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

Abstract

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 Br 2 to give 30.5 mg BrCl 6-MBPs along with lower proportions of Br 2Cl 5-, Br 3Cl 4-, Br 4Cl 3- and traces of Br 5Cl 2-MBPs. Longer UV-irradiation in the presence of Br 2 even allowed for the detection of Br 6Cl-MBPs and traces of Br 7-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 BrCl 6-MBPs were then further fractionated by non-aqueous RP-HPLC. A pure isolate of the major BrCl 6-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 BrCl 6-MBP enantiomers could be trapped.