Applications of enyne metathesis: Forming new methods and expanding scopes for use in natural product synthesis
Kalbarczyk, Kyle Patrick
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Chapter 1. The biologically active epoxyquinoids are found to be inhibitors of cancer in tumor cell lines. In particular, the pentaketide dimer epoxyquinol A 1 , is known to inhibit angiogenesis (new blood vessel formation) specifically NFκB inhibitors involved with VEGF, believed to be a key requirement in metastasis and tumor growth. The unique 1,3 diene found in the monomer structure of Epoxyquinol A and other epoxyquinoids has led to an enyne metathesis approach to the synthesis of epoxyquinoids. This approach entails the use of asymmetric aldol reactions to install the three stereochemical centers of epoxyquinol followed by a key ring-closing enyne metathesis. The success of this metathesis will allow for vast functionalization and the formation of numerous natural and unnatural products of epoxyquinoids.* Chapter 2. The utility of enyne metathesis has grown tremendously over the years but a few difficulties arise. The cleanup of these reactions requires a good deal of attention. With the help of isocyanides we have developed a method for both quenching metathesis based catalysts and reducing ruthenium content in products to less than 1 ppm. Another problem that has been recently addressed is the use of metathesis substrates that contain free alcohols previously thought to be not capable of undergoing metathesis. In this chapter I will provide examples of not only unprotected alcohols but an accelerating affect so strong that stoichiometric ratios can be dropped to 1:1 of alkyne to alkene. Chapter 3. Enyne metathesis has become a synthetically powerful method for synthesizing conjugated dienes catalytically. However, cross enyne metathesis is limited by the number of substitution patterns of the conjugated dienes synthesized. Using a tandem approach, the combination of cross enyne metathesis and subsequent Ireland ester enolate Claisen rearrangement, new substitution patterns can be accessed, resolving a weakness in cross enyne metathesis. Our research demonstrates the wide versatility of the Ireland ester enolate Claisen rearrangement using conjugated dienes. In addition, we demonstrate stereogenicity transfer to make α-chiral centers. The dienes are all synthesized by enyne metathesis methods previously developed in our labs.* Enyne metathesis furnishes dienes which can be functionalized by cycloadditions. However, the availability of additional, distinct functionalization reactions will increase the versatility of the diene synthesis. In this presentation, the development of a new acid promoted diene functionalization reaction is described. Our findings demonstrate that this is an effective synthesis for a variety of heterocycles and can be conducted in an efficient, one-pot transformation. *Please refer to dissertation for diagrams.