Asymmetric Conjugated Additions of Exocyclic Enones with Alkylzirconocene Nucleophiles

Asymmetric conjugated additions are very intriguing transformations with great potential for synthesis of biological or pharmaceutical products. With the potential to form carbon-carbon bonds yielding chiral products these transformations have been thoroughly studied by several groups over the years. Many groups have developed different methodologies involving several organometallic reagents (Grignard reagents, trialkylaluminiums and dialkylzincs). Our group has developed an alternative copper catalysed strategy for cyclic and linear substrates utilizing alkylzirconocene nucleophiles with a phosphoramidite chiral ligand. By mixing the Schwartz reagent (Cp2ZrHCl) with an alkene, we can form a versatile range of alkylzirconocene nucleophiles by hydrometallation. This is a comparative advantage as it increases the variety of possible nucleophiles and therefore products obtained.
In this project I will aim to adapt the developed strategy for exocyclic substrates in order to obtain products with high enantiomeric excess and yield. Even though the transformation is seemingly similar there are a few further complications. Firstly, in this reaction two stereocentres are formed in a single step leading to diastereoisomers. The diastereomeric ratio now becomes an important variable to consider. Furthermore, there is considerably less literature regarding this transformation when compared to asymmetric conjugate additions of cyclic or linear substrates. This fact presents the currently studied reaction as a relatively unknown transformation in the chemical world.
The first objective in this project consists in developing (via ligand design and possibly statistical modelling) a chiral ligand to achieve high enantiomeric excess and yield. First, I will find a lead ligand which achieves at least moderate enantiomeric excess. After synthetizing such ligand, I will derivatize it and find an optimal structure which achieves high levels of yields and enantiomeric excess.
After developing an optimal ligand for the studied reaction, I will be testing the robustness of this methodology using a scope of exocyclic substrates and different alkenes and alkynes. I will address on the strengths and weaknesses of this chemistry.
Additionally, I will try to elucidate on the mechanism of this reaction by several techniques often used in mechanistic studies. These techniques might include kinetic experiments such as initial rates, Variable time normalisation analysis (VTNA) or kinetic isotope effects and DFT calculations between other possible techniques. I will be highlighting similarities and differences between this mechanism and the comparable reaction of asymmetric conjugated addition of linear enones, developed previously by the group.
A simple and versatile reaction as the one I am studying can generate two stereo centres in one step, something not only very fascinating in a chemical standpoint but also a very useful stereoselective sp3 carbon-carbon bond formation reaction which could help meet the demands of an ever-growing synthetic industry.
This project falls within the EPSRC field of physical sciences in the areas of catalysis and synthetic organic chemistry.
Vertex Pharmaceuticals is involved in this project.