Recent Advances in the Synthetic Chemistry of Bicyclo[1.1.1]pentane

Abstract

Utilization of three-dimensional cyclic scaffolds is important in modern drug discovery, both to provide greater opportunities for optimizing drug candidates and to expand the available chemical space of drugs. Among these scaffolds, bicyclo[1.1.1]pentane (BCP) is a high-value bioisostere for 1,4-disubstituted phenyl rings, internal alkynes, and the tert-butyl group, generally offering high passive permeability, high water solubility, and improved metabolic stability. However, the lack of methods for functionalizing BCP remains a significant challenge, and in particular, a versatile strategy for synthesizing a wide range of unsymmetrically 1,3-difunctionalized BCP derivatives has been lacking. In this account, we review recent advances in the synthetic chemistry of BCP, focusing especially on our recently developed radical multicomponent carboamination of [1.1.1]propellane.

1 Introduction

2 Overview of the Synthetic Chemistry of [1.1.1]Propellane, the Most Promising Precursor of Bicyclo[1.1.1]pentane

3 Recent Advances in the Synthetic Chemistry of Unsymmetrically 1,3-Disubstituted Bicyclo[1.1.1]pentane Derivatives

4 Radical Multicomponent Carboamination of [1.1.1]Propellane Permits Direct Synthesis of 3-Substituted Bicyclo[1.1.1]pent-1-ylamine Derivatives

5 Conclusion

Key words

three-dimensional cyclic scaffolds - bioisosteres - radical multicomponent carboamination - density functional theory - propellanes - bicyclopentanes

• References and Notes

• 1 Mullard A. Nat. Rev. Drug Discov. 2018; 17: 81
• 2a Ledford H. Nature 2011; 477: 526
• 2b Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Nat. Biotechnol. 2014; 32: 40
• 3a Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
• 3b Ritchie TJ, Macdonald SJ. F. Drug Discovery Today 2009; 14: 1011
• 3c Lovering F. Med. Chem. Commun. 2013; 4: 515
• 3d Estrada AA, Shore DG, Blackwood E, Chen Y.-H, Deshmukh G, Ding X, DiPasquale AG, Epler JA, Friedman LS, Koehler MF. T, Liu L, Malek S, Nonomiya J, Ortwine DF, Pei Z, Sideris S, St-Jean F, Trinh L, Truong T, Lyssikatos JP. J. Med. Chem. 2013; 56: 3090
• 4a Carreira EM, Fessard TC. Chem. Rev. 2014; 114: 8257
• 4b Zheng Y, Tice CM, Singh SB. Bioorg. Med. Chem. Lett. 2014; 24: 3673

For examples of bioisostere for 1,4-disubstituted phenyl ring, see:
• 5a Pellicciari R, Raimondo M, Marinozzi M, Natalini B, Costantino G, Thomsen C. J. Med. Chem. 1996; 39: 2874
• 5b Stepan AF, Subramanyam C, Efremov IV, Dutra JK, O’Sullivan TJ, Dirico KJ, McDonald WS, Won A, Dorff PH, Nolan CE, Becker SL, Pustilnik LR, Riddell DR, Kauffman GW, Kormos BL, Zhang L, Lu Y, Capetta SH, Green ME, Karki K, Sibley E, Atchison KP, Hallgren AJ, Oborski CE, Robshaw AE, Sneed B, O’Donnell CJ. J. Med. Chem. 2012; 55: 3414
• 5c Nicolaou KC, Vourloumis D, Totokotsopoulos S, Papakyriakou A, Karsunky H, Fernando H, Gavrilyuk J, Webb D, Stepan AF. ChemMedChem 2015; 11: 31
• 5d Auberson YP, Brocklehurst C, Furegati M, Fessard TC, Koch G, Decker A, La Vecchia L, Briard E. ChemMedChem 2017; 12: 590
• 5e Goh YL, Cui YT, Pendharkar V, Adsool VA. ACS Med. Chem. Lett. 2017; 8: 516
• 5f Measom ND, Down KD, Hirst DJ, Jamieson C, Manas ES, Patel VK, Somers DO. ACS Med. Chem. Lett. 2017; 8: 43

For examples of bioisosteres for tert -butyl group, see:
• 6a Barbachyn MR, Hutchinson DK, Toops DS, Reid RJ, Zurenko GE, Yagi BH, Schaadt RD, Allison JW. Bioorg. Med. Chem. Lett. 1993; 3: 671
• 6b Westphal MV, Wolfstädter BT, Plancher J.-M, Gatfield J, Carreira EM. ChemMedChem 2015; 10: 461
• 7 For example, of bioisosteres for internal alkynes, see: Makarov IS, Brocklehurst CE, Karaghiosoff K, Koch G, Knochel P. Angew. Chem. Int. Ed. 2017; 56: 12774

For reviews of [1.1.1]propellane, see:
• 8a Levin MD, Kaszynski P, Michl J. Chem. Rev. 2000; 100: 169
• 8b Dilmaç AM, Spuling E, de Meijere A, Bräse S. Angew. Chem. Int. Ed. 2017; 56: 5684
• 9 Wiberg KB, Walker FH. J. Am. Chem. Soc. 1982; 104: 5239
• 10a Semmler K, Szeimies G, Belzner J. J. Am. Chem. Soc. 1985; 107: 6410
• 10b Belzner J, Bunz U, Semmler K, Szeimies G, Opitz K, Schlüter A.-D. Chem. Ber. 1989; 122: 397
• 10c Werner M, Stephenson DS, Szeimies G. Liebigs Ann. 1996; 1705
• 11 Applequist DE, Renken TL, Wheeler JW. J. Org. Chem. 1982; 47: 4985
• 12 Wu W, Gu J, Song J, Shaik S, Hiberty PC. Angew. Chem. Int. Ed. 2009; 48: 1407
• 13 Wiberg KB, Waddell ST, Laidig K. Tetrahedron Lett. 1986; 27: 1553
• 14 Kaszynski P, Michl J. J. Org. Chem. 1988; 53: 4593
• 15 Elliott LD, Knowles JP, Koovits PJ, Maskill KG, Ralph MJ, Lejeune G, Edwards LJ, Robinson RI, Clemens IR, Cox B, Pascoe DD, Koch G, Eberle M, Berry MB, Booker-Milburn KI. Chem. Eur. J. 2014; 20: 15226
• 16 Kaszynski P, Michl J. J. Am. Chem. Soc. 1988; 110: 5225
• 17 Wiberg KB, Waddell ST. J. Am. Chem. Soc. 1990; 112: 2194
• 18 Kaszynski P, McMurdie ND, Michl J. J. Org. Chem. 1991; 56: 307
• 19 Marinozzi M, Fulco MC, Rizzo R, Pellicciari R. Synlett 2004; 1027
• 20 Bunz U, Szeimies G. Tetrahedron Lett. 1990; 31: 651
• 21 Messner M, Kozhushkov SI, de Meijere A. Eur. J. Org. Chem. 2000; 1137
• 22 Rehm JD. D, Ziemer B, Szeimies G. Eur. J. Org. Chem. 1999; 2079
• 23 Wiberg KB, McMurdie N. J. Am. Chem. Soc. 1994; 116: 11990
• 24 Goh YL, Adsool VA. Org. Biomol. Chem. 2015; 13: 11597
• 25 Thirumoorthi NT, Shen CJ, Adsool VA. Chem. Commun. 2015; 51: 3139
• 26 Thirumoorthi NT, Adsool VA. Org. Biomol. Chem. 2016; 14: 9485
• 27 Caputo DF. J, Arroniz C, Dürr AB, Mousseau JJ, Stepan AF, Mansfield SJ, Anderson EA. Chem. Sci. 2018; 9: 5295
• 28a Kung P.-P, Meng JJ. WO 2010018481, 2010
• 28b Andrews MD, Bagal SK, Gibson KR, Omoto K, Ryckmans T, Skerratt SE, Stupple PA. US 2014364415, 2014
• 28c Bacon EM, Balan G, Chou C.-H, Clark CT, Cottell JJ, Kim M, Kirschberg TA, Link JO, Phillips G, Schroeder SD, Squires NH, Stevens KL, Taylor JG, Watkins WJ, Wright NE, Zipfel SM. WO 2017007689, 2017
• 28d Johnson TW, Richardson PF, Collins MR, Richter DT, Burke BJ, Gajiwala K, Ninkovic S, Linton MA, Le PT. Q, Hoffman JE. CA 2915356, 2016
• 28e Sidrauski C, Pliuschchev M, Frost JM, Black LA, Xu X, Sweis RF, Shi L, Zhang QI, Tong Y, Hutchins CW, Chung S, Dart MJ. WO 2017193041, 2017
• 29a Wiberg KB, Williams VZ. Jr. J. Org. Chem. 1970; 35: 369
• 29b Della EW, Kasum B, Kirkbride KP. J. Am. Chem. Soc. 1987; 109: 2746
• 29c Toops DS, Barbachyn MR. J. Org. Chem. 1993; 58: 6505
• 29d Bunker KD, Sach NW, Huang Q, Richardson PF. Org. Lett. 2011; 13: 4746
• 29e Goh YL, Tam EK. W, Bernardo PH, Cheong CB, Johannes CW, William AD, Adsool VA. Org. Lett. 2014; 16: 1884
• 29f Bunker KD, Miller KJ. WO 2015089170, 2015
• 30a Gianatassio R, Lopchuk JM, Wang J, Pan C.-M, Malins LR, Prieto L, Brandt TA, Collins MR, Gallego GM, Sach NW, Spangler JE, Zhu H, Zhu J, Baran PS. Science 2016; 351: 241
• 30b Lopchuk JM, Fjelbye K, Kawamata Y, Malins LR, Pan C.-M, Gianatassio R, Wang J, Prieto L, Bradow J, Brandt TA, Collins MR, Elleraas J, Ewanicki J, Farrell W, Fadeyi OO, Gallego GM, Mousseau JJ, Oliver R, Sach NW, Smith JK, Spangler JE, Zhu H, Zhu J, Baran PS. J. Am. Chem. Soc. 2017; 139: 3209
• 31 Kanazawa J, Maeda K, Uchiyama M. J. Am. Chem. Soc. 2017; 139: 17791
• 32 Della EW, Pigou PE, Schiesser CH, Taylor DK. J. Org. Chem. 1991; 56: 4659

Dialkyl azocarboxylates have been used as a carbon radical-trapping agents; see:
• 33a Huisgen VR, Jakob F, Siegel W, Cadus A. Liebigs Ann. Chem. 1954; 590: 1
• 33b Shah A, George MV. Tetrahedron 1971; 27: 1291
• 33c Lee D, Otte RD. J. Org. Chem. 2004; 69: 3569
• 33d Waser J, Gaspar B, Nambu H, Carreira EM. J. Am. Chem. Soc. 2006; 128: 11693
• 34 We examined other substrates for the generation of C-radicals, but these were not applicable to the present radical multicomponent reaction, and did not afford the target molecule; see Supporting Information for ref. 31.
• 35 Taniguchi T, Sugiura Y, Zaimoku H, Ishibashi H. Angew. Chem. Int. Ed. 2010; 49: 10154
• 36 We synthesized 2 in pentane by a slight modification of the method reported in ref. 30; see Supporting Information for ref. 31. For details of optimizations, see Supporting Information for ref. 31.
• 37a Liu W, Li Y, Liu K, Li Z. J. Am. Chem. Soc. 2011; 133: 10756
• 37b Cheng J.-K, Loh T.-P. J. Am. Chem. Soc. 2015; 137: 42