Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines

Enantiopure aliphatic amines are frequently encountered as chiral auxiliaries and synthetic intermediates for bioactive compounds. We report a mild nickel-catalyzed asymmetric reductive hydroalkylation to convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives.

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Chiral amines are important chiral auxiliaries and key synthetic intermediates of pharmaceuticals and natural products. More than 30% of the top 200 drugs by retail sales in 2019 contain chiral amine structure. Countless efforts have been devoted to the development of the efficient and convenient synthesis of chiral amines. And great achievements have been made in the fields of imine or enamine hydrogenation, imine alkylation, C-H amination, and hydroamination of alkenes.

 In our recent work published in Nature Communications (2021, 12, 1313; DOI: 10.1038/s41467-021-21600-x), we report an alternative strategy to prepare chiral aliphatic amines, namely, nickel catalyzed asymmetric reductive hydroalkylation of enamides and enecarbamates with alkyl halides. This method can supplement the shortcomings of conventional synthesis methods in the synthesis of dialkyl substituted chiral aliphatic amines.


Our story began with a discovery in 2016, which was inspired by the Cu-H catalyzed hydroamination developed by Prof. Buchwald (MIT), Prof. Miura and Prof. Hirano (Osaka University). Under the guidance of Prof. Yao Fu (University of Science and Technology of China) and Prof. Lei Liu (Tsinghua University), we realized a nickel-catalyzed reductive olefin hydrocarbonation, in which alkenes were used as alkylmetallic equivalents. Our reaction enables the C(sp2)–C(sp3) and C(sp3)–C(sp3) bond formation with simplified synthesis steps, enriched substrate scope, and improved functional group compatibility, which seems to be an attractive complement to traditional electrophile-nucleophile cross-coupling reactions using alkyl organometallic reagents. (Nat. Commun. 2016, 7, 11129; Chem. Eur. J. 2016, 22, 11161)


Under this background, we attempt to realize an asymmetric version of reductive olefin hydrocarbonation, which combines the great achievements in enantioconvergent radical coupling (G. Fu at Caltech made historic contributions in this field) with our “reductive olefin hydrocarbonation” concept. We are delighted to achieve the reductive hydroalkylation of olefins with α- phosphorus or sulfur alkyl electrophiles to prepare enantioenriched phosphonates, alkyldiarylphosphine oxides, sulfonamides, and sulfones. (J. Am. Chem. Soc. 2020, 142, 214) To the best of our knowledge, it was the first time for a phosphorus-containing group to react as an auxiliary group in asymmetric radical coupling. Our method could be used for the synthesis of antimalarial drug Fosmidomycin analog and ligand DPPPe analog.


In our recently published work, we report the asymmetric reductive hydroalkylation of enamides and enecarbamates with alkyl halides. In this reaction, enamides and alkyl halides, which are chemically stable and easy to obtain, are used as raw materials to prepare protected chiral aliphatic amines with high enantioselectivity. This reaction is competent for the efficient synthesis and modification of a variety of natural products and drug molecules. This reaction was used for the total synthesis of alkaloids, such as coniine and coniceine. We also used this method for the synthesis of various isotope- or fluorine-labeled pharmaceutical agents, such as trifluoromethyl-labeled Carmoterol, fluorine-labeled Lisdexamfetamine, and Tamsulosin. Besides, the asymmetric reductive hydroalkylation of enamides with α-haloboronates can be realized to prepare β-aminoboronates containing two chiral centers with high enantioselectivity and adequate diastereoselectivity. In combination with the conversion of alkyl boronates (e.g., oxidation, arylation, etc.), our method will be helpful for the synthesis of chiral amines with highly complex structures. With the help of mechanism experiments, we demonstrated that syn-addition of Ni-H across double bonds was the enantio-determining step.

 Our study provides a new strategy for the modular synthesis of chiral aliphatic amines through the nickel-catalyzed alkyl-alkyl coupling. Our reaction enables the synthesis of chiral amine-containing drug molecules, natural products, and nitrogen-containing complex chiral molecules, and maybe a useful supplement to the conventional synthetic strategies of chiral amines.

 Finally, I want to explain an issue. My friends asked me that “How to define ‘reductive’ hydrocarbonation in the titles of your papers?” “Are there ‘oxidative’ or ‘redox-neutral’ hydrocarbonation reactions?” I do think “reductive” is necessary to describe the reductive conditions used in our catalytic system. Many reported examples do not emphasize but indeed “redox-neutral” hydrocarbonation. Please see (1) “Linear-Selective Hydroarylation of Unactivated Terminal and Internal Olefins with Trifluoromethyl-Substituted Arenes” reported by Hartwig and co-workers (J. Am. Chem. Soc. 2014, 136, 13098); (2) “Ligand-Enabled Ni-Catalyzed Enantioselective Hydroarylation of Styrenes and 1,3-Dienes with Arylboronic Acids” reported by Zhou and co-workers (CCS Chem. 2019, 1, 328). Considering these reasons, we insist on the concept of “reductive hydrocarbonation”.

Xi Lu

Professor, University of Science and Technology of China