Isolation of Paraphaeoketones: A Plausible Biosynthetic Explanation for Paraphaeolactones via a Benzilic Acid Rearrangement Rather than a Favorskii Rearrangement

Paraphaeoketones A-C (<b>1</b>-<b>3</b>) were isolated from the culture broth of <i>Paraphaeosphaeria</i> sp. KT4192. Their structures and relative configurations were determined using spectroscopic analysis and verified through density functional theory (DFT)-based chemical shift calculations. The absolute configurations of these compounds were determined by comparing the experimental electronic circular dichroism (ECD) spectra with those based on DFT calculations. We also propose a plausible biosynthetic route to <b>1</b>-<b>3</b>. While our prior studies on the isolation and structural elucidation of paraphaeolactones (e.g., <b>4</b>) led us to suggest a Favorskii rearrangement for their biosynthesis, the isolation of <b>2</b> prompted the proposal of an alternative biosynthesis for <b>4</b>, featuring a benzilic acid rearrangement of <b>2</b>. Moreover, an in vitro conversion of <b>2</b> into <b>4</b> was achieved successfully, suggesting that a biosynthetic pathway for paraphaeolactones involving a benzilic acid rearrangement is more plausible than the previously presumed Favorskii rearrangement pathway. Arguments based on DFT calculations for these pathways are also described.