Iodide Enhances the Production of Pseurotin D over Pseurotin A by Inverting the Preference for the S_N2 versus the S_N2′ Product in the Final Nonenzymatic Step

Nonenzymatic reactions, though critical in natural product biosynthesis, are significantly challenging to control. Adding 3% NaI to the culture medium of <i>Penicillium janczewskii</i> significantly increased pseurotin D (<b>1</b>) production and decreased pseurotin A (<b>2</b>) production. Previously, <b>1</b> and <b>2</b> were suggested to be produced via a nonenzymatic reaction, where the epoxide at C-10 undergoes S_N2 (<b>2</b>) or S_N2' (<b>1</b>) reactions. We confirmed that <b>1</b> was isolated as a 1:1 mixture of C-13 epimers by spectral elucidation via CP3 analysis aided by selective excitation NMR methods, which supported that <b>1</b> was produced through a nonenzymatic S_N2' reaction. We propose that NaI increased the ratio of <b>1</b> by causing steric hindrance at the C-11 position of the transient intermediate, which makes C-13 more preferred in the S_N2/S_N2' competition.