Practical Synthesis of Fluorinated Piperidine Analogues Based on the 2-Azaspiro[3.3]heptane Scaffold

Abstract

The synthesis of a set of conformationally restricted fluorinated analogues of piperidine, based on a 2-azaspiro[3.3]heptane scaffold, is reported. Different pattern of fluorine substitution within the rigid skeleton make the analogues excellent candidates for use in drug design. The overall simplicity of the experimental procedures and the availability of inexpensive starting materials allow for multigram-scale syntheses of the described compounds.

Key words

piperidine analogues - fluorinated building blocks - azaspiro[3.3]heptane - deoxofluorination - azetidine derivatives

• References and Notes

• 1 Hagmann WK. J. Med. Chem. 2008; 51: 4359
• 2 Mann A In The Practice of Medicinal Chemistry . Wermuth CG. Elsevier; Amsterdam: 2008. 3rd ed., 363-379
• 3 Fluorine in Medicinal Chemistry and Chemical Biology. Ojima I. Wiley-Blackwell; Chichester: 2009
• 4 Marson CM. Chem. Soc. Rev. 2011; 40: 5514
• 5 Hu X.-G, Hunter L. Beilstein J. Org. Chem. 2013; 9: 2696
• 6 Lovering F. Med. Chem. Commun. 2013; 4: 515
• 7 Senten K, Van der Veken P, De Meester I, Lambeir A.-M, Scharpé S, Haemers A, Augustyns K. J. Med. Chem. 2004; 47: 2906
• 8 Mimura M, Hayashida M, Nomiyama K, Ikegami S, Iida Y, Tamura M, Hiyama Y, Ohishi Y. Chem. Pharm. Bull. 1993; 41: 1971
• 9 Surmont R, Verniest G, De Weweire A, Thuring J, Macdonald G, Deroose F, De Kimpe N. Synlett 2009; 1933
• 10 Verniest G, Surmont R, Van Hende E, Deweweire A, Deroose F, Thuring JW, De Kimpe N. J. Org. Chem. 2008; 73: 5458
• 11 Deng X, Liang JT, Liu J, McAllister H, Schubert C, Mani NS. Org. Process Res. Dev. 2007; 11: 1043
• 12 Jean DJ. S. Jr, Fotsch C. J. Med. Chem. 2012; 55: 6002
• 13 Venkatraman S, Lebsack AD, Alves K, Gardner MF, James J, Lingham RB, Maniar S, Mumford RA, Si Q, Stock N, Treonze KM, Wang B, Zunic J, Munoz B. Bioorg. Med. Chem. Lett. 2009; 19: 5803
• 14 Kerekes AD, Esposite SJ, Doll RD, Tagat JR, Yu T, Xiao Y, Zhang Y, Prelusky DB, Tevar S, Gray K, Terracina GA, Lee S, Jones J, Liu M, Basso AD, Smith EB. J. Med. Chem. 2011; 54: 201
• 15 Shook BC, Charavarty D, Barbay JK, Wang A, Leonard K, Alford V, Powell M, Beauchamp DA, Rassnick S, Scannevin R, Carroll K, Wallace N, Crooke J, Ault M, Lampron L, Westover L, Rhodes K, Jackson PF. Med. Chem. Commun. 2011; 2: 950
• 16 Isensee K, Amon M, Galaparti A, Ligneau X, Camelin J.-C, Capet M, Schwartz J.-C, Stark H. Bioorg. Med. Chem. Lett. 2009; 19: 2172
• 17 Woods JR, Mo H, Bieberich AA, Alavanja T, Colby DA. J. Med. Chem. 2011; 54: 7934
• 18 Selivanova SV, Honer M, Combe F, Isensee K, Stark H, Krämer SD, Schubiger PA, Ametamey SM. Bioorg. Med. Chem. 2012; 20: 2889
• 19 Carreira EM, Fessard TC. Chem. Rev. 2014; 114: 8257
• 20 Chernykh AV, Radchenko DS, Grygorenko OO, Daniliuc CG, Volochnyuk DM, Komarov IV. J. Org. Chem. 2015; 80: 3974
• 21 Radchenko DS, Pavlenko SO, Grygorenko OO, Volochnyuk DM, Shishkina SV, Shishkin OV, Komarov IV. J. Org. Chem. 2010; 75: 5941
• 22 Guerot C, Tchitchanov BH, Knust H, Carreira EM. Org. Lett. 2011; 13: 780
• 23 tert-Butyl 3-Cyclopropylideneazetidine-1-carboxylate (2) NaHMDS (1 M solution in THF, 312 mL, 312 mmol) was added to a suspension of (3-bromopropyl)triphenylphosphonium bromide (69.00 g, 148.70 mmol) in toluene (600 mL) under an Ar atmosphere at –30 °C. The orange solution was stirred for 2 h at room temperature, and then the solution of compound 1 (23.00 g, 134.35 mmol) in THF (100 mL) was slowly added dropwise to reaction mixture at –78 °C. The reaction mixture was stirred at –78 °C for 1 h, slowly warmed up to room temperature overnight, refluxed for 3 h, and poured into cold sat. aq NH₄Cl. The mixture was extracted with EtOAc. The organic phase was dried over Na₂SO₄, filtered, and evaporated. The resulting solid was washed with hexanes–EtOAc (7:1, 3 × 100 mL), and the combined organic extracts were evaporated. The residue was purified by column chromatography (hexanes–EtOAc = 7:1); yield 13.90 g (71.19 mmol, 53%); white solid; mp 90–93 °C. TLC: R_f  = 0.37 (hexanes–EtOAc = 7:1). ¹H NMR (500 MHz, CDCl₃): δ = 4.55–4.50 (m, 4 H), 1.44 (s, 9 H), 1.08–1.03 (m, 4 H). ¹³C NMR (126 MHz, CDCl₃): δ = 156.7, 116.9, 113.4, 91.4, 79.6, 28.5, 2.4. HRMS (EI): m/z calcd for C₁₁H₁₇O₂N [M⁺]: 195.1254; found: 195.1253.
• 24 Van Brabandt W, Verniest G, De Smaele D, Duvey G, De Kimpe N. J. Org. Chem. 2006; 71: 7100
• 25 Van Hende E, Verniest G, Deroose F, Thuring J, Macdonald G, De Kimpe N. J. Org. Chem. 2009; 74: 2250
• 26 Chernykh AV, Feskov IO, Chernykh AV, Daniliuc CG, Tolmachova NA, Volochnyuk DM, Radchenko DS. Tetrahedron 2016; 72: 1036
• 27 Meyers MJ, Muizebelt I, van Wiltenburg J, Brown DL, Thorarensen A. Org. Lett. 2009; 11: 3523
• 28 Radchenko DS, Grygorenko OO, Komarov IV. Amino Acids 2010; 39: 515
• 29 The CCDC numbers 1451977–1451979 for compounds 5, 15, and 19 contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.