Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin

Area of Science:

• Organic Chemistry
• Process Chemistry
• Flow Chemistry

Background:

• Goniothalamin is a natural product with potential therapeutic applications.
• Efficient and scalable synthetic routes are crucial for its further investigation and development.
• Traditional batch synthesis methods can be time-consuming and challenging to scale.

Purpose of the Study:

• To develop an integrated batch and continuous flow process for the gram-scale synthesis of goniothalamin.
• To optimize key reaction steps, including Grignard addition, acylation, asymmetric allylation, and ring-closing metathesis, in both batch and flow regimes.
• To evaluate the utility of flow chemistry for organometallic processing and reaction telescoping in this synthesis.

Main Methods:

• Telescoped continuous flow Grignard addition followed by acylation for precursor synthesis.
• Asymmetric Brown allylation under continuous flow conditions using (-)-Ipc2B(allyl).
• Ring-closing metathesis explored in batch and flow reactors, including a tube-in-tube reactor for ethylene removal.

Main Results:

• Gram-scale synthesis of a goniothalamin precursor (16) achieved with 7 g·h⁻¹ productivity.
• Asymmetric synthesis yielded an (S)-goniothalamin intermediate with 98% yield and 91.5% enantiomeric excess.
• Optimized flow ring-closing metathesis achieved good yield and selectivity with a residence time of 16 minutes.
• Total synthesis yielded 7.75 g of goniothalamin (1).

Conclusions:

• The developed integrated batch and flow process enables efficient gram-scale synthesis of goniothalamin.
• Flow chemistry proves advantageous for organometallic reactions and reaction telescoping, improving productivity and scalability.
• This approach provides a robust platform for the synthesis of goniothalamin and related compounds.