Synthesis of enantiomerically pure fluorocyclopentanols

Abstract

Functionalized and optically pure cyclopentanes carrying a single fluorine atom on the ring are usually synthesized through substitution of a fluorine for an hydroxyl residue. Here we describe an approach of total asymmetric synthesis in which the five-membered carbocycle is formed starting from a chiral and linear precursor already containing the fluorine atom. The crucial step in the synthetic sequence is an Intramolecular Nitrile Oxide Cyclization (INOC) reaction. The (2R,3R,E)-2-benzyloxy-3-fluoro-5-hexenal oxime 2 was synthetized in high yield through a modified Pummerer rearrangement of the (2S,3R,R s)- sulfoxide 1. By simple treatment of this oxime with sodium hypochlorite and catalytic amounts of triethylamine, the corresponding nitrile oxide was formed. It underwent a spontaneous intramolecular cyclization reaction to afford isoxazoline 3 as a mixture of epimers at the newly formed carbon stereocentre. Other similar cyclizations will be presented and the diastereoselection of the process will be discussed. ▪