Asymmetric Palladium-Catalyzed Reactions for the Synthesis of Pyrrolidines and Other Heterocycles.

Abstract

The synthesis of nitrogen-containing heterocycles is important due to the fact that many biologically active molecules contain these motifs. Over the past 10 years, the Wolfe group has developed efficient and highly diastereoselective Pd-catalyzed carboamination reactions for the synthesis of pyrrolidines, ureas, pyrazolidines, isoxazolidines, morpholines and benzodiazepines in good yields. These transformations involve syn-insertion of an alkene into a Pd–N bond of an intermediate Pd-amido species followed by C‒C bond forming reductive elimination. However, enantioselective variants that involve syn-aminopalladation are rare, and only two reports of enantioselective syn-aminopalladation have appeared in the literature. An enantioselective synthesis of 2-(arylmethyl)- and 2-(alkenylmethyl)pyrrolidines via Pd-catalyzed alkene carboamination reactions of N-Boc-pent-4-enylamines and aryl or alkenyl bromides is described. These transformations generate enantiomerically enriched pyrrolidine products with up to 94% ee. The application of this method has been demonstrated for the concise asymmetric synthesis of phenanthroindolizidine alkaloid (‒)-tylophorine. Studies on asymmetric Pd-catalyzed desymmetrization reactions for the formation of cis-2,5-disubstituted pyrrolidines are also described. A new enantioconvergent route for the asymmetric synthesis of (+)-aphanorphine has been accomplished using an asymmetric carboamination/Friedel-Crafts alkylation strategy. Enantioselective Pd-catalyzed carboamination reaction of a racemic aminoalkene derivative provides a 1:1 mixture of enantiomerically enriched diastereomers. This mixture of diastereomers is then converted to one stereoisomer via Friedel-Crafts reaction, which generates a quaternary stereocenter. Three additional steps provide the natural product. Lastly, studies on asymmetric Pd-catalyzed reactions for the enantioselective synthesis of imidazolidin-2-ones, isoxazolidines, pyrazolidines and tetrahydrofurans are described. Promising ligand scaffolds have been identified and promising leads are being followed up by current group members.