Chiral Catalyst Breakthrough: Pioneering the Kinetic Resolution of Unactivated Alkenes

Significance 

The isolation of enantioenriched compounds from racemic mixtures is an essential process in the pharmaceuticals, agrochemicals, and fine chemicals industries. Many biologically active compounds, like drugs, exhibit different biological activities based on their enantiomeric form. Therefore, producing compounds with high enantiopurity is essential for ensuring efficacy and safety. Kinetic resolution is a technique used in chemistry to separate enantiomers (mirror-image isomers) in a racemic mixture (a mixture with equal amounts of two enantiomers). This process relies on the difference in reaction rates between the two enantiomers with a chiral catalyst or reagent. In the context of isolating enantioenriched compounds, one enantiomer reacts faster than the other, leading to an increase in the proportion of the slower-reacting enantiomer in the mixture. The method effectively separates and enriches one enantiomer, providing a practical approach to obtain chiral compounds with high enantiopurity, which is valuable in pharmaceutical and chemical industries.

Unactivated alkenes are those that don’t have electron-donating or electron-withdrawing groups near the double bond, making them less reactive compared to activated alkenes. The resolution of these compounds can be more challenging due to their lower reactivity. The resolution process often involves the use of chiral agents or catalysts that can selectively react with one enantiomer over the other. By forming diastereomers, which have different physical properties, the enantiomers can be separated using various techniques such as chromatography, crystallization, or distillation. The development of efficient methods for resolving racemic mixtures of unactivated alkenes is an ongoing area of research in organic chemistry because such method holds significant importance in several fields, particularly in the synthesis of chiral molecules.

In a new study published in Journal Angewandte Chemie International Edition by Hyung-Joon Kang, Changseok Lee, and led by Professor Sungwoo Hong from the Department of Chemistry at Korea Advanced Institute of Science and Technology, the researchers developed a method for the kinetic resolution of α-substituted unconjugated carbonyl alkenes. They utilized a chiral nickel complex to achieve high enantioselectivity in the hydroamination process. The method involved systematic ligand optimization to control enantio-, diastereo-, and regioselectivity. The process was applied to various substrates, demonstrating its efficiency and versatility in preparing chiral compounds with high enantiomeric purity. This approach represents a significant advance in asymmetric catalysis, offering new possibilities for synthesizing complex chiral molecules.

To elaborate, Initially, the team tested the hydroamination reaction without a chiral ligand, which resulted in no reaction progress, highlighting the necessity of a chiral catalyst. They started with a phenyl bisoxazoline ligand (L1) with a 4-tert-butyl benzyl sidearm. The reaction yielded the product with unproductive diastereoselectivity, indicating a need for further ligand refinement. Subsequent trials with different sidearm modifications (L2 to L6) showed varying degrees of selectivity, demonstrating the significant impact of the ligand structure on the reaction outcome. The researchers hypothesized that the core structure of the bisoxazoline ligand was critical. They experimented with dimethyl-substituted ligands (L4 to L7), finding that an indane core-based bisoxazoline (L7) improved diastereoselectivity. A series of ligands with modified sidearms (L8 to L13) were tested. The 3,5-tert-butyl benzyl sidearm (L10) was found to dramatically enhance the kinetic resolution, yielding the desired product with excellent enantio-, diastereo-, and regioselectivity. The team tested different phenyl substituents on the enamide substrates. They found that a wide range of functional groups were compatible, enabling access to various enantioenriched syn-β-amino acid derivatives and unconjugated carbonyl olefins. Alkenes with various α-substituents were tested, including ethyl, isopropyl, and other functional groups. This demonstrated the method’s flexibility and broad application potential.

The researchers explored different amine coupling partners, including complex pharmaceutical agents like paroxetine and duloxetine. This demonstrated the method’s utility in late-stage functionalization of drug molecules. These experiments were conducted to ascertain the hydride source. The use of deuterated silane (Ph2SiD2) resulted in the incorporation of deuterium into the product, confirming the silane’s role as the hydride donor. The team monitored the reaction over time to understand the kinetic resolution process. They found that the (S)-enantiomer of the substrate preferentially reacted, with increasing enantiomeric excess in the unreacted (R)-enamide. By using a pure (S)-enamide and its reaction with both L10 and its enantiomer (ent-L10), they demonstrated the importance of matching the chirality of the ligand with the substrate for effective kinetic resolution. The authors conducted computational studies to gain insight into the transition state structures and the energy barriers of the migratory insertion step. These studies corroborated the experimental findings on chiral recognition and reaction dynamics.

The innovation lies in the unique architecture of the chiral nickel complex used, which enables excellent kinetic resolution efficiency and enantioselective C-N bond construction. The authors detailed how their approach allows for the practical and versatile synthesis of various chiral compounds with high enantiomeric purity. The team conducted extensive studies to optimize the process, including exploring the impact of different ligands and reaction conditions. Their findings demonstrate a significant advance in enantioselective catalysis, offering a new paradigm for asymmetric hydroamination of unactivated alkenes. The new method’s potential for wide application in the synthesis of value-added chiral compounds is especially noteworthy for its implications in medicinal chemistry and the broader chemical industry.

The series of experiments conducted by Professor Hong and his team convincingly demonstrated the efficacy and versatility of their nickel-catalyzed kinetic resolution method. The research work successfully identified the optimal ligand structure, explored the broad scope of the reaction with various substrates, and provided detailed mechanistic insights through both experimental and computational means. The findings represent a significant advance in asymmetric catalysis, with potential applications in the synthesis of complex, chiral pharmaceutical and chemical products.

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About the author

Sungwoo Hong is a Professor at the Department of Chemistry at Korea Advanced Institute of Science and Technology (KAIST, Korea) and an Associate Director of the Center for Catalytic Hydrocarbon Functionalizations at the Institute for Basic Science (IBS). He graduated from Seoul National University (Korea), where he gained his BS and MS degrees. He then went on to Pennsylvania State University for his PhD program. After he had finished his postdoctoral course at Harvard University, under the supervision of Prof. E. J. Corey, he joined GlaxoSmithKline (GSK, USA) as a Principal Scientist. In 2009, he started independent work at KAIST. His research interests are in the field of development of new reactions and synthesis, medicinal chemistry and bioorganic chemistry.

About the author

Changseok Lee earned his BS degree in Chemistry from the Gwangju Institute of Science and Technology (GIST) in 2018. Subsequently, he relocated to the Korea Advanced Institute of Science and Technology (KAIST) to pursue his doctoral studies under the supervision of Professor Sungwoo Hong. In 2023, he successfully completed his doctoral program and proceeded to take on a postdoctoral research position at the Institute for Basic Science (IBS). His research focuses on regioselective hydrofunctionalization of alkenes through nickel catalysis.

About the author

Hyung-Joon Kang was born in Seoul, South Korea, and earned his B.Sc. degree in Chemistry from Carleton University. He continued his graduate studies at Hanyang University, obtaining his M.Sc. degree in 2021 under the guidance of Professor C.-G. Cho. Since September 2021, he has been pursuing his Ph.D. under the supervision of Professor Sungwoo Hong at Korea Advanced Institute of Science and Technology (KAIST). His research primarily focuses on developing innovative synthetic methodologies through the application of metal-hydride catalysis.

Reference

Kang HJ, Lee C, Hong S. Nickel-Catalyzed Kinetic Resolution of Racemic Unactivated Alkenes via Enantio-, Diastereo-, and Regioselective Hydroamination. Angew Chem Int Ed Engl. 2023 ;62(24):e202305042. doi: 10.1002/anie.202305042.

Go to Angew Chem Int Ed Engl.

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