L2 – L5 and our results are shown in Scheme 5.…”

“…We have recently found that the Trost ligand series is effective in promoting enantioselective additions to the Pd π‐allyl intermediate derived from 1 [5c,d] and opted to investigate the enantioselective allylation with this catalyst system. Employing optimal conditions previously developed by us on a related system, [5c] we screened Trost ligands L2 – L5 and our results are shown in Scheme 5. L2 generated 3 b with a promising level of enantiocontrol, albeit in modest yield.…”

The Catalytic Asymmetric Allylic Alkylation of Acyclic Enolates for the Construction of Quaternary and Tetrasubstituted Stereogenic Centres

“…In 2022, Harrity and co‐workers reported the palladium‐catalysed AAA reaction of acyclic α‐fluoro‐β‐ketoesters 73 with cyclic carbonate 74 as the electrophile (A, Scheme 15). [27] In the presence of ( R , R )‐DACH phenyl Trost ligand ( R , R )‐ L8 , product 75 a was formed in 78 % yield and 75 % ee. The reactivity and enantioselectivity did not change significantly when varying the electronics of the ketone aryl substituent, giving 75 b in 68 % yield and 74 % ee, and 75 c in 82 % yield and 81 % ee.…”