Diastereoselective Preparation of Saturated S- N- and O- Incorporated Heterocycles from a Rhodium Catalysed Hydroacylation Cascade

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This project falls within the EPSRC Synthetic Organic Chemistry research area.N-, S- and O-containing saturated heterocycles feature in a vast array of natural products and other bioactive compounds; motifs associated with this general scaffold are therefore considered highly attractive to drug industry. A key structural feature involves the variation in 3-dimensional space such motifs can occupy, influenced by relative ring substituent configuration; this is a trait highly beneficial to selectivity and potency in enzyme active-site binding. Other key assets include high aqueous solubility, leading to enhanced pharmacokinetic profiles for related drug molecules and their extensive incorporation into the structures of metal-free catalysts. There have been numerous lucrative organometallic strategies towards the preparation of various saturated heterocyclic units; many saturated motifs can be effectively prepared through palladium-catalysed Tsuji-Trost and other iron and indium catalysed activated allylic alcohol cyclisations. Furthermore, a diverse range of N- and O- containing saturated heterocyclic scaffolds have been recently prepared by Willis and co-workers, through an intramolecular N/O heteroatom assisted intramolecular cyclisation formed via a rhodium(I) catalysed hydroacylation, in the same reaction pot. Rhodium(I) catalysed hydroacylations have previously offered atom-efficient routes towards enones, from the employment of aldehydes across alkenes/alkynes, at low catalyst loadings. These reactions generally deliver excellent control of both regio- and enantioselectivity, however issues with undesired a reductive-decarbonylation pathway have previously led to catalyst deactivation. This limitation can be overcome by use of aldehyde tethers, capable of chelating to the rhodium-metal centre and prevent formation of inactive Rh(I)-CO complex.The initial aim of this Dphil project is to develop saturated heterocycles through thydroacylation cascade reaction, incorporating racemic chiral alkynes that produce diastereoselective 6-exo-trig six-membered ring closure. Initial rotation work on this reaction delivered the successful diastereoselective preparation of 1,4-dioxanes. Future work on this initial 1,4-dioxane system will look into the degree of which substituent alterations, at all potential positions around the forming heterocycle, will affect reaction selectivity.It would also be of potential benefit to alter the heteroatom, in order to expand the substrate scope towards morpholine and sulfur analogues of the medicinally valuable 1,4-heterocyclic motif. Chiral protected alkyne substrates for the morpholine analogues have shown to be obtainable from a readily available precursor, however cyclisation dr could not be easily detected via crude 1H NMR spectroscopy. Accordingly, refining the cyclisation step in future work is thus critical in order to quantify selectivity for morpholine formation. As for the present work done towards sulfur analogue preparation, hydroacylation of SR protected alkynes has been achieved but subsequent deprotection/cyclisation must also be refined.Another considerable aim for this project would be to showcase this methods ability to additionally harness 5/7-membered cyclic motifs, by substrates that would form enone intermediates capable of 7- and 5-exo-trig ring closure. Utilising chiral alkynes towards these altered ring sizes would provide insight to the effect of relative ring puckering constraints upon cyclisation dr. Alongside high dr, retention of ee to product, when starting from an enantiomerically pure chiral alkyne, under the optimised reaction conditions is equally valuable.