Precise control of three-dimensional molecular structure can be used to improve, alter or modulate a range of physiochemical and pharmo-kinetic properties in potential drug molecules. Key properties that will influence the efficacy and toxicity of a drug - lipophilicity, aqueous solubility, acidity/basicity and stability against metabolic degradation - are all influenced by the three-dimensional arrangement of functional groups in chemical space. Despite these clear incentives for investigating small-molecule drug candidates that possess complex three-dimensional architectures, many small-molecule libraries used for screening are characterised by flat two-dimensional structures, based on extensive sp2-hybridisation in the carbon skeleton. Thus, the development of methods that allow rapid, modular access to novel three-dimensional molecular architectures is of immense value.
Four-membered rings, which include cyclobutanes, azetidines, oxetanes and thietanes, possess unique three-dimensional structures due to their limited flexibility. In particular, the exit vectors (substituents) of four-membered rings are well-defined in their spatial disposition and thus allow for the orientation of key functional groups along pre-selected vectors. As part of an ongoing effort to develop effective synthetic methods for the generation of large, diverse libraries of biologically-relevant small molecules, this research programme outlines three interconnected strategies for the synthesis of densely-functionalised and structurally diverse four-membered ring molecular architectures.
The proposed research is founded on the remarkable strain-release properties of the bicyclo[1.1.0]butane motif, which is a fascinating molecular structure comprising a cyclobutane moiety with a sigma bond between two carbon atoms on opposite sides of the ring. This sigma bond exhibits ambiphilic behaviour, which means that it engages in both electrophilic and nucleophilic reactivity. The proposed research programme aims to exploit this unique reactivity to develop new methods that will enable the rapid generation of varied cyclobutane-based molecular libraries.
Specifically, the first strategy will investigate the generation of bicyclo[1.1.0]butyl zincate complexes, which will undergo a diastereoselective 1,2-migration - ring opening - electrophile trapping process to generate complex cyclobutane-substituted alkylzinc complexes. These can then undergo further transformation through a wealth of transition metal-catalysed cross-coupling processes. In this way, three points of diversification can be controlled, allowing the introduction of a variety of functional groups along specific spatial vectors about the cyclobutane core.
In a second strategy, key building block bicyclo[1.1.0]butyl lithium will be reacted with a range of enantioenriched substituted three-membered rings, such as epoxides, aziridines and thiiranes, leading to new, diversely functionalised heterospirocycles.
Both these research strategies will also be explored with the azabicyclo[1.1.0]butane motif, which will lead to diverse libraries of azetidine-based structures. Using enantiomerically enriched azabicyclo[1.1.0]butyl sulfoxide as a building block, a sulfoxide-directed lithiation - electrophile trapping strategy will also be developed to enable access to enantiopure densely functionalised azetidine-based small molecule libraries.
These methodologies, all based on exploiting the powerful reactivity embedded within the (aza)bicyclo[1.1.0]butane motif, will provide a broad strategy for the generation of diverse small molecule libraries, based on four-membered mono- and spiro-cyclic architectures. These libraries will be invaluable in accessing poorly explored regions of chemical space and driving forward successful drug discovery programmes.
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