Recent advances in the synthesis of chiral α-tertiary amines via transition-metal catalysis.

The significance of chiral α-tertiary amines in medicinal chemistry and drug development has been unquestionably established in the last few decades. α-Tertiary amines are attractive structural motifs for natural products, bioactive molecules and pharmaceuticals and are preclinical candidates. Their syntheses have been the focus of intensive research, and the development of new methods has continued to attract more and more attention. In this review, we present the progress in the last decade in the development of synthetic methods for the assembly of chiral ATAs via transition-metal catalysis. To date, the effective approaches in this area could be categorized into three strategies: enantioselective direct and indirect Mannich addition to ketimines; umpolung asymmetric alkylation of imine derivatives; and asymmetric C-N cross-coupling of tertiary alkyl electrophiles. Several related developing strategies for the synthesis of ATAs, such as hydroamination of alkenes, HAT amination approaches and the C-C coupling of α-aminoalkyl fragments, are also described in this article. These strategies have emerged as attractive C-C and C-N bond-forming protocols for enantioselective construction of chiral α-tertiary amines, and to some extent are complementary to each other, showing the prospect of application in medicinal chemistry and chemical biology.

Site-Selective Radical Trifluoromethylaminoxylation of Olefins for the Modular Synthesis of Diverse ß-Trifluoromethyl Trisubstituted Hydroxylamines and Beyond.

A highly site-selective trifluoromethylaminoxylation of activated and unactivated olefins was reported under metal-free conditions. The method provides direct access to diverse ß-trifluoromethyl trisubstituted hydroxylamines, tertiary alcohols, isoxazolines, isoxazolidines, and amino alcohols. The SET process between hydroxylamine and the hypervalent iodine-CF3 reagent is proposed to produce two free radicals for the regio- and diastereoselective addition to alkenes. The synthetic potential of the protocol was established via the late-stage functionalization of the products and a series of postreaction modifications.

Regioselective Synthesis of Unsymmetrical Vicinal Diamines via Azidoimination of Alkenes with TMSN3 and Ketimines.

2-Azidoimines are versatile precursors to value-added vicinal unsymmetrical diamines, which are among the most common motifs in biologically active compounds. Herein, we report their operationally simple synthesis through a highly regioselective intermolecular azidoamination of olefins under metal-free conditions. The approach proceeded through azide and iminyl, two differentiated N-centered radicals. The synthetic potential of the protocols was further established via the condensation/amination sequential cascade and chemoselective, orthogonal transformations to access vicinal primary diamines.

Pd-Catalyzed C-O Bond Formation Enabling the Synthesis of Congested N,N,O-Trisubstituted Hydroxylamines.

A Pd-catalyzed C-O cross-coupling of O-acyl hydroxylamines and tertiary or secondary alkyl electrophiles was reported without the cleavage of the rather fragile N-O bond. The described strategy provides direct access to congested N,N,O-trisubstituted hydroxylamines bearing an α-quaternary carbon center under mild conditions in high yields and features exclusively chemoselective C-O bond formation, a broad substrate scope, and excellent functional group tolerance. The synthetic potential of the cross-coupling was established via pharmaceuticals derivatizations and a series of postcatalytic modifications.