The Discovery and Study of Peptide-Based Catalysts for Organic Synthesis: Synthetic Methods and Infrared Spectroscopy

With the overall goal to develop novel catalytic strategies for the efficient synthesis of complex molecular architectures, the Miller Lab has introduced a diverse range of peptide-based catalysts for selective and highly challenging chemical transformations. This dissertation presents advances in catalytic phosphate and phosphite bond forming reactions in the context of asymmetric inositol phosphate synthesis and site-selective natural product deoxygenation.;A previously developed asymmetric catalytic phosphorylation strategy for the synthesis of myo-inositol natural products is extended to the total synthesis of phosphatidylinositol-5-phosphate and its enantiomer. Closer examination of the Mitsunobu reaction, a key step for dioctanoylglycerol phosphate ester synthesis, and more judicious selection of protecting groups to control the site of phosphate delivery on the myo-inositol ring enables the efficient synthesis of both enantiomers of phosphatidylinositol-5-phosphate from a common meso starting materials.;Although highly selective, the generality of catalytic asymmetric phosphorylation is limited due to a dependence on a single chlorophosphate reagent, diphenyl chlorophosphate. This limitation is addressed in the development of a novel catalytic asymmetric phosphorylation strategy employing tetrazole-based peptide catalysts and phosphoramidites to differentiate nearly identical enantiotopic hydroxyl groups. Through mechanistic investigations, a highly selective kinetic resolution of a protected inositol monophosphate is discovered, and applied to a streamlined asymmetric synthesis of myo-inositol-6-phosphate.;The broader utility of catalytic phosphoramidite activation with tetrazole-based peptide catalysts is applied to the challenging arena of site-selective natural product deoxygenation, where a readily synthesized phosphoramidite reagent can be employed for the formation of phosphite-based deoxygenation precursors. This chemistry is used to site-selectively deoxygenate erythromycin A, overcoming notorious challenges with unprotected erythromycin A.;For many catalytic mechanisms multidentate hydrogen-bonded motifs have been implicated as key asymmetry inducing interactions; yet these processes are difficult to study experimentally. The potential of gas-phase infrared spectroscopy to elucidate the nature of such interactions is examined in the context of a peptide catalyst and biaryl substrate. Through isotopic substitutions key hydrogen bonding interactions are identified. Combined with harmonic electronic structure analysis, this technique demonstrates the capacity to identify key hydrogen bonding partners in catalytic systems.