Catalytic enantioselective α,β,γ-trioxygenation and anti-1,2-diol from α-oxyaldehydes and its application in total synthesis of oxylipins isolated from Dracontium loretense

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Abeykoon, Gayan
Major Professor
Jason S. Chen
George A. Kraus
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The Department of Chemistry seeks to provide students with a foundation in the fundamentals and application of chemical theories and processes of the lab. Thus prepared they me pursue careers as teachers, industry supervisors, or research chemists in a variety of domains (governmental, academic, etc).

The Department of Chemistry was founded in 1880.

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Mother nature creates structurally diverse interesting secondary metabolites often with unexpected biological activity, but in scarce quantities. Target-oriented total synthesis provides access to such natural products in sufficient amounts for further exploration of bioactivity. In target-oriented total synthesis, there is a never ending demand for the development of new reaction methodologies in order to address challenges in the synthesis and also to improve current synthetic protocols. Taking this idea to heart, we have worked on novel asymmetric method development and applied some of the methodologies that we developed to total synthesis. This thesis is composed of five chapters. Chapter 1 provides a general introduction to the research work discussed in Chapter 2, 3 and 4. Also, the introduction at the beginning of each chapter discusses the relevant background of the research so as to provide sufficient understanding about the significance of the work and the results. Moreover, some of the research in chapters 2 and 3 was published in Org. Lett. in 2014 and rest is from the manuscript which is currently in preparation. Also, the work disclosed in chapter 4 is published in Org. Lett. in full in 2015.

Chapter 2 describes the development of a novel method for the synthesis of differentially protected chiral anti-1,2-diol via organomagnesium or organolithium addition to α-oxyaldehydes synthesized via organocatalytic oxidative incorporation of TEMPO. Excellent diastereoselectivity was observed in these reactions, regardless of the hybridization or presence or absence of branching of the incoming carbon nucleophile. Further attempts to access masked syn-1,2-diols using the same method via promoting chelation control was unsuccessful. But, degradation of initial diastereoselectivity was often observed. Therefore, oxidation-reduction sequence was used to deliver syn-1,2-diols, despite of the low diastereoselectivity.

Chapter 3 describes the application of the methodology discussed in Chapter 2, to a short synthesis of unnamed oxylipins isolated from Dracontium loretense. This chapter discuss our two successful approaches to in synthesizing oxylipins. Our first generation synthesis describes a stereoflexible synthesis of all possible diastereomers, which led to the absolute stereochemical determination of natural oxylipins isolated from the Dracontium loretense. Moreover, a second generation synthesis provides the shortest route ever to immunostimulatory oxylipin with highest ever overall yield (33%).

Chapter 4 discusses the first ever α,β,γ-trifunctionalization of enals using organocatalysis. Subjecting an enal to catalytic enantioselective aldehyde α-oxygenation condition led to discovery of the first ever α,β,γ-trioxygenation. Moderate yields and enantioselectivity for trioxygenation of enals were observed when using tryptophan based chiral imidazolidinone catalyst in fluorinated aromatic solvents.

Chapter 5 is the conclusion of the thesis. Furthermore, it discusses future directions of the work is described in Chapter 4.

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