Enantioselective Synthesis of Chiral Oxime Ethers: Desymmetrization and Dynamic Kinetic Resolution of Substituted Cyclohexanones

Abstract

Axially chiral cyclohexylidene oxime ethers exhibit unique chirality because of the restricted rotation of C=N. The first catalytic enantioselective synthesis of novel axially chiral cyclohexylidene oximes has been developed by catalytic desymmetrization of 4-substituted cyclohexanones with O-arylhydroxylamines and is catalyzed by a chiral BINOL-derived strontium phosphate with excellent yields and good enantioselectivities. In addition, chiral BINOL-derived phosphoric acid catalyzed dynamic kinetic resolution of α-substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities.

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…In continuation of our efforts to understand the stereoselectivity of organocatalyzed reactions, particularly in the context of KRs, we have examined the KR of axially chiral biaryls reported by Sibi and co‐workers in 2014 (Scheme ) . In this reaction, chiral DMAP catalyst A serves as a highly selective catalyst when paired with isobutyric anhydride as the acylating agent.…”

“…[14][15][16][17][18][19] Studying such reactions computationally not only enriches our understanding of thesep rocesses but also creates opportunities to improvetheir efficiency. [20][21][22][23][24][25][26][27] In continuationo fo ur efforts to understandt he stereoselectivity of organocatalyzed reactions, [29] particularly in the context of KRs, [30,31] we have examined the KR of axially chiral biaryls reported by Sibi and co-workersi n2 014 (Scheme 1). [28] In this reaction, chiral DMAP catalyst A serves as ah ighly selective catalystw hen paired with isobutyric anhydride as the acylating agent.A lthough there have been previousc omputational studieso fo therK Rs of alcohols, [10,[32][33][34][35] the reactioni n Scheme 1p resents an umber of unique features.F irst, it is the seminale xample of an organocatalyzed KR that providese xcellent selectivities for axially chiral alcohols, yet has not been explored computationally.S econd, it exhibits high degreeso fs electivity despite the use of ah ighly-fluxional chiral catalyst.…”

Recent Advances in (Dynamic) Kinetic Resolution and Desymmetrization Catalyzed by Chiral Phosphoric Acids

“…In 2017, Antilla and co-workers reported the dynamic kinetic resolution of racemic 2-substituted cyclohexanones 80 through oxime formation with O-arylhydroxylamine 81 enabled by CPA catalyst (CPA-3), which provided the chiral 2-substituted cyclohexanone oxime ethers 82 in good yields and high enantiose- lectivities, even with the 2-alkyl and 2-chloro groups (Scheme 28). [40] In addition, the authors demonstrated that this method was also applicable in the enantioselective desymmetrization of 4-substituted cyclohexanones 83, which upon treatment with O-arylhydroxylamine 84 and catalytic amount of Sr(CPA-3) 2 generated a serious of novel axially chiral cyclo-hexylidene oxime ethers 85 with good yields and enantioselectivities…”

Organocatalytic Dynamic Kinetic Resolution: An Update

“…Inspired by the work reported in 2010 by List et al, dealing with asymmetric reductive amination of α-substituted cyclohexanones with p-anisidine through DKR catalyzed by a chiral BINOL-derived phosphoric acid, [21] Antilla et al investigated in 2017 related reactions by using O-phenylhydroxylamine 66 as the nucleophilic partner. [22] Therefore, the reaction of a range of α-substituted cyclohexanones 67 with O-phenylhydroxylamine 66 performed in toluene at low temperature (À 70 to À 50 °C) in the presence of 5 mol% of chiral phosphoric acid (R)-50 allowed the corresponding chiral cyclohexylidene oxime ethers 68 to be synthesized in good to high yields (56-86 %) and uniformly high enantioselectivities (84-94 % ee). As presented in Scheme 15, electron-donating groups as well as electron-withdrawing groups were tolerated as substituents on the cyclohexanone moiety.…”