Enecarbamates as platforms for the synthesis of diverse polycyclic scaffolds Alexandra Hindle, Professor Steve Marsden and Professor Adam Nelson University of Leeds, UK Saturated nitrogen heterocycles are prevalent subunits of many important organic molecules, including those of pharmaceutical and medicinal relevance. Their sp 3 -rich nature makes them a desirable starting point for fragment design. C-H functionalisation approaches for these motifs are therefore paramount to facilitate the synthesis of lead-like compounds and enable fragment elaboration. A toolkit of strategies which would allow fragment growth via multiple vectors from a common precursor would therefore be of high value. 1,2 The main project aim was to develop novel approaches towards the synthesis of valuable small molecule building blocks from simple, inexpensive precursors. To do this, well-established Shono oxidation methodology was employed to deliver hemiaminal ethers as common intermediates which then served as handles for further elaboration via the beta vector (through elimination to the enecarbamate). 4 Exploitation of the reactivity of these common intermediates using a toolkit of cutting-edge photoredox methodologies enabled the preparation of a library of complex and diverse 3D ring systems which lie within lead-like chemical space. 5,6 Of most significance, a 3-step procedure, utilising photoredox-catalysed hydroamination chemistry as the key step enabled the production of a series of bridged, bicyclic lactams and anilines in good yields. These scaffolds display modulated electronic properties due to their twisted nature and so we have performed several studies to explore the resulting physical and biological properties. 7 We have also showcased complimentary photoredox-mediated routes for the synthesis of valuable spirocyclic and fused ring systems. 8
References 1. Campos K.R., Soc. Rev. 2007, 36 , 1069–84. 2. Lovering F., Bikker J. and Humblet C., Med. Chem. 2009, 52 , 6752–6 3. Nadin A., Hattotuwagama C. and Churcher I., Chem. Int. Ed. 2012, 51 , 1114–22. 4. Shono T., Tsubata K. and Okinaga N., Org. Chem. 1984, 49 , 1056–9. 5. Trindade F., Faulkner E. L., Leach A. G., Nelson A. and Marsden S. P., Commun. , 2020, 56 , 8802–8805.
6. Francis D., Nelson A. and Marsden S.P., , A Eur. J. 2020, 26 , 14861–5. 7. Hassan H., Marsden S. P. and Nelson A., Med. Chem. 2018, 26 , 3030–3033. 8. Hindle A., Marsden S., Nelson A. and Cox D., Manuscript in preparation .
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