| Research is nothing if not collaborative; computational chemists have a wide variety of tools available at their disposal and can greatly facilitate the progress of research beyond what is possible using only traditional synthetic techniques. On the whole, computational chemistry has steadily gained acceptance in the scientific community. Advantages include no purifications of intermediates, virtually no exposure to toxic chemicals in the laboratory, and (relatively) quick turnarounds. When modeling specific reactions, the difficulty arises in interpreting the Potential Energy Surface (PES) and building a predictive model of reactivity rather than exhaustively examining every possibility. The use of computers as a tool to aid the modern chemist is examined within these chapters and explored in the context of small molecule inhibitor design and Density Functional Theory (DFT) mechanistic studies.;Section 1 -- Design and synthesis of potential therapeutics: The rationale design of new therapeutics is a key application of computational chemistry. The chapters within this section serve as an introduction to the potential applications and utility of these methods.;Chapter 1: This chapter introduces the need for new antibiotics and the basics of the computational methods used in the following chapters.;Chapter 2: The design and synthesis of potential bacterial cell division modulators is explored. The need for new antibiotics is readily documented in the literature as modern antibiotics form an evolutionary pressure. Understanding the mechanisms by which bacterial cells divide, and thus propagate, could lead to novel therapeutics. SulA naturally modulates the bacterial cell division protein FtsZ, and disrupting this interaction with a small molecule allows for study without the need for inducing a genetic mutation. Two inhibitor scaffolds for disrupting this protein interface were designed using the Openeye suite of programs. Additionally, the screening of large molecular libraries from the ZINC database was accomplished against both the SulA and FtsZ protein receptors, leading to identification of commercially available compounds that could be assayed against both protein targets. Chapter 3: The generation and screening of a novel library based on Gyramide A for LogD and other molecular descriptors from commercially available benzaldehydes and sulfonamides was accomplished.;Section 2 -- Pericyclic reactions: Pericyclic reactions allow for complex transformations of organic skeletons in a concerted fashion, thereby preserving stereochemical information. These reactions are not only relevant to the synthetic world, but are found in nature as well.;Chapter 4: The [3,3] sigmatropic shift reaction, known as the Cope rearrangement, is explored. In the addition of alkynyl sulfones and tertiary amines, ring expansion is found to be dictated largely by steric considerations, while a lone pair on carbon acts largely as a substituent instead of a nucleophile.;Chapter 5: A bio-mimetic variation of the Cope rearrangement utilizing Globiferin is explored. An intriguing catalytic effect was discovered when a protonated tertiary amine was used to try to find a stepwise pathway, but a concerted process with a substantially lower barrier for rearrangement was found instead, having a potentially substantial affect on our understanding of biosynthetic pathways.;Chapter 6: The viability of Nitrone-Alkene (3+2) cyclizations is explored in the formation of Fluggine A. One of the reactants can undergo a competing (3+2) cyclization intramolecularly. However, this is found to have a higher barrier. This is consistent with the observation of Fluggine A formation when the required norsecurinine substrate is present, and cyclization with itself to form virosaine B when norsecurinine is absent.;Section 3 -- Synthetic Collaborations/Heterocycle reactions: The projects within this section are collaborations with synthetic groups at other universities and illustrate the utility in direct collaborations between computational chemists and other researchers. Each chapter in this section covers the formation of heterocycles, which are a privileged scaffold and known to possess biologically relevant activity. As such, the formation of new heterocycles is of great scientific interest.;Chapter 7: Bryostatin 1 is of biological interest due to antitumor activity, and its complex chemical structure. The formation of tetrahydropyran analogs of bryostatin 1 derived via silyl-Prins cyclization is examined computationally in this chapter. The stabilization of a tertiary cation by a beta-silyl substituent is key for explaining the observed selectivity.;Chapter 8: The possibility of a pericyclic six-electron electrocyclization in the formation of indolines is explored but found to be significantly higher than the comparable 5-endo-trig cyclization. The competing mechanisms were found to arise from different imine reactant geometries, allowing for different orbital alignments in their respective TS geometries. The cinchona alkaloids are found to affect enantioselectivity through more than a simple counter-ion effect.;Chapter 9: This chapter describes a collaborative project between three academic groups---specialists in synthetic methods, quantum chemical computations, and kinetic studies---to reconcile differences in data obtained while studying a heterocycloisomerization reaction for the creation of annulated aminopyrroles. Through collaboration, a complete picture of the mechanism was obtained, which would have been insufficient/inadequate had any one research group been removed. |
