Total synthesis of pectenotoxin-2

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Marine Natural Products

Background:

• Pectenotoxin-2 (PTX2) is a marine shellfish toxin containing a challenging non-anomeric spiroacetal moiety.
• The selective synthesis of this non-anomeric spiroacetal has been a significant hurdle in PTX2 total synthesis.

Purpose of the Study:

• To achieve the stereoselective total synthesis of Pectenotoxin-2 (PTX2).
• To develop a method for the selective construction of the non-anomeric spiroacetal in PTX2.
• To investigate the cytotoxicity of synthetic PTX2 analogs.

Main Methods:

• Stereoselective total synthesis of PTX2 via isomerization of pectenotoxin-2b (PTX2b).
• Synthesis of PTX2b involving sulfone-mediated assembly of spirocyclic and bicyclic acetals.
• Macrocyclization using ring-closing olefin metathesis.
• Acid-catalyzed isomerization of PTX2b to PTX2 with early termination of dynamic equilibrium.
• Synthesis of [6,6]-spiroacetal pectenotoxin-2c (PTX2c) from PTX2b.

Main Results:

• Successful stereoselective total synthesis of PTX2.
• PTX2 was synthesized by controlled isomerization of PTX2b.
• PTX2b and PTX2c were also synthesized and characterized.
• Cytotoxicity assays revealed the potency order: PTX2 > PTX2b > PTX2c against HepG2 and Caco2 cells.

Conclusions:

• The developed method enables the selective construction of the non-anomeric spiroacetal in PTX2.
• Early termination of the dynamic isomerization process is key to selective PTX2 synthesis.
• Synthetic PTX2 analogs exhibit varying cytotoxic potencies, with PTX2 being the most potent.