Skip to main content
Open Access Publications from the University of California

Theoretical Investigations of the Stereoselectivities and Mechanisms of Organic Reactions Catalyzed by Vicinal Diamines and Transition Metal Complexes

  • Author(s): Simon, Adam
  • Advisor(s): Houk, Kendall N
  • et al.

This dissertation describes the elucidation of reaction mechanisms and the sources of asymmetric induction in organic reactions with density functional theory. Modern density functional theory is used to develop and propose models for the stereoselectivity of complex organocatalytic reactions. Computations of reactions catalyzed by vicinal diamines, which involve a broad scope of substrates and reactivity, are described in Chapters 1-3. A series of collaborations with experimental research groups are elaborated on in Chapters 4-7.

Chapter 1 describes a computational study of aldol reactions catalyzed by the vicinal diamine class of organocatalysts. The computations and DFT benchmark of the entire transition state landscape of a theoretical model for the simplest aldol reaction catalyzed by ethylene diamine were performed. In addition, the first successful experimental report of a vicinal diamine-catalyzed aldol reaction was studied computationally. The computations revealed a nine-membered cyclic transition state in well-defined conformations of cyclooctane. We identified that the crown (chair-chair) conformation accounted for the observed stereoselectivity in these aldol reactions.

Chapter 2 elaborates on the findings in Chapter 1 of the dissertation by exploring five modern and complex examples of aldol chemistry involving elaborate vicinal diamine catalysts by density functional theory. The computations revealed the sources of stereoselectivity, reactivity, and substituent effects both in catalyst and substrates for aldol reactions catalyzed by vicinal diamines. We proposed a stereoselectivity model based on the conformations of cyclooctane that serves as a predictive model for further aldol chemistry, as well as for the design of new reactions.

Chapter 3 continues the exploration of vicinal diamine catalysis in the realm of Nazarov chemistry. Density functional theory was used to determine the mechanism, stereoselectivity, and source of product inhibition in Nazarov reactions of ketoenones catalyzed by vicinal diamines. The formation of an enamine-iminium ion was determined, and the stereoselectivity was found to be caused by the cyclohexane conformation formed in the enamine-iminium complex. The dihedral angle of the diamine preferred one helicity of the electrocyclization transition state.

Chapter 4 summarizes a collaboration between our group and the research group of Prof. Patrick Harran, where they developed new methods to synthesize macrocyclic pyrroloindolines by alkylating tryptophan-based oligopeptides. Computations were performed to understand the regiodivergent nature of the macrocyclization reactions. We determined that both the endo- and exo-pyrroloindolines form, but the exclusive observation of endo-pyrroloindolines is due to the propensity for the exo-intermediates to rapidly rearrange to thermodynamically preferred C2-linked isomers.

In Chapter 5, a collaboration between our group and Prof. Neil Garg’s research group on the arylations of chiral enamines with arynes. The Garg lab discovered and developed the synthetic methodology for arylating the alpha position of chiral enamines to form stereodefined quaternary centers. We performed density functional theory calculations to understand the mechanism and source of stereoselectivity in the reaction of benzyne and chiral enamines, as well as predict better-performing substituents.

Chapter 6 describes a collaboration between our group and Prof. Karl Anker J�rgensen’s research group in Aarhus, Denmark. The J�rgensen group discovered and developed hetero-[6+4] and [6+2] reactions of heteroaromatic compounds to yield highly complex scaffolds from simple pyrrole aldehydes and olefins. With density functional theory calculations, we determined the nature of the [6+4] and [6+2] reaction mechanisms to be stepwise zwitterionic pathways. The enantio-controlling step was identified as the cyclization step. DFT was used to predict better-performing catalysts for the hetero-[6+2] reaction.

In Chapter 7, we describe a collaboration with Prof. Scott Denmark on the Soai reaction. Prof. Denmark’s group has discovered a new autocatalytic reaction system where detailed kinetics and mechanistic investigations revealed the intricacies of the autocatalytic Soai mechanism. We performed density functional theory calculations to probe the transition state model of enantioselectivity in the autocatalytic mechanism, and the source of autocatalysis.

Main Content
Current View