The ring-closing metathesis of vinyl fluoro- and bromo-containing dienes synthesis of (+-)-deoxygalanthamine

Abstract

Metathesis-based methodology has been developed for the synthesis of a variety of heterocyclic and carbocyclic molecules containing fluorinated double bonds.  The introduction of fluoro-olefins into acyclic and cyclic compounds is a valuable synthetic method and is relevant to the synthesis of fluorine containing biologically significant molecules.  Cyclic sulfamides containing fluoro-olefins, which are novel analogues of potent HIV protease inhibitors have been synthesised, via the ring-closing metathesis reaction.  Competition experiments were designed to compare the reactivity of fluorinated olefins with unfluorinated olefins.  These metathesis reactions showed that fluoro-olefins were less reactive than their unfluorinated analogues reactions in the presence of the ruthenium alkylidene species 4.  The methodology has been used to synthesise various vinyl-fluoride carbocycles and heterocycles in good to excellent yield.  RCM of vinyl bromides was also investigated, and found to proceed efficiently in a few cases.  However, the RCM of vinyl bromides using Grubbs-type catalysts appears to be more limited in scope that the corresponding reactions of vinyl fluorides and vinyl chlorides.  Significant limitations to the bromo-olefins metathesis included formation of 5-membered and 6-membered ring systems.

The synthesis of (±)-deoxygalanthamine has been developed successfully using Mitsunobu reaction to synthesise the precursor for the subsequent enyne ring-closing metathesis. The resulting 1,3-diene cyclised product underwent hydroboration-oxidation in order to control the selectivity of an intramolecular Heck reaction to create the quaternary carbon centre of the galanthamine ring system.

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