58th Annual Report on Research 2013 Under Sponsorship of the ACS Petroleum Research Fund

Annual Report

We have been developing an integrative atom-transfer catalysis program at Georgia State University under the auspice of ACS Petroleum Research Fund.

1.                   Iron-catalyzed stereoselective atom transfer reactions for organic synthesis

Unlike oxygen atom transfer, the stereoselective nitrogen atom transfer to organic compounds, especially olefins and dienes has been rarely explored.  However, it is a very important research topic because numerous biologically active alkaloids and pharmaceuticals contain stereogenic nitrogen atoms.  We are setting up a promising research program to apply the newly designed iron (one of the most abundant metals on earth) catalysts for stereoselective nitrogen atom transfer.

Late last year, we published some of preliminary results of iron-catalyzed stereoselective aminohydroxylation of olefins with functionalized hydroxylamines (J. Am. Chem. Soc. 2013, 135, 3343).  Since then, we have been in the process of developing a general and unique approach for stereoselective aminohydroxylation for a wide range of olefins and dienes and recently published an iron-catalyzed asymmetric indole aminohydroxylation reaction (Org. Lett. 2013, 15, 3910). This discovery allows us to synthesize a variety of 3-amino indoline based natural products and pharmaceutical agents a group of biologically important complex molecules that are currently obtained only by chemical resolution.

2.                   Copper-Catalyzed CF₃ Group Transfer for Selective Construction of Trifluoromethylated Stereogenic Centers

Fluorinated compounds and perfluorinated alkyl groups (especially the CF₃ group) are often associated with unique electronic, lipophilic and metabolic properties that are desirable in drug discovery.  Therefore, extensive research efforts have been devoted to selectively incorporate the CF₃ group to organic molecules. In spite of many achievements in this area, the stereoselective functionalization of olefins, dienes, and imines with generation of the CF₃-containing stereogenic centers has not been reported.  We recently published a copper(I)-catalyzed diastereoselective hydroxytrifluoromethylation of dienes, which is evidently accelerated by bulky mono-phosphine ligands (Chem. Sci. 2013, 4, 2478). This discovery enables expedient transformations from readily available unfunctionalized dienes to allylic alcohol derivatives with CF₃-containing stereogenic centers, which are otherwise difficult to access.  The ligand accelerated effect also allows for the control of reactivity and selectivity by catalyst engineering.

The CF₃ group containing amines and heterocycles are important building blocks for organic synthesis and pharmaceutical research.  Therefore, the imine trifluoromethylation and the direct heteroarene C-H oxidative trifluoromethylation are probably two of the most straightforward approaches to access those building blocks.  We also discovered a copper(II)-catalyzed direct C-H aerobic oxidative trifluoromethylation and an imine trifluoromethylation under anaerobic conditions (Org. Biomol. Chem. 2013, 11, 6242).