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Total Synthesis of (–)-Quinine


   Department of Chemistry

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Total Synthesis of (–)-Quinine

Supervisor: Peter O’Brien

Background

(–)-Quinine is one of the most famous molecules in organic chemistry and is an important compound from a medicinal perspective (anti-malarial) and as a chiral catalyst. Historically, it has played a key role as a target for both structural elucidation and total synthesis, and has a well-documented synthetic history.[1,2] Since Stork’s total synthesis of (–)-quinine in 2001,[3] there have been several reports on the asymmetric synthesis of (–)- or (+)-quinine, with recent ones reported by Maulide,[4] Chen[5] and Ishikawa.[6] Apart from Maulide and Chen’s reports, most of the previous synthetic approaches are based on disconnection of the N1-C8 bond. In contrast, we propose to make use of a new C–N disconnection, the N1-C2 bond, which would produce a 2,4-disubstitued piperidine as the key intermediate. Given our group’s longstanding interest in the lithiation-trapping of N-Boc heterocycles, we recognised an opportunity to use such methodology in a novel approach to (–)-quinine.

Objectives

1. To develop a new diastereoselective synthesis of racemic quinine

2. To develop new methodology for Csp3-Csp2 Suzuki-Miyaura cross-coupling reactions of heterocyclic primary boronates

3. To complete the asymmetric total synthesis of (–)-quinine

Experimental Approach

A new approach for the total synthesis of quinine is proposed. To start with, a key a 2,4-disubstitued piperidine intermediate will be prepared. First, lithiation-trapping of a 4-substituted N-Boc piperidine will be carried out. After further homologation, a primary boronate will be prepared and subjected to Suzuki-Miyaura cross-coupling. Then, a 1,3-diol will be constructed at the 4-piperidine position which will then be cyclised to the quinuclidine. Finally, further functionalisations via oxidation, Wittig reaction and stereoselective oxygenation should deliver a novel route to racemic quinine. As part of this approach, new methodology for the Csp3-Csp2 Suzuki-Miyaura cross-coupling reactions of heterocyclic primary boronates will be explored, including a full scope study. Finally, methods for the control of absolute stereochemistry will be investigated with a view to completing the total synthesis of (–)-quinine in around 10 steps via a novel N1-C8 bond disconnection.

Novelty

A novel approach for the total synthesis of (–)-quinine is proposed.

Training

This project will provide state-of-the-art training in modern synthetic methodology.

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. Seeman, J. I. Angew. Chem. Int. Ed. 2007, 46, 1378.
2. Smith, A. C.; Williams, R. M. Angew. Chem. Int. Ed. 2008, 47, 1736.
3. Stork, G. et al. J. Am. Chem. Soc., 2001, 123, 3239.
4. Maulide, N. et al. Angew. Chem. Int. Ed. 2018, 57, 10737.
5. Lee, J.; Chen, D. Y. K. Angew. Chem. Int. Ed. 2019, 131, 488.
6. Ishikawa, H. et al. Chem. Sci. 2019, 10, 9433.

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