Asymmetric transfer hydrogenation of ketones : Catalyst development and mechanistic investigation

• Main Author: Ahlford, Katrin
• Format: Doctoral Thesis
• Language: English
• Published: Stockholms universitet, Institutionen för organisk kemi 2011
• Subjects: Asymmetric catalysis; reduction; amino acid; rhodium; mechanistic investigation; kinetic study; Organic chemistry; Organisk kemi
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-55412; http://nbn-resolving.de/urn:isbn:978-91-7447-234-9

The development of ligands derived from natural amino acids for asymmetric transfer hydrogenation (ATH) of prochiral ketones is described herein. In the first part, reductions performed in alcoholic media are examined, where it is found that amino acid-derived hydroxamic acids and thioamides, respectively, are simple and versatile ligands that in combination with [RhCp*Cl2]2 efficiently catalyze this particular transformation. Selectivities up to 97% ee of the corresponding secondary alcohols are obtained, and it is furthermore observed that the two different ligand classes, albeit based on the same amino acid scaffold, give rise to products of opposite configuration. The highly interesting enantioswitchable nature of the two abovementioned catalysts is studied in detail by mechanistic investigations. A structure/activity correlation analysis is performed, which reveals that the diverse behavior of the catalysts arise from different interactions between the ligands and the metal. Kinetic studies furthermore stress the catalyst divergence, since a difference in the rate determining step is established from initial rate measurements. In addition, rate constants are determined for each step of the overall reduction process. In the last part, catalyst development for ATH executed in water is discussed. The applicability of hydroxamic acid ligands is further extended, and catalysts based on these compounds are found to be efficient and compatible with aqueous conditions. The structurally even simpler amino acid amide is also evaluated as a ligand, and selectivities up to 90% ee are obtained in the reduction of a number of aryl alkyl ketones. The very challenging reduction of dialkyl ketones is moreover examined in the Rh-catalyzed aqueous ATH, where a modified surfactant-resembling sulfonylated diamine is used as ligand, and the reaction is carried out in the presence of SDS-micelles. A positive effect is to some extent found on the catalyst performance upon addition of phase-transfer components, especially regarding the catalytic activity in the reduction of more hydrophobic substrates. === At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: In press.