Two Awarded Chemistry Nobel for Efficient Methods to Make Medicinal Molecules

 

The Swedish Nobel Committee has announced that the 2021 Nobel Prize in Chemistry will be shared by Benjamin List and David W. C. MacMillan for developing new tools to make complex molecules of interest in research and medicinal chemistry.  

The tools are particularly useful in synthesizing molecules that have structures that have what might be called "handedness."  That is like our right hand and our left hand these molecules have variations that seem similar but are actually mirror images of one another.  In chemistry this property is called "chirality" and most molecules important in biological systems have chirality.  In medicine the right handed version of a molecule may be beneficial, but the left-handed version may be harmful.  Methods to make specifically only the one or the other are therefore very valuable.

2021 Nobel Prize

Benjamin List

David W. C. MacMillan

The chiral feature is the relationship between the left hand and the right hand, which can be mirrored but not completely overlapped in space. 19 of the natural 20 amino acids have chiral characteristics. Polypeptides, proteins, and various cysts in the dynamic life process formed by using this as a basic unit have a special spatial fingerprint code, and each is distinguished from the other. Whether the transformation process is possible or not, identify the upper and lower sides of each reaction's potential. In comparison, the development of transition metal asymmetric catalysis has more context. As the first tool for humans to explore asymmetric organic synthesis, from the asymmetric cyclopropanation reported by Nozaki and Noyori to the homogeneous asymmetric catalytic hydrogenation reported by Knowles , To the asymmetric epoxidation reaction reported by Sharpless.

It was not until 2000 that this field was shaped by two important reports:

1. Reported by Professor Benjamin List, Professor Richard A. Lerner, and the late famous synthetic chemist Professor Carlos F. Barbas III, the first case of asymmetric Aldol mediated by a small organic molecule of proline via enamine intermediates The reaction, based on a similar reaction mechanism, uses small molecules to mimic the conversion process catalyzed by enzymes (Hajos-Eder-Sauer-Wiechert reaction)

2. The asymmetric Diels-Alder reaction of a chiral secondary amine via iminium, which was first reported by Professor David WC MacMillan. It is the first conceptually to clarify that "organic catalysis" can be atom-economy and environmentally friendly. A sexual approach to achieve the target reaction, and based on key intermediates, the types of reactions can be broadly expanded.

From the establishment of the concept of "organic catalysis", scientists have gradually clarified its core competitiveness: 1. Generally speaking, it is not sensitive to water and oxygen, and the technical difficulty of use, storage, and amplification is relatively low, and the reaction can be universally adapted based on the catalytic mechanism. Iterative design of types has high predictability; 2. The core framework is generally derived from naturally occurring biogenic pathways, and generally has optically pure properties, and the cost of derivative applications is low, which can facilitate the construction of catalyst libraries; 3. Small molecules generally have low toxicity, natural environment-friendly properties, separation difficulty, and low cost, especially to meet the needs of medicinal chemists. Based on the above consensus, chemists have gradually invested in the exploration of general catalytic models, which of course include the enrichment and improvement of the "enamine" and "iminium" catalytic systems based on secondary amines. With the help of enamine, the α-position of aldehydes and ketones can be achieved. A series of asymmetric functionalization and the carbonyl group of the product is used as the "reaction relay" to realize the transmission of chiral framework information, playing a key chemical synthon to participate in the construction of more complex molecules; with the help of imine ions, unsaturated aldehydes can be realized The asymmetric modification of the β-site of the compound includes the construction of heteroatom chiral center and cyclization modification. In the follow-up development, the asymmetric modification of more distant sites is gradually realized. At present, the catalysis around "amine" (enamine, iminium) is still the largest and most systematic branch in the field of asymmetric catalysis of organic small molecules, and there are still continuous outstanding achievements emerging, including being the founder and expanding The “SOMO catalysis” strategy based on single-electron transfer proposed by Professor David WC MacMillan of the author.

Among the above, proline does not only play the Lewis base catalytic function of the secondary amine, but the carboxylic acid of the side chain also plays the role of activating Brønsted acid, and this later forms another complete organic surrounding the chiral protic acid. Small molecule catalytic systems, including the Mannich-Type reaction by Takahiko Akiyama using chiral phosphoric acid in 2004, and the Aza-Friedel-Crafts alkylation of furan by Masahiro Terada. These two reports are generally considered to be the first works of chiral protic acid catalysis. Benjamin List also has an important participation in this field. In addition to further broadening the universality of classical chiral phosphoric acid, it also proposed the concept of "asymmetric counteranion-directed catalysis (ACDC)" and developed proton acidity. A stronger library of chiral organic acid molecules continues to extend the upper limit of the activation threshold under this mechanism.

From the perspective of drug creation, the core logic lies in the innovation of targets, mechanisms of action, and drug skeletons. Synthetic chemists are exploring and exploring in this range. On the one hand, they analyze the synthetic pathways and methods of active natural product molecules. Combining medicinal chemistry and biology to derive the modification, modification, assembly, and splicing of pharmacodynamic functional groups. Focusing on novel catalytic mechanisms, combined with the design and modification of catalyst frameworks, chemists explore the extension space of inherent synthesis modes, derive the construction paradigm of chiral centers (molecular fragments) containing different heteroatoms, and use this as an index and support for innovative capabilities. The theoretical support of the direction of medicinal chemistry specifically modifies the molecular skeleton of potential drugs and builds a library to link the development of the general direction of life and health. In the corner of asymmetric catalysis of organic small molecules, all members have expectations for the Nobel Prize in Chemistry. If we consider the contribution to the development of the entire field, we imagine that the two professors, Benjamin List and David WC MacMillan, deserve this prize.

Reference:

1. Benjamin List, Richard A. Lerner, Carlos F. Barbas III, J. Am. Chem. Soc. 2000, 122, 2395-2396.

2. Kateri A. Ahrendt, Christopher J. Borths, David W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 4243-4244.

3. Hye-Young Jang, Jun-Bae Hong, David W. C. MacMillan, J. Am. Chem. Soc. 2007, 129, 7004-7005.

4. Takahiko Akiyama, Junji Itoh, Koji Yokota, Kohei Fuchibe, Angew. Chem. Int. Ed. 2004, 43, 1566-1568.

5. Daisuke Uraguchi, Keiichi Sorimachi, Masahiro Terada, J. Am. Chem. Soc. 2004, 126, 11804-11805.

6. Ilija Čorić, Benjamin List, Nature 2012, 483, 315-319.

7. Sébastien Prévost, Nathalie Dupré, Markus Leutzsch, Qinggang Wang, Vijay Wakchaure, Benjamin List, Angew. Chem. Int. Ed. 2014, 53, 8770-8773.

8. Matthew S. Sigman, Eric N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901-4902.

9. Anna G. Wenzel, Eric N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 12964-12965.

10. Yong Huang, Aditya K. Unni, Avinash N. Thadani, Viresh H. Rawal, Nature 2003, 424, 146-146.

11. Sarah E. Reisman, Abigail G. Doyle, Eric N. Jacobsen, J. Am. Chem. Soc. 2008, 130, 7198-7199.

12. Ronald Breslow, J. Am. Chem. Soc. 1958, 80, 3719-3726.