Total synthesis of (+)-madangamine D

Area of Science:

• Marine Natural Products Chemistry
• Organic Synthesis
• Medicinal Chemistry

Background:

• Madangamines are a class of bioactive alkaloids isolated from marine sponges.
• These compounds possess a unique and unprecedented diazapentacyclic skeletal structure.
• The biological activities and structural complexity of madangamines necessitate synthetic exploration.

Purpose of the Study:

• To achieve the first enantioselective total synthesis of madangamine D.
• To establish a synthetic route for accessing the madangamine alkaloid family.
• To confirm the absolute configuration of madangamine D and related compounds.

Main Methods:

• Utilized a phenylglycinol-derived lactam as an enantiomeric scaffold.
• Employed stereoselective methods for the construction of the diazatricyclic ABC core.
• Developed strategies for the subsequent assembly of peripheral macrocyclic rings.

Main Results:

• Successfully accomplished the enantioselective total synthesis of madangamine D.
• Provided the first pure sample of madangamine D.
• Confirmed the absolute configuration of the madangamine alkaloid family.

Conclusions:

• The total synthesis validates the proposed structure and absolute configuration of madangamine D.
• This synthetic achievement opens avenues for the exploration of other madangamine analogs.
• The established synthetic methodology can be applied to the broader class of marine sponge alkaloids.