Rationalization and innovative design of asymmetric organocatalysts through computational investigation Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/bz60d098b

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  • My work on computing complex catalyzed organic transformations reveals that only a few subtle chemical factors, e.g. non-classical hydrogen bonding, (hyper)conjugation and steric effects, common across different catalyst manifolds are critical for catalysis and selectivity. Rational manipulation and exploitation of these factors has led to improved catalyst designs, which has previously been an oft-promised but rarely delivered endeavor. Hydrogen bonding is critical to stabilizing structures in both the ground and transition state across many branches of chemistry and life. C-H bonds polarized through either hybridization or proximity to a developing or full positive charge can provide stabilization through interaction with negatively charged atoms in a C-H···O non-classical hydrogen bond (NCHB). In the transition state, where a molecule experiences temporarily amplified polarization, these hydrogen bonds can serve to stabilize the structures and differentiate between diastereomeric TSs A joint experimental and computational investigation on a diaryl prolinol silyl ether-catalyzed Michael cascade reaction to complex furanyl/pyranyl products uncovered the synergistic relationship between catalyst and substrate beyond the basic enamine activation and steric control. NCHBs were discovered to stabilize the transiently polar transition state. The kinetic resolution of addition products was afforded by virtue of the conformation of the substrate preventing or allowing hyperconjugation. An N-heterocyclic carbene-catalyzed dynamic kinetic resolution of β-ketoesters was discovered to display an unusual resolution mechanism. Rapid substrate epimerization early in the aldol mechanism allowed routing through the lowest energy diastereomeric pathway, which also differs in mechanism from the other diastereomeric TSs. Facial control arises from the presence or absence of a single chiral NCHB donor stabilizing the developing alkoxide. Diastereocontrol is afforded by the configuration of the epimerizable β-stereocenter hydrogen affecting the conjugative ability of the keto aryl group. This same control arises in the rapid and enantioselective retro-[2+2] decarboxylations of the product bicyclic β-lactones to cyclopentenes. A study on the origins of enantioselectivity of an NHC-catalyzed homoaldol with acylphosphonates uncovered stereodifferentiating pockets of NCHB akin to an oxyanion hole between the catalyst aryl groups and the phosphonyl (P=O) oxygen. Computations predicted an increase of selectivity by blocking the sites stabilizing the minor transition state. Synthesis and test of the catalyst verified computational predictions. A chiral bifunctional aminothiourea has been developed for the Michael addition of acrylates to α-ketones to generate asymmetric all-carbon quaternary centers. This catalyst both activates the nucleophile via enamine catalysis and employs hydrogen bonding catalysis to activate the carbonyl-bearing electrophile. A joint experimental and computational study reveals the mechanism of this process and seeks to uncover the origins of selectivity. Computations predict that deletion of the catalyst β-phenyl group would increase selectivity; however, experimental synthesis and test led to unforeseen catalyst decomposition.
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