Late-Stage Alpha-Alkylation of Cyclic Amines

Lead Research Organisation: University of Cambridge
Department Name: Chemistry


Year 1: General skills training and lab rotations

Years 2-4: The aim of this project is to develop a novel platform for the late-stage alpha-alkylation of cyclic amines, via amine oxidation and subsequent iminium ion functionalisation. Within this challenging transformation there are three key objectives: optimisation of conditions for selective formation of the endo-iminium ion, development of compatible conditions to enable alkylation in a single synthetic sequence, and investigation into the scope and generality of this procedure in its application to complex molecules.

The Polonovski-Potier reaction will be used as a basis for the selective formation of endo-iminium ions. It is well known that the required N-oxides can be easily synthesised using m-CPBA to oxidise the equivalent aliphatic amine. However, the regioselectivity of the C-H elimination step is essentially unknown. Therefore, extensive investigations into the optimization of reaction conditions for the selective formation of the endo-iminium ion in a wide array of cyclic amines will be undertaken, with a particular focus on the influence of temperature, solvent, and acetylating agent on selectivity. Compared to conventional strategies for iminium ion formation via direct sp3 C-H oxidation, the excellent chemoselectivity and high functional group tolerance exhibited by these methodologies means this platform will meet the criteria outlined previously for late-stage functionalisation.

Subsequent alkylation of the in situ generated iminium ions will be inspired by the CAA and Zn CAA protocols developed by Gaunt, providing a suit of conditions for this transformation. Reaction conditions compatible with the C-H elimination step will first be developed to enable alkylation in a one-pot process. The influence of TMS-OTf equivalents, reaction concentration and order of addition will be investigated, as these proved successful during CAA optimization studies. After this, the substrate scope will be expanded to explore the selectivity of this protocol in more complicated systems, such as 2 or 3-substituted and bridged cyclic amines.

Finally, the generality of this procedure for the alkylation of complex molecules will be investigated by applying this reaction to a broad range of common drug fragments, such as noscapine, flavoxate, N-Boc tritoqualine and N-Boc valbenazine.

Planned Impact

Who might benefit from this research? How might they benefit from this research?

(a) The major beneficiaries of the CDT will, of course, be the students that train on the program. They will be equipped with a set of skills that will be highly desirable in the organic molecule making industries. Although the proposal is directing towards a need in the pharmaceutical industry, the training and research skills are totally transferable to industries like the argochemical sector (this is an almost seamless transition as the nature of the needs are near identical to that of pharma) but also the fine chemicals industries, CRO's who serve all of these industries. With some adaptation of the skills accrued then the students will also be able to apply their knowledge to problems in the materials industries, like polymers, organic electronics and chemical biology.

(b) Synthesis will also be evolving in academia and students equipped with skills in digital molecular technologies will be at a significant advantage in being apply to implement the skills acquired while training on the CDT. These students could be the rising stars of academia in 10 years time.

(c) The non-research based training will benefit the students by providing a set of transferable skills that will see them thrive in any chosen career.

(d) The industry contacts that will be generated from the variety of interactions planned in the CDT will give students both experience and insight into the machinations of the industrial sector, helping them to gain a different training experience (form industry taught courses) and hands on experience in industrial laboratories.

(e) All student in UCAM will be able to benefit in some way form the CDT. Training courses will not be restricted to CDT students (only courses that require payment will be CDT only, and even then, we will endeavour to make additional places available for non-CDT students). The overall standard of training for all students wil be raised by a CDT, meaning that benefit will be realised across the students of the associated departments. In additional, non CDT students can also be inspired by the research of the CDT and can immerse new techniques into their own groups.

Academic researchers in related fields (PIs)
(a) new research knowledge that results from this program will benefit PIs in UCAM and across the academic community. All research will be pre-competitive, with any commercial interests managed by Cambridge Enterprise

(b) a change in mnidset of how synthetic research is carried out

(c) new collaborations will be generated withing UCAM, but also externally on a national and international level.

(d) better, more closely aligned, interactions with industry as a result of knowledge transfer

(e) access to outstanding students

Broader public
(a) in principle, more potential medicines could be made available by the research of this CDT.

(a) a new highly skilled workforce literate in disciplines essential to industry needs will be available
(b) higher productivity in industry, faster access to new medicines
(c) spin out opportunities will create jobs and will stimulate the economy
(d) automation will not remove the need for skilled people, it will allow the researchers to think of solutions to the problems we dont yet understand leading to us being able to discover solutions faster


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S024220/1 31/05/2019 30/11/2027
2638405 Studentship EP/S024220/1 30/09/2021 29/09/2025