Asymmetric Clip-Cycle Reactions of Cyclic Amines

Background:
Cyclic amines are privileged pharmacophores present in many drug molecules and biologically active natural products, with the 5- and 6-membered rings by far and away the most prevalent. Significantly, cyclic amines occur in 59% of FDA approved drug molecules. Within this subset, piperidines are the most abundant, followed by piperazines in 3rd place, and pyrrolidines in 5th place. Natural products such as alkaloids are also loaded with these structural units, which are key to their biological activity. As the chemical synthesis of new compounds is the limiting factor in drug discovery, new methods to synthesise efficiently these privileged ring systems, with control over regio-, diastereo- and enantioselectivity is of paramount importance.

Objectives:
The group has developed a highly enantioselective synthesis of functionalised chiral pyrrolidines, via an aza-Michael aminocyclisation reaction, and we now wish to extend this strategy to the synthesis of piperidines, morpholines, azetidines and piperazines. To this end, the proposal aims to: (i) develop an operationally simple, scalable and general catalytic asymmetric method for the synthesis of substituted cyclic amines as single enantiomers, from either acyclic achiral or racemic starting materials and, (ii) apply it to the synthesis of pharmaceutical and natural products containing these heterocyclic units.

Experimental Approach:
Synthetic organic chemistry techniques will be used to synthesise clip-cycle precursors. These precursors will be activated by ’clipping’ them to an activating group using a metathesis reaction and the ’cylisation’ Michael reaction will be promoted by a chiral Bronsted acid.

Novelty:
This approach is novel as it can produce cyclic amines of any ring size. Current methods are hindered by their ability of produce only a single specific ring size of cyclic amine.

Training:
All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. All research students take the core training package which provides both a grounding in the skills required for their research, and transferable skills to enhance employability opportunities following graduation. Core training is progressive and takes place at appropriate points throughout a student’s higher degree programme, with the majority of training taking place in Year 1. In conjunction with the Core training, students, in consultation with their supervisor(s), select training related to the area of their research.

The Clarke group trains all members in contemporary synthetic organic chemistry techniques including the handling of air sensitive reagents, toxic chemicals, and reaction safety analysis and structure determination by advanced spectroscopic methods. This project will also require the student to be trained in HPLC and GC techniques for the monitoring of reactions and determination of product enantioselectivies. The student will attend weekly group meetings focusing on the development of literature awareness, presentation of results, problem solving and mechanistic skills. Guidance will also be given on project management and project specific scientific issues. As part of the Organic Chemistry section the student will be exposed to a wide range of visiting speakers through a vibrant external seminar program. The student will also be encouraged to present their work as a poster and as oral presentations at least two different national or international meetings.

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/. This PhD project is available to study full-time or part-time (50%).

This PhD will formally start on 1 October 2020. Induction activities will start on 28 September.