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Development of Enzymatic Screening Methods for Reaction Discovery and Optimization. A New Thiocyanopalladation/Carbocyclization Transformation
Abstract
The field of organometallic chemistry has greatly benefited from the emergence of rapid reaction screening techniques. One such technique developed in the Berkowitz lab utilizes enzymes as reporting agents for organometallic reactions. This In Situ Enzymatic Screening (ISES) method has seen various applications, from information-rich screens for catalyst stereoselectivity, to higher throughput colorimetric assays for the discovery of new reactions and their optimization. This technique will be framed within the field of screening approaches currently available to the organometallic chemist. A previous ISES screen to determine the stereopreference of metal salen catalysts via UV-vis spectroscopy has been miniaturized utilizing a 16 well micromulticell format. Stereochemical information is obtained by comparing the relative rates of formation for each enantiomer of product as reported by complementary alcohol dehydrogenases. This miniaturized screen was employed to identify a new salen ligand based on a carbafructopyranosyl-1,2-diamine that shows excellent stereoselectivity for the hydrolytic kinetic resolution for a range of terminal epoxides (E values for several matched substrates >100) . Additionally, an entirely new transformation, the thiocyanopalladation/carbocyclization was discovered through a broad reaction, screen utilizing a colorimetric ABTS dye to indicate successful reactions with a color change visible to the naked eye. This screen has been adapted to tolerate the higher temperature necessary for the title transformation and utilized to optimize the reaction conditions (96 conditions screened in an afternoon). The optimized reaction was parametrized across nearly 30 substrates of various steric and electronic constraints and proved to be remarkably stereoselective. Thus, allylic substituents in the substrate induce 1,2-anti:syn ratios >10:1, while propargylic substrates provide near absolute (>30:1) 1,3-syn control of relative stereochemistry in the carbocyclization. The title transformation has been applied to the synthesis of the oxabicyclo[3.2.1]octyl core of that natural products annuionone A and massarilactone G. This core was then elaborated by a set of reactions that focus on the SCN functionality and that decorate the core, including S-CN cleavage with RMgX , azide-SCN cycloaddition and Pd-mediated S-CN addition across an alkyne . This work sets the stage for future efforts to employ such chemistry to diversity-oriented synthesis for chemical biology.
Subject Area
Organic chemistry
Recommended Citation
Swyka, Robert A, "Development of Enzymatic Screening Methods for Reaction Discovery and Optimization. A New Thiocyanopalladation/Carbocyclization Transformation" (2018). ETD collection for University of Nebraska-Lincoln. AAI10791439.
https://digitalcommons.unl.edu/dissertations/AAI10791439