The Development of Reactions for the Stereoselective Synthesis of Heterocycles and Benzylic Amines, and Exploration of Bisisoxazolidines as Small Molecule Transcriptional Activation Domains.

Abstract

Chapter 1 provides a brief introduction. Chapters 2 and 3 of this thesis describe the development new methods for the synthesis of nitrogen containing heterocycles via palladium catalyzed carboamination reactions. The development of conditions for the synthesis of functionalized pyrrolidines from N-protected gamma-aminoalkenes and aryl bromides or triflates mediated by weak base and palladium catalysis is described in Chapter 2. These conditions, which use Cs2CO3 or K3PO4 in place of the strong base NaOtBu, tolerate the presence of a broad array of functional groups and significantly expand the scope of the methodology. Chapter 3 describes the development of a four-step synthesis of cis-3,5-disubstituted morpholines from enantiomerically pure amino alcohols. The key step in the synthesis is a Pd-catalyzed carboamination reaction between a substituted ethanolamine derivative and an aryl or alkenyl bromide. The morpholine products are generated in good diastereoselectivity with full retention of enantiopurity. This chapter also describes the synthesis of fused bicyclic morpholines, 2,3- and 2,5-disubstituted morpholines, and 3,4-dihydro-2H-1,4-oxazine products. Chapter 4 describes the development of a simple step-wise procedure to achieve a room temperature Curtius rearrangement of benzylic and heteroarylmethyl carboxylic acids. The developed conditions provide an alternative to previously described one-pot procedures that require heating or the use of Lewis acids, and the mild conditions allow the Curtius rearrangement to occur while preventing the formation of unwanted ester byproducts or other deleterious side reactions. The investigation of synthetic small molecule transcription activation domains (TADs) is described in Chapter 5. The synthesis of a small library of compounds intended to replicate key aspects of potent natural TADs is described. The compounds are functionally evaluated as either activators or inhibitors of transcription in cells. Chapter 6 describes efforts to expand the scope of tandem Wittig rearrangement/aldol reactions to allow the synthesis of anti-α-alkyl-α,β-dihydroxy esters and anti-α-alkyl-α,γ-dihydroxy esters. Strategies focusing on the use of dialkyl acetals or Lewis acid activated aldehydes as electrophiles are discussed. An alternative approach involving use of Ti, Al, or Sc enolates as nucleophiles is reported. Preliminary work on the utilization of pyridinium salt electrophiles for the preparation of substituted piperidines is also discussed.