Collective Asymmetric Synthesis of Thiosilvatins

Area of Science:

• Natural Product Synthesis
• Medicinal Chemistry
• Organic Chemistry

Background:

• Thiosilvatins are biologically active sulfenylated diketopiperazine natural products known for over 40 years.
• The total synthesis of thiosilvatins has been a long-standing challenge in organic chemistry.

Purpose of the Study:

• To achieve the first collective total synthesis of the parent epidithiodiketopiperazine, (-)-dithiosilvatin, and ten related thiosilvatins.
• To develop and apply novel synthetic methodologies for constructing complex thiosilvatin analogs.

Main Methods:

• Catalytic asymmetric sulfenylation of triketopiperazines to control stereochemistry.
• Diastereoconvergent installation of cis-oriented sulfur atoms.
• Tandem epidisulfide formation and O-prenylation under Mitsunobu conditions.
• Late-stage diversification of bis(methylthio)diketopiperazines.

Main Results:

• Successful synthesis of (-)-dithiosilvatin and ten related thiosilvatins.
• Structural revision of several natural product targets.
• Efficient control of absolute configuration at thioaminal units.
• Mild and effective methods for epidisulfide formation and functionalization.

Conclusions:

• The developed synthetic strategies provide a robust platform for accessing thiosilvatins.
• This work facilitates systematic exploration of the thiosilvatin 3D-pharmacophore.
• Enables the generation of stereochemically pure analogs for biological evaluation.