STEREOCONVERGENT TRANSFORMATIONS OF CARBONYLS FOR EXPEDIENT SYNTHESIS OF STEREOCHEMICALLY COMPLEX SMALL MOLECULES Public Deposited

Downloadable Content

Download PDF
Last Modified
  • March 20, 2019
Creator
  • Goodman, Clifford
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • I. A Primer on Dynamic Kinetic Resolutions and Extant Methods for Oxo-Ester Synthesis: A two part overview that details: 1) the principles of dynamic kinetic resolution and its application in modern asymmetric catalysts and 2) current synthetic methods for generation of enolizable β-substituted α-keto esters and α-substituted β-oxo esters. II. Asymmetric Transfer Hydrogenation-Dynamic Kinetic Resolution of β-Stereogenic α-Keto Esters: Two systems for dynamic kinetic resolution via asymmetric transfer hydrogenation (DKR-ATH) of racemic β-stereogenic-α-keto esters yielding optically active α-hydroxy esters are presented. In the first of these reports a previously unreported Stetter addition of ethyl gloxylate provides β-stereogenic-α,δ-diketo esters, which are reduced to α-hydroxy δ-keto esters. Stereo- and chemoselective mono-reduction provides formal glycolate Michael products. In the second disclosure, β-amino α-keto esters are reduced to the corresponding anti-β-amino α-hydroxy esters. Both reports employ formic acid as the organic reductant , and use a Ru(II)-amido complex bearing a bulky m-terphenylsulfonamide ligand which imparts remarkable levels of diastereo- and enantiocontrol. III. N-Heterocyclic Carbene-Catalyzed Dynamic Kinetic Resolutions of β-Stereogenic α-Keto Esters: The development of two distinct N-Heterocyclic carbene catalyzed dynamic kinetic resolutions of β-halo-α-keto esters are discussed. In the first of these, an asymmetric cross-benzoin addition is described. The resulting fully substituted β-halo glycolic ester products are obtained with high levels of enantio- and diastereocontrol, and the reaction products undergo highly diastereoselective substrate-controlled reduction to give functionalized stereotriads. Mechanistic studies show that the high chemoselectivity observed is a result of greater electrophilicity of the α-keto ester toward the Breslow intermediate. In the second report development of an asymmetric homoenolate (a3 − d3-umpolung addition) of α,β-enals, forming γ-butyrolactones with three contiguous stereocenters is described. The addition occurs with high regio-, diastereo-, and enantiocontrol and constitutes the first stereoconvergent homoenolate process. IV. Complexity Generating Dynamic Kinetic Resolutions of β-Oxo Acid Derivatives: Dynamic kinetic resolutions of α-stereogenic-β-formyl amides in asymmetric 2-aza-Cope rearrangements are described. Chiral phosphoric acids catalyze this rare example of a non-hydrogenative DKR of a β-oxo acid derivative. The [3,3]-rearrangement occurs with high diastereo- and enantiocontrol, forming β-imino amides that can be deprotected to the primary β-amino amide or reduced to the corresponding diamine.
Date of publication
Keyword
DOI
Resource type
Rights statement
  • In Copyright
Advisor
  • Dempsey, Jillian
  • Miller, Alexander
  • Meek, Simon
  • Johnson, Jeffrey
  • Gagne, Michel
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
Language
Parents:

This work has no parents.

Items