Automated radial synthesis of organic molecules

Area of Science:

• Organic Chemistry
• Chemical Engineering
• Drug Discovery

Background:

• Automated synthesis platforms streamline molecule preparation, overcoming physical barriers in organic synthesis.
• Current automated multistep syntheses often involve compromises in versatility and equipment usage, relying on iterative or linear processes.
• There is a need for more flexible and efficient automated synthesis methods to access diverse molecular targets.

Purpose of the Study:

• To introduce a new approach for the automated synthesis of small molecules.
• To develop a versatile platform capable of both linear and convergent syntheses without manual reconfiguration.
• To demonstrate the platform's capabilities in optimizing reactions and synthesizing complex molecules and libraries.

Main Methods:

• A novel automated synthesis platform utilizing radially arranged continuous flow modules around a central switching station.
• Sequential, non-simultaneous reactions are combined for multistep processes with variable flow rates and reactor reuse.
• Inline dilutions for concentration variation and a dedicated photochemical module for specific reactions.

Main Results:

• The platform successfully performed automated linear and convergent syntheses without instrument reconfiguration.
• Demonstrated optimization of reaction conditions and multistep synthesis of the anticonvulsant rufinamide.
• Synthesized eighteen compounds from two derivative libraries using diverse reaction pathways and chemistries, including metallaphotoredox couplings.

Conclusions:

• The developed automated synthesis platform offers enhanced versatility and efficiency for small molecule synthesis.
• This approach removes physical barriers, providing unrestricted access to molecules through reproducible chemical processes.
• The system's adaptability facilitates rapid exploration of chemical space and accelerates the synthesis of complex targets and compound libraries.