Dichloromethyl-Containing Derivatives from <i>Streptomyces agglomeratus</i> 5-2-6, a Soil Bacterium Isolated from the Qinghai–Tibet Plateau

Six novel dichloromethyl-containing polyketides (<b>1</b>-<b>6</b>), including four pyranone analogs (<b>1</b>-<b>4</b>) and two furanone isomers (<b>5</b>, <b>6</b>), were isolated from <i>Streptomyces agglomeratus</i> 5-2-6, which was obtained from the Qinghai-Tibet Plateau, China. Additionally, two new linear dichloromethyl compounds (<b>7</b>, <b>8</b>) were obtained via heterologous expression of <i>agg(A-K)</i> in <i>Streptomyces coelicolor</i> M1152. The structures and absolute configurations of these compounds were primarily elucidated via high-resolution ESIMS, NMR, Mo₂(OAc)₄-induced electronic circular dichroism, and application of the modified Mosher's method. Notably, <b>1</b>-<b>6</b> feature a dichloromethyl moiety, which is reported for the first time in pyranone- and furanone-type natural products. Furthermore, the results of in vivo gene deletion, isotope labeling, and in vitro enzyme reaction experiments revealed a rare single-component flavin-dependent halogenase, AggA, which catalyzes the dichlorination of activated sp³-methylene groups.