Catalytic Asymmetric Oxidation of Amines to Hydroxylamines

Abstract

Chiral hydroxylamines are increasingly common structural elements in pharmaceuticals and agrochemicals, but their asymmetric synthesis remains challenging. Although enantioselective oxidation is the most straightforward method to prepare chiral oxides with a higher oxidation state, asymmetric and even nonasymmetric amine oxidation to hydroxylamines has been poorly addressed. We report a titanium-catalyzed asymmetric oxidation of racemic amines providing a broad range of structurally diverse chiral hydroxylamines with excellent chemo- and enantioselectivity. Notably, hydroxylamines bearing diverse substituent patterns on the stereocenters, including α,α-ester-alkyl, α,α-amide-alkyl, α,α-aryl-alkyl, α,α-alkynyl-alkyl, and α,α-dialkyl, are well tolerated with good functional group compatibility. Catalyst turnover numbers up to 5000 and selectivity factors up to 278 are observed. This finding offers a democratized platform to chiral hydroxylamines as design elements for drug discovery and provides insights into metal-catalyzed asymmetric oxidation of challenging substrates.

Hafnium(IV)-Salen-Catalyzed Highly Reactive and Enantioselective Epoxidation Directed by Amides

“…The combination of salen and group 4 transition-metals have enabled various exceptional asymmetric oxidations, ,− where structural characterizations of catalysts facilitated the mechanism elucidations. Since the Hf-salen complex was able to achieve outstanding reactivity in epoxidation, its catalysis model was worth studying.…”

Late-Stage Chemo- and Enantioselective Oxidation of Indoles to C3-Monosubstituted Oxindoles

“…Kinetic experiments were next performed to further elucidate the reaction mechanism (Figure , E–G). First, the kinetic profile of C9 -catalyzed oxidation implies that formation of the real oxygen-transferring titanium species is not a slow process (Figure E) . Second, the kinetic analysis revealed a pseudo-first-order dependence of the reaction rate on the concentration of the indole substrate, suggesting that the initial reactivity between real oxygen-transferring titanium species and the indole is overall rate-limiting (Figure F) .…”

Rhodium‐Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of 1,3‐Dipolar Nitrones

“…Despite their significance, chiral hydroxylamines suffer from a dearth of effective synthetic methods, [3] resulting in limited knowledge and further applications about these compounds. Existing reports for the synthesis of hydroxylamines predominantly center on the catalytic asymmetric hydrogenation of oximes, [4] the oxidative kinetic resolution of racemic amines, [5] asymmetric hydroaminoxylation of conjugated diene [6] etc. [3] Given the structural resemblance between oximes and nitrones, the catalytic addition of dihydrogen to nitrones undoubtedly presents advantageous prospects for constructing chiral hydroxylamines, which are versatile synthons and could be further transformed to a myriad of bioactive compounds.…”