Generation and analysis of mixed chlorinated/brominated homologs of the halogenated natural product heptachloro-1′-methyl-1,2′-bipyrrole

The 2,3,3′,4,4′,5,5′-heptachloro-1′-methyl-1,2′-bipyrrole (Q1, MBP-79) and further halogenated 1′-methyl-1,2′-bipyrroles (MBPs) are a class of marine natural products repeatedly detected in seafood and marine mammals from all over the world. Only Q1 is currently commercially available as reference standard and the full synthesis of mixed brominated-chlorinated compound is rather complicated. For this reason, synthetic Q1 (240 mg) was transferred into bromine-containing MBPs by UV-irradiation in the presence of bromine. Bromine, which rapidly vanished from the solutions, was re-newed during the reaction in order to generate higher amounts of Br-containing MBPs. A total of ∼150 mg Q1 was transferred after ∼10 min irradiation with high amounts of Br2 to give 30.5 mg BrCl6-MBPs along with lower proportions of Br2Cl5-, Br3Cl4-, Br4Cl3- and traces of Br5Cl2-MBPs. Longer UV-irradiation in the presence of Br2 even allowed for the detection of Br6Cl-MBPs and traces of Br7-MBP. However, this reaction also provided some unknown by-products. A sample stored in the dark and later in in-door light (no UV irradiation) also eliminated Q1 after 76 d in favour of heptahalogenated MBPs with up to three bromine substituents. The irradiation products were separated on silica, and fractions containing only Q1 and BrCl6-MBPs were then further fractionated by non-aqueous RP-HPLC. A pure isolate of the major BrCl6-MBP (∼1.5 mg) was characterized by GC/MS and 13C NMR to be 2-bromo-3,3′,4,4′,5,5′-hexachloro-1-methyl-1,2′-bipyrrole (Br-MBP-75). Partial GC enantioseparation of the axially chiral Br-MBP-75 was achieved on a β-PMCD column. A full enantioseparation was managed by enantioselective HPLC using a NUCLEOCEL DELTA S column. Low amounts of pure BrCl6-MBP enantiomers could be trapped.

► Halogenated methyl-bipyrroles (MBPs) are environmentally relevant natural products.
► We produced mixed brominated-chlorinated MBPs via UV-irradiation of Q1 in the presence of bromine.
► The major bromo-hexachloro-MBP, Br-MBP-75, was isolated and characterized by NMR.
► The chiral Br-MBP-75 standard was enantioseparated by GC and HPLC using chiral stationary phases.
► Harsh UV/bromine conditions allowed to produce traces of heptabromo-MBP from hexachloro-MBP.