Carboamination Methodology to the Synthesis of 2,5-trans-Pyrrolidines and Isoxazolidines.

Palladium Catalyzed Carboamination;Pyrrolidine Synthesis;Isoxazolidine Synthesis;Hetereocycles;Tandem Reaction;Palladium Catalysis;Chemistry;Science;Chemistry

Lemen, Georgia S.Sanford, Melanie ;

University of Michigan

关键词: Palladium Catalyzed Carboamination;    Pyrrolidine Synthesis;    Isoxazolidine Synthesis;    Hetereocycles;    Tandem Reaction;    Palladium Catalysis;    Chemistry;    Science;    Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/86479/geolemen_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

This thesis details the development of new methods for the synthesis of four classes of biologically relevant heterocycles: 2,5-trans-pyrrolidines, benzofused 1-azabicyclo[3.3.0]octanes, benzofused 1-azabicyclo[4.3.0]nonanes, and 3,5-cis and 4,5-trans isoxazolidines. This methodology inolves palladium-catalyzed carboamination reactions of alkenes bearing pendant heteroatom nucleophiles with aryl/alkenyl halides. The scope and limitations of these new methods are described; models for the stereochemical outcome of these transformations are presented. The synthesis of 2,5-trans-disubstituted pyrrolidines is accomplished via Pd-catalyzed carboamination reactions of 4-(but-3-en-1-yl)oxazolidin-2-ones. The requisite substrates are synthesized in 5 to 8 steps from serine methyl ester, and can be generated in enantiopure form from the nonracemic amino acid. The carboamination reactions between these substrates and aryl or alkenyl halides afford tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one products with up to three stereocenters in excellent diastereoselectivity. The oxazolidinone can be cleaved to yield 2,5-trans-disubstitued pyrrolidines via either reduction or hydrolysis. These heterocyclic products contain an alcohol side-chain, which could be used for further synthetic manipulations.A tandem intramolecular N-arylation/carboamination process allows for the generation of benzofused 1-azabicyclo[3.3.0]octanes and benzofused 1-azabicyclo[4.3.0]nonanes from 1-(2-bromophenyl)hex-5-en-2-amine and 1-(2-bromophenyl)hept-6-en-3-amine derivatives. A straightforward one-pot reaction with a single catalyst effects the tandem coupling of these substrates with a variety of aryl chlorides. This affords tricyclic products in moderate to good yield and diastereoselectivity. These transformations illustrate the influence of amine nucleophilicity on the relative rates of carbon nitrogen bond forming reductive elmination vs. alkene aminopalladation of palladium(aryl)(amido) complexes.Finally, the synthesis of substituted isoxazolidines via Pd-catalyzed carboamination reactions of O-butenyl hydroxylamines is described. These reactions afford cis-2,5-disubstitued products in excellent diastereoselectivities (up to >20:1), which are considerably higher than those obtained in related carboetherification reactions of N-butenyl hydroxylamines. Studies on the influence of the nitrogen subsituent on the stereochemical outcome of both the carboamination and the carboetherication reactions are described, along with experiments that have led to an expansion in scope of previously described carboetherification reactions of N-butenyl hydroxylamines.