Enantioselective Hydrogenation of Olefins: Introduction to Asymmetric Catalysis

Summary

This video script delves into the challenges and breakthroughs in the synthesis of chiral molecules, specifically focusing on the development of catalytic enantioselective reactions in the 1980s. It highlights the contributions of chemists William Knowles and Ryoji Noyori in enantioselective alkene hydrogenation, leading to significant advancements in asymmetric synthesis. The script also explores the role of chiral phosphine ligands and metal-ligand complexes in achieving high enantioselectivity, with real-world applications in the pharmaceutical industry, such as the synthesis of L-DOPA and Sitagliptin. The overall progress in catalytic hydrogenation methods has revolutionized organic chemistry, enabling efficient and sustainable production of fine chemicals and drugs.

Takeaways

• 😀 Chirality and stereospecificity are crucial for synthesizing organic products with chiral centers.
• 😀 Synthesizing chiral molecules in enantiomerically pure form using a catalytic amount of chiral material is a challenging task.
• 😀 Before 1980, synthesis of chiral molecules involved targeting racemates and separating enantiomers or using stoichiometric amounts of chiral inducers.
• 😀 Major breakthroughs in enantioselective reactions in the 1980s were recognized with Nobel Prizes in 2001, with one of the key advances being enantioselective hydrogenation.
• 😀 Enantioselective hydrogenation was developed by William Knowles and Ryoji Noyori using rhodium catalysts and chiral ligands, which enabled the synthesis of chiral molecules efficiently.
• 😀 The alkene to be hydrogenated must be prochiral, meaning it can become chiral after the hydrogenation reaction.
• 😀 The concept of 're' and 'si' faces explains how hydrogenation can result in different stereochemistry based on the face of the alkene attacked.
• 😀 The introduction of chiral ligands to metal catalysts, such as rhodium, enables selective formation of one enantiomer over the other, leading to enantiomeric excess.
• 😀 Tertiary phosphines are configurationally stable and can be used as chiral ligands without worrying about inversion under mild conditions.
• 😀 The use of chiral bidentate phosphines like (R,R)-diPAMP allowed Knowles to achieve a high enantiomeric ratio (97.5:2.5) for the hydrogenation of dehydroamino acid A, which was important for synthesizing L-DOPA for Parkinson’s disease treatment.
• 😀 Noyori popularized BINAP ligands with ruthenium catalysts, leading to highly efficient enantioselective hydrogenations, such as the synthesis of Naproxen.
• 😀 Over the last 40 years, the development of chiral phosphine ligands has expanded, enabling effective enantioselective hydrogenations for various fine chemicals and drugs like Sitagliptin.

Q & A

What is the main challenge in synthesizing chiral molecules with chiral centers?

The main challenge in synthesizing chiral molecules with chiral centers is achieving enantiomerically pure products using only a catalytic amount of chiral material. This is difficult due to the need for precise control over the stereochemistry of the products.

How were chiral molecules synthesized before 1980?

Before 1980, chiral molecules were often synthesized by targeting the racemate and then painstakingly separating the enantiomers, or by using stoichiometric amounts of chiral inducers such as templates or resolving agents.

What are the two major breakthroughs in catalytic enantioselective reactions that were recognized with Nobel prizes in 2001?

The two major breakthroughs were in the areas of enantioselective alkene hydrogenation and epoxidation reactions. The Nobel prizes recognized the contributions of William Knowles and Ryoji Noyori for their work in enantioselective hydrogenation.

What does the term 'prochiral' mean in asymmetric synthesis?

A 'prochiral' molecule is one that is not chiral on its own but can become chiral upon undergoing a chemical reaction. For example, an alkene that can form a chiral center upon hydrogenation is considered prochiral.

How do the 're' and 'si' faces of an alkene relate to its hydrogenation?

The 're' face refers to the top face of a planar alkene that leads to the R configuration at the newly created stereogenic center, while the 'si' face refers to the bottom face that leads to the S configuration upon hydrogenation.

Why is hydrogenation of prochiral alkenes not a simple process?

Hydrogenation of prochiral alkenes is not simple because it requires selective coordination of the alkene to a metal catalyst, and the addition of hydrogen must occur in a stereospecific manner, which can be influenced by ligands attached to the metal.

How did William Knowles use chiral ligands to improve enantioselective hydrogenation?

William Knowles used chiral ligands, such as chiral phosphines, in metal-ligand complexes to introduce chirality into the hydrogenation process. By replacing triphenylphosphine with a chiral ligand, he was able to selectively produce one enantiomer over the other.

What is the significance of Knowles’s work with (R,R)-diPAMP ligand?

Knowles’s work with the (R,R)-diPAMP ligand allowed him to achieve an enantiomeric ratio of 97.5:2.5 in favor of the desired S enantiomer, which was crucial for the commercial production of the Parkinson’s disease drug L-DOPA.

What is the difference between chiral phosphines and BINAP-style ligands used by Noyori?

Chiral phosphines are complex to produce and are used in asymmetric synthesis, while BINAP-style ligands, developed by Noyori, are simpler to resolve and have an axis of chirality. BINAP ligands are particularly useful in catalytic hydrogenation reactions due to their stability and high selectivity.

How has enantioselective catalytic hydrogenation been applied in the pharmaceutical industry?

Enantioselective catalytic hydrogenation has been widely applied in the pharmaceutical industry to produce enantiomerically pure drugs. For example, the anti-diabetic drug Sitagliptin was produced using rhodium-catalyzed hydrogenation to control stereochemistry at a specific center.