Development of diastereodivergent dynamic kinetic transformations

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry

Abstract

The development of methods for the stereoselective synthesis of organic molecules for medical drugs, agrochemicals and fragrances is highly desired. The Fletcher Group has recently shown that non-stabilized sp3 alkyl zirconium and sp2 boronic acid nucleophiles can be used for asymmetric allylic transformations applying DYKATs. One of the major challenges in modern asymmetric synthesis is the selective formation of each of all diastereomeric products that have two or more stereogenic centers (diastereodivergent). In the last decade, remarkable contributions to this field have been achieved with the help of two cooperatively acting catalysts each controlling the absolute stereochemistry of one of the formed stereogenic centers. In 2011 and 2012, Maulide and co-workers have extended the DYKAT concept to palladium catalyzed asymmetric allylic alkylation with stabilized nucleophiles. All four stereoisomers of 4-chlorocyclobut-2-ene-1-carboxylic acid were transformed by ligand control into a single stereoisomer of the desired product. We envision that diastereodivergent DYKATs could become a powerful strategy for the synthesis of chiral compounds that have multiple stereogenic centers. In this PhD project Wieland is planning to develop stereodivergent DYKATs with non-stabilized nucleophiles in asymmetric allylic alkylation and arylation. His first attempts will focus on the development of diastereodivergent variants of the already established enantiodivergent DYKATs in our group to prove the concept that diastereodivergent DKYATs can also be realized with nonstabilized nucleophiles. Two main requirements have to be fulfilled for this as discussed using a monosubstituted six-membered allylic compound. First, fast isomerization between all stereoisomers have to be enabled using two mechanistic pathways: The isomerization might occur on the metal 'pi'-allyl complex (Strategy A) or the isomerization might also occur between the syn and anti stereoisomers of the starting material with assistance of additives or a cocatalyst (Strategy B). Second, two distinct catalytic systems have to be developed, which show opposite diastereoselectivity. Ligand control, leaving group, counterions, solvent, additives and different transition metals might are the most promising strategies for achieving the desired selectivities. Furthermore, this methodology could be applied to novel non-stabilized nucleophiles for DYKATs. It is hoped that this project will find novel methods that enable a more rapid access to highly complex chiral molecules. This project falls within the EPSRC Catalysis research area.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509711/1 01/10/2016 30/09/2021
1947333 Studentship EP/N509711/1 01/10/2017 30/09/2020 Friedrich Wieland Goetzke
 
Description We have developed as series of rhodium-catalyzed enantio- and diastereo-selective Suzuki-Miyaura type coupling reactions where sp2-hybrized boronic acids add to racemic bicyclic structures. We have published a part of this work recently in Angewandte Chemie - one of the worlds premier general chemistry journal - and the article was selected as a "Hot Paper" by the journal's editors.
Exploitation Route We are developing methods to make complex molecules from simple building blocks. We believe that theses methods can be applied in drug discovery programms in pharmaceutical research and in academic laboratories.
Sectors Agriculture, Food and Drink,Healthcare

 
Description Studentship with Vertex Pharmaceuticals
Amount £17,500 (GBP)
Organisation Vertex Pharmaceuticals 
Sector Private
Country United States
Start 10/2017 
End 03/2021