Total synthesis of the aspercyclides

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Aspercyclides are eleven-membered biaryl ether lactones.
• These compounds can interfere with immunoglobulin E binding to its receptor.
• Developing efficient synthetic routes is crucial for studying their biological activity.

Purpose of the Study:

• To disclose two distinct synthetic strategies for constructing the core structure of aspercyclide family lactones.
• To compare the applicability and limitations of ring-closing olefin metathesis (RCM) and chromium-mediated Nozaki-Hiyama-Kishi (NHK) reactions for synthesizing these strained cyclic ethers.
• To optimize challenging esterification steps involving sterically hindered substrates.

Main Methods:

• Ring-closing olefin metathesis (RCM) for macrocycle formation.
• Chromium-mediated Nozaki-Hiyama-Kishi (NHK) reaction for diastereoselective C-C bond formation.
• Palladium-catalyzed ortho-iodination, copper-catalyzed Ullmann coupling, and Takai-Utimoto olefination for precursor synthesis.
• Esterification using acid fluorides for sterically hindered substrates.

Main Results:

• Both RCM and NHK reactions were employed to forge the core structure of the target lactones.
• The NHK reaction demonstrated broader applicability compared to the RCM approach, which was sensitive to substrate substitution.
• The synthesis of key precursors involved multiple palladium, copper, and olefination steps.
• Acid fluorides were successfully used to overcome challenges in esterifying sterically hindered components, yielding excellent results where other methods failed.

Conclusions:

• Two viable synthetic routes to aspercyclide lactones were established, utilizing RCM and NHK reactions.
• The NHK reaction is presented as a more general and robust method for accessing these strained biaryl ether lactones.
• The study highlights the utility of acid fluorides in challenging esterification reactions within complex molecule synthesis.