Waiting in line: A sequenced approach to the antibacterial pleuromutilin
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
Resistance to antibiotics is a major concern worldwide and has led to an urgent need to identify antibiotics and antibacterials with modes of action distinct from the established classes. The antibacterial natural product pleuromutilin is such a candidate. Pleuromutilin is known to target the 'protein factories' or ribosomes in bacteria, stopping them making the molecules they need to survive.Unfortunately, pleuromutilin has a complex 3D structure and is difficult to synthesise. The other problem is that pleuromutilin has poor 'pharmacokinetic' properties. Pharmacokinetics is the study of what the body does to a drug. In the case of pleuromutilin, the compound is readily metabolised by enzymes in biological systems. Although the natural product itself is not a very good drug, analogues of pleuromutilin look promising, but how can we prepare analogues of the natural product when the structure is so challenging?One solution is to develop a way of building pleuromutilin from scratch. In this project, we will develop chemistry that allows us to do this. To keep the synthesis short, we propose to develop a new chemical process that will construct the skeleton of pleuromutilin in one reaction. To do this we will use the lanthanide reagent SmI2 to orchestrate the chemical 'sequence' so that we get a high yield while achieving good control over the shape or 'stereochemistry' of the product. Our research will produce powerful organic reactions for other chemists to use and will improve our understanding of the way reactions work. Our route to pleuromutilin will allow access to analogues that would otherwise be impossible to prepare. These analogues could go on to to become future drugs.
Organisations
People |
ORCID iD |
David Procter (Principal Investigator) |
Publications
Findley TJ
(2008)
A flexible, stereoselective approach to the decorated cis-hydrindane skeleton: synthesis of the proposed structure of faurinone.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Helm M
(2009)
SmI2-mediated dialdehyde 'radical then aldol' cyclization cascades: a feasibility study
in Tetrahedron
Helm M
(2009)
SmI2-mediated dialdehyde cyclization cascades
in Tetrahedron Letters
Helm MD
(2009)
A dialdehyde cyclization cascade: an approach to pleuromutilin.
in Angewandte Chemie (International ed. in English)
Findley TJ
(2011)
A stereoselective, Sm(II)-mediated approach to decorated cis-hydrindanes: synthetic studies on faurinone and pleuromutilin.
in Organic & biomolecular chemistry
Fazakerley NJ
(2013)
Total synthesis of (+)-pleuromutilin.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Fazakerley N
(2014)
Synthesis and synthetic chemistry of pleuromutilin
in Tetrahedron
Ruscoe RE
(2016)
Copper-Catalyzed Double Additions and Radical Cyclization Cascades in the Re-Engineering of the Antibacterial Pleuromutilin.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Yeung K
(2016)
Enantioselective Generation of Adjacent Stereocenters in a Copper-Catalyzed Three-Component Coupling of Imines, Allenes, and Diboranes.
in Angewandte Chemie (International ed. in English)
Description | We have developed a method for synthesising the antibacterial natural product pleuromutilin. This has allowed us to synthesise novel analogues of the natural product that can not be prepared from the natural product. |
Exploitation Route | Industry may develop new antibacterials. |
Sectors | Chemicals,Healthcare |