Development of Reactions for the Stereoselective Synthesis of Heterocycles and Enantioselective Synthesis of Diols and Amino-Alcohols.

Part One of this thesis describes the synthesis of heterocycles containing two heteroatoms via palladium-catalyzed carboamination and carboetherification reactions. The development of a new stereoselective synthesis of cis- and trans-disubstituted pyrazolidines from N-butenyl hydrazine derivatives is described. The products are generated with good to excellent diastereoselectivity and chemical yield and can be transformed to synthetically useful pyrazolines or 1,3-diamines via oxidation or reduction. Importantly, these experiments also demonstrate that allylic strain interactions can be manipulated through a simple substrate modification (N2-protection vs. no N2-protection) to allow for control of relative stereochemistry in Pd-catalyzed reactions. Upon completion of this work, we became interested in whether manipulation of allyic strain as a means to control product stereochemistry would be applicable in the synthesis of other heterocycles. Thus, application of this concept in isoxazolidine synthesis is described. A new method for pyrrolidinone synthesis via Pd-catalyzed carboamination of γ,δ-unsaturated amides with aryl or alkenyl bromides is also described. The pyrrolidinone products are accessed in good to excellent yields, and have the potential to be useful precursors in a variety of other interesting transformations. Part Two of this thesis describes new methods for the enantioselective synthesis of diols and amino-alcohols. The research presented in Chapters VI-VII describe development of a tandem reaction sequence towards a new method for the formation of enantioenriched α-alkyl-α,β-dihydroxy esters (Wittig rearrangement/aldol reactions) and α-alkyl-α-hydroxy-β-amino esters (Wittig rearrangement/Mannich reactions) involving reaction of chiral glycolate esters with various electrophilic coupling partners. The asymmetric Wittig/Aldol reactions are the first examples of tandem reactions involving enolate [1,2]-Wittig rearrangements that afford nonracemic products, and are also the first asymmetric aldol reactions of α-alkyl-α-hydroxy ester enolates that generate unprotected diol products with both high syn:anti selectivity and high ee. In addition, these results have led to the development of the first asymmetric Mannich reactions of ester enolates that afford both syn- and anti-α-alkyl-α-hydroxy-β-amino esters with both high dr and ee. These are also the first examples of asymmetric Mannich reactions that proceed via tetrasubstituted enolboronate intermediates.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/77680/1/ncg_1.pd