Organic Chemistry, Invited Lecture
OC-011

Ring Expansion Approaches for the Synthesis of Functionalised Macrocycles

W. P. Unsworth1
1University of York, York, YO10 5DD (UK), e-mail:

This talk concerns the development of two ring enlargement new way to construct functionalised macrocycles (12+ membered rings) and medium-sized rings (8–11-membered). These ring  systems are usually difficult to make, with one of the key challenges being the effective control of intra- and intermolecular reaction during end-to-end cyclisation.[1,2] Both approaches I will discuss in this talk are based on strategies by which the difficult end-to-end cyclisation step can be completely avoided. First, I will describe an iterative ring enlargement approach known as ‘Successive Ring Expansion’ (SuRE).[3-6] SuRE works be enabling the controlled insertion of amino acid and hydroxy acid fragments into ring enlarged products via a telescoped acylation/rearrangement reaction sequence. Background, methods development, substrate scope/limitations, the synthesis of compound libraries for biological evaluation[4] and DFT calculations[7] will all be covered. Second, a new ring expansion cascade strategy[8,9] will be introduced, that enables the atroposelective synthesis of medium sized rings directly from linear precursors.[10]

   
[1]  Ring Enlargement in Organic Chemistry, M. Hesse, 1991, VCH
[2]  W. P. Unsworth, J. R. Donald, Chem. Eur. J. 2017, 23, 8780–8799.
[3]  C. Kitsiou, J. J. Hindes, P. I’Anson, P. Jackson, T. C. Wilson, E. K. Daly, H. R. Felstead, P. Hearnshaw, W. P. Unsworth, Angew. Chem. Int. Ed. 2015, 54, 15794–15798.
[4]  L. G. Baud, M. A. Manning, H. L. Arkless, T. C. Stephens, W. P. Unsworth, Chem. Eur. J. 2017, 23, 2225–2230.
[5]  T. C. Stephens, M. Lodi, A. Steer, Y. Lin, M. Gill, W. P. Unsworth, Chem. Eur. J. 2017, 23, 13314–13318.
[6]  T. C. Stephens, A. Lawer, T. French, W. P. Unsworth, Chem. Eur. J. 2018, 24, 13947–13953.
[7]  A. Lawer, R. G. Epton, T. C. Stephens, K. Y. Palate, M. Lodi, E. Marotte, K. J. Lamb, J. K. Sangha, J. Lynam, W. P. Unsworth, Chem. Eur. J. 2020, doi: 10.1002/chem.202002164.
[8]  T. C. Stephens, W. P. Unsworth, Synlett 2020, 31, 133–146.
[9]  A. K. Clarke, W. P. Unsworth, Chem. Sci., 2020, 11, 2876–2881.
[10] A. Lawer, J. A. Rossi-Ashton, T. C. Stephens, B. J. Challis, R. G. Epton, J. M Lynam, W. P. Unsworth, Angew. Chem., Int. Ed. 2019, 58, 13942–13947.