Nazarov reaction : Development towards asymmetric cyclopentannelation using chiral auxiliaries and metal catalysis

Thesis (Ph.D.)--University of Hawaii at Manoa, 2008.Five-membered rings are common structural motifs in many important natural products. In general, the synthesis of highly functionalized five-membered rings, particularly with stereocontrol, is not as highly developed as that for six-membered rings. Thus, the pursuit of new methodologies towards this end is of great importance in synthetic chemistry. While there are several strategies for making five-membered rings, the Nazarov reaction is one that is particularly efficient in installing multiple stereogenic centers through a single operation. This thesis describes some recent progress for this reaction.In Chapter 1, the Nazarov reaction is introduced. A mechanism of the reaction is first described and a discussion of recent advances follows. The recent advances are discussed in the context of new variations of the reaction and the pioneering work towards asymmetric cyclopentannelation.In Chapter 2, we discuss how the synthesis and screening of a number of sugar-derived auxiliaries have paved the way to two superior chiral auxiliaries for the allene and the optimization of the reaction conditions for the Nazarov cyclization. The scope of each sugar-derived allene under the optimized conditions has been demonstrated through their reactions with a variety of morpholino enamides and in one case, an alpha,beta-unsaturated butyrolactone. Additionally, we report a more detailed, well-substantiated mechanistic hypothesis for the asymmetric allenyl ether Nazarov reaction that rationalizes the stereochemical outcome of our products. This model will aid in the design of simpler chiral allenyl ethers with non-sugar based scaffolds.In Chapter 3, we describe a triply-convergent cyclopentannelation reaction. This work is an extension of an existing methodology developed by our group that expands the scope and versatility of our allenyl ether Nazarov reaction.Lastly, in Chapter 4 we discuss ongoing work towards the development of a catalytic asymmetric Nazarov cyclization. Two approaches are described using alpha-alkoxy-substituted divinyl ketones. In the first approach, asymmetry is introduced through the use of chiral oxophilic Lewis acids. In the second approach, chiral ligands are employed as a means for transferring chiral information in our unique palladium(II)-catalyzed Nazarov reaction.Includes bibliographical references.Also available by subscription via World Wide Web233 leaves, bound 29 c