Function-Oriented Synthesis toward Peloruside A Analogues.

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Peloruside A is a complex natural product with potential anticancer properties.
• Developing efficient synthetic routes to peloruside A and its analogues is crucial for further biological evaluation and drug discovery.

Purpose of the Study:

• To develop a convergent and rapid synthesis of novel C2,C3-unsaturated, C11,C13-keto-enol macrocycles featuring the peloruside A skeleton.
• To establish a versatile platform for generating diverse peloruside A analogues.
• To evaluate the antiproliferative activity of synthesized analogues.

Main Methods:

• A four-fragment synthetic strategy was employed.
• Two aldol-type couplings utilizing TES-diazoacetone as a central building block were performed.
• A late-stage ring-closing metathesis was utilized for macrocyclization.

Main Results:

• The synthesis successfully yielded original unsaturated macrocycles with the peloruside A core structure.
• The developed strategy allowed for the creation of peloruside A analogues with high diversity.
• Enantiopure analogue 18ab demonstrated antiproliferative activity in the low micromolar range against NCI and MCF7 tumor cell lines.

Conclusions:

• A rapid and convergent synthetic route to peloruside A macrocycles has been established.
• The synthesized macrocycles serve as valuable platforms for accessing diverse peloruside A analogues.
• The identified antiproliferative activity of analogue 18ab warrants further investigation for potential therapeutic applications in oncology.