The Development of Enantioselective Rhodium-Catalysed Aziridination Reactions Directed by a Chiral Cation

Aziridines are versatile precursors to prepare chiral nitrogen-containing compounds. Whilst great advances have been developed in asymmetric intermolecular aziridination, there remain significant gaps in the scope of alkenes that can be accommodated with present protocols. Chapter 2 discusses the development of an enantioselective aziridination method for alkenyl alcohols, achieved through a close collaboration with Dr Alexander Fanourakis and Nicholas J. Hodson. The reaction is substrate-directed and exploits a network of attractive non-covalent interactions between the substrate, an achiral dianionic rhodium (II,II) tetracarboxylate dimer and its two associated cinchona alkaloid-derived chiral cations. This catalyst design demonstrated a broad reaction scope with respect to the alkene substitution and alcohol chain length. Notably, it proved effective for a variety of unactivated di- and trisubstituted alkenes, which had previously posed challenges for existing asymmetric aziridination methods. Finally, a thorough evaluation of compatible alkenes has enabled the development of a practical mnemonic to predict reaction outcomes. Although the aziridination of alkenyl alcohols was successful across various chain lengths, only moderate enantioselectivity was achieved with allylic alcohols. Chapter 3 examines the extension of chiral ion-paired Rh(sulfonesp) catalysts to the asymmetric aziridination of allylic carbamates as a strategy to expand the reaction to the corresponding allylic alcohols. Although modular in design, the preparation of the discrete ion-paired Rh(sulfonesp) catalysts precludes the ability to quickly prepare a large library of catalysts for testing. To address this, a more efficient workflow was developed for the optimisation of the aziridination reaction, whereby the active Rh catalyst is generated in situ from the sulfonic acid variant of the Rh dimer with the chiral cation bromide. Upon reaction completion, ee determination of the crude reaction mixtures was achieved with supercritical fluid chromatography-mass spectrometry (SFC/MS), a technique proven to be reliable for high-throughput asymmetric catalysis campaigns. Through this workflow, 13 chiral cation bromides were screened against four different classes of allylic carbamates. Preliminary results revealed that the cis-styrenyl class of allylic carbamates was particularly effective in the aziridination reaction. In collaboration with Christian Zachau, a series of cis-styrenyl allylic carbamates was successfully transformed (up to 97% ee) to highly functionalised carbonate products, which arises from intramolecular aziridine opening with the carbamate directing group. Finally, preliminary success was achieved for the enantioselective benzylic C(sp3)-H amination of phenethyl alcohol-derived carbamates.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Lit Mun Jun, Arthur

Advisor dc:contributor.advisor

• Phipps, Robert

• Asymmetric Catalysis
• Enantioselective Aziridination

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9208d30f-d948-486b-9e02-6caa6ba32767/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.115924

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/379954