Crafting Chiral Space for Asymmetric Induction in a Catalytic Synthetic Reaction, Keynote Lecture 1
Barry Trost’s opening lecture contained a comprehensive review of the many of approaches to asymmetric induction that have been studied by his group. One example in the field of asymmetric allylation chemistry that may be of interest to process chemists concerns the chemistry shown below.
The first time this reaction was run the product was obtained in 90% ee. A repeat run gave a product with much lower ee. The difference in the two reactions turned out to be the age of the butyl lithium (BuLi) used. The original reaction contained BuLi from an old bottle, while the second reaction was carried out using fresh BuLi. The result from the original reaction could be reproduced with fresh BuLi if butanol was added to the reaction mixture. In another twist to this tale the reaction was tried with a lower catalyst loading (0.5 mol %) and the ee of the product improved.
This result was later explained in Guy Lloyd-Jones’s excellent lecture on “Some Mechanistic aspects of Selectivity in Pd-Catalysis”. This was a physical organic examination of asymmetric allylic alkylation reaction and provided some fascinating mechanistic insights. Deuterium labelling experiments showed how enantiomeric substrates of a racemic mixture react at different rates and what might otherwise have been thought to be an indifferent catalyst (in asymmetric induction terms) may in fact just have been used on the wrong substrate. So for example an ee of 50% can arise from one enantiomer (of a racemic mixture of allylic acetates for example) giving 100% ee and the other enantiomer not showing any asymmetric induction.
In a study of the example described by Barry Trost above where the ee of the product increases as the catalyst loading decreases, detailed 31P nmr experimentation led to an understanding of what was happening. When a catalyst with an asymmetric ligand such as the Trost ligand (see below) is used the monomeric form of the catalyst shown below is the
desired form, which creates the asymmetric pocket that allows product with a high ee to be obtained. At low catalyst loadings this form predominates but at higher catalyst loadings an oligomeric form predominates. Solutions of these two forms exhibit different rotations with the monomer having [a]D = + 640 and the oligomer having [a]D = - 150.
Recent Advances in Asymmetric Transfer Hydrogenation, Keynote Lecture 2
Professor Takao Ikariya discussed his work on including a dynamic kinetic resolution of a–substituted ketones. If a racemic a–substituted ketones is subjected to transfer hydrogenation conditions using a chiral ruthenium catalyst [RuCl[(S,S)-Tsdpen](p-cymene)] and triethylamine / formic acid, four possible products ([R,R], [R,S], [S,R], [S,S]) can be formed as shown below. The relative amounts of each product depends on the relative rates of hydrogenation of the two enantiomeric ketones, the rate of inversion of the ketones and the effectiveness of the catalyst in asymmetric induction.
In many cases (X = OH, OCH3, OiPr) over 93% of the product is the [R,R] diastereomer, for X = OAc 85% of the product is the [R,R] product, whilst for X = OBz the reaction is far less effective. In this case the product contains all 4 possible diastereomers ([R,R] 32%, [R,S] 30%, [S,R] 29%, and [S,S] 9%).