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

This thesis research presents the synthesis and first application of bis-amino acid-based spiroligomers towards the development of organocatalysis, from small molecules to moderate size spiroligomers, and to macromolecules. By synthesizing a toolbox of cyclic monomers called "bis-amino acids", the Schafmeister group has developed an approach to construct both small and macromolecules named "Spiroligomers". These molecules arrange catalytic functional groups in a shape-persistent and programmable backbone. Unlike proteins and small peptides, spiroligomers do not fold; rather, their polycyclic backbone structures are controlled by the sequence and stereochemistry of the component monomers. Firstly, we demonstrated a structure/catalytic activity relationship together with computational modeling that suggests that a specific hydrophobic interaction between the modified pro4 catalyst and the aldehyde substrate is responsible for an observed rate enhancement in the aldol reaction. For the moderate size molecules, several spiroligomer libraries were prepared through solid phase or solution phase synthesis and screened for either the alcohol kinetic resolution reaction or the aldol reaction. The poor activity and selectivity suggest that the scaffolds involved cannot create the necessary chiral environment for asymmetric catalysis. Finally, a synthetic method of macromolecules using cross metathesis coupling was developed and a series of tetra-functionalized macrocyclic spiroligomers were synthesized. Three of these macromolecules were examined as asymmetric catalysts in the aldol reaction and gave moderate activity and selectivity. The NMR analysis of these macromolecules indicates their dynamic nature. As the first application of bis-amino acid based macromolecules in organocatalysis area, although these catalysts only generated moderate activity and selectivity, they provided evidence that changing the configuration of one stereocenter of the fourteen available within these macromolecules can alter the selectivity. This synthetic methodology also provides an effective way to create more complicated pocket like spiroligomer macromolecules for the future applications in catalysis and molecular recognition. / Chemistry