This thesis presents the development of bis-amino acid-based spiroligomer applications in the areas of molecular recognition and organocatalysis. By taking advantage of the high degree of functionality and chirality of the unique bis-amino acid building blocks, spiroligomer backbones can be synthesized with predefined shapes, functioning as molecular hosts or as enzyme active-site-like pockets. Firstly, we demonstrated that spiroligomers can be designed to act as anion receptors. We designed a collection of spiroligomers that each display two urea groups. The spiroligomer that displayed the two urea groups in a way that they pointed at each other acts as an anion receptor and binds hydrogen pyrophosphate H2PPi anion (H2P2O72−), as demonstrated by an NMR titration experiment. Other spiroligomers that displayed the two ureas demonstrated a variety of behaviors including self-association and gel formation. In later work we explored the use of spiroligomers to develop catalysts. We attempted to design bipyridine/TEMPO-based bifunctional catalysts but they failed to achieve a faster alcohol oxidation rate than the background reaction. We then demonstrated the successful incorporation of metal-salen functional groups into spiroligomers in Chapter 4. Several bis-amino acid-based metal-salen complexes were synthesized and examined as asymmetric catalysts. Although only moderate enantio-selectivity was detected from synthesized Mn-salen catalyzed epoxidation reactions, it provides the first direct evidence that chiral bis-amino acid backbone can act as a chiral pocket that influence substrate selection and the stereochemical outcome of reactions. / Chemistry

Ever since traditional medicine developed thousands of years ago, humans have looked to natural substances as remedies for maladies. Today, many isolation and natural product chemists have begun revisiting ancient folk medicines in an attempt to isolate the compound(s) responsible for effective treatment. In addition to the examination of traditional remedies, the secondary metabolites of many newly discovered species, especially bacteria, get tested against a wide array of pathogenic cells. Isolated from the myxobacterium Sorangium cellulosum, the secondary metabolite carolacton was discovered to be lethal to Streptococcus mutans cells transitioning to the biofilm state. This was a significant finding since S. mutans is the main causative agent of dental caries, the most prevalent chronic childhood and adolescent disease worldwide. Herein, our efforts to design, synthesize, and biologically evaluate a 16-member library of carolacton-inspired analogs is described. In addition to natural product inspired research, two projects borne from a target-oriented templated approach are also described. The first, the synthesis of the antitumor compound FRAX-1036, was completed as part of a collaboration with the Chernoff group at Fox Chase Cancer Center to provide them with more material for murine testing. The second, the synthesis of macrocycles for the formation of atomically precise membranes, was conducted using spiroligomer building blocks and unnatural amino acids to furnish a triangle-shaped macrocycle via solution and solid phase techniques. This dissertation highlights the usefulness of the techniques of diverted total synthesis and building block synthesis in organic chemistry. / Chemistry

Binding to protein surfaces or shallow grooves with synthetic molecules poses a unique challenge, since this inherently requires large areas to facilitate interactions. Peptoids have been shown to interact with proteins, and combinatorial libraries of peptoids have been proven to be effective in discovering new ligands for protein binding. Unfortunately, most peptoids are flexible and lack the surface area required to compete with larger protein interactions. To combat these problems, we have created spiroligomers that have a rigid backbone, exhibit functionality comparable to proteins, and are resistant to proteases. To facilitate the rapid installment of spiroligomers into peptoid subunits, we required a more streamlined approach for functionalization of spiroligomers. To this end we applied a single-pot alkylation method, with which we installed over 25 unique functional groups onto different spiroligomer hydantoins. These spiroligomer hydantoins are spirocycles that possesses two stereocenters, of which we have complete control, as well as a protected proline amino acid. These new proline amino acids (enhanced prolines) have been incorporated into peptides via Fmoc-SPPS. Finally, we have functionalized these enhanced proline residues with another functional group and a protected primary amine, which allow for their use in peptoid synthesis. We developed methods to tether multiple spiroligomers together utilizing a peptoid backbone, as well as being able to incorporate spiroligomers into peptoid macrocycles. These spiroligomer-peptoid hybrids are large, diverse, and preorganized structures that have a large potential interacting surface area for binding to protein surfaces or shallow grooves. / Chemistry

This research presents a new approach to creating large, complex molecules to carry out molecular recognition and catalytic functions mimicking biological proteins. Development of new therapeutics that bind protein surfaces and disrupt protein-protein interactions was first addressed targeting the envelope transmembrane protein in HIV-1, gp41. In this work, spiroligomer inhibitors of gp41 were designed and synthesized, and then the biochemical activity was tested. Rationally designed inhibitors were developed using computational modeling with the Molecular Operating Environment software (MOE). To build the desired molecular shape according to the design, C-2 alkylation of a bis-amino acid monomer was investigated to synthesize the higher degree of bis-amino acids with various reaction conditions for access to all possible diastereomers. Based on this design and synthetic methodology, a spiroligomer targeting gp41 was built by synthesizing each monomer and then linking them together by diketopiperazine (DKP). For the biological evaluation, the gp41-5 gene was transformed into E. coli and the protein was expressed, purified, and refolded for an in vitro binding test. A direct binding, fluorescence polarization assay was used to evaluate the binding affinity of the functionalized spiroligomer to the gp41-5 protein. Its antiviral activity was assessed in collaboration with the Chaiken lab at Drexel University. In addition, investigation into how the unique structures provided by the spiroligomer backbone allow for various uses, such as functionalized struts in porous organic polymers (POPs). In the large internal space of a POP, a nucleophilic, catalytic spiroligomer was installed to increase the reaction rate for the hydrolysis of methyl paraoxon (a neurotoxin G agent stimulant). Spiroligomers were designed and synthesized with backbone DMAP moieties, and the activity of these catalysts was analyzed in collaboration with the Hupp lab at Northwestern University. / Chemistry

This dissertation presents the development of a synthetic strategy to produce various spiroligomer-based macrocycles that bridge the gap between organic molecules and small proteins. “Spiroligomers” (formerly known as “bis-peptides”) are a class of molecules produced by the assembly of “bis-amino acids”, molecules containing two amino acid regions on a single cyclic core. Each bis-amino acid is connected through pairs of amide bonds to form a diketopiperazine consequently eliminating single bond rotation and, therefore, avoids the complicated folding process common to the field of peptidomimetics. Spiroligomers are shape-programmable since the three-dimensional structure is controlled by the stereochemistry of the bis-amino acid monomers used in the synthesis, the connectivity of the monomers, and the number of monomers used. Furthermore, bis-amino acids can contain additional functional groups attached to multiple locations on the monomer which allows each spiroligomer, once synthesized, the ability to display these functional groups in predictable three-dimensional coordinates, with respect to each other. The synthesis of large spiroligomer-based structures requires the production of large amounts of bis-amino acid monomers. To this end, the scale of the synthesis of proline-based bis-amino acids from inexpensive trans-4-hydroxy-L-proline has been increased roughly 5-fold with respect to the previously published method. In addition to the time and solvent savings as a result of increasing the scale, the synthetic steps have been altered with considerations to ensure the production takes place in a convenient and environmentally friendly manner. Additionally, the desire to synthesize large spiroligomer-based structures means that the synthesis of each spiroligomer fragment must be as efficient and high-yielding as possible. To achieve this goal, a new synthetic approach to highly functionalized spiroligomers on solid support has been developed that results in increased yields relative to previously published methods. This new approach makes use of a protecting group, para-nitrobenzyl carbamate, which has not previously been incorporated in bis-amino acids as well as a pentafluorophenol ester activation strategy that also has not been in the synthesis of spiroligomers. Finally, an extendable synthetic route to spiroligomer-based macrocycles has been developed and representative macrocycles have been synthesized. This approach uses solid support to assemble multiple spiroligomers together through amino acids linkers before being cyclized in solution at dilute concentration to yield the desired macrocycles. Minimal functionality was included in the representative macrocycles to simplify structural information, confirmed by NMR and other means, and the macrocyclic structures were further investigated for host-guest activity using fluorescent, solvatochromic dyes. / Chemistry