Novel methods for the synthesis and functionalisation of sulfoximines and sulfonimidamides: new pharmacophores for the medicinal chemist’s toolbox

Izzo, Flavia (2019) Novel methods for the synthesis and functionalisation of sulfoximines and sulfonimidamides: new pharmacophores for the medicinal chemist’s toolbox. PhD thesis, University of Nottingham.

[img] PDF (Thesis - as examined) - Repository staff only until 17 July 2021. Subsequently available to Repository staff only - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (10MB)

Abstract

Sulfoximines, the monoaza analogues of sulfones, have recently gained considerable recognition as a new and versatile structural motif in the life sciences.Therefore our group, in collaboration with Bayer AG (Berlin), is investigating a simple scalable and efficient methodology to make valuable chiral sulfoximines with control of stereochemistry.

In the first chapter of this report we describe a novel synthetic route towards sulfoximine synthesis. Two types of key precursors are investigated: sulfoxides and phenylalanine templates. With these substrates in hand, we investigated their use in S(O)=N transfer chemistry to obtain enantioenrieched sulfoximines.

Synthetic methodology for sulfoximine preparation has progressed significantly over the last decade. In contrast, sulfonimidamides, the monoaza-analogues of sulfonamides have been neglected in the life sciences so far, even though they seem to offer very interesting properties. It can be speculated that the use of sulfonimidamides in the life sciences has been hampered substantially by the lack of commercial availability and limited synthetic methods. In this context, we also investigated a facile synthesis of NH sulfonimidamides by NH transfer to tertiary sulfinamides. Racemic NH sulfonimidamides have been prepared in yields from good to excellent in a one-pot transformation.

Given the limited availability of synthetic methods to produce enantioenrieched sulfonimidamides, we expanded our work towards the synthesis of tertiary enantiopure sulfinamides, which will be used as starting material for sulfonimidamide synthesis.

Sulfonimidamides, like sulfoximines, offer an additional point for substitution, the =NH group. We have now developed new methods for the functionalisation of this NH group by arylation, alkylation, trifluoromethylation, cyanation, sulfonylation, alkoxycarbonylation, and aminocarbonylation.

Finally, to gain further insight into the medicinal relevant properties of sulfonimidamides, a variety of structurally diverse sulfonimidamides were analysed in the same in vitro panel.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Stockman, Robert A.
Keywords: Chiral sulfoximines; Stereochemistry; Sulfoximine synthesis; Sulfonimidamides
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry > QD415 Biochemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 55798
Depositing User: Izzo, Flavia
Date Deposited: 17 Jul 2019 04:40
Last Modified: 07 May 2020 12:30
URI: http://eprints.nottingham.ac.uk/id/eprint/55798

Actions (Archive Staff Only)

Edit View Edit View