Iridium Catalysed Borylation as a Platform for Exploring the Use of Non-Covalent Interactions to Control Regio- and Enantioselectivity

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Genov, Georgi Rosenov  ORCID logo

Transition metal catalysed C-H activation is a highly desirable strategy for the functionalization of organic molecules. It allows for a rapid generation of structurally complex products from simple precursors in an atom- and step-economic fashion. Iridium catalysed borylation of arenes is a powerful yet mild C-H activation transformation which yields synthetically useful boronate esters. Interestingly the selectivity of this reaction is largely based upon steric considerations. As a result, the process is highly effective for 1,3-disubstituted arenes but produces a statistical mixture of regioisomers for 1,2-disubstituted arenes. Non-covalent interactions are a very powerful tool, utilized beautifully in enzymatic catalysis to address issues of regio- and enantioselectivity. In sharp contrast however their utilisation in directing the same aspects of selectivity in transition metal catalysed transformations is rather underexplored. This doctoral thesis aims to explore the use of non-covalent interactions in this setting. Chapter 2 of this thesis discloses the evaluation of an anionic sulfonated bipyridine ligand, previously reported within the group, to act as a hydrogen-bond acceptor to interact with aromatic amides. This interaction was shown to be crucial for the development of a meta-selective borylation process with excellent levels of meta-selectivity seen on three distinct substrate classes: benzylamine, phenethylamine and phenylpropylamine derived amides. Chapter 3 explores the further development of the sulfonated bipyridine scaffold with the introduction of a chiral counter-cation. The approach allows for the formation of a chiral environment around the metal centre via a chiral counter-ion directed catalysis and was demonstrated on the example of desymmetrising iridium catalysed borylation of arenes. The design and development of a modified version of the sulfonated bipyridine ligand bearing a cinchona alkaloid derived counter-cation is presented. The novel ligand design has enabled the borylation of meta-substituted benzhydrylamides and phosphinamides giving enantioenriched products in great enantioselectivities and good yields. When utilised for borylation of ortho-substituted benzhydrylamides, the process was demonstrated not only to be enantioselective, but also regioselective for the meta-position. The reaction represented a rare case of utilising a chiral cation to direct enantioselectivity of a transition metal catalysed process, enabling a challenging enantioselective remote C-H activation to yield highly versatile boronate ester products.

Phipps, Robert
Catalysis, Chiral cation, Borylation, Asymmetric synthesis, Organic chemistry
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge