Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates: Application to a Modular Synthetic Platform for the Optimisation of Fragment Hits to 3-D Lead Compounds for Medicinal Chemistry


   Department of Chemistry

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  Prof P O'Brien  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Background

A long-standing fundamental challenge in cross-coupling chemistry is the formation of stereodefined carbon-carbon bonds using Csp3-Csp2 Suzuki-Miyaura cross-coupling. Secondary, enantiopure alkyl boron reagents are readily accessible, bench-stable and configurationally stable, and thus can be considered as the ideal cross-coupling partners – the pre-installed stereochemistry can be perfectly translated into the targeted products. However, Suzuki-Miyaura cross-coupling reactions with cyclic systems have been challenging to develop[1,2] – and this topic will be directly addressed in this project, with the focus on bifunctional nitrogen-containing heterocyclic boronates. The pharmaceutical industry has highlighted the need for a general method: “With the success of the Suzuki-Miyaura coupling reaction in generating biaryl motifs, a variant allowing routine sp3–sp2 and sp3–sp3 couplings – ideally in an enantioselective manner – is both highly desirable and could fundamentally change the motifs being generated.”[3] This is one of the last remaining problems to solve in cross-coupling chemistry –the key to unlocking the potential of such reactions is a combination of medium throughput experimentation, statistical analysis of rich data and in-depth mechanistic studies – and all will be explored in this project. Once the new Csp3-Csp2 cross-coupling reactions have been developed, they will be applied in the O’Brien group’s modular synthetic platform for elaborating 2-D fragment hits to 3-D lead compounds in medicinal chemistry programmes.

Objectives

1. Optimisation of Csp3-Csp2 cross-coupling of saturated heterocyclic boronates using medium throughput experimentation, rich data analysis and ligand design

2. Exploration of the scope and limitations of the Csp3-Csp2 cross-coupling methodology (boronates and aryl halides)

3. Medicinal chemistry applications: use of the new Csp3-Csp2 cross-coupling methodology in the elaboration of 2-D fragment hits to 3-D lead compounds

Experimental Approach

Bench-stable, stereodefined, heterocyclic alkyl boronate building blocks will be synthesised and used in stereospecific Csp3-Csp2 Suzuki-Miyaura cross-coupling reactions. The heterocyclic alkyl boronate building blocks will typically contain a N-Boc cyclic amine and an alkyl boronate (could be part of a cyclopropyl or cyclobutyl group). Synthetic methods will need to be developed for the synthesis of different classes of heterocyclic alkyl boronates. Once the racemic substrates have been prepared, their Csp3-Csp2 Suzuki-Miyaura cross-coupling will be explored and optimised via medium throughput experimentation. For successful systems, the heterocyclic alkyl boronate will then be prepared in enantiopure form, and asymmetric synthetic routes will need to be devised. The stereospecificity of the reaction and other mechanistic details will then be explored. Finally, the utility of the heterocyclic alkyl boronate building blocks in the O’Brien group’s modular synthetic platform for fragment elaboration will be explored to demonstrate their potential for use in medicinal chemistry programmes. This will involve cross-coupling with medicinally relevant aryl/heteroaryl halides together with N-functionalisation reactions to produce lead-like compounds.

Novelty

There is currently no method for the general stereospecific Csp3-Csp2 Suzuki-Miyaura cross-coupling of enantiopure saturated heterocyclic boronates with aryl halides. This project will deliver such a process to enable non-traditional disconnections, fundamentally changing the way that three-dimensional saturated nitrogen heterocycles can be constructed. Given the ubiquity of cyclic molecules containing stereodefined Csp3-Csp2 bonds in drugs, the process could become an enabling and transformative technology for medicinal chemistry programmes, including the O’Brien group’s novel modular synthetic platform for fragment elaboration in 3-D.

Training

This project will provide state-of-the-art training in modern synthetic methodology, medium throughput experimentation, catalysis, rich data analysis and medicinal chemistry. The PhD student will be equipped with experience and knowledge to obtain a future position as a synthetic and/or medicinal chemist.

References

1. Sigman, M. S.; Biscoe, M. R. et al. Science 2018, 362, 670.

2. Burke, M. D. et al. Nat. Commun. 2019, 10, 1263.

3. Blakemore, D. C. et al. A. Nat. Chem. 2018, 10, 383.

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/training/idtc/idtctraining/

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/  

For more information about the project, click on the supervisor's name above to email the supervisor. For more information about the application process or funding, please click on email institution

This PhD will formally start on 1 October 2023. Induction activities may start a few days earlier.

To apply for this project, submit an online PhD in Chemistry application: https://www.york.ac.uk/study/postgraduate/courses/apply?course=DRPCHESCHE3

You should hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject. Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/


Chemistry (6)

Funding Notes

This project requires applicants to provide their own funding for tuition fees and living costs.
Tuition fees: https://www.york.ac.uk/study/postgraduate-research/fees/
Living costs: https://www.york.ac.uk/study/postgraduate-research/fees/living-costs/
You may like to apply for our Wild Prize or Wild Bursary to provide some additional financial support. You will need to have been made an offer of a place before being able to apply for these awards.
https://www.york.ac.uk/chemistry/postgraduate/research/funding/wild-prizes-and-bursaries/
You should hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject.
Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/

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