Enantioselective Access to Dialkyl Amines and Alcohols via Ni-Catalyzed Reductive Hydroalkylations

Wang, Shan; Zhang, Tianyi; Zhang, Jianxin; Meng, Hua; Chen, Bi-Hong; Shu, Wei

doi:10.21203/rs.3.rs-128934/v1

Cited by 1 publication

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“…Because a chiral dialkyl carbinamine subunit is found in a wide array of bioactive molecules (e.g., Figure A), the development of efficient methods for its synthesis, particularly catalytic and enantioselective processes, is an important objective in synthetic organic chemistry . A variety of approaches have been described to date, each of which has limitations, including the addition of alkyl nucleophiles to imines of aliphatic aldehydes (limited scope with respect to the nucleophile), the reduction/hydrogenation of imines of unsymmetrical dialkylketones (modest enantioselectivity when the alkyl groups are similar) and enamines, − and the hydroamination of olefins (modest regioselectivity for many internal olefins). − After our study was completed, several groups independently demonstrated that nickel-catalyzed asymmetric reductive couplings of olefins and alkyl halides can provide access to protected dialkyl carbinamines. − …”

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confidence: 99%

The Asymmetric Synthesis of Amines via Nickel-Catalyzed Enantioconvergent Substitution Reactions

Yang

Freas

2021

J. Am. Chem. Soc.

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Chiral dialkyl carbinamines are important in fields such as organic chemistry, pharmaceutical chemistry, and biochemistry, serving for example as bioactive molecules, chiral ligands, and chiral catalysts. Unfortunately, most catalytic asymmetric methods for synthesizing dialkyl carbinamines do not provide general access to amines wherein the two alkyl groups are of similar size (e.g., CH 2 R versus CH 2 R 1 ). Herein, we report two mild methods for the catalytic enantioconvergent synthesis of protected dialkyl carbinamines, both of which use a chiral nickel catalyst to couple an alkylzinc reagent (1.1-1.2 equivalents) with a racemic partner, specifically, an α-phthalimido alkyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected α-amino acid. The methods are versatile, providing dialkyl carbinamine derivatives that bear an array of functional groups. For couplings of NHP esters, we further describe a one-pot variant wherein the NHP ester is generated in situ, allowing the generation of enantioenriched protected dialkyl carbinamines in one step from commercially-available amino acid derivatives; we demonstrate the utility of this method by applying it to the efficient catalytic enantioselective synthesis of a range of interesting target molecules.

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