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.
Organisations
People |
ORCID iD |
Stephen Fletcher (Primary Supervisor) | |
Friedrich Goetzke (Student) |
Publications
Fletcher S
(2021)
Additions to Racemates: A Strategy for Developing Asymmetric Cross-Coupling Reactions
in Synlett
Goetzke F
(2019)
Enantio- and Diastereoselective Suzuki-Miyaura Coupling with Racemic Bicycles
in Angewandte Chemie
Goetzke F
(2010)
Patai's Chemistry of Functional Groups
Goetzke FW
(2021)
A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes.
in Nature chemistry
Goetzke FW
(2021)
Catalytic asymmetric hydrometallation of cyclobutenes with salicylaldehydes.
in Chemical science
Goetzke FW
(2019)
Enantio- and Diastereoselective Suzuki-Miyaura Coupling with Racemic Bicycles.
in Angewandte Chemie (International ed. in English)
González J
(2019)
Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides.
in Nature protocols
Kucera R
(2020)
An Asymmetric Suzuki-Miyaura Approach to Prostaglandins: Synthesis of Tafluprost.
in Organic letters
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
EP/N509711/1 | 30/09/2016 | 29/09/2021 | |||
1947333 | Studentship | EP/N509711/1 | 30/09/2017 | 29/09/2020 | Friedrich Goetzke |
Description | Chiral and C(sp3)-rich molecules (and thereby more 3-dimensional molecules) have received extraordinary attention in drug discovery as privleged scaffolds. We have developed as series of rhodium-catalyzed enantio- and diastereoselective C(sp2)-C(sp3) cross-coupling reactions. Synthetic utility of these methods has been demonstrated with concise (formal) syntheses of the bioactive molecules Niraparib, Tafluprost, Belaperidone and PF-04862853. We have also performed brief mechanistic studies in order to understand their underlying mechanisms, which will guide the development of other new transformations. We have published this work in the leading chemistry journals in Angewandte Chemie, Nature Chemistry and Chemical Science. |
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 | AFR PhD |
Amount | € 66,000 (EUR) |
Funding ID | 11588566 |
Organisation | Luxembourg National Research Fund (FNR) |
Sector | Public |
Country | Luxembourg |
Start | 09/2017 |
End | 07/2021 |
Description | Studentship with Vertex Pharmaceuticals |
Amount | £17,500 (GBP) |
Organisation | Vertex Pharmaceuticals |
Sector | Private |
Country | United States |
Start | 09/2017 |
End | 03/2021 |