Iodide Enhances\nthe Production of Pseurotin D over\nPseurotin A by Inverting the Preference for the S<sub>N</sub>2 versus\nthe S<sub>N</sub>2′ Product in the Final Nonenzymatic Step

Nonenzymatic\nreactions, though critical in natural product biosynthesis,\nare significantly challenging to control. Adding 3% NaI to the culture\nmedium of <i>Penicillium janczewskii</i> significantly increased\npseurotin D (<b>1</b>) production and decreased pseurotin A\n(<b>2</b>) production. Previously, <b>1</b> and <b>2</b> were suggested to be produced via a nonenzymatic reaction,\nwhere the epoxide at C-10 undergoes S<sub>N</sub>2 (<b>2</b>) or S<sub>N</sub>2′ (<b>1</b>) reactions. We confirmed\nthat <b>1</b> was isolated as a 1:1 mixture of C-13 epimers\nby spectral elucidation via CP3 analysis aided by selective excitation\nNMR methods, which supported that <b>1</b> was produced through\na nonenzymatic S<sub>N</sub>2′ reaction. We propose that NaI\nincreased the ratio of <b>1</b> by causing steric hindrance\nat the C-11 position of the transient intermediate, which makes C-13\nmore preferred in the S<sub>N</sub>2/S<sub>N</sub>2′ competition.