Total Synthesis of Morusalisin A

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Morusalisin A is a nonclassical mulberry Diels-Alder-type adduct (MDAA) featuring a unique tricyclic skeleton.
• MDAAs are a class of natural products with potential biological activities, often synthesized via intermolecular Diels-Alder reactions.

Purpose of the Study:

• To report the first total synthesis of morusalisin A.
• To explore the application of intramolecular Diels-Alder (IMDA) strategies in synthesizing MDAAs.

Main Methods:

• A nine-step synthesis starting from commercially available 2,4,6-trihydroxybenzaldehyde.
• Utilized a stereoselective intramolecular Diels-Alder (IMDA) reaction of a benzo-tethered butadienyl cinnamate.
• Employed a strategic ortho-protecting group on the diene moiety to control IMDA reactivity and stereochemistry.

Main Results:

• Successfully synthesized morusalisin A with an overall yield of 7.3%.
• Efficiently constructed the tricyclic tetrahydro-6H-benzo[c]chromen-6-one core with three contiguous stereogenic centers via the IMDA reaction.
• Demonstrated the pivotal role of the protecting group in accommodating the IMDA and controlling stereochemical outcomes.

Conclusions:

• The developed synthetic route provides the first total synthesis of morusalisin A.
• The study highlights the utility of IMDA reactions in constructing complex tricyclic skeletons found in MDAAs.
• This approach is expected to broaden the application of IMDA strategies for synthesizing other challenging MDAAs.