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CC BY 4.0 · SynOpen 2024; 08(04): 387-400
DOI: 10.1055/a-2501-4247
graphical review

Transition-Metal-Catalyzed Asymmetric Reduction of 2-Pyridine Ketones

Vidhul Vasudevan
,
M S Harishankar
,
Thierry Ollevier  ∗
This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) (Discovery Grant RGPIN-2023-03591), the FRQNT Centre in Green Chemistry and Catalysis (CGCC) Strategic Cluster FRQNT-2020-RS4-265155-CCVC, and Université Laval. V.V and H.M.S. thank MITACS for Globalink Research Innovation award scholarships.
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Abstract

This graphical review provides a concise overview of transition-metal-catalyzed asymmetric reduction of 2-pyridine ketones to produce enantiopure chiral 2-pyridine aryl/alkyl alcohols, which are present in many chiral ligands and pharmaceuticals. Key methods include metal-catalyzed hydrogenation, transfer hydrogenation, and hydrosilylation, with a focus on sustainable catalysts like iron and manganese. This review serves as a foundation for future advancements in sustainable and enantioselective keto group reductions.


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Key words

asymmetric reduction - ketones - transfer hydrogenation - hydrogenation - hydrosilylation - iron catalysis

Biosketches

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Vidhul Vasudevan was born in Kerala, India, and obtained his BS-MS dual degree in chemistry from the Indian Institute of Science Education and Research, Kolkata, India. He was a MITACS Globalink Intern at Université Laval (Québec, Canada) under the supervision of Prof. Thierry Ollevier during the summer of 2023. His research was focused on the development of new bipyridine-based chiral ligands. Currently, he is a Ph.D. student at McGill University (Montréal), Canada.

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Harishankar M. S was born in Kerala, India, and obtained his BS-MS dual degree in chemistry from the Indian Institute of Science Education and Research, Bhopal, India. He was a MITACS Globalink Intern at Université Laval (Québec, Canada) under the supervision of Prof. Thierry Ollevier during the summer of 2023, where he worked on the development of new bipyridine-based chiral ligands.

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Thierry Ollevier was born in Brussels and obtained his B.Sc. (1991) and Ph.D. (1997) at the Université of Namur (Belgium) under A. Krief, and was a research associate at the Université catholique de Louvain (Belgium) under I. E. Markó (1997), a NATO postdoctoral fellow at Stanford University under B. M. Trost (1998–2000), then a postdoctoral fellow at the Université de Montréal under A. B. Charette (2000–2001). After an assistant professor appointment (2001) at Université Laval (Québec, Canada), he became associate professor (2006) and is currently a full professor. Current research in his group aims at designing novel catalysts, developing catalytic reactions, and applying these methods to chemical synthesis. He is active in the areas of iron catalysis, ligand design, asymmetric catalysis, fluorine chemistry, diazo and diazirine chemistry, flow chemistry, and bismuth chemistry. He has published more than 85 papers and 35 encyclopedia articles and book chapters. He served as an Associate Editor of RSC Advances from 2015 to 2022 and was admitted as a Fellow of the Royal Society of Chemistry (2016). After 5 years served as an Advisory Board member of SynOpen, he was appointed as Editor-in-Chief of SynOpen in 2023.

The development of catalytic methods for the asymmetric reduction of keto groups, particularly in 2-pyridine ketones, has garnered considerable interest due to the transformative potential of these reactions in the synthesis of enantiomerically pure compounds. Enantiopure chiral 2-pyridine aryl/alkyl alcohols are not only essential intermediates in creating chiral ligands, such as Bolm’s ligand, but are also foundational in the synthesis of complex, stereochemically defined molecules in fields like pharmaceuticals and materials science. As a result, there has been substantial effort to design catalysts that facilitate these reductions with high enantioselectivity, efficiency, and versatility.

A wide array of catalytic approaches has emerged for the asymmetric reduction of 2-pyridine ketones, utilizing transition metals such as iron, manganese, ruthenium, copper, rhodium, and iridium. These systems often differ significantly in their mechanistic pathways, with some involving direct hydrogenation, others employing transfer hydrogenation, and others relying on hydrosilylation. Each method offers unique advantages, yet also presents challenges related to reaction scope, operational simplicity, cost, scalability, and environmental impact, with green chemistry principles driving much of the recent innovation in this field.

Despite these advancements, there remain open questions and unsolved challenges, particularly in the quest for more sustainable, non-precious metal catalysts and methods that maximize atom economy. Furthermore, the sheer pace of development in this area can sometimes obscure which transformations have reached maturity and which require further optimization or exploration. This graphical review seeks to clarify these developments, providing a structured overview of current catalytic systems for asymmetric reduction of 2-pyridine ketones. By highlighting well-established techniques alongside emerging approaches, it aims to illuminate future directions for research, particularly in the context of eco-friendly synthetic methodologies and the expanding role of iron-based catalysis in asymmetric synthesis.

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Figure 1 Catalytic asymmetric transfer hydrogenation using iridium and iron[1]
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Figure 2 Catalytic asymmetric transfer hydrogenation using iron and rhodium[2]
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Figure 3 Catalytic asymmetric transfer hydrogenation using rhodium and ruthenium[3]
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Figure 4 Ruthenium-catalyzed asymmetric transfer hydrogenation[4]
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Figure 5 Ruthenium-catalyzed asymmetric transfer hydrogenation (cont.)[5]
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Figure 6 Iridium-catalyzed asymmetric hydrogenation[6]
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Figure 7 Catalytic asymmetric hydrogenation using iridium, iron and manganese[7]
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Figure 8 Catalytic asymmetric hydrogenation using manganese, rhodium and ruthenium[8]
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Figure 9 Catalytic asymmetric hydrogenation using ruthenium and other reactions[9]
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Figure 10 Copper-catalyzed asymmetric hydrosilylation[10]
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Figure 11 Catalytic asymmetric hydrosilylation using copper, iron and rhodium[10h] [11]

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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Thierry Ollevier
Département de chimie, Université Laval
1045 avenue de la Médecine, Québec, QC, G1V 0A6
Canada   

Publication History

Received: 08 November 2024

Accepted after revision: 11 December 2024

Accepted Manuscript online:
13 December 2024

Article published online:
19 December 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

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Figure 1 Catalytic asymmetric transfer hydrogenation using iridium and iron[1]
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Figure 2 Catalytic asymmetric transfer hydrogenation using iron and rhodium[2]
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Figure 3 Catalytic asymmetric transfer hydrogenation using rhodium and ruthenium[3]
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Figure 4 Ruthenium-catalyzed asymmetric transfer hydrogenation[4]
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Figure 5 Ruthenium-catalyzed asymmetric transfer hydrogenation (cont.)[5]
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Figure 6 Iridium-catalyzed asymmetric hydrogenation[6]
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Figure 7 Catalytic asymmetric hydrogenation using iridium, iron and manganese[7]
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Figure 8 Catalytic asymmetric hydrogenation using manganese, rhodium and ruthenium[8]
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Figure 9 Catalytic asymmetric hydrogenation using ruthenium and other reactions[9]
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Figure 10 Copper-catalyzed asymmetric hydrosilylation[10]
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Figure 11 Catalytic asymmetric hydrosilylation using copper, iron and rhodium[10h] [11]