Modular approach to structurally diverse four-membered (spiro)cycles using highly strained precursors

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.

There are four broad areas where this research will have an impact:

1. Advancing scientific knowledge through the exploration of strain release strategies as a new reactivity platform for the synthesis of small complex molecules. The research will lead to innovations in the field of synthetic methodology, while also having major impact on medicinal chemistry programmes through providing access to diverse small molecule libraries.

2. Providing well-trained scientists who have expertise in, among other areas, synthesis, organometallic chemistry, asymmetric synthesis, heterocyclic chemistry, physical organic chemistry and spectroscopy. The cohort of highly skilled and accomplished researchers who will be involved in this research programme will also be trained in managing research, leadership and communication skills, both through pathways established in the PIs laboratory and by the University. These researchers will support the needs of both the academic and industrial sectors. In particular, the UK chemical and pharmaceutical industries, who are major contributors to UK wealth, rely on this output. In the last year alone, members of our groups are pursuing both academic (RS URF; postdoctoral position with John Hartwig) and industrial (positions in Roche, Charles River, Pharmaron, CRUK) career paths, demonstrating our success in training the next generation of scientists.

3. Economic impact on Pharmaceutical, Agrochemical and Fine Chemical Industries. These industries are interested in reactions and strategies that provide greater efficiency and selectivity in transformations. They are also interested in new transformations that lead to molecular structures that access previously unexplored regions of chemical space. This research programme is directly focused on the development of new methods for accessing novel and diverse classes of four-membered mono- and spiro-cyclic molecular architectures, which will have considerable value in drug discovery programmes. The rapid, mild and modular nature of the proposed methodologies will also ensure greater efficiency in generating large screening libraries.

4. The societal benefit of this research programme will be two-fold: (i) providing diverse chemical compound libraries, which will enable the development of pharmaceutical and medicinal chemistry programmes, which are essential if we are to meet future societal healthcare needs, and (ii) providing a new general synthetic approach that will allow researchers in the UK and internationally to develop innovative chemistries towards valuable three-dimensional molecular structures.