Enantioselective Grignard Reactions in Total Synthesis: Development of Asymmetric Methodology, Exploration of New Targets and their Biological Testing

In Chapter 1, a study investigating the effects of variation of the halogen atom of the Grignard reagent revealed that the enantioselectivity of the 1,2-addition reaction could be increased if a ‘mixed-halogen’ stepwise addition method was used. Improvements were noted in over 70% of different Grignard reagent/ ketone combinations, with increases of up to 23% ee achieved. There was no discernible trend observed for a single halide (Cl, Br or I) performing better than the others in terms of selectivity. Developments to the stepwise asymmetric methodology included the discovery of the ability to use an inexpensive, “sacrificial” Grignard reagent to deprotonate the ligand, thereby halving the amount of the required, potentially valuable, Grignard reagent for 1,2-addition. Further developments to the method resulting in a new ‘optimised stepwise addition’ saw drastic improvements, increasing the enantioselectivity in 100% of reactions tried, with variations to the ligand, ketone and Grignard reagent all successful. In Chapter 2, two asymmetric routes were modified and optimised for the large scale synthesis of (R,R,R)-a-tocopherol, producing almost 0.5 g of the target compound in 82 : 18 dr (RRR: SSS). A key adjustment to the synthesis was the use of EtMgBr as a “sacrificial” Grignard reagent. Thus, 50% of the required Grignard reagents for the synthesis (each prepared over 5 steps) were preserved, marking significant cost and time savings. An asymmetric synthesis of the drug target vatiquinone was developed from commercially available starting materials and incorporated the use of “sacrificial” Grignard reagent. This 7 step route constitutes the first reported enantioselective total synthesis of this target. In Chapter 3, the highly pure (R,R,R)-a-tocopherol material prepared in Chapter 2 was applied in wound healing studies of HaCaT cells using the scratch assay method in collaboration with Dr Margaritha Mysior and Prof Jeremy Simpson of the School of Biology and Environmental Science, UCD. Three other tocopherol sources plus controls were tested: DL-(all-rac)-a-tocopherol, DL-a-tocopherol acetate and mixed tocopherols (low a-type). Both (R,R,R)-a-tocopherol and the mixed tocopherols had the fastest rate of wound closure, indicating that either the (R,R,R) stereoselectivity of the tocopherols or the presence of ¿-tocopherol (or both) play an important role in wound repair. In addition, DL-a-tocopherol acetate was found to have no impact whatsoever on wound healing and instead slightly hindered the natural healing process. In Chapter 4, a new ligand-mediated, single metal-based Grignard methodology was developed for the enantio- and chemoselective 1,4-addition to a,ß-unsaturated ketones. Up to 92% ee and 100% conversion to the 1,4-products have been obtained for the addition of alkyl Grignard reagents to aryl-alkyl enones in the absence of a metal catalyst (e.g. copper). Application of the ‘optimised stepwise addition’ method was found to increase enantioselectivities by up to 47% ee.