Synthesis and Ring-opening of NH-aziridine-2-carboxylates, and Preparation of Novel Pyrazolo[3,4-d]pyrimidines for Kinase-substrate Identification
Author(s)
Ferguson, Alexandra
Type
Thesis
Abstract
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
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
Date Issued
2013-01
Date Awarded
2013-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Armstrong, Alan
Sponsor
Engineering and Physical Sciences Research Council
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)