Exploring novel strategies for C-H functionalisation of aryl boronates and asymmetric synthesis of functionalised azetidines
File(s)
Author(s)
Sahay, Aditya
Type
Thesis
Abstract
The development of synthetic strategies that enable rapid and efficient access to structurally diverse molecules is a key objective in medicinal chemistry, where the vastness of chemical space necessitates both speed and breadth in exploration. Among the most powerful tools for this purpose are C-H functionalisation and the incorporation of small ring motifs.
C-H functionalisation offers a direct route to build molecular complexity, yet the ubiquity of C-H bonds presents significant hurdles in achieving regioselective transformations. Building on previous work involving a dual protecting-directing group strategy for meta-selective C-H functionalisation of aryl boronates, the first part of this thesis investigates strategies to extend this approach towards para-selectivity. Through the application of Catellani-type palladium/norbornene relay catalysis, preliminary evidence for shift in selectivity was obtained. This was further complemented by the design and synthesis of a new generation of directing templates to modulate control over regioselectivity. While notable progress was made, including investigation into a novel C-H arylation, the work highlights challenges associated with the stability of aryl boronate substrates and reaction inhibition. A potential solution to these challenges has been proposed which should provide a foundation for the future development of efficient catalytic transformations.
The second part of the thesis focuses on the synthesis and derivatisation of azetidines, nitrogen-containing heterocycles valued for their impact on pharmacological properties. An enantioselective route to spiro-oxindole azetidines was finalised, and subsequent derivatisation efforts revealed an unexpected racemisation phenomenon. Mechanistic studies into the origin of this not only identified the underlying cause but also enabled its strategic exploitation. Insights gained led to the development of a novel condition-controlled ring N-acylation or ring expansion, enabling programmed scaffold hopping.
Taken together, these investigations contribute to the advancement of regio- and stereoselective methods for the functionalisation of molecules, offering new frontiers for chemical space navigation in drug discovery.
C-H functionalisation offers a direct route to build molecular complexity, yet the ubiquity of C-H bonds presents significant hurdles in achieving regioselective transformations. Building on previous work involving a dual protecting-directing group strategy for meta-selective C-H functionalisation of aryl boronates, the first part of this thesis investigates strategies to extend this approach towards para-selectivity. Through the application of Catellani-type palladium/norbornene relay catalysis, preliminary evidence for shift in selectivity was obtained. This was further complemented by the design and synthesis of a new generation of directing templates to modulate control over regioselectivity. While notable progress was made, including investigation into a novel C-H arylation, the work highlights challenges associated with the stability of aryl boronate substrates and reaction inhibition. A potential solution to these challenges has been proposed which should provide a foundation for the future development of efficient catalytic transformations.
The second part of the thesis focuses on the synthesis and derivatisation of azetidines, nitrogen-containing heterocycles valued for their impact on pharmacological properties. An enantioselective route to spiro-oxindole azetidines was finalised, and subsequent derivatisation efforts revealed an unexpected racemisation phenomenon. Mechanistic studies into the origin of this not only identified the underlying cause but also enabled its strategic exploitation. Insights gained led to the development of a novel condition-controlled ring N-acylation or ring expansion, enabling programmed scaffold hopping.
Taken together, these investigations contribute to the advancement of regio- and stereoselective methods for the functionalisation of molecules, offering new frontiers for chemical space navigation in drug discovery.
Version
Open Access
Date Issued
2025-09-20
Date Awarded
01/12/2025
License URL
Advisor
Spivey, Alan
Bull, James
Davies, Rob
Sponsor
Engineering and Physical Sciences Research Council
Grant Number
EP/S023232/1
Publisher Department
Department of Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)