Asymmetric Catalysis with Brønsted Acids: Experiments and Calculations

The research described herein focuses on enantioselective catalysis using BINOL-based Brønsted acids. The initial part of this work comprises the development of chiral phosphoric acids and N-triflylphosphoramides having alternative groups at the 3,3’- positions, different from the widely common aryl scaffolds. These motifs include heavily hindered silyl groups and aryl sulfones. Such catalysts were used to design enantioselective ring-closing reactions to furnish nitrogen-based heterocycles via iminium ions as reactive intermediates. Two of the transformations presented in this work include imino-Diels-Alder and Pictet-Spengler reactions. Moreover, a S,O-thioacetalization reaction to furnish 1,3-oxathiolanes enantioselectively is presented. In the latter project, after thorough and systematic screenings, it was noteworthy that the catalyst loading of N-triflylphosphoramides could be lowered down to 0.5 mol%, showcasing these catalysts as an efficient diversion from phosphoric acids in asymmetric synthesis. In addition to the experimental work, computational investigations were conducted. Molecular modelling focused on accounting for the stereochemical output of an enantioselective aza-Darzens reaction that uses a bulky chiral BINOL-based phosphoric acid. For such, hybrid Quantum Mechanics / Molecular Mechanics methods—mostly the ONIOM approach to calculate such large systems with the whole catalyst structure—were used in order to find diastereomeric transition states and to understand how the catalyst induces chirality during the enantiodetermining step. Furthermore, through these DFT calculations, an alternative mode of activation for the imine substrate was envisaged, different from the usual N-H hydrogen bonding with the catalyst. Therein, the imine is protonated by the acid; however, the resulting iminium ion interacts with the catalyst through non-classical C-H hydrogen bonds. The calculated transition states for this quite unusual mode of activation showed to be the lowest in energy. Moreover, with such model, the predicted sense and amount of enantioinduction was in accordance with the values reported experimentally.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Caballero Garcia, Guillermo

Advisor dc:contributor.advisor

• Goodman, Jonathan

• BINOL-based Brønsted acids
• enantioselective catalysis
• molecular modelling
• asymmetric synthesis of N-containing heterocycles
• ONIOM
• transition state modelling

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/2f651102-4531-4f02-b8c7-1f0a2c8d5707/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-8693-9136

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/315054