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Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates: Applications in Medicinal Chemistry


Department of Chemistry

York United Kingdom Organic Chemistry Pharmaceutical Chemistry Synthetic Chemistry

About the Project

Background

A long-standing and ongoing fundamental challenge in cross-coupling chemistry is the formation of stereodefined carbon-carbon bonds using Csp3-Csp2 Suzuki-Miyaura cross-coupling.[1,2] 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, whilst there have been notable stereospecific Suzuki-Miyaura cross-coupling successes with acyclic alkyl boron reagents,[3-5] the analogous reactions with cyclic systems have been far more challenging to develop[4,5] – and this topic will be directly addressed in this project, with the focus on 3-D pharmaceutically-relevant saturated nitrogen and oxygen heterocycles.

Objectives

1. To use automated high throughput experimentation and rich data analysis to optimise conditions for Csp3-Csp2 cross-coupling of saturated heterocyclic boronates

2. To explore the scope and limitations of the cross-coupling methodology

3. To apply the methodology to targets of relevance to medicinal chemistry, including covid-19 proteins

Experimental Approach

In this project, we will synthesise bench-stable, stereodefined, enantiopure heterocyclic alkyl boronate building blocks and deploy them in stereospecific Csp3-Csp2 Suzuki-Miyaura cross-coupling reactions. The pharmaceutical industry has specifically highlighted the need for a general stereoselective 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.”[6] This is one of the last remaining problems to solve in cross-coupling chemistry – it is our conjecture that the key to unlocking the potential of such reactions is a combination of high throughput experimentation, statistical analysis of rich data and in-depth mechanistic studies. Reaction discovery and optimisation of suitable catalytic protocols will be driven by automated high throughput experimentation, rich data analysis and rigorous mechanistic studies. Given the ubiquity of cyclic molecules containing stereodefined Csp3-Csp2 bonds in FDA-approved drugs, the process could become an enabling and transformative technology for use within medicinal chemistry programmes. The methods will also be used for the synthesis of libraries of elaborated fragments from fragment hits generated against covid-19 proteins.[7,8]

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 aims to deliver such a process to enable non-traditional disconnections, fundamentally changing the way that three-dimensional saturated nitrogen and oxygen heterocycles can be constructed.

Training

This project will provide state-of-the-art training in modern synthetic methodology and medicinal chemistry. The graduating PhD student will be fully equipped for a future career in the pharmaceutical industry. 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.

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/.

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/

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


Funding Notes

This project is available to students from any country who can fund their own studies.

The Department of Chemistry at the University of York is pleased to offer Wild Fund Scholarships. Applications are welcomed from those who meet the PhD entry criteria from any country outside the UK. Scholarships will be awarded on supervisor support, academic merit, country of origin, expressed financial need and departmental strategy. For further details and deadlines, please see our website: View Website

References

1. Reisman, S. E. et al. Chem. Rev. 2015, 115, 9587.
2. Rygus, J. P. G.; Crudden, C. M. J. Am. Chem. Soc. 2017, 139, 18124.
3. Crudden, C. M. et al. J. Am. Chem. Soc. 2009, 131, 5024.
4. Sigman, M. S.; Biscoe, M. R. et al. Science 2018, 362, 670.
5. Burke, M. D. et al. Nat. Commun. 2019, 10, 1263.
6. Blakemore, D. C. et al. A. Nat. Chem. 2018, 10, 383.
7. https://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem.html
8. https://www.diamond.ac.uk/covid-19/for-scientists/NSP3-macrodomain-structure-and-XChem.html

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