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Title: Synthesis and ring-opening of NH-aziridine-2-carboxylates, and preparation of novel pyrazolo[3,4-d]pyrimidines for kinase-substrate identification
Author: Ferguson, Alexandra
ISNI:       0000 0004 2736 9297
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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1: The ring-opening of aziridine-2-carboxylates dominates their reactivity, providing diverse, biologically relevant compounds. Less is known about the chemistry of NH-aziridine-2-carboxylates, owing to multi-step preparation, and lack of N-functionality to aid ring-opening. Building on the recent disclosure of an NH-aziridination methodology applicable to enones, the substrate scope was expanded to include enoates. Aziridination provided access to NH-aziridine-2-carboxylates in a single step from readily available starting materials. Treatment of the resulting aziridine-2-carboxylates with nucleophiles proceeded with high regio- and stereoselectivity, providing access to natural and unnatural amino acid derivatives (Scheme 1).[Molecular structure diagrams appear here. To view, please open pdf attachment] Scheme 1: The synthesis and ring-opening of aziridine-2-carboxylates 2: Identification of kinase protein-substrate sets is crucial to further understand cellular processes, but is challenging with known methodology. Previous study had proposed a new methodology, incorporating two known strategies, bump-hole inhibition and photo-affinity labelling. Novel C3-aryl pyrazolo[3,4-d]pyrimidines were designed for the purpose (Fig. 1), although preparation of the compounds had proved challenging, with several key steps in the synthesis of analogues low-yielding and lengthy. A new synthetic route was developed, using hydrazone allylation to establish the α-tertamine functionality of the pyrazolo[3,4-d]pyrimidines. A late-stage oxidative cleavage was used to re-connect with the original synthetic strategy, to provide access to the C3-hydro analogues. Application of the revised route to the synthesis of the target compounds, using an alternative enol ether for C3-aromatic installation, provided access to two novel pyrazolo[3,4-d]pyrimidines for testing. [Molecular structure diagrams appear here. To view, please open pdf attachment] Fig. 1: C3-aryl pyrazolo[3,4-d]pyrimidines
Supervisor: Armstrong, Alan Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral