Transition-Metal-Catalyzed Asymmetric Couplings of α-Aminoalkyl Fragments to Access Chiral Alkylamines

Abstract

Enantiomerically pure alkylamines are pivotal structural elements in a broad range of pharmaceuticals, agrochemicals, natural products, and chemical building blocks. The development of useful methodologies for the preparation of these alkyamines is one of the central and long-standing challenges facing synthetic chemistry. In recent years, transition-metal-catalyzed enantioselective coupling reactions of α-aminoalkyl species have emerged as appealing C–C bond-forming approaches for the construction of chiral alkylamines. This useful technique is remarkable for its substantial advantages in functional group compatibility, substrate scope, molecular complexity, and synthetic practicality, which provides complementarity and orthogonality to traditional metal-catalyzed approaches to chiral amine synthesis. This Review underscores recent advances in transition-metal-catalyzed asymmetric alkylamine bond forming reactions organized by the type of key α-aminoalkyl intermediates, including (1) couplings of α-aminoalkyl-metal species, (2) couplings of α-aminoalkyl radicals, (3) couplings of imines with carbon electrophiles, and (4) couplings of enamines mediated by M–H species. In addition, the synthetic practicalities of such remarkable tools have also been highlighted by the total syntheses of selected natural and biologically interesting molecules and the stereoselective assembly of challenging target compounds.

Tuning an Imine Reductase for the Asymmetric Synthesis of Azacycloalkylamines by Concise Structure‐Guided Engineering

“…[1b] Traditional chemical methods of asymmetric reductive amination commonly require expensive transition-metal complexes or chiral ligands, coupled with side reactions, such as reduction of ketone/aldehyde or overalkylation, making them unsustainable in industrial processes. [2] Given the apparent advantages in terms of selectivity, sustainability, and evolvability, [3] enzyme families of reductive amination, such as amine dehydrogenase [4] and imine reductase (IRED), [5] are the research frontiers in academia and industry. A subfamily of IREDs were classified as reductive aminases (RedAms) by Turner and co-workers, and their reductive-amination activity is proposed as a consequence of promiscuity.…”

One-Pot Biocatalytic Synthesis of Primary, Secondary, and Tertiary Amines with Two Stereocenters from α,β-Unsaturated Ketones Using Alkyl-Ammonium Formate

“…The development of efficient and highly selective catalytic methods for the synthesis of α-chiral amines in optically pure form is of great importance for the pharmaceutical industry. , Therefore, several organometallic-, organo-, and photoredox-catalysts possessing improved activity and selectivity have been developed during the past 2 decades for the synthesis of α-chiral amines starting from prochiral substrates. − In this context, biocatalysis has made a tremendous contribution since an arsenal of enzymes from different families is now available for the synthesis of α-chiral amines in high optical purity; − these enzyme families comprise hydrolases, − ω-transaminases, − ammonia lyases, , amine oxidases, ,− imine reductases/reductive aminases, − amine dehydrogenases, , engineered cytochromes P450, − and Pictet-Spenglerases. − …”

Enantioselective synthesis of N-alkylindoles enabled by nickel-catalyzed C-C coupling

“…As a part of our interest in chiral alkylamine-bearing molecules 25 , 68 , here, we show a catalytic enantioselective coupling of in-situ generated α-N -alkyl nickel species with aryl/alkenyl/alkynyl bromides, analogous to the C(sp 3 )–C(sp 2 )/C(sp) cross-coupling reaction, enabling a unified method toward structually diverse chiral N -alkylindoles in high yields and ee’s (Fig. 1D ).…”