Enantioselective Decarboxylation of β-Keto Esters with Pd/Amino Alcohol Systems: Successive Metal Catalysis and Organocatalysis

• Published in: Chemistry : a European journal 2008-03, Vol.14 (9), p.2699-2708
• Main Authors: Kukula, Pavel, Matoušek, Václav, Mallat, Tamas, Baiker, Alfons
• Format: Article
• Language: English
• Subjects: alkaloids; Amino Alcohols - chemistry; asymmetric catalysis; Catalysis; Decarboxylation; Esters - chemistry; Ketones - chemical synthesis; Ketones - chemistry; kinetic resolution; Kinetics; Molecular Structure; Organometallic Compounds - chemistry; palladium; Palladium - chemistry; Stereoisomerism; Time Factors; β-keto esters
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200701652

The kinetics and mechanisms of one‐pot cascade reactions of racemic β‐keto esters to give chiral ketones in the presence of Pd/C‐chiral amino alcohol catalyst systems were studied. Transformation of 2‐methyl‐1‐tetralone‐2‐carboxylic acid benzyl ester (1) into 2‐methyl‐1‐tetralone (4) in the presence of Pd/C and cinchona alkaloids or ephedrine was chosen as a model reaction. After the first reaction step, the Pd‐catalysed debenzylation of 1 to afford the corresponding β‐keto acid (2), there are two possible reaction routes that may be catalysed by the chiral amino alcohol in solution or by Pd0 sites on the metal surface in cooperation with the adsorbed amino alcohol. The reaction intermediate 2 was synthesized, and the kinetics of decarboxylation were followed by NMR, UV and IR spectroscopy. The studies revealed that the role of Pd is to trigger the reaction series by deprotection of 1. The subsequent dominant reaction route from the racemic β‐keto acid 2 to the chiral ketone 4 is catalysed by the chiral amino alcohol in the liquid phase. It is shown that kinetic resolution of the diastereomeric salt of rac‐2 and the chiral amino alcohol plays a key role in the enantioselection. High enantioselectivity necessitates an amino alcohol/rac‐2 ratio of at least 2. A high ratio favours the formation of 1:1 amino alcohol/acid diastereomeric complexes, and the second amino alcohol molecule may be responsible for the enantioselective protonation of 2 in the diastereomeric complex. Pull the trigger: Kinetic analysis and in situ spectroscopy (NMR, UV, ATR‐IR) reveals that the cascade reaction (see figure) is triggered by debenzylation of the β‐keto ester on Pd, but that decarboxylation of the keto acid is catalysed by the chiral base in solution.