Efficient Synthesis of Polysubstituted 1,5-Benzodiazepinone Dipeptide Mimetics via an Ugi-4CR-Ullmann Condensation Sequence

Abstract

An efficient three-step synthesis towards 3-amino-1,4-benzodiazepin-2-one derivatives is presented. The versatile Ugi-4-component reaction (Ugi-4CR) and Boc deprotection is followed by a ligand-free Ullmann condensation. This protocol allows the rapid construction of a diverse array of substituted 1,5-benzodiazepinones. Since Ugi-based products are typically limited by their ‘inert’ C-terminal amides, the use of a convertible (‘cleavable’) isocyanide was envisaged and resulted in building blocks that can be made SPPS compatible. To demonstrate the potential of this novel synthetic route, the design and preparation of novel phenylurea-1,5-benzodiazepin-4(5H)-one dipeptide mimetics with potential CCK2-antagonist properties is reported.

Key words

1,5-benzodiazepinone - Ugi multicomponent reaction - Cu-catalyzed Ullmann cyclization - constrained dipeptides.

• References and Notes

• 1 Van der Poorten O, Knuhtsen A, Sejer Pedersen D, Ballet S, Tourwé D. J. Med. Chem. 2016; 59: 10865
• 2 Mason JM. Future Med. Chem. 2010; 2: 1813
• 3 Groß A, Hashimoto C, Sticht H, Eichler J. Front. Bioeng. Biotechnol. 2016; 3: 211
• 4 Breslin HJ, Kukla MJ, Ludovici DW, Mohrbacher R, Ho W, Miranda M, Rodgers JD, Hitchens TK, Leo G. J. Med. Chem. 1995; 38: 771
• 5 Micale N, Kozikowski AP, Ettari R, Grasso S, Zappalà M, Jeong J.-J, Kumar A, Hanspal M, Chishti AH. J. Med. Chem. 2006; 49: 3064
• 6 Ettari R, Zappalà M, Micale N, Grazioso G, Giofrè S, Schirmeister T, Grasso S. Eur. J. Med. Chem. 2011; 46: 2058
• 7 Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Carver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu T. Bioorg. Med. Chem. Lett. 2005; 15: 765
• 8 Koblish HK, Zhao S, Franks CF, Donatelli RR, Tominovich RM, LaFrance LV, Leonard KA, Gushue JM, Parks DJ, Calvo RR. Mol. Cancer Ther. 2006; 5: 160
• 9 Leonard K, Marugan JJ, Raboisson P, Calvo R, Gushue JM, Koblish HK, Lattanze J, Zhao S, Cummings MD, Player MR, Maroney AC, Lu T. Bioorg. Med. Chem. Lett. 2006; 16: 3463
• 10 Grossi G, Di Braccio M, Roma G, Ballabeni V, Tognolini M, Calcina F, Barocelli E. Eur. J. Med. Chem. 2002; 37: 933
• 11 Rudolph U, Möhler H. Curr. Opin. Pharmacol. 2006; 6: 18
• 12 Griffin CE, Kaye AM, Bueno FR, Kaye AD. Ochsner J. 2013; 13: 214
• 13 Rosenström U, Sköld C, Lindeberg G, Botros M, Nyberg F, Karlén A, Hallberg A. J. Med. Chem. 2006; 49: 6133
• 14 Banfi L, Basso A, Cerulli V, Guanti G, Lecinska P, Monfardini I, Riva R. Mol Diversity 2010; 14: 425
• 15 Iden HS, Lubell WD. J. Org. Chem. 2007; 72: 8980
• 16 Sañudo M, García-Valverde M, Marcaccini S, Delgado JJ, Rojo J, Torroba T. J. Org. Chem. 2009; 74: 2189
• 17 Lauffer DJ, Mullican MD. Bioorg. Med. Chem. Lett. 2002; 12: 1225
• 18 Vezenkov LL, Sanchez CA, Bellet V, Martin V, Maynadier M, Bettache N, Lisowski V, Martinez J, Garcia M, Amblard M, Hernandez J.-F. ChemMedChem 2016; 11: 302
• 19 Qian J, Liu Y, Cui J, Xu Z. J. Org. Chem. 2012; 77: 4484
• 20 Curini M, Epifano F, Marcotullio MC, Rosati O. Tetrahedron Lett. 2001; 42: 3193
• 21 Prakash GS, Vaghoo H, Venkat A, Panja C, Chacko S, Mathew T, Olah GA. Future Med. Chem. 2009; 1: 909
• 22 Jiang Y.-J, Cai J.-J, Zou J.-P, Zhang W. Tetrahedron Lett. 2010; 51: 471
• 23 Kumar R, Chaudhary P, Nimesh S, Verma AK, Chandra R. Green Chem. 2006; 8: 519
• 24 Balakrishna MS, Kaboudin B. Tetrahedron Lett. 2001; 42: 1127
• 25 Sangshetti JN, Kokare ND, Shinde DB. Chin. Chem. Lett. 2007; 18: 1305
• 26 Sivamurugan V, Deepa K, Palanichamy M, Murugesan V. Synth. Commun. 2004; 34: 3833
• 27 Chen W.-Y, Lu J. Synlett 2005; 1337
• 28 Bariwal J, Kaur R, Voskressensky LG, Van der Eycken EV. Front. Chem. 2018; 6: 557
• 29 Zhi S, Ma X, Zhang W. Org. Biomol. Chem. 2019; 17: 7632
• 30 Fouad MA, Abdel-Hamid H, Ayoup MS. RSC Adv. 2020; 10: 42644
• 31 Tempest P, Pettus L, Gore V, Hulme C. Tetrahedron Lett. 2003; 44: 1947
• 32 Banfi L, Basso A, Guanti G, Kielland N, Repetto C, Riva R. J. Org. Chem. 2007; 72: 2151
• 33 Cuny G, Bois-Choussy M, Zhu J. J. Am. Chem. Soc. 2004; 126: 14475
• 34 Kalinski C, Umkehrer M, Ross G, Kolb J, Burdack C, Hiller W. Tetrahedron Lett. 2006; 47: 3423
• 35 Faggi C, Marcaccini S, Pepino R, Cruz Pozo M. Synthesis 2002; 2756
• 36 Koopmanschap G, Ruijter E, Orru RV. Beilstein J. Org. Chem. 2014; 10: 544
• 37 Obara N, Watanabe T, Asakawa T, Kan T, Tanaka T. Synlett 2017; 28: 1183
• 38 Arora N, Dhiman P, Kumar S, Singh G, Monga V. Bioorg. Chem. 2020; 97: 103668
• 39 Hollanders C, Elsocht M, Van der Poorten O, Jida M, Renders E, Maes BU. W, Ballet S. Chem. Commun. 2021; 57: 6863
• 40 Olson GL, Bolin DR, Bonner MP, Bos M, Cook CM, Fry DC, Graves BJ, Hatada M, Hill DE. J. Med. Chem. 1993; 36: 3039
• 41 Pellegrini M, Weitz IS, Chorev M, Mierke DF. J. Am. Chem. Soc. 1997; 119: 2430
• 42 Ramajayam R, Girdhar R, Yadav MR. Mini-Rev. Med. Chem. 2007; 7: 793
• 43 Horton DA, Bourne GT, Smythe ML. Chem. Rev. 2003; 103: 893
• 44 Raboisson P, Marugán JJ, Schubert C, Koblish HK, Lu T, Zhao S, Player MR, Maroney AC, Reed RL, Huebert ND, Lattanze J, Parks DJ, Cummings MD. Bioorg. Med. Chem. Lett. 2005; 15: 1857
• 45 Micale N, Vairagoundar R, Yakovlev AG, Kozikowski AP. J. Med. Chem. 2004; 47: 6455
• 46 Lauffer DJ, Mullican MD. Bioorg. Med. Chem. Lett. 2002; 12: 1225
• 47 Amblard M, Daffix I, Bergé G, Calmès M, Dodey P, Pruneau D, Paquet J.-L, Luccarini J.-M, Bélichard P, Martinez J. J. Med. Chem. 1999; 42: 4193
• 48 Rosenström U, Sköld C, Lindeberg G, Botros M, Nyberg F, Karlén A, Hallberg A. J. Med. Chem. 2004; 47: 859
• 49 Liesch JM, Hensens OD, Springer JP, Chang RS. L, Lotti VJ. J. Antibiot. 1985; 38: 1638
• 50 Evans BE, Bock MG, Rittle KE, DiPardo RM, Whitter WL, Veber DF, Anderson PS, Freidinger RM. Proc. Natl. Acad. Sci. U.S.A. 1986; 83: 4918
• 51 Liu J.-F, Kaselj M, Isome Y, Chapnick J, Zhang B, Bi G, Yohannes D, Yu L, Baldino CM. J. Org. Chem. 2005; 70: 10488
• 52 Al-Said NH, Al-Qaisi LS. Tetrahedron Lett. 2006; 47: 693
• 53 Sañudo M, García-Valverde M, Marcaccini S, Delgado JJ, Rojo J, Torroba T. J. Org. Chem. 2009; 74: 2189
• 54 Ramanathan SK, Keeler J, Lee H.-L, Reddy DS, Lushington G, Aubé J. Org. Lett. 2005; 7: 1059
• 55 Molecular Operating Environment (MOE), 2019.01; Chemical Computing Group ULC, 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2019.
• 56 Case DA, Darden TA, Cheatham TE. III, Simmerling CL, Wang J, Duke RE, Luo R, Crowley M, Walker RC, Zhang W, Merz KM, Wang B, Hayik S, Roitberg A, Seabra G, Kolossváry I, Wong KF, Paesani F, Vanicek J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Mathews DH, Seetin MG, Sagui C, Babin V, Kollman PA. AMBER 10. University of California; San Francisco: 2008
• 57 Gerber PR, Müller K. J. Comput.-Aided Mol. Des. 1995; 9: 251
• 58 Némethy G, Printz MP. Macromolecules 1972; 5: 755
• 59 Van der Poorten O, Van Den Hauwe R, Hollanders K, Maes BU. W, Tourwé D, Jida M, Ballet S. Org. Biomol. Chem. 2018; 16: 1242
• 60 Amblard M, Raynal N, Averlant-Petit M.-C, Didierjean C, Calmès M, Fabre O, Aubry A, Marraud M, Martinez J. Tetrahedron Lett. 2005; 46: 3733
• 61 Amblard M, Daffix I, Bergé G, Calmès M, Dodey P, Pruneau D, Paquet J.-L, Luccarini J.-M, Bélichard P, Martinez J. J. Med. Chem. 1999; 42: 4193
• 62 Amblard M, Daffix I, Bedos P, Bergé G, Pruneau D, Paquet J.-L, Luccarini J.-M, Bélichard P, Dodey P, Martinez J. J. Med. Chem. 1999; 42: 4185
• 63 Rose GD, Glerasch LM, Smith JA. In Advances in Protein Chemistry,Vol. 37. Elsevier; Amsterdam: 1985: 1
• 64 Kawasaki D, Emori Y, Eta R, Iino Y, Hamano H, Yoshinaga K, Tanaka T, Takei M, Watson SA. Cancer Chemother. Pharmacol. 2008; 61: 883
• 65 Magnan R, Escrieut C, Gigoux V, De K, Clerc P, Niu F, Azema J, Masri B, Cordomi A, Baltas M, Tikhonova IG, Fourmy D. J. Am. Chem. Soc. 2013; 135: 2560
• 66 Hirst GC, Aquino C, Birkemo L, Croom DK, Dezube M, Dougherty RW, Ervin GN, Grizzle MK, Henke B, James MK, Johnson MF, Momtahen T, Queen KL, Sherrill RG, Szewczyk J, Willson TM, Sugg EE. J. Med. Chem. 1996; 39: 5236
• 67 General Procedure of Ugi-4CR towards 2a In a flame-dried round-bottom flask were combined Cbz-Dap(Boc)-OH (2.96 mmol, 1 equiv), aniline (1 equiv), aldehyde (1 equiv), and t-Bu-isocyanide (1 equiv) in MeOH (0.25 M) at room temperature. The flask was closed with a rubber septum, evacuated/backfilled with argon (3 cycles), and the reaction mixture was stirred at room temperature. The reaction conversion was monitored by RP-HPLC and TLC analysis. Upon reaction completion, the volatiles were removed in vacuo. The crude Ugi-4CR products 2a–g were finally purified via silica gel automated flash column chromatography (EtOAc/petroleum ether gradient). General Procedure of Boc Deprotection To a solution of the N-Boc-protected Ugi-4CR dipeptide (1 equiv) in CH₂Cl₂ (0.1 M), TFA (20% v/v) was added dropwise with a polytetrafluoroethylene (PTFE) syringe. The reaction mixture was stirred for 15 min and concentrated in vacuo upon completion. The crude N-deprotected Ugi-4CR products were used in the following reaction step without purification. General Procedure of Ullmann Condensation towards 3a In a flame-dried microwave vial, the N-Boc-deprotected Ugi-4CR product (1 equiv), CuI (0.2 equiv), and Cs₂CO₃ (2 equiv) were combined. The vial was closed with a cap and evacuated/backfilled with argon (3 cycles). Anhydrous and degassed DMF (0.03 M) was added via a syringe at room temperature. The mixture was stirred for 16 h under argon atmosphere. The reaction conversion was monitored by RP-HPLC. Upon reaction completion, the mixture was evaporated in vacuo. The resulting crude reaction product was redissolved in DMF, centrifuged, and directly purified via automated reverse-phase column chromatography (AcN/H₂O gradient (0.1 % TFA)). The diastereoisomers were fully separable using preparative HPLC. MS (ES+): m/z = 425 [M + H]⁺, 447 [M + Na]⁺; HRMS (ESI+): m/z calcd for [C₂₃H₂₈N₄O₄]⁺: 425.2189; found: 425.2168 [M + H]⁺. ¹H NMR (CDCl₃, 250 MHz, 298 K): δ = 1.23 (9 H, s, t-Bu), 3.15 (2 H, m, H_β,BDP), 4.11 (1 H, d, J = 16.1 H_{α, Gly}), 4.71 (1 H, d, J = 16.1 Hz, H_α′,Gly), 5.11 (2 H, m, –CH₂ Cbz), 5.56 (1 H, s, H_α,BDP), 6.65 (1 H, s, H_arom), 6.91–7.13 (2 H, m, H_arom), 7.22 (5 H, s, H_arom,Cbz), 7.62 (1 H, d, J = 7.62 Hz, H_arom), 8.22 (1 H, br s, N–H). ¹³C NMR (CDCl₃, 63 MHz, 298 K): δ = 28.5 (t-Bu), 38.5 (C_β,BDP), 46.5 (C_α,Gly), 55.1 ( C_α,BDP ), 69.1 (CH₂ Cbz), 115.4, 142.1, 125.9, 126.5, 128.3, 128.5, 130.8, 135.0 (C_arom), 153,8 (C=O BDP), 166.0, 166.3 (C=O). General Procedure of Urea Synthesis towards 12a Into a flame-dried microwave vial, Boc-BDP-Gly-NHR (0.10 mmol, 1 equiv) was dissolved in anhydrous CH₂Cl₂ (2 mL). The solution was cooled at 0 °C prior to the addition of phenyl isocyanate (16.3 μL, 0.15 mmol, 1.5 equiv). The mixture was stirred at 0 °C for 30 min. Then water (0.1 mL) was added, and the mixture was stirred for another 10 min. The mixture was concentrated under reduced pressure and the desired product was isolated using preparative HPLC (AcN/H₂O gradient (0.1 % TFA)). MS (ES+): m/z 486 [M + H]⁺. HRMS (ESP+): m/z calcd for [C₂₈H₃₂N₅O₃]⁺: 486.2505; found: 486.2499 [M + H]⁺. ¹H NMR (CDCl₃, 500 MHz, 298 K): δ = 1.41 (9 H,s, t-Bu), 3.59 (1 H, dd, J = 14.3, 3.8 Hz, H_β), 3.94–4.06 (m, 2 H, H_β and H_α,Gly), 4.63 (1 H, t, J = 4.6 Hz, H_α), 5.28 (1 H, d, J = 16.5 Hz, H_α,Gly), 5.93 (1 H, s, NH), 6.28 (1 H, br s, NH), 6.70 (1 H, br s, NH), 6.73–6.82 (3 H, m, H_arom), 6.95–7.02 (2 H, m, H_arom), 7.06–7.11 (2 H, m, H_arom), 7.25–7.28 (2 H, m, H_arom), 7.31–7.35 (2 H, m, H_arom). ¹³C NMR (CDCl₃, 125 MHz, 298K): δ = 28.9 (t-Bu), 42.0 (C_β), 46.0 (C_α,Gly), 52.6 (C _t-Bu), 62.8 (C_α), 114.5, 118.8, 120.2, 120.5, 121.1, 122.2, 123.4, 124.1, 124.3, 129.0, 129.3, 129.8, 132.6, 138.4, 144.7 (C_arom), 156.3, 166.7, 167.5 (C=O).