Routes to Disubstituted Nitrogen and Oxygen Heterocycles: Stereoselective Functionalisation of 3- and 4-Substituted Piperidines and Tetrahydropyrans

Lead Research Organisation: University of York
Department Name: Chemistry


Saturated nitrogen and oxygen heterocycles such as piperidines and tetrahydropyrans are common sub-structures in blockbuster pharmaceuticals. In particular, arylated piperidines and tetrahydropyrans are motifs that are currently attracting the interest of medicinal chemists and, as a result, the development of new methods for sp3-sp2 carbon-carbon bond formation is topical. This new methodology will then be available to be incorporated into the toolkit of reactions for use in medicinal chemistry.

Vision and Objectives
Despite all of the advances in synthetic chemistry in the last 20 years, there are rather limited methods to access disubstituted piperidines and tetrahydropyrans. These are very important motifs that commonly occur in the development of potential pharmaceuticals. Therefore, we propose to work on these types of nitrogen and oxygen heterocycles in this project. We will be primarily involved in the development of novel organometallic chemistry - focusing on organolithium reactions and Negishi cross-coupling or organozinc species. Negishi cross-coupling requires the use of a Pd(0)/phosphine catalyst system. We plan to explore methods that will control where the lithiation occurs (regiochemistry) and also how the new bonds a related in space to each (stereochemistry). Since, chiral blockbuster drugs need need to be accessible as single enantiomers and diastereomers, these key aspects must be explored as part of general methodology development. In particular, there are few stereoselective routes (i.e. where the stereochemistry is controlled) to disubstituted piperidines and tetrahydropyrans that contain one aryl substitutent and one heteroatom substituent (e.g. fluoro-, alkoxy-, dialkylamino-). Hence, the primary aim of this project is to develop methodology for the arylation of 3- and 4-fluoro, alkoxy and dialkylamino-substituted piperidines and tetrahydropyrans which will allow access to particular substitution patterns with regio-, diastereo- and enantiocontrol. This will deliver new disubstituted 6-ring saturated heterocycles for use in medicinal chemistry.
There are four reseach-specific objectives:
(i) alpha-arylation of 4-substituted piperidines - diastereo- and enantioselectivity;
(ii) alpha-arylation of 3-substituted piperidines - regio-, diastereo- and enantioselectivity;
(iii) alpha-arylation of 4- and 3-substituted tetrahydropyrans;
(iv) beta-arylation of 4- and 3-substituted piperidines and tetrahydropyrans.

Using nitrogen- or oxygen-directed alpha-lithiation followed by transmetallation to an organozinc species and Negishi coupling, the direct arylation of 3- and 4-substituted piperidines and tetrahydropyrans will be explored in this project. This will give access to disubstituted nitrogen and oxygen heterocycles in a regio-, diastereo- and enantiocontrolled way.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S513945/1 30/09/2018 29/09/2023
2107318 Studentship EP/S513945/1 30/09/2018 30/11/2022 Matthew Gill