Planar chirality due to a polysulfur ring in natural pentathiepin cytotoxins. Implications of planar chirality for enantiospecific biosynthesis and toxicity.

A low-energy pathway for pentathiepin racemization has been found using density functional theory (DFT) calculations. 3-[1,2,3,4,5]pentathiepin-6-yl-propylamine served as a model compound for tunicate-derived pentathiepins. Pentathiepin racemization becomes a low-energy process in the presence of a thiolate ion nucleophile. It is unknown whether the biosynthetic process for pentathiepins is enantiospecific (Bentley, R. (2005) Chem. Soc. Rev. 34, 609) or whether toxicity differs between enantiomers. However, the ease of thiolate ion attack on the polysulfur ring suggests that nucleophiles may induce optical instability on the laboratory time scale. The DFT study predicts that enantiospecific behaviors such as toxicity differences between P- and M-pentathiepins would be difficult to determine experimentally. The computed results fit into a broader picture that nucleophiles assist in ring-opening and equilibration reactions of polysulfanes.