Cytochrome P450s are one of the most versatile oxidases that catalyze significant and unique chemical transformations for the construction of complex structural frameworks during natural product biosynthesis. Here, we discovered a set of P450s, including SdnB, SdnH, SdnF, and SdnE, that cooperatively catalyzes the reshaping of the inert cycloaraneosene framework to form a highly oxidized and rearranged sordarinane architecture. Among them, SdnB is confirmed to be the first P450 (or oxidase) that cleaves the C-C bond of the epoxy residue to yield formyl groups in pairs. SdnF selectively oxidizes one generated formyl group to a carboxyl group and accelerates the final Diels-Alder cyclization to furnish the sordarinane architecture. Our work greatly enriches the enzyme functions of the P450 superfamily, supplies the missing skills of the P450 synthetic toolbox, and supports them as biocatalysts in further applications toward the synthesis of new chemical entities.