Source: Dissertation Abstracts International, Volume: 76-07(E), Section: B.

Adviser: Scott J. Miller.

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The site-selective oxidation of complex molecules is an enduring challenge in chemical synthesis. In this dissertation, we describe our efforts to apply short peptide catalysts to a sub-problem, the site-selective epoxidation of polyenes. To address this challenge, we applied a previously reported catalytic cycle, wherein aspartic acid is the catalytic residue, in the development of a one-bead-one-catalyst approach for the discovery of selective oxidation catalysts. First, the screening approach was validated in the context of oxidation reactions by the discovery (and rediscovery) of enantioselective catalysts for epoxidation of an allylic urethane. We also document our exploration of on-bead catalyst screening libraries, which led to the discovery of another enantioselective catalysts for the same allylic urethane.

The combinatorial screening approach was next applied to find peptide catalysts that demonstrate site selectivity in the epoxidation of the sesquiterpene, farnesol. An on-bead catalyst displaying selectivity for the allylic olefin of farnesol was used as a template for a biased split-and-pool library, which after an additional round of combinatorial evolution resulted in other sequences that were further developed for allylic epoxidation. When modified for study in solution, the most site-selective catalysts were also found to deliver excellent enantioselectivity in the epoxidation of farnesol, other terpene alcohols, and an array of other allylic alcohols. A number of studies aimed at uncovering the details by which selectivity is achieved for allylic olefins were performed, advancing our understanding of how the catalyst operates.

In the course of screening, another on-bead peptide sequence was found to display slight selectivity for the internal, 6,7-olefin of farnesol. Further combinatorial evolution, followed by study of a number of peptides in solution, yielded a catalyst that delivers good site selectivity in epoxidation of the 6,7-position of both farnesol and the diterpene, geranylgeraniol. Investigations into the mode of operation of the hexamer catalyst indicated that it is hydroxyl-directed and that a truncated, trimer peptide still retains some of the 6,7-selectivity. Analysis of the results from on-bead libraries, catalyst analogues, and NMR studies culminated in models for how the intriguing remote selectivity is achieved.

Both the allylic and remote epoxidation catalysts were also used in tandem to selectively synthesize the 2,6-diepoxides derived from farnesol. In the course of our investigations of these catalysts, we also found another catalyst that delivers similar selectivity to the 6,7-selective epoxidation catalyst in the epoxidation of 2,3-epoxyfarnesol. We explored the advancement of this different catalyst using a surrogate substrate, citronellol, which ultimately led to a slightly improved catalyst.

With our models of how a catalyst is directed by the hydroxyl group of farnesol to deliver selectivity for the 6,7-position, we endeavored to design catalysts for both alternate selectivity as well as catalysts directed by groups other than a hydroxyl. We found success in the application of our design approach in the epoxidation of the 6,7-olefin of various farnesyl ethers. One application of these ether-directed catalysts was to the selective epoxidation of difarnesyl ether, a constitutional isomer of squalene oxide.

This dissertation describes the discovery of several catalysts, some of which could be further developed for enhanced or altered selectivity. We note some similarities between the different epoxidation catalysts and reflect on our ability to achieve our project goals. The techniques used, and knowledge gleaned, in the study of the catalysts documented herein may prove useful in future studies in the selective modification of organic molecules.