Chiral Vicinal Diamines

Winner: 2024 Organic 91AV Horizon Prize: Robert Robinson Prize in Synthetic Organic 91AV

For the development of asymmetric reductive coupling of imines to form chiral vicinal diamines through the discovery of diboron-enabled [3,3]-sigmatropic rearrangements.

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Chiral Vicinal Diamines is a collaboration between Professor Wenjun Tang’s team at the Shanghai Institute of Organic 91AV and Professor Lung Wa Chung’s team at the Southern University of Science and Technology in Shenzhen, China.

The team has developed a new way to make a special kind of molecule called a ‘chiral vicinal diamine’.

A general, practical, convenient, and enantioselective synthesis of chiral vicinal diamines is developed by chiral diboron-templated asymmetric homocoupling. The method features high enanantioselectivity and diastereoselectivity, a single reaction step from readily available starting materials, mild reaction conditions, and a new reaction mechanism—diboron-participated [3,3]-sigmatropic rearrangement.

A library of chiral vicinal diamines, most otherwise inaccessible, is efficiently built that can be applied as chiral catalysts, building blocks, and materials. In particular, chiral 1,2-diphenylethylenediamine, a widely used chiral auxiliary and ligand, has been produced in metric ton scale by using method, significantly reducing its cost and increasing its availability.

The discovery of this transformation not only facilitates the development and application of chiral vicinal diamines in organic synthesis but also enriches the diboron chemistry and pericyclic reactions.

Fantastic! The work started with a very serendipitous finding and brought the idea of the crazy rearrangement. Then the beautiful calculations from Professor Chung’s group showed its credibility, providing the synthetic group the confidence to further extend its scope and potential. It’s absolutely a team effort and a journey to be further explored. The prize is particularly exciting to the talented graduate students!.

The team

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Dongping Chen, Graduate Student, Shanghai Institute of Organic 91AV, CAS

Xiao-Xuan Chen, Graduate Student, Southern University of Science and Technology

Lung Wa Chung, Professor, Southern University of Science and Technology

Wei Dong, Research Associate, Shanghai Institute of Organic 91AV, CAS

Kaidi Li, Graduate Student, Shanghai Institute of Organic 91AV, CAS

Yaodong Lin, Graduate Student, Shanghai Institute of Organic 91AV, CAS

Wenjun Tang, Research Professor, Shanghai Institute of Organic 91AV, CAS

Guangqing Xu, Research Associate Professor, Shanghai Institute of Organic 91AV, CAS

Ronghua Xu, Graduate Student, Shanghai Institute of Organic 91AV, CAS

Mingkang Zhou, Graduate Student, Shanghai Institute of Organic 91AV, CAS

Qinghai Zhou, Postdoctoral Fellow, Southern University of Science and Technology

Q&A

What was your role within the team?

Mingkang Zhou: I am the developer of diboron chemistry, and under the guidance of predecessors, I have developed the reductive coupling of aldimines and ketimines.

Lung Wa Chung: I am involved in the computational chemistry part, which helps our teams to understand the reaction mechanism and origin of stereoselectivity.

Xiao-Xuan Chen: My role within the team was focused on theoretical computational research. I contributed to understanding the underlying principles and mechanism through systematic DFT studies, providing the insights on uncovering the factors responsible for the excellent enantioselectivity observed in the synthesis of chiral vicinal tetrasubsubstituted diamines.

Qinghai Zhou: Part of computational work. Under the supervision of Professor Chung, calculating the stereoselectivity of reductive coupling of isoquinolines templated by chiral diborons.

Guangqing Xu: Discovered the reductive coupling of isoquinoline templated by bis(pinacolato)diboron, and developed the general systems of reductive coupling of imines.

Mingkang Zhou: How to obtain a stable and high-purity dialdimine starting material has become the greatest challenge. How to obtain a stable and high-purity dialimine starting material has become the greatest challenge.

Lung Wa Chung: Achieving high stereoselectivity to form vicinal tetrasubstituted diamines is very challenging synthetically. The Tang group developed a series of new and functionalised chiral diborons to attain such a goal. Meanwhile, these functionalized chiral diborons can adopt many possible conformations, which poses a challenge for our computational study in order to understand the origin of the stereoselectivity at an atomic resolution.

Kaidi Li: From my perspective, upon recognising the great potential of this approach, we became eager to know its practicality for large-scale synthesis. The original process, commencing from S-Mandelic acid, led to unsatisfactory results, limiting the scope of elaboration and application. After months of efforts, the team moved to a protected mandelic ester, which brought the opportunity for a green and efficient chiral diboron synthesis.

Why is this work so important and exciting?

Xiao-Xuan Chen: This research is groundbreaking due to its introduction of a novel asymmetric synthesis method for vicinal tetrasubstituted diamines, achieving remarkable enantioselectivity and yields, paving the way for diverse applications in creating therapeutic agents and bioactive molecules, and advancing catalysis through the innovative use of chiral diborons, thereby opening up new avenues in chemical reaction processes.

Guangqing Xu: This work was not only valuable for synthetic organic chemistry but also made a breakthrough for pericyclic reaction theory.

Kaidi Li: Over centuries, chemists have utilised chiral amines for the development of biologically active small molecules and the synthesis of chiral ligands, necessitating a general and efficient approach to generate diverse libraries. This chemistry paves the way in this direction, streamlining processes and simplifying endeavours.

Where do you see the biggest impact of this technology/research being?

Mingkang Zhou: It provides a brand-new chiral source and a recyclable synthesis strategy, making the synthesis of chiral diamine-derived catalysts and ligands highly efficient and convenient.

Guangqing Xu: The development of this project provides a practical and highly efficient method for asymmetric synthesis of a wide range of chiral vicinal diamines. This will significantly facilitate the chemistry of chiral vicinal diamines as ligands and building blocks for pharmaceutical and fine chemistry.

What is the importance of collaboration in the chemical sciences?

Xiao-Xuan Chen: Collaboration in the chemical sciences is vital for fostering interdisciplinary research, accelerating innovation, and solving complex problems by combining diverse expertise and resources. It’s the cornerstone of scientific advancement and breakthrough discoveries.

Wenjun Tang: Collaboration makes the impossible a wonder.

What does good research culture look like or mean to you?

Dongping Chen: Freedom, encouragement, support.

Lung Wa Chung: Critical and open-minded thinking; encouraged to overcome challenges; solving problems in unique ways; cross-disciplinary collaboration.

Wenjun Tang: A good research culture should be collaborative, inspiring, communicative, hardworking, and productive.