Total Synthesis of Viridiofungins A and B

Total Synthesis of Viridiofungins A and B

Author: ChemistryViews.org

Viridiofungins A and B (pictured, R = OH for viridiofungin A, R = H for viridiofungin B) are part of a family of bioactive alkyl citrate natural products and were first isolated from a fungus. The compounds feature a fairly long alkyl chain and a citric acid unit and can be challenging to synthesize in a stereoselective manner. Existing syntheses of viridiofungin A have 16 or more steps [1].

Mark A. Rizzacasa, The University of Melbourne, Victoria, Australia, and colleagues have developed a highly stereoselective total synthesis of viridiofungins A and B via a common β-lactone intermediate in 13 steps. The team started from commercially available (S)-(+)-γ-hydroxymethyl-γ-butyrolactone, which was protected and then subjected to a formal [2+2] cycloaddition with di-t-butylacetylene dicarboxylate. The resulting cyclobutene diester underwent an HF-mediated rearrangement to give a bicyclic lactone. This lactone was converted to the desired common alkene-functionalized β-lactone intermediate via a ring-opening, a lactonization, and an alkene isomerization.

The team subjected this intermediate to an olefin cross-metathesis reaction to introduce the side chain of the target compounds. Then, a ring-opening of the β-lactone was used to form the amide unit and introduce the correct aromatic substituent for viridiofungin A or B, and a final deprotection step gave the desired products in high yields. According to the researchers, the stable β-lactone intermediate could also be useful as a precursor for other viridiofungins or their analogues for further studies.


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