Polybrominated aromatics, such as polybrominated diphenyl ethers (PBDEs) and their derivatives dibenzo-p-dioxins have attracted attention due to their exceptional toxicity. The origin of such compounds in the marine environment has been ambiguous because some PBDEs and their derivatives have been shown to be natural products while the majority of PBDEs are produced industrially as flame retardants. Recently isolated from Pseudoalteromonas collected from nudibranchs, 2,3,5,7-tetrabromobenzofuro[3,2-b]pyrrole (TBFP), a polybrominated aromatic metabolite, has shown anti-MRSA (methicillin resistant Staphylococcus aureus) activities and possesses 3-phenoxypyrrole ether linkage similar to that of dibenzo-p-dioxins. To elucidate TBFP’s biogenesis and to provide a facile access to this anti-MRSA compound with a novel scaffold, a biocatalytic synthesis of TBFP was pursued. To this end, the putative biosynthetic precursor for TBFP, pentabromopsuedilin (PBP) was synthesized in two-steps utilizing the MIDA boronate ester Suzuki-Miyaura coupling. Cytochrome P450 is a ubiquitous enzyme with remarkably diverse catalytic activities and they have been the target of many directed evolution studies for innovative chemistries. The bacterial cytochrome P450 enzyme involved in the biosynthesis of PBP is being engineered to catalyze the intramolecular Ullmann-type coupling necessary for conversion of PBP to TBFP through a substrate-walking strategy. This enzyme is under further investigation for its applicability in the synthesis of other medicinally important natural products where it is challenging to form an aromatic linkage by conventional synthetic means.

Aromatic natural product synthesis through directed evolution of marine bacterial cytochrome P450

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