Non–nucleophilic grignard synthesis of chiral bridged pyridine–oxazoline ligands for asymmetric catalysis
Sutton, Grace
Sutton, Grace
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Publication Date
2024-08-26
Type
doctoral thesis
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Abstract
The enantioselective synthesis of chiral compounds, such as those required by the pharmaceutical industry, is an important tool in synthetic organic chemistry. Chiral catalysis is one tool used to achieve these syntheses and as such development of chiral enantiopure ligands is of upmost importance. Pyridine–oxazoline ligands have found widespread application in asymmetric catalysis. Surprisingly, however, research into PYOX ligands containing a carbon spacer between the pyridine and oxazoline rings has remained limited to just a few reports in the literature, and an extensive investigation into their synthesis and use as asymmetric catalysts has never been completed. Chapter 2 details the development of a synthetic route to novel bridged pyridine–oxazoline ligands. The ligands were prepared in two efficient steps (Scheme 1), initially preparing 2– pyridyl alkylnitriles, followed by their conversion into oxazolines ligands using chiral amino alcohols and zinc chloride. The 2–pyridyl nitriles were prepared via a novel SNAr alkylation reaction of 2–bromopyridine with alkyl nitriles using methylmagnesium chloride as a non– nucleophilic base in conjunction with an amine mediator. Metal complexes of these ligands were applied to several transition–metal catalysed test reactions including the allylic alkylation, Alder–Ene, Henry and the cyclopropanation reaction. The palladium complexes gave good conversions (up to 100%) and moderate enantioselectivities (up to 68%) in the asymmetric allylic alkylation reaction. This research has resulted in a recent publication in Synlett. The copper complexes of these ligands gave modest conversions (up to 73%) but low ee values (32%) in the asymmetric Alder–Ene. In the asymmetric Henry reaction, the copper complexes provided high conversions (up to 97%) and moderate ee values (up to 68%). The ligands were also screened in the asymmetric cyclopropanation reaction, where conversions of up to 84% were achieved, but low ee values (up to 30%). The work clearly established that functionalisation on the bridging carbon has a substantial impact on the resulting catalysts stereoselectivity. Scheme 1: Two–step synthetic route to chiral PYOX ligands Chapter 3 provides an in–depth exploration of the synthesis of phenyl–substituted bridged PYOX ligands. The synthesis of the nitriles again used a SNAr reaction. The corresponding phenyl–substituted bridged PYOX ligands were successfully synthesized. These ligands were very liable with easy reaction at the acidic bridgehead C–H. This led to difficulty in isolating single stereoisomers of the ligands. The discovery of zinc complexes of the ligands opened up an alternative approach for isolation of zinc complexes of single stereoisomers of these ligands (Scheme 2). This newfound method facilitates the isolation process but also allows their application as catalytic precursors in asymmetric catalytic reactions. Scheme 2: Synthesis of a phenyl–substituted PYOX–ZnCl2 ligand. In Chapter 4, a novel three–step synthetic pathway for the production of alkyl phenyl– substituted bridged PYOX ligands is outlined (Scheme 3). The ligand synthesis allowed for two stereochemistries at the bridgehead with a single chiral configuration at the oxazoline. The resulting diastereomers could in most cases be separated allowing access to single enantiomers of diastereomers for testing. The stereochemistry of the stereocentre at the bridging carbon of a novel PYOX ligand was determined by X–ray crystallography of a PYOX–CuCl2 complex. The ligands were applied to three asymmetric reactions and the catalytic results are reported.
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University of Galway
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Attribution-NonCommercial-NoDerivatives 4.0 International