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Final Report Summary - DIRENICC (Direct Enantioselective N-Acyl Iminium Cyclisation Cascades)

The main objectives of the project were to develop new highly enantioselective powerful methodologies, such as asymmetric Bronsted acid catalysed cyclisation cascades in order to access to complex heterocyclic core structures.

During the fellowship we successfully developed three new cyclisation cascades catalysed by chiral Bronsted Binol phosphoric acids. These methodologies allowed us to access to a large variety of complex azacyclic compounds as summarised in scheme 1.

Starting from an amine bearing a β-ketoester 1 and a lactone 2, we were able to synthesise new tetracyclic compounds 3 via a N-acyl iminium cyclisation cascade with good yield and moderate enantioselectivity (scheme 1, a)).

Using a similar methodology but starting from a tryptamine urea derivative 4 and a vinyl ketone 5 we successfully prepared a range of azabicycles 6 in good yield and excellent enantioselectivity, via an enantioselective Michael addition, iminium cyclization cascade (scheme 1 b)). This work has been submitted for publication to Angewandte Chemie International Edition.

In addition, we developed the first asymmetric nitro-Mannich / lactamisation cascade, starting from nitroester 7 and an imine 8 with moderate to good yields and enantioselectivities (scheme 1, c)).

Furthermore, we synthesised some new chiral phosphoric acid derivatives and evaluated their efficiency in a range of asymmetric transformations. The best results were obatained for the cyclisation of nitrones (scheme 2).

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THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom
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