Development of a novel geminal-difluorination method and its application in the synthesis of 18F-labeled fatty acid analogues as potential myocardial imaging agents

An efficient two-step fluorination procedure for transforming a ketone or aldehyde to the corresponding gem-difluoro compound has been developed. The gem-difluoro compounds can be prepared by first forming the corresponding 1,3-dithiolane followed by reaction with 1,3-dibromo-5,5-dimethylhydantoin and pyridinium poly(hydrogen fluoride). The reaction requires 2 equivalents of Br+ and appears to proceed through a sequence of two bromosulfonium ions that open and cleave, respectively, to sulfur- and fluorine-stabilized carbocations that are trapped by fluoride ion. A convenient, general synthetic route to functionalized fatty acids has been developed and utilized in the synthesis of [16-18F],6,6-trifluorohexadecanoic acid and [16-18F]7,7-trifluorohexadecanoic acid as potential myocardial imaging agents. Corey's 2-lithio-1,3-dithiane methodology was employed both to link two terminally difunctionalized carbon chains, thereby producing the fatty acid precursor, and to introduce the 1,3-dithiane which would ultimately become a gem-difluoromethylene group