Photocatalytic Deracemisation of Amines

Project Information

PhotoDeRac

Grant agreement ID: 886224

DOI

10.3030/886224

Project closed

EC signature date 31 March 2020

Start date 1 July 2020

End date 2 April 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 230 416,32

EU contribution

€ 230 416,32

Coordinated by

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Periodic Reporting for period 2 - PhotoDeRac (Photocatalytic Deracemisation of Amines)

Reporting period: 2022-01-01 to 2022-12-31

Summary of the context and overall objectives of the project

Amine functional groups are of prime importance for the synthesis and application of established and emerging medicines for the betterment of humankind. Therefore, methods to synthesise these groups, particularly in a stereocontrolled manner, are always desirable. In this project, we leveraged two central properties of amines — their basicity, and their nucleophilicity — to i) discover a method for the photochemical deracemization of chiral alkyl amines, and to ii) develop a new and general annulation reaction for the synthesis of amine heterocycles through the union of photochemical reductive proton-coupled electron transfer (reductive PCET) and oxidative radical polar crossover (oxidative RPC) processes. In the course of this work, we also carried out a thorough review of documented photochemical and electrochemical applications of proton-coupled electron transfer in organic synthesis. This exercise assisted with the planning and execution of our project aims, in addition to providing a valuable and accessible practitioners guide to this emerging area of study for members of our broader research community.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

This action has so far achieved proof-of-concept results demonstrating the feasibility of a method for the deracemization of chiral alkyl amines through a new selectivity-determining mechanism. In a simple test system we demonstrate that all elementary steps required to drive such a process occur as desired and that this can be driven catalytically without requiring exogenous reagents, and operating at room temperature. This process too should allow for existing known methods for enantiomer separation to be adapted for study here, thus we are able to carry forward existing knowledge without having to start our studies from scratch in each amine system we explore. We are beginning to move towards the application of this method to real world examples of complex amine drugs and drug intermediates that are currently difficult to prepare in an efficient manner.

During the course of this work, we also devised a new method for the synthesis of medicinally-relevant heterocycles – pyrrolidines, piperidines, tetrahydrofurans, morpholines, dioxanones, and lactones. The process uses readily available monomer sets and is achieved under mild conditions with commercially available materials. Some of these types of substrates were those under study for amine deracemization and through this method we have streamlined their access compared to existing routes. We have fully optimized and demonstrated the scope of this novel annulation reaction and are preparing for publication of the results.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Existing methods for two-component annulation tended to be very product-specific – one type of heterocycle (pyrrolidine, piperidine, tetrahydrofuran, etc…) of one specific ring size (4, 5, 6, etc…), one specific type of contained heteroatom (nitrogen, oxygen, sulfur, etc…), and one specific type of substitution pattern. These too often involved disparate sets of reaction conditions – a set of reagents and reaction conditions giving access to pyrrolidine products would rarely be applicable to the synthesis of morpholines, for example. What we have discovered and developed however checks all of these desirable boxes – one common set of reagent precursors, one common set of reaction conditions, yielding a multitude of heterocyclic products in a quick and easy manner, from readily available monomer sets. This will greatly simplify a medicinal chemists job in the preparation of a library of molecules for SAR study – where the same starting material can be used to access many different products for drug development.

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