10-Membered Azaenediyne Fused to a Benzothiophene through the Nicholas Macrocyclization: Synthesis and DNA Cleavage Ability

Abstract

The Nicholas-type macrocyclization through NH-tosyl functional group has been found to be an efficient technique for the synthesis of a 10-membered azaenediyne system annulated with a benzothiophene. To compare the activity of azaenediyne synthesized with similar oxa- and carbocyclic enediynes the Bergman cyclization activation energies and the ability of enediynes to cleave DNA (pBR322 plasmid) were investigated. The order of reactivity predicted by DFT calculations (N-enediyne < C-enediyne < O-enediyne) was confirmed by DSC analysis data. Surprisingly azaenediyne was found to be more active in the DNA cleavage assay than the C-analogue.

Key words

Nicholas reaction - Bergman cyclization - iodocyclization - enediyne - alkyne - benzothiophene - pBR322 plasmid

• References and Notes

• 1 Nicholas KM, Pettit R. J. Organomet. Chem. 1972; 44: C21
• 2 Connor RE, Nicholas KM. J. Organomet. Chem. 1977; 125: C45
• 3 Green JR. Curr. Org. Chem. 2001; 5: 809
• 4 Teobald BJ. Tetrahedron 2002; 58: 4133
• 5 Nicholas KM. J. Org. Chem. 2015; 80: 6943
• 6 Bavetsias V, Henderson EA, McDonald E. Tetrahedron 2007; 63: 1537
• 7 Henderson EA, Bavetsias V, Theti DS, Wilson SC, Clauss R, Jackman AL. Bioorg. Med. Chem. 2006; 14: 5020
• 8 Amin J, Motevalli M, Richards CJ. J. Organomet. Chem. 2015; 776: 43
• 9 Wells SM, Widen JC, Harki DA, Brummond KM. Org. Lett. 2016; 18: 4566
• 10 Closser KD, Quintal MM, Shea KM. J. Org. Chem. 2009; 74: 3680
• 11 Kaneda K, Naruse R, Yamamoto S. Org. Lett. 2017; 19: 1096
• 12 Kaneda K, Fujita M, Naruse R. Heterocycles 2016; 92: 291
• 13 Asamizu T, Naruse R, Yongxue G, Kaneda K. Tetrahedron Lett. 2015; 56: 4674
• 14 Christie SD. R, Davoile RJ, Jones RC. F. Org. Biomol. Chem. 2006; 4: 2683
• 15 Akimura N, Fujii A, Kamada F, Nogiwa R, Yamamoto S, Sato T, Ishikawa S, Okazaki T, Kaneda K. Synthesis 2016; 48: 3931
• 16 Hernández JN, Ramírez MA, Rodríguez ML, Martín VS. Org. Lett. 2008; 10: 2349
• 17 Grammatoglou K, Bolsakova J, Jirgensons A. RSC Adv. 2017; 7: 27530
• 18 Igawa K, Aoyama S, Kawasaki Y, Kashiwagi T, Seto Y, Ni R, Mitsuda N, Tomooka K. Synlett 2017; 28: 2110
• 19 Carrillo R, Martín T, López-Rodríguez M, Crisóstomo FP. Org. Lett. 2014; 16: 552
• 20 Ni R, Mitsuda N, Kashiwagi T, Igawa K, Tomooka K. Angew. Chem. Int. Ed. 2015; 54: 1190
• 21 Hagendorn T, Braese S. RSC Adv. 2014; 4: 15493
• 22 Prudhomme M. In Anticancer Agents from Natural Products, Second Edition . Gordon M, Cragg DG. I, Kingston DJ. N. CRC Press; Boca Raton, FL: 2011: 647
• 23 Kar M, Basak A. Chem. Rev. 2007; 107: 2861
• 24 Basak A, Roy S, Roy B, Basak A. Curr. Top. Med. Chem. 2008; 8: 487
• 25 Klein M, Walenzyk T, König B. Collect. Czech. Chem. Commun. 2004; 69: 945
• 26 Basak A, Mandal S, Bag SS. Chem. Rev. 2003; 103: 4077
• 27 Bhattacharya P, Basak A, Campbell A, Alabugin IV. Mol. Pharmaceutics 2018; 15: 768
• 28 Shain JC, Khamrai UK, Basak A. Tetrahedron Lett. 1997; 38: 6067
• 29 Basak A, Mandal S, Das AK, Bertolasi V. Bioorg. Med. Chem. Lett. 2002; 12: 873
• 30 Hatial I, Jana S, Bisai S, Das M, Ghosh AK, Anoop A, Basak A. RSC Adv. 2014; 4: 28041
• 31 Basak A, Kar M. Bioorg. Med. Chem. 2008; 16: 4532
• 32 Du Y, Creighton CJ, Yan Z, Gauthier DA, Dahl JP, Zhao B, Belkowski SM, Reitz AB. Bioorg. Med. Chem. 2005; 13: 5936
• 33 Poloukhtine A, Popik VV. J. Am. Chem. Soc. 2007; 129: 12062
• 34 Dutta S, Basak A, Dasgupta S. Bioorg. Med. Chem. 2009; 17: 3900
• 35 Hatial I, Addy PS, Ghosh AK, Basak A. Tetrahedron Lett. 2013; 54: 854
• 36 Kaiser J, Esseveldt BC. J, van Segers MJ. A, Delft FL, van Smits JM. M, Butterworth S, Rutjes FP. J. T. Org. Biomol. Chem. 2009; 7: 695
• 37 Magnus P. Tetrahedron 1994; 50: 1397
• 38 Roy S, Anoop A, Biradha K, Basak A. Angew. Chem. Int. Ed. 2011; 50: 8316
• 39 Roy B, Basak A. Synlett 2006; 2804
• 40 Basak A, Shain JC, Khamrai UK, Rudra KR, Basak A. J. Chem. Soc., Perkin Trans. 1 2000; 1955
• 41 Banfi L, Guanti G. Eur. J. Org. Chem. 1998; 1543
• 42 Roy SK, Basak A. Chem. Commun. 2006; 1646
• 43 Lyapunova AG, Danilkina NA, Rumyantsev AM, Khlebnikov AF, Chislov MV, Starova GL, Sambuk EV, Govdi AI, Bräse S, Balova IA. J. Org. Chem. 2018; 83: 2788
• 44 Lyapunova AG, Danilkina NA, Khlebnikov AF, Köberle B, Bräse S, Balova IA. Eur. J. Org. Chem. 2016; 4842
• 45 Kulyashova AE, Ponomarev AV, Selivanov SI, Khlebnikov AF, Popik VV, Balova IA. Arabian J. Chem. 2018; DOI: in press; https://doi.org/10.1016/j.arabjc.2018.05.005. 11
• 46 Danilkina N, Nieger M, Selivanov S, Brase S, Balova I. Eur. J. Org. Chem. 2012; 5660
• 47 Danilkina NA, Lyapunova AG, Khlebnikov AF, Starova GL, Bräse S, Balova IA. J. Org. Chem. 2015; 80: 5546
• 48 Geometry optimization of reactants and transition states were performed using B3LYP with the 6-31G++(d,p) basis set. Because of the open shell nature of the transition states, calculations on these structures were performed using BS-UB3LYP (broken-spin symmetry, unrestricted) calculations. For further computational details see the Supporting Information.
• 49 Danilkina NA, Kulyashova AE, Khlebnikov AF, Bräse S, Balova IA. J. Org. Chem. 2014; 79: 9018
• 50 Danilkina NA, Bräse S, Balova IA. Synlett 2011; 517
• 51 Danilkina NA, Gurskaya LY, Vasilyev AV, Balova IA. Eur. J. Org. Chem. 2016; 739
• 52 Lyapunova AG, D’yachenko AS, Danilkina NA. Russ. J. Org. Chem. 2017; 53: 800
• 53 Arnanz A, Moreno C, Marcos M.-L, González-Velasco J, Delgado S. Eur. J. Inorg. Chem. 2007; 5215
• 54 Arnanz A, Marcos ML, Delgado S, González-Velasco J, Moreno C. J. Organomet. Chem. 2008; 693: 3457
• 55 η2-Co₂(CO)₆-Complex 11To an argon-flushed stirred solution of Co complex 10 (280 mg, 0.395 mmol) in absolute DCM (395 mL, c = 0.001 M) at room temperature was added BF₃·OEt₂ (84.0 mg, 73.0 μL, 0.593 mmol, 1.5 equiv). The resulting mixture was stirred at this temperature for 1 h and quenched with a saturated aqueous solution of NaHCO₃. The organic layer was separated, washed with water, dried with anhydrous Na₂SO₄, and concentrated under reduced pressure to yield a crude product, which was purified by column chromatography using hexane/ethyl acetate (7:1) as the eluent to give 11 (193 mg, 72%) as a burgundy solid. The complex decomposed without melting upon heating to 300 °C. ¹H NMR (400 MHz, CDCl₃ ): δ = 7.93 (d, J = 8.3 Hz, 1 H), 7.87 (d, J = 8.1 Hz, 2 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 2 H), 7.47–7.43 (m, 2 H), 4.97 (s, 2 H), 3.73 (t, J = 5.2 Hz, 2 H), 2.84 (t, J = 5.2 Hz, 2 H), 2.46 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.1, 151.5, 145.0, 139.8, 139.4, 136.2, 130.9 (two CH signals overlap), 128.6, 126.5, 123.6, 123.5, 116.8, 101.4, 99.0, 80.6, 79.4, 57.7, 56.4, 23.6, 21.4. HRMS (ESI): m/z calcd for C₂₈H₁₇Co₂NNaO₈S₂ [M + Na]⁺: 699.8957; found: 699.8921.
• 56 Jones GB, Wright JM, Rush TM, Plourde GW, Kelton TF, Mathews JE, Huber RS, Davidson JP. J. Org. Chem. 1997; 62: 9379
• 57 4-Tosyl-1,2,7,8-tetradehydro-3,4,5,6-tetrahydrobenzo[4,5]thieno[2,3-e]azecine (1; Conditions f)To a cooled to 0 °C stirred solution of Co₂(CO)₆ complex 11 (30.7 mg, 0.04546 mmol) in acetone (4.5 mL) in an Ar atmosphere tetrabutylammonium fluoride hydrate ( 143 mg, 0.543 mmol calculated for TBAF·monohydrate) was added in three portions with an interval of 20 min. After completion of the reaction (TLC control, 90 min) the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried over anhydrous Na₂SO₄, and the solvent was evaporated under reduced pressure. The crude product loaded on silica gel was purified by column chromatography using hexane/acetone (3:1) as the eluent to give enediyne 1 (8.0 mg, 45%) as a beige solid. The mp cannot be measured, because the Bergman cyclization occurs prior to melting. ¹H NMR (400 MHz, CDCl₃): δ = 7.97 (d, J = 6.9 Hz, 1 H), 7.83 (d, J = 7.9 Hz, 2 H), 7.78 (d, J = 6.9 Hz, 1 H), 7.52–7.46 (m, 2 H), 7.44 (d, J = 7.9 Hz, 2 H), 4.38 (s, 2 H), 3.64 (t, J = 4.4 Hz, 2 H), 2.97 (t, J = 4.4 Hz, 2 H), 2.41 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 144.8, 138.9, 136.5, 136.4, 130.8, 130.3, 129.0, 128.3, 127.2, 126.4, 124.0, 123.4, 105.0, 102.3, 82.5, 79.3, 52.2, 43.3, 23.4, 21.4. HRMS (ESI): m/z calcd for C₂₂H₁₇NNaO₂S₂ [M + Na]⁺: 414.0598; found: 414.0583.
• 58 ASTM E698-01, Standard Test Method for Arrhenius Kinetic Constants for Thermally Unstable Materials. ASTM International: West Conshohocken, PA: 2001 DOI: 10.1520/E0698-01 www.astm.org
• 59 For the copies of thermograms, T onset and T peak values, Arrhenius plots and Ea calculation, see the Supporting Information.
• 60 Prall M, Wittkopp A, Fokin AA, Schreiner PR. J. Comput. Chem. 2001; 22: 1605
• 61 Mohamed RK, Peterson PW, Alabugin IV. Chem. Rev. 2013; 113: 7089
• 62 Gold B, Dudley GB, Alabugin IV. J. Am. Chem. Soc. 2013; 135: 1558
• 63 Harris T, dos Passos Gomes G, Ayad S, Clark RJ, Lobodin VV, Tuscan M, Hanson K, Alabugin IV. Chem. 2017; 3: 629
• 64 Basak A, Bdour HM. D, Shain JC, Mandal S, Rudra KR, Nag S. Bioorg. Med. Chem. Lett. 2000; 10: 1321
• 65 Haberhauer G, Gleiter R, Fabig S. Org. Lett. 2015; 17: 1425
• 66 Zeidan TA, Kovalenko SV, Manoharan M, Alabugin IV. J. Org. Chem. 2006; 71: 962
• 67 For the details of HRMS studies, see the Supporting Information.
• 68 Povirk LF, Wübker W, Köhnlein W, Hutchinson F. Nucleic Acids Res. 1977; 4: 3573