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Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates


   Department of Chemistry


About the Project

Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates

Main supervisor: Peter O’Brien

Co-supervisor: Ian J S Fairlamb

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. Optimisation of Csp3-Csp2 cross-coupling of saturated heterocyclic boronates using automated high 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. To apply the methodology to targets of relevance to medicinal chemistry

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.

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, automation, catalysis and rich data analysis. The PhD student will be fully integrated unto both the O’Brien and Fairlamb groups which will provide them with a unique training experience.

  • 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/cdts/
  • 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/ .

Funding Notes

This project is open to students who can fund their own studies or who have been awarded a scholarship separate from this project. The Chemistry Department at York is pleased to offer Wild Fund Scholarships to new students who will pay tuition fees at the overseas rate. Scholarships are competitive and awarded based on academic ability and financial need. For further information see: View Website

References

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.

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