Concise Chemoenzymatic Synthesis of Gedunin.

Area of Science:

• Organic Synthesis
• Medicinal Chemistry
• Natural Product Synthesis

Background:

• Limonoids are complex natural products with significant medicinal potential.
• Efficient synthetic routes to intact or ring D-seco limonoids remain challenging.
• Gedunin, a ring D-seco limonoid, exhibits heat shock protein 90 (HSP90) inhibitory activity.

Purpose of the Study:

• To report the first de novo synthesis of the complex ring D-seco limonoid, gedunin.
• To establish a versatile synthetic strategy for accessing oxidized limonoids.

Main Methods:

• A 13-step synthetic sequence was designed and executed.
• Modern catalytic transformations were employed to construct key quaternary centers.
• Biocatalytic oxidation at the C3 position was utilized to introduce a functional handle.

Main Results:

• The first de novo synthesis of gedunin was successfully achieved.
• The synthesis strategy effectively established the complex carbocyclic core and A-ring enone motif.
• The developed methodology provides a pathway to a broader range of oxidized limonoids.

Conclusions:

• The reported synthesis represents a significant advancement in accessing complex limonoids.
• This strategy opens avenues for the exploration of gedunin analogs and related compounds for therapeutic applications.
• The synthetic approach may facilitate the discovery of novel HSP90 inhibitors.