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Quantum Mechanical Elucidations of the Mechanisms, Reactivities, and Selectivities of Organocatalysis and Cycloadditions

  • Author(s): He, Cyndi Qixin
  • Advisor(s): Houk, Kendall N
  • et al.
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Abstract

Organocatalysis, the use of small organic molecules to accelerate organic reactions, has been of significant interest to synthetic chemists, and publications in this field have increased rapidly since the beginning of this century. In the meanwhile, density functional theory has been extensively applied to explore the origins of catalysis and selectivities observed in these transformations. The first portion of this dissertation reports the theoretical findings of a broad scope of reactions catalyzed by primary and secondary amines, aminoalcohols, and squaramides. The second part focuses on the understanding and the development of cycloadditions including the Diels–Alder and hetero-Diels–Alder reactions, 1,3-dipolar cycloadditions, and higher-order cycloadditions.

Two examples of asymmetric catalyses with cinchona-alkaloid-derived primary amines are described in Chapters 1 and 2: (1) an intramolecular alkylation towards the synthesis of a migraine drug candidate, and (2) higher-order cycloadditions between tropone and cyclopentenone. We showed that three key interactions are responsible for enantioselectivity of the first reaction, and they are achieved with less distortion in the preferred transition state (TS). Modeling with the counterion is proved crucial to reproducing experimental stereoselectivities. Our TS model for the second example suggests the hydrogen bond formed between the quinuclidinium and the tropone oxygen determines periselectivity.

The reaction between an oxyallyl cation and indoles catalyzed by a novel aminoalcohol developed in the MacMillan group is presented in Chapter 3. The uncatalyzed addition of indole to oxyallyl cation is predicted to have a high (S,S)/(R,R) diastereoselectivity. Two hydrogen bonds and a cation–π interaction facilitate binding of the oxyallyl cation to the catalyst. The cyclohexane moiety, a new addition to the Hayashi–J�rgensen catalyst, controls enantioselectivity. Chapter 4 reports the computational design, synthesis, and applications of a new chiral hydrogen-bond donor catalyst. In addition to the bidentate hydrogen-bond donor motif, the squaramide catalyst features three chiral centers and hydrogen-bond acceptors. DFT calculations indicate that C−H���O hydrogen-bonding is crucial to the enantioselective Friedel–Crafts alkylation catalyzed by the squaramide. Chapter 5 discusses the experimental development of an unnatural amino acid mutagenesis method and the computational investigation of cation–π interactions in methyllysine reader proteins. Our results suggest that the two tyrosines in the binding pocket of a model reader protein interact with the methyllysine cation to a different extent. This work suggests the degree of contacts between reader proteins and cationic substrates may be exploited to enhance selective inhibition.

Chapters 6–9 consist of DFT studies of the mechanisms, reactivities, and selectivities of a collection of cycloadditions. The remarkable reactivities of transannular Diels–Alder (TADA) reactions are investigated and discussed in Chapter 6. Among 13 TADA reactions computed, 12-membered macrocycles have the largest rate acceleration. This is due to the lowering of distortion energy from the strained reactant to the TS. TADA reactivities are further improved by fine-tuning the ring size, namely by incorporating heteroatoms such as oxygen and nitrogen and alkyne to the macrocycle. Chapter 7 explores the mechanism and selectivity of [6 + 4] cycloadditions of tropone (T) and dimethylfulvene (F), a classic reaction reported in 1967 by Houk and Woodward. An ambimodal [6T + 4F]/[4T + 6F] TS is located using DFT calculations. Reaction dynamics simulations reveal the initial product distribution and predict high [6 + 4] periselectivity. Chapter 8 focuses on the regioselectivity of 1,3-dipolar cycloadditions of benzo- and mesitylnitrile oxides with alkynyl pinacol and MIDA boronates. The electronic energies of activation are mainly controlled by distortion energies. In Chapter 1, the N,N-diquaternized cinchona-alkaloid-derived amine catalyzes an intramolecular alkylation reaction, and the last chapter is a second example of quaternary ammonium salts as powerful Lewis acidic organocatalysts. The mechanism of the aza-Diels–Alder reaction catalyzed by onium salts is predicted to be concerted asynchronous when modeled with a counter anion.

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This item is under embargo until March 22, 2020.