Development of Multiple Local Computational Models in Retrosynthetic Analysis: Total Synthesis of (-)-Deoxylimonin

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Computational Chemistry

Background:

• Limonoids are a diverse class of natural products with significant biological activities.
• The A,D-seco limonoid subclass presents unique synthetic challenges due to its fragmented ring structure.

Purpose of the Study:

• To establish a de novo synthetic strategy for accessing A,D-seco limonoids.
• To synthesize deoxylimonin, a characteristic member of this subclass.
• To integrate computational modeling into retrosynthetic analysis for efficient route design.

Main Methods:

• Development of a robust synthetic route featuring resilient chemistry.
• Construction of a key carbocyclic tricycle intermediate in eight steps.
• Application of a modern oxy-Michael reaction for ring cleavage and formation.
• Utilization of two local computational models to guide retrosynthetic analysis.

Main Results:

• Successful synthesis of deoxylimonin via the developed de novo strategy.
• Efficient assembly of the core carbocyclic tricycle.
• Demonstration of computational models augmenting transform-based and structure-goal-based retrosynthetic approaches.

Conclusions:

• The developed strategy provides a viable route to A,D-seco limonoids.
• The integration of computational modeling enhances synthetic planning and efficiency.
• This work expands the synthetic accessibility of complex natural product scaffolds.