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

[摘要] 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 pyrrolidinoneproducts 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.

[发布机构] University of Michigan

[效力级别] Enantioselective Synthesis of Diols and Amino-Alcohols Via Asymmetric Wittig/Aldol and Wittig/Mannich Reactions

[关键词] Stereoselective Synthesis of Heterocycles Via Carboamination and Carboetherification Reactions;Enantioselective Synthesis of Diols and Amino-Alcohols Via Asymmetric Wittig/Aldol and Wittig/Mannich Reactions;Chemistry;Science;Chemistry