Highly Regioselective Oxirane Ring-Opening of a Versatile Epoxypyrrolidine Precursor of New Imino-Sugar-Based Sphingolipid Mimics

An in-depth study of the oxirane ring-opening reaction of a pivotal epoxypyrrolidine is reported. The introduction of various carbon- and heteroatom-centered nucleophiles at C4 has been achieved with high regiocontrol. The structures of the major products were assigned on the basis on an X-ray crystallographic study of six examples. A mechanistic study carried out at the B3LYP/6-31G** level of theory suggested that the steric control of the vinyl substituent was responsible for the regioselectivity. Finally, this approach was used to design and prepare imino-sugar-based sphingolipid mimics. A highly cytotoxic C-octylpyrrolidine is described. This compound was shown to interfere with the metabolism of sphingolipids in murine melanoma cells, notably in inhibiting the production of glucosylceramide. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)