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The Competing Enantioselective Conversion Method for the Determination of Absolute Configuration of Stereogenic Carbinols

  • Author(s): Wagner, Alexander J.
  • Advisor(s): Rychnovsky, Scott D
  • et al.
Creative Commons 'BY-NC-ND' version 4.0 license
Abstract

The development of the Competing Enantioselective Conversion (CEC) method for the determination of absolute configuration of enantioenriched stereogenic carbinols is described. This methodology utilizes each enantiomer of the chiral acyl-transfer catalyst homobenzotetramisole (HBTM) in parallel reactions with the carbinol of interest. The difference in rate of each reaction is evaluated by measuring conversion at a fixed time. Identification of the matched HBTM enantiomer, leading to a faster reaction, and comparison to an established mnemonic provides the configuration of the stereocenter. The CEC method was initially applied to secondary benzylic, propargylic, and α-aryl carbinols on milligram scale using 1H NMR spectroscopy to provide a quantifiable measure of reaction conversion. The substrate scope was then expanded with additional enriched benzylic and α-heterocyclic secondary carbinols on milligram scale. Thin-layer chromatography (TLC) was developed as a reliable method of qualitatively assigning the relative fast reaction via spot density, resulting in the first method to determine absolute configuration with a TLC analysis. The CEC method with TLC was converted to an undergraduate organic chemistry laboratory, which has now been conducted by over 3,000 students. Four syntheses of HBTM were completed, resulting in two synthetic schemes capable of large-scale production (up to 50 gram scale), which ultimately led to commercialization of R-HBTM and S-HBTM with Sigma-Aldrich. A one-use CEC method kit was developed, designed for 16 μmol of substrate, with the potential for commercialization. A nanomole scale CEC method has been developed with TLC and was applied to benzylic and homobenzylic systems. Both the CEC kit and nanomole scale conditions operate through pseudo-first order conditions, providing the opportunity to greatly reduce the carbinol concentration and achieve the same outcome as long as reaction progress can be detected. The first detailed kinetic study of a chiral organocatalytic acyl-transfer reaction was also reported with HBTM.

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