Organocatalyzed Kinetic Resolution of α-Functionalized Ketones: The Malonate Unit Leads the Way

Abstract

Developing a catalytic kinetic resolution (KR) protocol affording enantioenriched α-functionalized ketones with broad substrate scope and high efficiency has been a longstanding challenge. Here, we report a successful protocol toward addressing this issue via an organocatalyzed cascade annulation. The protocol could afford 11 classes of enantioenriched α-functionalized ketones using a single catalytic system and avoid the frequent alterations of reaction conditions used in conventional methods. Up to 684 of the selectivity factor (s) is observed, and in most case, the s values are higher than 100. An aminolactam additive proves essential in promoting the resolution efficiency. Moreover, many previously unavailable enantiopure α-functionalized ketones are now accessible, and the annulation products are also useful building blocks and can be further transferred to densely substituted ketones without erosion of the optical purity. Mechanistically, in sharp contrast to the currently used direct one-step resolution patterns, a two-key-step resolution mode, wherein the enantiomer discrimination happens at the second aldol step and the enatioenriched ketones are recovered by the reversible initial Michael reaction, is proposed, which provides opportunities addressing the challenging tasks that could not be solved by conventional resolution techniques.

Kinetic Resolutions Enabled by N-Heterocyclic Carbene Catalysis: An Update

“…[28] In 2020, an efficient kinetic resolution protocol affording 11 classes of chiral α-functionalized ketones with up to 684 of the selectivity factor (s) was disclosed by Fang and co-workers using a two-key-step resolution mode (Scheme 22). [29] α-Methylated, α-benzylated, α-allylated, α-estermethylated, α-aminomethylated, and α-thiomethylated ketones, and ketones with α-acetamino, α-alkylthio, α-alkyoxy, α-deuterium, and α-fluoro groups were all accessible with high enantioselectivities. The addition of aminolactam additive plays a crucial role in achieving the resolution.…”

Recent Progress toward the Construction of Axially Chiral Molecules Catalyzed by an N-heterocyclic Carbene

“…The umpolung strategy generates acyl nucleophiles (Breslow intermediates) and homoenolate equivalents, which can react with carbonyl compounds (benzoin condensation), Michael acceptors (Stetter reaction), and carbon–carbon multiple bonds (hydroacylation) . Moreover, NHCs can also act as excellent catalysts to generate the acyl azolium intermediates that are involved in non-umpolung processes. − In addition, NHCs can serve as nucleophilic catalysts by reacting with Michael acceptors to form NHC–nucleophile adducts through conjunction or function as a bases to activate amines, alcohols, and diketones. − In summary, a variety of catalytic activation modes have been discovered and a great number of remarkable synthetic transformations have been realized. − …”

Streamlined Catalytic Enantioselective Synthesis of α-Substituted β,γ-Unsaturated Ketones and Either of the Corresponding Tertiary Homoallylic Alcohol Diastereomers

“…Catalytic enantioselective protocols for synthesis of acyclic α-substituted ketones have been reported, but several key problems remain “still unconquered”, as characterized in a recent review article . The great majority of transformations deliver products where the carbonyl group and/or the stereogenic center are aryl-substituted, a significant restriction considering total synthesis of many bioactive molecules calls for α-substituted aliphatic ketones (see Scheme ). There are a small number of strategies for enantioselective synthesis of α-alkyl-substituted ketones, but these necessitate a priori generation of an enolate equivalent.…”