Over the last few years there has been a desire by the pharmaceutical industry for an increase in the availability of small molecules that occupy a more structurally diverse area of chemical space. Originally this was manifested in the desire for “unique” aromatic heterocyclic systems, but now medicinal chemists are looking to further expand the areas of chemical space they can work in by the inclusion of a greater number of structurally diverse 3D-heterocyclic fragments.
It is desirable for these fragments to have a number of properties: (i) a clogP ≤2, (ii) the number of hydrogen-bond acceptors or donors ~2 and (iii) RMM <200, often termed the “Rule of Two”. This will allow the fragment to act as a core unit for further modification or as a late stage diversity enhancing unit to be appended onto a core structure. The Clarke group has been developing new variations of the Maitland-Japp reaction for the one-pot synthesis of highly functionalised heterocyclic systems (Scheme 1).2 The diastereoselectivity for 2,6-cis and 2,6-trans products can be influenced by the Lewis acid used; and for X=O we have developed a highly enantioselective reaction >97% e.e.3 This project will explore the further development of the one-pot Maitland-Japp reaction to the synthesis of structurally diverse 3D-heterocyclic fragments.
The project will have 3 goals: (i) the synthesis of small novel reagents that obey the “Rule of Two” can be used to elaborate core structures and are much sought after by medicinal chemists. The Maitland-Japp reaction can provide access to these structures in just a few steps; (ii) the synthesis of fused and bridged bicyclic systems; (iii) the development of an asymmetric synthesis of N-heterocycles based on the Maitland-Japp reaction. This project is co-funded by GSK
Project Title: Maitland-Japp Inspired Synthesis of Structurally Diverse 3D-Heterocyclic Fragments Supervisor Name(s): Paul A. Clarke Supervisor(s) Contact details: paul.clarke@york.ac.uk; 01904 322614
Eligibility: UK/EU/Overseas