Total synthesis evolution: from structure confirmation to efficient drug discovery routes
Evolving Goals in Total Synthesis:
Once focused on structure confirmation and producing scarce natural products, the field now emphasizes efficiency – shorter, more inventive synthetic routes that inspire new methodologies and drug development.
Technological and Methodological Advances:
Innovations include radical cross-coupling, domino reactions, enzyme cascades, and late-stage diversification strategies, enabling faster access to complex molecules and derivative families.
AI's Emerging Role:
While creativity in route design remains human-driven, machine learning and quantum-informed tools are being developed to predict selectivity and improve computer-aided synthesis planning for complex molecules.
Challenges and Future Outlook:
Despite pharmaceutical interest in complex molecules, funding declines, academic metrics, and regional disparities threaten the sustainability of total synthesis research, raising concerns about training future medicinal chemists.
Emotional Statement and Controversy Hooks:
Jieping Zhu from EPFL in Lausanne, Switzerland, shares his passion for total synthesis, inspired by Stuart Warren's book, 'Organic Synthesis: The Disconnection Approach'. This highlights the emotional connection many scientists have with the field. However, the challenge of funding and academic metrics, particularly in the UK and China, could lead to a decline in total synthesis projects. The question arises: How can we ensure the sustainability of this crucial research and the training of future medicinal chemists?
Natural Products and Their Significance:
Natural products, relatively small molecules with diverse structures, are the result of millions of years of evolution. They offer immense potential for drug development, with around 50% of approved drugs in the EU and US being natural products or derivatives. Voclosporin, derived from a fungus, is an example of a natural product approved for immunosuppressant use.
Training the Next Generation of Medicinal Chemists:
Total synthesis projects provide valuable training for medicinal chemists, offering problem-solving skills and a breadth of experience. Phil Baran from Scripps Research emphasizes the importance of hiring individuals trained in total synthesis, while Jinghan Gui from the Chinese Academy of Sciences highlights the opportunity for students to experience various organic reactions.
Improved Route Planning and Technological Developments:
The goal has evolved from being the first to synthesize a target molecule to creating complex molecules using the shortest route possible. Radical cross-coupling reactions, such as those developed by Baran and Gui, enable unique disconnections and rapid access to complex 3D molecular motifs. These innovations inspire new synthetic methodologies and drug development.
Enzyme-Based Domino Reactions:
Enzymes can be utilized in domino reactions, acting as catalysts to pass molecules from one to another in a factory-like assembly line. This approach is particularly powerful in synthesizing families of molecules, as demonstrated by Mouncey and Goss.
AI Assistance in Natural Product Synthesis:
While creativity in route design remains human-driven, AI tools are being explored to assist in natural product synthesis. Machine learning models can predict site selectivity, preventing chemists from encountering challenges mid-synthesis. Ryan Shenvi uses quantum-mechanical and statistical modeling to improve computer-aided synthesis planning software.
Challenges and Future Concerns:
Despite the field's progress, there are concerns about funding, academic metrics, and regional disparities affecting the sustainability of total synthesis research. The publish-or-perish culture and changing research funding priorities in China and the UK pose challenges for young chemists pursuing total synthesis projects. The future of this crucial research and the training of medicinal chemists is at stake, prompting the question: How can we ensure the continued growth and support of total synthesis in the face of these challenges?
