The design and synthesis of C₃ symmetric ligands for lanthanide Lewis acid catalysis of the inverse demand hetero Diels-Alder reaction




Clouston, Laurel L.

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The inverse demand hetero Diels-Alder reaction has been shown to be catalysed by commercially available, air-sensitive lanthanide Lewis acid catalysts such as Yb(fod)₃ . To date there have been no reported examples of enantioselective Lewis acid catalysed reactions of ethyl vinyl ether with crotonaldehyde, the inverse demand hetero Diels-Alder reaction of interest. This Diels-Alder reaction yields dihydropyran products which are key in the synthesis of a number of natural product target molecules, such as carbohydrates. The lack of stereospecificity achieved with known chiral NMR shift reagents has been attributed to fluxional behaviour of the ligands on the large lanthanide metal centre. This lack of conformational rigidity was proposed to be controlled by the use of sterically demanding C₃ symmetric multidentate ligand systems. By carefully designing a suitable ligand system the binding of the crotonaldehyde moiety in the Lewis acid catalysed reaction was anticipated to occur with facial selectivity, resulting in enantioselective Diels-Alder products. It was determined that lanthanide complexes of fluorinated β-diketone ligands with sufficiently low pKa's effectively catalyse the desired inverse demand hetero Diels-Alder reaction. These functionalities were incorporated into a multidentate, achiral, C₃ symmetric ligand system which upon lanthanide complexation was shown to be an air-stable efficient Lewis acid catalyst. Two chiral C₃ symmetric ligand systems were also prepared but were shown to be unsuitable for lanthanide substitution due to insufficiently robust functionalities present in the ligand framework, such as sulfonyl esters and Molecular modelling studies of these ligand systems reveal that the incorporation of camphor into the ligand framework is ideal for the preparation of a facially selective aldehyde binding site. Thus, concluding work probed other possible ligand functionalities which would result in camphor containing, chiral, C₃ symmetric ligand systems that are stable as lanthanide Lewis acid complexes. This new class of ligand promises to be of interest as chiral C₃ symmetric ligand systems for substitution on lanthanide metal centres have yet to be reported. This work summarises several useful synthetic strategies for the preparation of chiral C₃ symmetric ligands in multigram quantities. The application of these higher order symmetry ligands in enantioselective catalysis remains an important area of research.



Lewis acids, Ligands, Diels-Alder reaction