Accessing diverse saturated heterocycles via rhodium-catalysed intermolecular hydroacylation/cyclisation

This project falls within the EPSRC Synthetic Organic Chemistry research area.
Nitrogen-, oxygen and sulphur-containing saturated heterocycles are ubiquitous amongst natural and bioactive compounds. These frameworks are becoming increasingly more desirable in therapeutic agents owing to their enhanced aqueous solubility and 3D structure. Saturated heterocycles with heteroarene appendages are particularly important for probing binding pocket interactions in drug discovery. While a plethora of syntheses exist for heteroaromatics, there are limited methods for constructing saturated N-, O- and S-heterocycles. Approaches to these frameworks must be general, convenient and employ easily accessible starting materials.
Metal-catalysed alkyne hydroacylation reactions, where a C-H bond is formally added across a pi-bond, generate enone compounds, in an atom-economical fashion. These compounds can then be transformed into diverse heterocycles via intramolecular conjugate addition. In recent years, hydroacylation reactions have been validated as a tool for heterocycle assembly. In 2014, the Dong group synthesised a- aryl ketone hydroacylation adducts, which were cyclised to benzofurans via cyclocondensation. Additionally, our group has reported syntheses of quinolines and hexahydroquinolines through TFA deprotection-cyclisation and Lewis acid-catalysed aza-conjugate addition, respectively.
Intermolecular hydroacylation has advanced significantly over the past decade. The adoption of substrate directing groups, which chelate the metal, effectively thwarts an undesirable reductive-decarbonylation pathway. This so-called chelate control was first demonstrated by Lochow and Miller. Since then, a variety of functional groups have proven successful in promoting intermolecular hydroacylation. To date, our group have established a robust chelate controlled intermolecular hydroacylation protocol; requiring low catalyst-loadings and mild conditions.
In this project, we aim to exploit hydroacylation to access novel, and synthetically attractive saturated N-,O-and S-heterocycles. Synthesis of heterocycles with multiple stereogenic centres is also desired, in order to probe the diastereoselectivity of cyclisation. Furthermore, our group has recently reported branched selective hydroacylation using PNP(Cy) ligand. We propose that intramolecular endo-cyclisation of branched enones, could be utilized to attain a much broader repertoire of saturated heterocycles. Moreover, preliminary investigations suggest the cyclisation reaction results in preferential formation of a single diastereomer. Consequently, we are also interested in designing an enantioselective synthesis of saturated heterocycles. Ultimately, we hope to realise a methodology that provides an atom-economical, mild and efficient route to a variety of novel scaffolds sought after in medicinal chemistry.