The need for user-friendly and rapid assays for enantiomeric excess (ee) is increasing due to the advent of high-throughput parallel synthesis protocols, directed enzyme evolution, and bead-based catalyst creation. If enabled with rapid protocols for ee, one can envision accommodating such routines involving thousands of reactions. Current HPLC-based protocols for ee analysis cannot accommodate such numbers. Due to the rapid nature and utility of our assays, we are fortunate that many chemists from around the world have contacted us to exploit our capabilities. However, under the guise of this NIH project, we focus on four collaborations that push various aspects of our methods. With Scott Miller (Yale) we will develop methods for bead-based catalyst screening. With John Hartwig (UC Berkeley) and Adrian Keatinge-Clay we will generate protocols that can readily analyze directed evolution of enzymatic catalysis. With chemists at Merck Rahway, we will facilitate base-metal reaction discovery. In each project, we will use our one-of-a-kind circular dichroism (CD) spectropolarimeter, along with methods of sample triage and standard workflow procedures. On a more basic science level, but still focused on translation to the synthetic community, we will explore multi-parameter fitting protocols (analogous to linear free energy relationships) that will remove the necessity of having enantioenriched samples to generate calibration curves. Second, for many of the collaborations, we will generate not only ee assays, but also techniques to determine diastereomeric ratio (dr) and reaction yield in a rapid parallel fashion. Further, to facilitate bead-based catalyst discovery, we will use microlithography to generate quartz plates for use in our spectropolarimeter. Hence, this project is translational while retaining hypothesis driven aspects. Our collaborative efforts will test the utility and generality of our methods, while also highlighting the power of supramolecular chemistry and physical-organic insights, to assist synthetic organic reaction discovery.
Public health is in part reliant upon pharmaceuticals. The synthetic procedures that create pharmaceuticals involve steps that form right- and left-handed chemical structures, called enantiomers. The work described in this NIH application improves public health by creating new and faster methods for analyzing the ratios of enantiomers created during synthetic protocols and pharmaceutical development.
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