Microfluidic light-driven synthesis of tetracyclic molecular architectures

Area of Science:

• Organic Synthesis
• Photochemistry
• Medicinal Chemistry

Background:

• Tetracyclic scaffolds are crucial pharmacophores in drug discovery.
• Efficient and diastereoselective synthesis of these cores remains a challenge.
• Photoenol chemistry offers a novel route to complex molecular architectures.

Purpose of the Study:

• To develop an effective synthetic method for directly assembling highly functionalized tetracyclic pharmacophoric cores.
• To explore the utility of photoenol intermediates in cycloaddition reactions for constructing complex molecules.
• To demonstrate the scalability and broad applicability of the developed synthetic strategy.

Main Methods:

• Utilized coumarins and chromones as starting materials.
• Employed light-generated photoenol intermediates in [4 + 2] cycloaddition reactions.
• Conducted reactions within a microfluidic photoreactor (MFP) for enhanced control and efficiency.
• Scaled up the reaction using a parallel setup.

Main Results:

• Achieved high yields (up to >98%) in the synthesis of tetracyclic cores.
• Demonstrated virtually complete diastereocontrol (>20:1 dr) in the cycloaddition reactions.
• Successfully scaled the process to produce 948 mg of product over 14 hours.
• Showcased the versatility of the tetracyclic scaffold through subsequent functionalization.

Conclusions:

• The developed method provides an effective and diastereoselective route to highly functionalized tetracyclic pharmacophores.
• The use of microfluidic photoreactors enables efficient and scalable synthesis with excellent stereochemical control.
• The accessible tetracyclic scaffolds serve as valuable precursors for biologically active molecules, advancing drug discovery efforts.