Catalytic assembly of enantiopure aliphatic amines from abundant and readily available precursors has long been recognized as a paramount challenge in synthetic chemistry. Herein, we describe a mild and general copper-catalyzed hydroamination that effectively converts unactivated internal olefins, an important yet unexploited class of abundant feedstock chemicals, into highly enantioenriched α-branched amines (≥ 96% enantiomeric excess) featuring two minimally differentiated aliphatic substituents. This method provides a powerful means to access a broad range of advanced, highly functionalized enantioenriched amines of interest in pharmaceutical research and other areas.

The chirality, or ‘handedness’, of a biologically active molecule can alter its physiological properties. For this reason, it is routine procedure in the drug discovery and development process to prepare and fully characterize all possible stereoisomers of a drug candidate for biological evaluation1,2. Despite many recent advances in asymmetric synthesis, the development of general and practical strategies to obtain all possible stereoisomers of an organic compound bearing multiple contiguous stereocenters remains a significant challenge3. In this manuscript, we report a stereodivergent copper-based approach for the expeditious construction of amino alcohols with high levels of chemo-, regio-, diastereo- and enantioselectivity. Specifically, these amino alcohol products were synthesized using the sequential copper hydride-catalyzed hydrosilylation and hydroamination of readily available enals and enones. This strategy provides a route to all possible stereoisomers of the amino alcohol products, which contain up to three contiguous stereocenters. Catalyst control and stereospecificity were simultaneously leveraged to attain exceptional control of the product stereochemistry. Beyond the utility of this protocol, the strategy demonstrated here should inspire the development of methods providing complete sets of stereoisomers for other valuable synthetic targets.

The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a longstanding goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective, and step-efficient synthesis of amines is still needed. In this work we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines, and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio-, and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine, and tolterodine.

Axially chiral biaryl scaffolds are essential structural units in chemistry. The asymmetric Pd-catalyzed Suzuki–Miyaura cross-coupling reaction has been widely recognized as one of the most practical methods for constructing atropisomers of biaryls. However, longstanding challenges remain in this field. For example, substrate scope is often narrow and specialized, functional groups and heterocycles can lead to reduced reactivity and selectivity, bulky ortho-substituents are usually needed, and reported methods are generally inapplicable to tetra-ortho-substituted biaryls. We have developed an unprecedented highly enantioselective N-heterocyclic carbene (NHC)-Pd catalyzed Suzuki–Miyaura cross-coupling reaction for the synthesis of atropisomeric biaryls. These reactions enable efficient coupling of aryl halides (Br, Cl) or aryl triflates with various types of aryl boron compounds (B­(OH)2, Bpin, Bneo, BF3K), tolerate a remarkably broad scope of functional groups and heterocycles (>41 examples), employ low loading of catalyst (0.2–2 mol %), and proceed under mild conditions. The protocol provided general and efficient access to various atropisomeric biaryls and heterobiaryls in excellent enantioselectivities (up to 99% ee) with no need of using bulky ortho-substituted substrates and was effective for the synthesis of tetra-ortho-substituent biaryls. Moreover, the method was successfully applied to the diastereo- and enantioselective synthesis of atropisomeric ternaphthalenes. Critical to the success of the reaction is the development and application of an extremely bulky C 2-symmetric chiral NHC, (R,R,R,R)-DTB-SIPE, as the ligand for palladium. To the best of our knowledge, this is the first highly enantioselective (>90% ee) example of a chiral NHC-metal-catalyzed C­(sp2)–C­(sp2) cross-coupling reaction.