Investigations of Catalysts Which Utilise Non-Covalent Interactions to Control Enantioselectivity in Rhodium-Catalysed Amination of C(sp3)–H Bonds

Investigations into enantioselective benzylic C(sp3)–H amination via bis-sulfonated rhodium(II) dimers ion-paired with N-quaternised Cinchona alkaloids are described herein. Design and initial synthesis of these novel catalysts was performed prior by Dr. Alex Fanourakis, and their application towards substrate-directed amination of aryl alcohols via a key alcohol-sulfonate hydrogen bond was already underway; the first section of this thesis describes the author’s contributions to this work, collaborating closely with Dr. Alex Fanourakis and Dr. Ben Williams. The second section of this thesis examines the corresponding amination of aryl tertiary amides, a deceptively divergent system given the loss of a substrate-based hydrogen bond-donor. This substrate class proved effective, however, and both yield and enantioselectivity here surpassed those for the analogous alcohol-directed methodology. Variation of the amide directing group, arene-based functionality, and methylene chain length were all viable and well tolerated, with collaborative work from Dr. Amit Dahiya in the latter. Additional contributions from Harry Palmer are also noted. Utilisation of these tertiary amide directing groups for site-selective unactivated C(sp3)–H amination was attempted, wherein the ion-paired dirhodium(II) catalyst displayed much higher reactivity relative to Du Bois’ Rh2(esp)2. Interesting effects on regioselectivity were also observed, but results here were ultimately uninspiring. The final section of this thesis sought to construct a possible binding model between the amide substrate and ion-paired catalyst, with control experiments and NMR titration performed to this effect. Both provided support for a central hydrogen bond between the substrate-based carbonyl and chiral cation-based hydroxyl, with ancillary binding also shown to be viable. Additionally, the key role of a hypervalent iodine additive was uncovered. Overall, this thesis seeks to expand the utility of ion-paired chiral cations for enantioselective C–H functionalisations, an under-developed strategy within asymmetric catalysis.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Paterson, Kieran

Advisor dc:contributor.advisor

• Phipps, Robert

• Rhodium
• C(sp3)–H amination
• Asymmetric catalysis
• Chiral cations
• Non-covalent interactions
• Cinchona alkaloids

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c226344c-c023-47cd-a4f0-4b7602beab32/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.108747

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/368605