Enantiospecific SuFEx reactions of sulfonimidoyl fluorides towards sulfonimidamides and sulfoximines
File(s)
Author(s)
Greed, Stephanie Julia
Type
Thesis
Abstract
A key goal in synthetic chemistry is to develop new methods to enable access to underexplored chemical space. The discovery of novel molecular entities is of great importance in medicinal, agricultural, and other chemical industries to more effectively and efficiently tackle the challenges of today’s world. Sulfoximines and sulfonimidamides, the chiral aza-analogues of sulfones and sulfonamides, offer an opportunity to modulate the properties of these ubiquitous S(VI) functional groups. However, until recently they have remained underexplored due to their lack of synthetic and commercial access, especially in enantioenriched forms. In this thesis, the development of new synthetic methods to access sulfoximines and sulfonimidamides are described.
Firstly, the chiral analogues to sulfonyl fluorides, sulfonimidoyl fluorides, were generated from sulfinamide salts, sulfinate salt analogues, and used in a Sulfur Fluorine Exchange (SuFEx) reaction with amines. It was found that the degenerate nucleophilic attack of fluoride ions in solution resulted in inversion of the sulfonimidoyl fluoride and so fluoride ion trapping strategies were employed to prevent racemisation. The resulting enantiospecific reaction sequence was the first facile route to access enantioenriched sulfonimidoyl fluorides and sulfonimidamides.
Secondly, the enantioenriched sulfonimidoyl fluoride intermediates were employed in an enantiospecific S–C bond formation reaction with organometallic reagents to furnish sulfoximines. As part of this study, new enantioenriched sulfinamide salts were generated and the effect of modifying the protecting group on the imide nitrogen was explored. This second SuFEx reaction of sulfonimidoyl fluorides was successful in generating enantioenriched sulfoximines in high yields and with very high ee.
Finally, as part of an ongoing project, the SuFEx reaction of an isoquinoline sulfonimidoyl fluoride with amines is being explored as a route to generate a library of analogues of a sulfonamide-containing marketed drug, Fasudil. These sulfonimidamide-containing compounds are to be generated and their physicochemical properties tested to determine their value as functional groups in drug discovery programmes. The synthesis of the starting material required significant investigation and so this third section focusses on the development of a robust method to furnish this sulfonimidoyl fluoride.
A summary of the conclusions and future work can be found in the penultimate section. All experimental details and data for the compounds synthesised during these studies can be found in the final section.
Firstly, the chiral analogues to sulfonyl fluorides, sulfonimidoyl fluorides, were generated from sulfinamide salts, sulfinate salt analogues, and used in a Sulfur Fluorine Exchange (SuFEx) reaction with amines. It was found that the degenerate nucleophilic attack of fluoride ions in solution resulted in inversion of the sulfonimidoyl fluoride and so fluoride ion trapping strategies were employed to prevent racemisation. The resulting enantiospecific reaction sequence was the first facile route to access enantioenriched sulfonimidoyl fluorides and sulfonimidamides.
Secondly, the enantioenriched sulfonimidoyl fluoride intermediates were employed in an enantiospecific S–C bond formation reaction with organometallic reagents to furnish sulfoximines. As part of this study, new enantioenriched sulfinamide salts were generated and the effect of modifying the protecting group on the imide nitrogen was explored. This second SuFEx reaction of sulfonimidoyl fluorides was successful in generating enantioenriched sulfoximines in high yields and with very high ee.
Finally, as part of an ongoing project, the SuFEx reaction of an isoquinoline sulfonimidoyl fluoride with amines is being explored as a route to generate a library of analogues of a sulfonamide-containing marketed drug, Fasudil. These sulfonimidamide-containing compounds are to be generated and their physicochemical properties tested to determine their value as functional groups in drug discovery programmes. The synthesis of the starting material required significant investigation and so this third section focusses on the development of a robust method to furnish this sulfonimidoyl fluoride.
A summary of the conclusions and future work can be found in the penultimate section. All experimental details and data for the compounds synthesised during these studies can be found in the final section.
Version
Open Access
Date Issued
2022-03
Date Awarded
2022-05
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Bull, James
Sponsor
Engineering and Physical Sciences Research Council
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)