New methodologies for hydrogen borrowing cascades in the synthesis of amine scaffolds and its application in Natural product and drug synthesis

Lead Research Organisation: University of Oxford
Department Name: Synthesis for Biology & Medicine CDT

Abstract

This project falls within the EPSRC Synthetic Organic Chemistry research area

The Donohoe group (University of Oxford) has established that pentamethylphenyl-ethanone acts as a privileged carbonyl scaffold. The Ortho substituents of the aromatic ring force it out of conjugation with the carbonyl, these substituents then sterically block the ketone from acting as an electrophile giving a unique reactivity profile. The electron rich nature of the ring allows for a retro-Friedel-Craft reaction to occur upon addition of bromine. This means the group can be unmasked as a highly reactive acid bromide when desired.

These properties have been best utilised in hydrogen borrowing (HB), here transition metal can reversibly oxidise substrates to give an active intermediate which can be transformed and the hydrogen returned in a redox efficient process. In HB carbonyl alkylations The Ph* ketones properties limit the redox and aldol processes available giving single products where other ketones produce a variety of C-C bond formations and variable oxidation states. This can replaces toxic alkyl halides in enolate alkylation or the need for stoichiometric oxidants and reductants in aldol chemistry.

Within the group the use of 1,4 and 1,5 diols in HB has been used to create N-heterocycles and carbocycles in formal [N+1] cyclizations. These form either 2 C-N or 2 C-C bonds respectively. We here propose that the use of amino ketones with the Ph* motif along with diols could allow for a diverse set of ring formations by the formation of both C-C and C-N bonds in a single pot. Previous work on ring formation suggests the reductions could be highly stereoselective. Preliminary research established that alpha amino Ph* ketone can be synthesised as a bench stable oil in 2 steps.

The Donohoe group has a history of synthesising elaborate natural products. These cyclizations would represent a novel retrosynthetic disconnection which could allow for highly divergent synthesis of medicinally relevant saturated N-heterocycles. The group has already used HB chemistry for the novel synthesis of small natural products (Lycorane g and Coniine). To build on this work we hope to combine the strategic use of HB, carbonyl chemoselectivity and cleavage that the Ph* Ketone allows us in the synthesis of alkaloid natural products.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/P510609/1 30/09/2016 29/09/2021
1923106 Studentship EP/P510609/1 30/09/2017 30/03/2022 Ciaran Lunt