Exploring the Nonenzymatic Origin of Duclauxin-like Natural Products

Chemical-biological efforts to increase the diversity of duclauxin (<b>1</b>)-like molecules for medicinal chemistry purposes unveiled the reactivity of duclauxin (<b>1</b>) toward amines and alcohols. To expand the compound class, a semisynthetic strategy conjugating amines to duclauxin (<b>1</b>) was employed. Insights gained from this approach led to the hypothesis that certain duclauxin-like "natural products" such as talaromycesone B (<b>2</b>), bacillisporin G (<b>3</b>), xenoclauxin (<b>4</b>), bacillisporins F (<b>5</b>/<b>6</b>), bacillisporins J (<b>8</b>/<b>9</b>), bacillisporins I (<b>12</b>/<b>13</b>), and verruculosin A (<b>38</b>) may be isolation artifacts rather than enzymatic products. Further experimentation, involving adsorption of <b>1</b> onto silica gel, resulted in the production of <b>2</b>-<b>6</b>. To gain insights into the conditions that generate such molecules, one-step reactions under mild conditions were set. Outcomes from both experiments confirmed that duclauxin-like molecules are generated via nonenzymatic reactions. This article presents analytical evidence, indicating that these molecules originate from <b>1</b>, with the epimeric mixture of bacillisporins J (<b>8</b> and <b>9</b>) acting as the primary intermediate.