A ‘clip-cycle’ approach towards enantioselective synthesis of substituted tetrahydropyrans Khadra Alomari 1,2 and Paul Clarke 2 1 Jazan University, Saudi Arabia, 2 University of York, UK Tetrahydropyrans are the fifth most prevalent heterocycle in pharmaceutical molecules 1 , therefore, the development of new methodologies for their asymmetric synthesis can provide access to novel biologically relevant molecules. 2 Despite the popularity of the intramolecular oxa-Michael reaction for the synthesis of substituted THPs, the control of enantioselectivity usually focus on intermolecular reactions, with only a few intramolecular variations reported. 3,4 An asymmetric ‘clip-cycle’ reaction has been developed toward the synthesis of 2,2- and 3,3-spirocyclic THPs with high enantioselectivity (up to 99%). The cyclisation precursors were initially prepared by ‘clipping’ together the alcohol fragment and an aryl thioacrylate ( via catalytic olefin metathesis), which was then followed by intramolecular oxa-Michael cyclization catalysed by chiral phosphoric acids (CPA) to yield the tetrahydropyran products. α, β-Unsaturated thioesters sit in the ‘Goldilocks zone’ of the reactivity 5 and enantioselectivity. They can be easily converted into a wide variety of different functional groups. 6 The absolute stereochemistry of cyclization was determined experimentally as ( S ).
References 1. R. D. Taylor, M. MacCoss and A. D. G. Lawson, J. Med. Chem. , 2014, 57 , 5845–5859. 2. I. Paterson and C. A. Luckhurst, Tetrahedron Lett. , 2003, 44 , 3749–3754. 3. Y. Lu, G. Zou and G. Zhao, ACS Catal. , 2013, 3 , 1356–1359. 4. L. Becerra-Figueroa, S. Movilla, J. Prunet, G. P. Miscione and D. Gamba-Sánchez, Org. Biomol. Chem. , 2018, 16 , 1277– 1286.
5. C. J. Maddocks, K. Ermanis and P. A. Clarke, Org. Lett. , 2020, 22 , 8116–8121. 6. H. Fuwa, N. Ichinokawa, K. Noto and M. Sasaki, J. Org. Chem. , 2012, 77 , 2588–2607.
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