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.

Conspectus Despite the astonishing diversity of naturally occurring biocatalytic processes, enzymes do not catalyze many of the transformations favored by synthetic chemists. Either nature does not care about the specific products, or if she does, she has adopted a different synthetic strategy. In many cases, the appropriate reagents used by synthetic chemists are not readily accessible to biological systems. Here, we discuss our efforts to expand the catalytic repertoire of enzymes to encompass powerful reactions previously known only in small-molecule catalysis: formation and transfer of reactive carbene and nitrene intermediates leading to a broad range of products, including products with bonds not known in biology. In light of the structural similarity of iron carbene (FeC­(R1)­(R2)) and iron nitrene (FeNR) to the iron oxo (FeO) intermediate involved in cytochrome P450-catalyzed oxidation, we have used synthetic carbene and nitrene precursors that biological systems have not encountered and repurposed P450s to catalyze reactions that are not known in the natural world. The resulting protein catalysts are fully genetically encoded and function in intact microbial cells or cell-free lysates, where their performance can be improved and optimized by directed evolution. By leveraging the catalytic promiscuity of P450 enzymes, we evolved a range of carbene and nitrene transferases exhibiting excellent activity toward these new-to-nature reactions. Since our initial report in 2012, a number of other heme proteins including myoglobins, protoglobins, and cytochromes c have also been found and engineered to promote unnatural carbene and nitrene transfer. Due to the altered active-site environments, these heme proteins often displayed complementary activities and selectivities to P450s. Using wild-type and engineered heme proteins, we and others have described a range of selective carbene transfer reactions, including cyclopropanation, cyclopropenation, Si–H insertion, B–H insertion, and C–H insertion. Similarly, a variety of asymmetric nitrene transfer processes including aziridination, sulfide imidation, C–H amidation, and, most recently, C–H amination have been demonstrated. The scopes of these biocatalytic carbene and nitrene transfer reactions are often complementary to the state-of-the-art processes based on small-molecule transition-metal catalysts, making engineered biocatalysts a valuable addition to the synthetic chemist’s toolbox. Moreover, enabled by the exquisite regio- and stereocontrol imposed by the enzyme catalyst, this biocatalytic platform provides an exciting opportunity to address challenging problems in modern synthetic chemistry and selective catalysis, including ones that have eluded synthetic chemists for decades.

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Current understanding of ligand effects in transition metal catalysis is mostly based on the analysis of catalyst-substrate through-bond and through-space interactions, with the latter commonly considered to be repulsive in nature. The dispersion interaction between the ligand and the substrate, a ubiquitous type of attractive non-covalent interaction, is seldom accounted for in the context of transition metal-catalyzed transformations. Herein we report a computational model to quantitatively analyze the effects of different types of catalyst-substrate interactions on reactivity. Using this model, we show that in the copper(I) hydride (CuH)-catalyzed hydroamination of unactivated olefins, the substantially enhanced reactivity of copper catalysts based on bulky bidentate phosphine ligands originates from the attractive ligand-substrate dispersion interaction. These computational findings are validated by kinetic studies across a range of hydroamination reactions using structurally diverse phosphine ligands, revealing the critical role of bulky P-aryl groups in facilitating this process.

Enantioenriched alcohols found in an array of bioactive natural products and pharmaceutical agents are often synthesized by asymmetric nucleophilic addition to carbonyls. However, this approach generally shows limited functional group compatibility, requiring the use of preformed organometallic reagents in conjunction with a stoichiometric or sub-stoichiometric amount of chiral controller to deliver optically active alcohols. Herein we report a copper-catalyzed strategy for the stereoselective nucleophilic addition of propargylic and other alkyl groups to ketones using easily accessible (poly)unsaturated hydrocarbons as latent carbanion equivalents. Our method features the catalytic generation of highly enantioenriched organocopper intermediates and their subsequent diastereoselective addition to ketones, allowing for the effective construction of highly substituted stereochemical dyads with excellent stereocontrol. Moreover, this process is general, scalable, and occurs at ambient temperature.

Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis, but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We describe a mild and efficient method for the copper-catalyzed allylation of ketones, using widely available 1,3-dienes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of product. A stereochemical model is provided to explain the high diastereo-and enantioselectivity of this process. Finally, this method was applied toward the preparation of an important drug, (R)-Procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.

An orthogonal set of catalyst systems has been developed for the Suzuki-Miyaura coupling of 3,3-disubstituted and 3-monosubstituted allylboronates with (hetero)aryl halides. These methods allow for the highly selective preparation of either the α- or the γ-isomeric coupling product.

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