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Open Access Publications from the University of California

Studies Toward the Synthesis of Ineleganolide

  • Author(s): Horn, Evan Joseph
  • Advisor(s): Vanderwal, Christopher D
  • et al.

The dissertation describes efforts to develop a chemical synthesis of the marine natural product ineleganolide. Chapter 1 of the dissertation focuses on the biological origin of ineleganolide and the interrelationship between ineleganolide and other related norcembranoids natural products including those isolated from species of Sinularia soft corals. In addition to the biosynthesis of ineleganolide, our strategy for the chemical synthesis of the natural products is described. Our synthetic strategy is centered around three key transformations; 1) a diastereoselective Mukaiyama-Michael reaction to join together two complex chiral fragments; 2) an epimerization at the α-position of a lactone by an enolization/kinetic protonation sequence; 3) an intramolecular Mukaiyama-aldol-type cyclization, mediated by the thermal fragmentation of a β-alkoxy vinyl triflate to generate a highly electrophilic oxocarbenium ion.

Chapter 2 of the dissertation describes the development of efficient diastereoselective syntheses of the two chiral coupling partners for the convergent Mukaiyama-Michael reaction.

Chapter 3 of the dissertation discusses the successful coupling of the two fragments to provide an advanced intermediate toward ineleganolide. This intermediate contains all of the carbons in the natural product, and six out of nine of the stereogenic centers with correct configuration. The remainder of this chapter details our unsuccessful efforts to epimerize the C12 stereogenic center of this intermediate by a lactone enolization and kinetic protonation sequence.

In Chapter 4 a modified strategy toward ineleganolide is discussed. We will attempt to open the lactone ring to afford conformation flexibility, hopefully allowing he pivotal cyclization in our synthesis with a substrate that contains the incorrect configuration about the C12 stereocenter. Through great efforts we are able to access substrates to evaluate the key cyclization; however, the instability of each of these substrates forced us to consider alternative methods for the cyclization reaction.

Chapter 5 details our efforts to induce the key cyclization toward ineleganolide using an oxidative coupling of enolate equivalents. While we were able to selectively functionalize substrates for this reaction, the pivotal step was never successfully achieved. In the final half of Chapter 5 we observed an unexpected Reformatsky cyclization reaction of an advanced intermediate. This reaction yields a product f natural product-like complexity that may be related to the ineleganolide architecture via a pinacol shift.

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