Benzene bioisosteres and beyond: general access to polysubstituted Bicyclo[2.1.1]hexanes Marius Reinhold, Justin Steinebach, Christopher Golz, Johannes C. L. Walker* Institut für Organische und Biomolekulare Chemie, Georg-August-Universität-Göttingen, Germany The exploration of the three-dimensional chemical space has become an important topic in medicinal chemistry, since drug candidates with more saturated carbon skeletons are more likely to progress through development than their saturated analogues. [1] Polycyclic and bridged-bicyclic ring systems such as bicyclo[2.1.1]hexanes (BCHs) are typical of the compounds currently sought after. [2,3] BCHs have been proposed as a general building block for a range of bioisosteres of ortho - and meta -substituted benzenes. [3,4] Additionally, the 10 linear exit vectors of BCHs offer access to chemical space beyond that of unsaturated, aromatic structures, opening up new possibilities in molecular design. [5] A general protocol for the synthesis of differently substituted BCHs would be a powerful tool for the development of new drugs and in organic synthesis. We present a method which allows for the synthesis of BCH scaffolds with 11 different substitution patterns, starting from 1,5-hexadienes. The photochemical cycloaddition reaction proceeds under mild reaction conditions using wildly available 456 nm blue LEDs. A broad functional group tolerance including boronate esters, aldehydes, esters, tertiary alcohols and pyridines was accessed. [5] To demonstrate the power of this method, we synthesised two saturated analogues of biological active compounds containing a trisubstituted benzene motif. References 1. (a) F. Lovering, J. Bikker, C. Humblet, J. Med. Chem . 2009 , 52 , 6752–6756; (b) F. Lovering, Med. Chem. Commun . 2013 , 4 , 515–519; (c) D. G. Brown, J. Boström, J. Med. Chem . 2016 , 59 , 4443–4458; (d) J. Boström, D. G. Brown, R. J. Young, G. M. Keserü, Nat. Rev. Drug Discov. 2018 2. M. A. M. Subbaiah, N. A. Meanwell, J. Med. Chem. 2021 , 64, 14046−14128. 3. P. K. Mykhailiuk, Org. Biomol. Chem. 2019 , 17 , 2839–2849. 4. (a) E. G. Tse, S. D. Houston, C. M. Williams, G. P. Savage, L. M. Rendina, I. Hallyburton, M. Anderson, R. Sharma, G. S. Walker, R. S. Obach, M. H. Todd, J. Med. Chem. 2020, 63 , 11585–11601; (b) B. A. Chalmers, H. Xing, S. Houston, C. Clark, S. Ghassabian, A. Kuo, B. Cao, A. Reitsma, C.-E. P. Murray, J. E. Stok, G. M. Boyle, C. J. Pierce, S. W. Littler, D. A. Winkler, P. V. Bernhardt, C. Pasay, J. J. De Voss, J. McCarthy, P. G. Parsons, G. H. Walter, M. T. Smith, H. M. Cooper, S. K. Nilsson, J. Tsanaktsidis, G. P. Savage, C. M. Williams, Angew. Chem. Int. Ed. 2016 , 55 , 3580–3585; (c) A. Denisenko, P. Garbuz, S. V. Shishkina, N. M. Voloshchuk, P. K. Mykhailiuk, Angew. Chem. Int. Ed. 2020. 59 , 20515– 20521. 5. M. Reinhold, J. Steinebach, J. C. L. Walker, 2023, 10.26434/chemrxiv-2023-wld91.
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