Total synthesis and structural confirmation of (+)-longicin

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Acetogenins are a class of natural products with potential biological activities.
• Mono-THF-acetogenins represent a specific subclass with a tetrahydrofuran ring.
• The total synthesis of complex natural products like (+)-longicin is crucial for structure-activity relationship studies.

Purpose of the Study:

• To achieve the first stereocontrolled total synthesis of (+)-longicin.
• To develop novel synthetic strategies applicable to acetogenin-type structures.
• To explore the utility of chiral pool starting materials and new reactions in complex molecule synthesis.

Main Methods:

• Utilized d- and l-glutamic acids as chiral building blocks (chirons).
• Employed Grubbs' ring-closing metathesis (RCM) reaction for chain elongation.
• Developed a new protocol for the incorporation of a butenolide moiety.

Main Results:

• Successfully synthesized (+)-longicin with defined stereochemistry.
• Demonstrated the effectiveness of glutamic acid derivatives as chirons for stereocenter installation.
• Showcased Grubbs' RCM as a viable strategy for constructing acetogenin backbones.
• Established a new method for butenolide ring formation.

Conclusions:

• The described synthetic route provides efficient access to (+)-longicin.
• The employed strategies offer a versatile platform for the synthesis of other acetogenins.
• This work contributes to the field of natural product synthesis and medicinal chemistry.