Iron Carbonyl Mediated Parallel Synthesis

Doctoral thesis, 2005

This thesis describes the examination and development of cationic iron carbonyl complexes for use in parallel synthesis both in solution phase and on solid phase. A solution phase methodology for carbon-carbon and carbon-heteroatom formation, utilizing polymer bound reagents and scavengers and amenable for automation has been successfully developed. Ten different nucleophiles (carbon, nitrogen, oxygen, and sulfur) were used, giving the targeted cyclohexadienoic amides in good yields and excellent purities. The solution phase methodology was transferred to a solid phase protocol, generating a diverse set of eighteen cyclohexadienoic amides of excellent purities and in good yields using nine different nucleophiles (carbon, nitrogen, oxygen, and phosphorous). Both methods use the same reaction conditions for all nucleophiles demonstrating the versatility of these methods in generating compound libraries of high diversity. Even sterically hindered nucleophiles like tert-butanol gave good results. Activated esters were also investigated as potential linkers for iron carbonyl mediated chemistry on solid phase, and a tetrafluorophenol linkage was found to be the most suitable for this purpose. Synthesis of oseltamivir analogues and galectin inhibitors based on cationic iron carbonyl chemistry has been undertaken and work is currently in progress to finalize these projects. This thesis also describes the investigation of a phosphate based linker for cationic iron carbonyl chemistry on solid phase. In solution phase, palladium and nickel catalyzed cross-coupling reaction cleaved the investigated enyl and dienyl phosphates to give the targeted olefins. However, when transferring to a solid phase protocol only traces of the desired olefin were detected. In summary, this thesis shows that cationic iron carbonyl chemistry is amenable for parallel synthesis both in solution and on solid phase using the same reaction conditions for a wide range of nucleophiles. Keywords: solid phase, parallel synthesis, scavenger, polymer bound reagent, iron carbonyl complex, cation, dienyl, active ester, linker, oseltamivir, galectin inhibitor