DIRENICC

Direct Enantioselective N-Acyl Iminium Cyclisation Cascades

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 Obiettivo del progetto (Objective)

'We wish to develop new asymmetric Brønsted acid catalysed cyclisation reactions through direct condensation that will allow the efficient and highly enantioselective construction of azabicyclic and azaspirocyclic structures from readily available starting materials. This will constitute a new, powerful and broadly applicable organocatalytic asymmetric strategy to such target molecules. The concept of our proposal is to generate and exploit reactive N-acyl iminium ions in cyclisation reactions whereby the chiral environment of an associated chiral conjugate base of a Brønsted acid HA* governs enantioselectivity. The starting materials for the reaction sequence would be readily available ketoesters (or ketoacids) and a primary amine tethered to a suitable pi-nucleophilic trap. Initial condensation of the starting materials would an enamide intermediate. On protonation by HA* in a low polarity solvent, tight ion pairing of the N-acyl iminium ion with the chiral conjugate base of the Brønsted acid should occur. Provided there is sufficient ordering and effective facial differentiation in this ion pair, attack of the pendant pi-nucleophile will give rise to enantioselectivity in the (irreversible) cyclisation step. With at least three points of diversity, numerous multicyclic structures bearing additional functionality and spectator groups can be readily accessed. This will enable the repeated application of the method in target synthesis. During the course of the Fellowship, through physical organic chemistry techniques and molecular modelling calculations we would like to elucidate the mechanistic pathway and origins of stereocontrol. Finally we wish to apply the methodology in the formal synthesis of an alkaloid natural product. Therefore this multidisciplinary Fellowship project will involve the development of innovative asymmetric organic methods, physical organic chemistry, computational chemistry and target oriented synthesis.'