Application Research of Nickel-Catalyzed Asymmetric Hydrogen Alkylation Reaction in the Synthesis of Chiral Fatty Amines and Fatty Alcohols
Research Background and Significance
Chiral fatty amines and fatty alcohols, as important organic structural units, hold irreplaceable value in drug chemistry and natural product synthesis. According to an analysis of global pharmaceutical sales data from 2019, over 50% of the compounds among the top 200 selling drug molecules contain chiral fatty amine or fatty alcohol frameworks. These structures are not only widely present in antibiotics, antitumor drugs, neuropharmaceuticals, etc., but also serve as key intermediates for constructing complex natural product molecules.
Traditional synthetic methods mainly construct such chiral centers through strategies like C-H bond amination/oxidation, asymmetric addition, and asymmetric hydrogenation. However, when target molecules possess two sterically hindered alkyl substituents with similar electronic effects, existing synthetic methods often struggle to achieve high stereoselectivity control. This technical bottleneck severely restricts the efficient synthesis and structural optimization of related drug molecules. Therefore, developing new efficient asymmetric synthesis methods—especially catalytic systems capable of precisely controlling the stereochemistry of similarly hindered groups—has become a significant research direction in contemporary organic synthesis chemistry.
Research Progress and Innovation
In 2016, Professor Fu Yao's research group at University of Science and Technology China made breakthrough progress in nickel-hydrogen catalysis by reporting for the first time a carbon-carbon coupling reaction between alkenes and alkyl/aryl halides under nickel-hydrogen catalytic systems. This pioneering work provided crucial insights for subsequent studies. Building on this foundation, Professor Shu Wei's team at Southern University of Science and Technology systematically developed a new strategy for highly efficient nickel-catalyzed asymmetric hydrogen alkylation reactions.
This catalytic system has several notable advantages: First, it employs inexpensive readily available nickel metal as a catalyst significantly reducing reaction costs; second it uses stable acyl alkenamines or enol esters as substrates avoiding cumbersome steps involving special protecting groups required by traditional methods; most importantly this reaction can construct chiral fatty amine and fatty alcohol derivatives with excellent yields (up to 90%)and outstanding enantioselectivity (up to 98% ee). Relevant research results were published in Nature Communications journal in 2021 (DOI:10.1038/s41467-021-22775-z).
Substrate Applicability Study
Under optimized reaction conditions systematic investigations were conducted on substrate applicability by the research team regarding tertiary alkenamide substrates showing broad applicability within reactions different chain lengths linear alkyl iodides (such as n-butyl,n-hexyl) along with branched-chain alkyl iodides smoothly participated within reactions especially noteworthy is that when heterocyclic structures such as carbazole indole thiophene exist within these alkyl iodides or functional groups including amide ester ether silicon ether halogen still maintained good compatibility during reactions. For secondary alkenamide substrates this catalytic system exhibited excellent performance various aromatic substituents substituted at carbon alpha position(including heteroaromatic) along with other branched substitutions efficiently converted into target products yielding ranges between49%-90% while achieving enantioselectivities reaching80%-96%ee even more excitingly this method successfully realized late-stage modifications on drug molecule structures providing novel tools for medicinal development.
Mechanistic Exploration
Based upon detailed mechanistic experiments alongside prior accumulated studies our team proposed two possible pathways concerning reactions.First pathway involves formation Ni(I)-H active species wherein catalyst precursor generates Ni(I)-H intermediate under influence silane base subsequently coordinates either alkenamide/enol ester forming complexes which undergo stereoselective hydrometalization producing critical aralkynickel intermediates ultimately obtaining desired products via oxidative addition/reductive elimination steps.Second potential route operates through Ni(II)-H intermediate whereupon initial single electron transfer occurs between catalyst precursor/alcoholic iodide generating both aralkyne radicals divalent nickel species followed reductively coordinating afterwards leading same hydrometalization process forming final cycle completion mechanisms offer theoretical basis understanding high stereoselectivity observed throughout processes involved herein .