New Routes to Substituted Nitrogen Heterocycles Using Negishi and Suzuki Cross-Coupling Reactions

Introduction
Saturated nitrogen heterocycles such as piperidines, pyrrolidines, morpholines and piperazines are common parts of blockbuster pharmaceuticals. In particular, arylated nitrogen heterocycles 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 the advances in synthetic chemistry in recent years, there are limited methods that allow access to substituted piperidines, pyrrolidines, morpholines and piperazines in an asymmetric fashion starting from the parent heterocycle. These are important sub-structures that frequently occur in the development of potential pharmaceuticals. Therefore, we propose to work on these types of nitrogen heterocycles in this project. Two approaches are envisioned - Suzuki reactions from stereodefined boronate derivatives and Negishi reactions of stereodefined orgnaozinc reagents. Both types of cross-coupling reactions will be carried out using a Pd(0)/phosphine catalyst system. To achieve our aims and objectives, it will be necessary to screen a wide range of Pd catalysts and ligands.
Since the development of blockbuster pharmaceuticals ultimately requires access to single enantiomers of chiral nitrogen heterocycles, the focus will be on diastereoselective and enantioselective methods. We will also work on substrates that contain functionality that is commonly found in drug molecules such as fluoro, amino, alkoxy and hydroxy groups. Our project will deliver a wide range of new building blocks for potential use in medicinal chemistry.

The overall aim of the project is to develop new cross-coupling methodology for the asymmetric synthesis of nitrogen heterocycles. We will also aim to translate our new methodology to the pharmaceutical industry -this will be achieved using strongly established links that are already in place.

There are three research-specific objectives:
(i) arylation of piperidines and pyrrolidines using Suzuki reactions;
(ii) arylation of piperidines using Negishi reactions;
(iii) extension of methods from (i) and (ii) to arylation of morpholines and piperazines.

Overview
Using nitrogen-directed lithiation followed by transmetallation to an organozinc species and Negishi coupling, the direct arylation nitrogen heterocycles will be explored. Separately, an approach using boronate building blocks will be investigated so that a Suzuki cross-coupling approach can also be studied. This will give access to a wide range of building blocks of interest to medicinal chemists in the pharmaceutical industry.