Total synthesis of xanthohumol

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Xanthohumol is a prenylated chalcone found in hops, known for its diverse biological activities.
• Efficient and scalable synthetic routes are crucial for accessing xanthohumol for further research and potential therapeutic applications.
• Previous synthetic efforts have faced challenges in controlling regioselectivity and preventing side reactions.

Purpose of the Study:

• To develop a concise and efficient total synthesis of xanthohumol.
• To establish a reliable method for introducing the prenyl group at the para position of the aryl ring.
• To optimize reaction conditions to maximize yield and minimize undesired byproducts.

Main Methods:

• The synthesis commenced with phloracetophenone.
• A key para-Claisen rearrangement was employed to install the prenyl group via a Mitsunobu reaction-derived prenyl ether.
• A Claisen-Schmidt condensation formed the chalcone core, followed by optimized deprotection of methoxymethyl (MOM) ethers.

Main Results:

• The total synthesis of xanthohumol was successfully achieved in six steps.
• An overall yield of 10% was obtained from the starting material, phloracetophenone.
• Optimized acidic deprotection conditions prevented the cyclization of the chalcone to the flavone.

Conclusions:

• This study presents a practical and efficient six-step total synthesis of xanthohumol.
• The developed methodology, particularly the para-Claisen rearrangement and optimized deprotection, offers a robust route to xanthohumol.
• The successful synthesis provides a valuable foundation for exploring xanthohumol's biological properties and developing related analogs.