Nobel Prize in Chemistry 2021 Part 2, Asymmetric Organocatalysis, Enantioselective Organic Chemistry

Explaining more of the science behind the Nobel Prize for Chemistry in 2021 on asymmetric organocatalysis, won by Prof. Benjamin List and Prof. David MacMillan. This video focuses on the use of imidazolidinone catalysts in Diels-Alder reactions that give high enantioselectivity for these cycloadditions (MacMillan). These transformations evolved the organic chemistry techniques that had previously been studied using transition metal catalysis as Lewis acids that can carry chiral ligands.

More Nobel Prize 2021 Chemistry: Proline catalysed aldol reactions (List)
   • Nobel Prize in Chemistry 2021 Part 1,...  

Use of chiral Lewis acids for enantioselective/asymmetric catalysis (CBS reduction):
   • CBS Reduction, Enantioselective Catal...  

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For control in Diels-Alder reactions, it is required that a dienophile with an electron-withdrawing group attached is used in reaction with a diene. This is to assist in molecular orbital energy matching and preventing over-reaction. The electron-withdrawing group is most effective it is part of a pi system that can conjugate effectively with the dienophile pi system, and so lower its LUMO in energy (LUMO = lowest energy molecular orbital). Cycloaddition reactions then proceed in a smooth and predictable way in high diastereoselectivity. These reactions tend to proceed via an endo transition state, rather than an exo transition state, as this one is relatively lower in energy due to additional secondary orbital interactions – a pi stacking interaction between an electron-rich pi system and an electron-poor pi system.

The LUMO of the dienophile can be further lowered in energy by coordination of this electron-withdrawing group to a Lewis acid. The Lewis acid can be used as a catalyst and could be based on either a main group element or a transition metal. Both of these options allow a chiral Lewis acid to be used by embedding an electron-deficient element (such as boron) in a chiral molecule or by employing designed chiral ligand specific for a metal centre and its preferred coordination geometry. If you ensure that the chiral Lewis acid structure is as one enantiomer, you can induce enantioselectivity into your Diels-Alder reaction as the chiral catalyst will be held close to the reacting centres in the transition state for the cycloaddition.

To introduce organocatalysis into the Diels-Alder reaction, it was recognised that you could turn a pi-conjugating electron-withdrawing group on a dienophile such as an aldehyde into an iminium ion which would drastically lower the LUMO energy of the dienophile’s pi system, not least that an iminium ion bears a full positive charge. If the iminium ion is made from a secondary amine that is chiral and has sufficient steric bulk to restrict conformation of molecules, chiral information can be brought very close to the reacting centres in the Diels-Alder transition state. As the iminium ion system lowers the LUMO energy of the dienophile so much, when it is formed the Diels-Alder reaction will be a lot faster than the equivalent reaction with the parent aldehyde-bearing dienophile, and so it is possible to use a secondary amine as an organocatalyst. Pyrollidine has long been used for forming both iminium ions and enamines in organic chemistry for tempering reactivity for selective reactions. The imidazolidinone catalysts developed by the MacMillan group are an evolution of the same idea using an amine catalyst based on a five-membered ring. It is possible to make imidazolidinone ring systems relatively easily from parent amino acids and the first generation catalysts developed for the asymmetric organocatalysis of the Diels-Alder reaction were derived from phenylalanine. Further work by MacMillan and other groups explored how to optimised this type of asymmetric organocatalysis for higher enantioselectivity and yields, but also explored how the same key transition state structure and reactive intermediate could be used in many other nucleophile/electrophile chemistry, such as asymmetric Michael additions and Friedel-Crafts reactions. The organic chemistry in this video explains some of the early successes in this widely expanded area of asymmetric organocatalysis since the turn of the millennium. Small molecule organic catalysts, particularly chiral ones in high optical purity (high ee), tend to be much cheaper and environmentally friendly when compared to their transition metal counterparts and equivalents. The environmental factors have attracted attention in identifying asymmetric organocatalysis as a field of study that has big applications in green chemistry largely as the need to dispose of often toxic and/or environmentally destructive metal waste is completely removed from any synthesis. Additionally, the organocatalysts can often be separated easily from reaction products and recycled whereas transition metal catalysts are often destroyed in work-up.