Heterocyclic inflation - efficient routes to medium rings by migratory ring expansion of alkenes

Lead Research Organisation: University of Bristol
Department Name: Chemistry

Abstract

Medium ring (8-12 membered) heterocycles form the core scaffold of a range of naturally occurring biologically active compounds, with the conformational constraints imposed by the cyclic structure attributed to improving the binding of medium ring-containing compounds to their target protein. Thus, these rings are attractive synthetic targets for medicinal chemistry. However, the synthesis of these scaffolds remains very challenging, due to the unfavourable transannular interactions upon ring closure; this is the likely reason for the marked underrepresentation of medium rings in drug discovery. Therefore, new methods are required to provide access to these structures, thereby enabling medicinal chemists to incorporate medium rings into fragment screening libraries and novel drug designs.

A ring expansion strategy is an appealing way to make medium-sized ring compounds, since this can partially reduce the entropic penalty in forming the medium-sized ring, and five- to seven-membered heterocycles are widely available. Previous work in the Clayden group has demonstrated that readily accessible arene-containing amide or urea substrates can undergo an intramolecular aryl migration to generate medium ring compounds. This research project aims to employ this powerful ring expansion strategy to achieve alkenyl migration, rather than aryl migration, which would broaden the scope and enrich the library of potentially bioactive medium ring scaffolds that could be accessed.

The project will begin with establishing a robust route to make a variety of alkene-containing starting materials. Some investigation into this has been carried out as part of an undergraduate's MSci research project, which will be further developed in this project to generate a more diverse set of substrates. The next stage will be to establish that the ring expansion via alkene migration is feasible on these types of substrates. It is envisaged that optimisation of this transformation could be carried out using Design of Experiments, which could be accelerated through use of Bristol Automated Synthesis Facility's Chemspeed platform. After robust conditions for the ring expansion have been found, they will be applied to a range of substrates, so as to investigate the functional group tolerance and scope of the process. This too could potentially be expedited using the Chemspeed robot to rapidly provide medium ring products that would be difficult to access by other methods.

The products of the ring expansion would have potential sites for further reaction, and therefore, we would like to showcase particular derivatisations that would demonstrate the versatility of medium ring products and their applicability to drug discovery. Regular meetings with Cancer Research UK throughout the project will guide the choice of scaffolds targeted and help ensure the transferability of this chemistry from academic laboratories to drug discovery research. The alkene migration is a very unusual reaction, and so we hope to undertake investigations its mechanism. The tools we could use to do this include experimental kinetic studies, in situ infrared spectroscopy measurements and computational modelling. The information gained from these studies could be valuable in developing further novel transformations.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S024107/1 30/09/2019 30/03/2028
2278808 Studentship EP/S024107/1 22/09/2019 29/09/2023 Mehul Harice Jesani
 
Description CDT Summer Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Presented my research at annual conferences ran by the CDT, discussing my work, future directions and potential applications with representatives from industry, other postgraduates and members of staff.
Year(s) Of Engagement Activity 2020,2021