This work describes the application of spiroligomers as serine hydrolases mimetics. Through collaboration with Kendall Houk's group, for the first time in the Schafmeister lab, we demonstrate that "theozymes" can be successfully used as models to design highly functionalized spiroligomer constructs for organocatalysis. We demonstrate a structure-function relationship between the structure of a series of bi-functional and tri-functional spiroligomer based transesterification catalysts and their catalytic activity. First, we designed and synthesized a series of stereochemically and regiochemically diverse bi-functional spiroligozymes to identify the best arrangement of a pyridine as a general base catalyst and an alcohol nucleophile to accelerate attack on vinyl trifluoroacetate as an electrophile. The best bifunctional spiroligozyme reacts with vinyl trifluoroacetate to form an acyl-spiroligozyme conjugate 2.7x103-fold faster than the background reaction with benzyl alcohol. We then incorporated an additional urea functional group to activate the acyl-spiroligozyme intermediate through hydrogen bonds and enable acyl transfer to methanol. The best trifunctional spiroligozyme carries out multiple turnovers and acts as a transesterification catalyst with k1/kuncat of 2.2x103 and k2/kuncat of 1.3x102. Quantum mechanical calculations identified four transition states in the catalytic cycle and provided a detailed view of every stage of the transesterification reaction. With the aim of accelerating the k2, we sought to design better oxyanion holes that hold multiple hydrogen bonding groups in close proximity of the catalytic groups. A macrocyclic motif would be a good candidate to force the oxyanion hole arm to arrange hydrogen-bonding groups in a precise three-dimensional constellation for transition state stabilization. In Chapter 4, we introduce an in silico designed macrocyclic spiroligomer, which overlays well with catalytic active site of an inhibitor bound-esterase. Finally, we detail our effort to develop new methodologies for rapidly synthesizing spiroligomers on solid-support. This would allow us to efficiently permute their structures for diverse applications such as organocatalysts, host molecules, and biologically related applications such as inhibiting protein-protein interactions. / Chemistry

This research study aims to enhance the effectiveness of the architectural design process regarding the exploration and framing of the best visual connections to the outside environment within built environments. Specifically, it aims to develop a framework for developing and integrating an inside-out design approach augmented and informed by digital 3D geospatial data as a way to enhance the explorative ability and decision-making process for designers regarding the visual connection to the outside environment. To do so, the strategy of logical argumentation is used to analyze and study the phenomenon of making visual connections to a surrounding context. The initial recommendation of this stage is to integrate an inside-out design approach that operates within the digital immersion within 3D digital representations of the surrounding context. This strategy will help to identify the basic logical steps of the proposed inside-out design process. Then, the method of immersive case study is used to test and further develop a proposed process by designing a specific building, specifically, an Art Museum building on the campus of Virginia Tech. Finally, the Delphi method is used in order to evaluate the necessity and importance of the proposed approach to the design process and its ability to achieve this goal. A multi-round survey was distributed to measure the consensus among a number of experts regarding the proposed design approach and its developed design tool. Overall, findings refer to a total agreement among the participating experts regarding the proposed design approach with some different concerns regarding the proposed design tool. / Doctor of Philosophy / Achieving a well-designed visual connection to one's surroundings is considered by many philosophers and theorists to be an essential aspect of our spatial experience within built environments. The goal of this research is to help designers to achieve better visual connections to the outside environment and therefore create more meaningful spatial experiences within the built environment. This research aims to enhance the ability of designers to explore the best possible views and make the right design decisions to frame these views of the outdoors from the inside of their buildings. Of course, the physical presence of designers at a building site has been the traditional method of determining the best views; however, this is not always possible during the design process for many reasons. Thus, this research aims to find a more effective alternative to visiting a building site in order to inform each design decision regarding the quality of its visual connection to the outdoors. To do so, this research developed a proposed inside-out design approach to be integrated into the design process. Specifically, it outlines a process that allows the designers to be digitally immersed within an accurate 3D representation of the surrounding context, which will help designers to explore views from multiple angles both inside the space and in response make the most suitable design decision. For further developing the proposed process, it was used during conducting this research to design an Art Museum on Virginia Tech Campus.