| The conversion of olefins into aldehydes by hydroformylation with rhodium catalysts is one of the largest homogeneously catalyzed industrial reactions, producing millions of tons of linear aldehydes per year. However, the production of chiral, branched aldehydes via asymmetric hydroformylation (AHF) remains underutilized in synthesis. To improve the application of rhodium BisDiazaphos catalyzed AHF, high selectivity for previously uninvestigated disubstituted olefins including enol esters and enamides is demonstrated, which yield more complex alpha-functionalized aldehyde building blocks. Additionally, process-scale asymmetric hydroformylation to yield chiral, enantioenriched aldehyde feedstocks has not yet been demonstrated. In collaboration with Eli Lilly, asymmetric hydroformylation in a research scale flow reactor is realized through the development of a flow synthesis of naproxen. To support scale-up of asymmetric hydroformylation technologies the synthesis of bisdiazaphospholane ligands is re-examined to optimize the cost of the material and synthesis on a larger scale is demonstrated. Access to enantiopure ligand via classical resolution in place of preparative SFC chromatography has also been developed, and will improve accessibility to selective AHF catalysts. Finally, the direct observation of catalytic intermediates and rate information in asymmetric hydroformylation by circulating high-pressure NMR will be described. |
