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Total synthesis and complete structural assignment of yaku'amide A
Takefumi Kuranaga1, Yusuke Sesoko, Komei Sakata
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Journal of the American Chemical Society
|March 19, 2013
Summary
Researchers synthesized yaku
Area of Science:
- Marine natural products chemistry
- Organic synthesis
- Medicinal chemistry
Background:
- Yaku'amide A is a potent cytotoxin isolated from a marine sponge.
- Its complete structure, including C4-stereochemistry, was previously undetermined.
- The molecule features unusual dehydro amino acid residues.
Purpose of the Study:
- To achieve the first total synthesis of yaku'amide A.
- To definitively assign the C4-stereochemistry of yaku'amide A.
- To develop novel synthetic methodologies for constructing highly unsaturated peptides.
Main Methods:
- Copper-mediated cross-coupling reactions for E/Z-selective dehydroamino acid synthesis.
- Stepwise peptide elongation from a tetrapeptide intermediate.
- Nuclear Magnetic Resonance (NMR) spectroscopy for stereochemical assignment.
- Biological assays using P388 mouse leukemia cells.
Main Results:
- Successful total synthesis of yaku'amide A and its C4-epimer.
- Complete stereochemical assignment of natural yaku'amide A as the C4S-epimer.
- Demonstration of comparable cytotoxicities between the C4-epimers.
- Development of efficient methods for assembling dehydroamino acid-containing peptides.
Conclusions:
- The synthetic strategies enable access to yaku'amide A analogs.
- The established methodologies facilitate further studies on structure-activity relationships.
- Understanding the role of dehydro amino acid conformation in cytotoxicity is now possible.
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