Graduate Thesis Or Dissertation


Computational Rationalizations of Mechanism and Stereocontrol in Small-Molecule Lewis Base Organocatalysis Public Deposited

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  • My work has focused on investigating synthetic organic reactions using applied computational methods. Non-covalent interactions are critical to catalysis, mechanism, and stereoselectivity, with the most prominent interaction for isothioureas being the S···O contact between the catalyst sulfur atom and the oxygen of the acyl group. A comprehensive joint experimental and computational investigation into the isothiourea-catalyzed transformation of allylic ammonium ester salt substrates into α- amino acid derivatives. Kinetic isotope effects (KIEs) and description of the potential energy surface allowed accurate corroboration of computed secondary KIEs with experiment. The turnover-limiting and stereodeterming transition state is a [2,3]- sigmatropic rearrangement of an allylic ammonium ylide. Stereoselectivity is afforded through rigidification of the catalyst-substrate complex through a S···O non-covalent interaction. In such an arrangement, rearrangement takes place endo, anti to the catalyst stereodirecting group, allowing a stabilizing π-cation between the substrate and planar positively-charged catalyst to select for the major TS. Isothiourea-catalyzed annulations of benzoxazoles and benzothiazoles were discovered to proceed to lactone or lactam products on the basis of the benzothiazole’s ability to engage in a second S···O interaction in addition the substrate-catalyst S···O interaction already present in both lactonization and lactamization TSs. In the absence of the second S···O, a C–H···O between the substrate and the catalyst oxygen atom favors lactonization. Computed TSs and truncated model systems discovered and detailed the interplay between the two non-bonding interactions (S···O and C–H···O), which ultimately leads to chemodivergence when using thiazole or oxazole derived substrates. Interactions between S and O atoms have previously been elements of enantiocontrol, but have never been evoked as central to chemoselectivity. A study on the scope and origins of stereocontrol in the kinetic resolution of tertiary oxindole alcohols illustrates the importance of the substrate amide C=O moiety interacting with the isothiourea catalyst (C=O···isothiouronium) as imparting high selectivity. Partial charge calculations of the acylated catalyst point to a positive charge on the central isothiourea carbon (isothiouronium) Computed TSs allowed the development of a stereocontrol model in which stabilization of the isothiouronium with the substrate amide C=O leads to faster acylation of the (S)-alcohol. Hammett parameters and amide C=O stretching frequencies of the substrate showed good correlation with the s factor, in agreement with theoretical predictions. Regiodivergent and catalyst-selective O- to C- or N-carboxyl transfer is disclosed, with DMAP catalysis favoring N-carboxylation and NHC catalysis leading to selective Ccarboxylation. Computations unveiled the mechanism and source of regiodivergence from the mechanistically shared enolate intermediate. Computed TSs for the N- and Ccarboxylation pathways for both DMAP and NHC catalysts showed that greater spatial overlap in the ion pair consisting of the overall negatively-charged enolate species and the positively-charged acylated catalyst leads to regiodivergence for each catalyst. A theoretical and experimental project studying the formation mechanism and reactivity of highly unstable aza-ortho-quinone methide (aoQM) intermediates in synthesis and asymmetric N-heterocyclic carbene (NHC) catalysis. Compared to their oxygen analogs (ortho-quinone methides), aoQMs were found to be >10 kcal/mol more unstable. A byproduct of aoQM formation in the presence of cesium carbonate base is cesium chloride, with a computed equilibrium in favor of cesium chloride of ~30 kcal/mol. A nucleophilic substitution pathway which bypasses aoQM formation was considered, but was found as consistently higher in energy than the aoQM pathway once the cesium carbonate equilibrium is considered. With the aoQM-mediated mechanism established, a stereocontrol model was developed for the NHC-catalyzed asymmetric synthesis of dihydroquinolones.
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