Total Synthesis of (–)-Quinine
Supervisor: Peter O’Brien
(–)-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, there have been several reports on the asymmetric synthesis of (–)- or (+)-quinine, with recent ones reported by Maulide, Chen and Ishikawa. 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.
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
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.
A novel approach for the total synthesis of (–)-quinine is proposed.
This project will provide state-of-the-art training in modern synthetic methodology.
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