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Final Report Summary - CHIRALTIPOCAT (Chiral Triamino Iminophosphorane Organocatalysts and their Reactions)

Bifunctional organocatalysts1 offer unlimited opportunities for the discovery of powerful new asymmetric carbon-carbon and carbon-heteroatom bond forming reactions due to their capacity of simultaneously organizing and activating electrophilic substrates (through H-bonding interactions) and pro-nucleophilic reagents (through deprotonation), thereby catalysing their stereocontrolled union. However, despite the surge of interest over the last decade, low reaction rates and high catalyst loadings remain the major limitations within the field. Furthermore low acidity pro-nucleophiles or low energy electrophiles often do not react at all in the presence of the existing best bifunctional organocatalysts, owing to negligible activation of the pro-nucleophile by the weak and untunable organic base. During this project, we have developed a new class of modular bifunctional iminophosphorane/thiourea catalysts which offer much broader scope and tunability whilst providing new and enhanced reactivity and maintaining high levels of enantiocontrol. We have used these new bifunctional systems in the first catalytic asymmetric metal-free scalable addition of nitromethane to ketimines (nitro-Mannich or aza-Henry reaction),2 a transformation in which the best-in-class bifunctional organocatalysts or even metal catalysts need high temperatures and/or long reaction times to perform. The resulting enantioenriched α-nitroamines allow the construction of important building blocks for asymmetric synthesis such as 1,2-diamines or α-amino acids bearing at least one fully substituted carbon atom.

Triaminoiminophosphoranes ((R1N)3P=NR 2 ) have been used extensively as organic bases for synthetic transformations. 3 However, to the best of our knowledge, trialkyl- or triaryliminophosphoranes have not, despite also possessing a strongly basic nitrogen. Hence, we envisaged that key to the success of our novel bifunctional catalyst design would be the presence of a strongly Brønsted basic and variable/tunable iminophosphorane (whose basicity could be modified by the use of different phosphines) linked to a variable/tunable H-bond donor group via a variable/tunable chiral scaffold (Fig. 2). Therefore, the overall objective of this work is to develop (by design, synthesis and testing) a new family of potent asymmetric iminophosphorane organocatalysts which can efficiently catalyse a broad range new of synthetically useful asymmetric reactions between pro-nucleophiles (NuH) and weakly electrophilic reagents with exceptionally high enantioselectivity. Furthermore the catalysts can be made in situ via a ‘Click’-type Staudinger reaction of an organoazide and a phosphine to generate the strongly Brønsted basic iminophosphorane from catalytically inactive precursors thus providing a combinatorial method for best catalyst identification and facilitating rapid optimization in any reaction of interest (Fig. 2).

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