An Organocatalytic Cascade Spirocycloaddition Reaction for the Construction of Spiro[indoline-3,3′-piperidin]-6′-ones

Abstract

A cascade intramolecular spirocycloaddition reaction of TBS-O-protected indole-alkynamides in the presence of a chiral bifunctional thiourea, which involves in situ deprotection, dearomatization, and intramolecular spirocycloaddition under mild conditions, is developed. This approach enables the efficient construction of a wide range of polycyclic spiro[indoline-3,3′-piperidin]-6′-one scaffolds in excellent yields (up to 98%) and with good enantioselectivities (up to 94:6 er).

Keyword

organocatalysis - spiroindolines - dearomatization - spirocycloaddition - cascade reaction

Publikationsverlauf

Eingereicht: 04. November 2024

Angenommen nach Revision: 11. Dezember 2024

Accepted Manuscript online:
11. Dezember 2024

Artikel online veröffentlicht:
17. Januar 2025

• References and Notes

• 1a van der Heijden R, Jacobs DI, Snoeijer W, Hallard D, Verpoorte R. Curr. Med. Chem. 2004; 11: 607
• 1b Ishikura M, Yamada K, Abe T. Nat. Prod. Rep. 2010; 27: 1630
• 1c Roche SP, Youte Tendoung J.-J, Tréguier B. Tetrahedron 2015; 71: 3549
• 1d Trost BM, Osipov M. Chem. Eur. J. 2015; 21: 16318
• 1e Pritchett BP, Stoltz BM. Nat. Prod. Rep. 2018; 35: 559
• 1f Zheng C, You S.-L. Nat. Prod. Rep. 2019; 36: 1589
• 2a Verpoorte R, Joosse FT, Groenink H, Svendsen AB. Planta Med. 1981; 42: 32
• 2b Jacobs DI, Snoeijer W, Hallard D, Verpoorte R. Curr. Med. Chem. 2004; 11: 607
• 2c Khazir J, Mir BA, Mir SA, Cowan D. J. Asian Nat. Prod. Res. 2013; 15: 764
• 2d Sears JE, Boger DL. Acc. Chem. Res. 2015; 48: 653
• 2e Ishikura M, Abe T, Choshi T, Hibino S. Nat. Prod. Rep. 2015; 32: 1389
• 3a Numata A, Takahashi Ch, Ito Y, Takada T, Kawai K, Usami Y, Matsumura E, Imachi M. Tetrahedron Lett. 1993; 34: 2355
• 3b Crawley SL, Funk RL. Org. Lett. 2006; 8: 3995
• 3c Jadulco R, Edrada RA, Ebel R, Berg A, Schaumann K, Wray VK. J. Nat. Prod. 2004; 67: 78
• 3d Blunt JW, Copp BR, Munro MH. G, Northcote PT, Prinsep MR. Nat. Prod. Rep. 2006; 23: 26
• 3e Pompeo MM, Cheah JH, Movassaghi M. J. Am. Chem. Soc. 2019; 141: 14411
• 4a Verbitski SM, Mayne CL, Davis RA, Concepcion GP, Ireland CM. J. Org. Chem. 2002; 67: 7124
• 4b Wu H, Xue F, Xiao X, Qin Y. J. Am. Chem. Soc. 2010; 132: 14052
• 4c Trost BM, Osipov M, Krüger S, Zhang Y. Chem. Sci. 2015; 6: 349
• 4d Wen Y.-H, Zhang Z.-J, Li S, Song J, Gong L.-Z. Nat. Commun. 2022; 13: 1344

For selected reviews, see:
• 5a James MJ, O’Brien P, Taylor RJ. K, Unsworth WP. Chem. Eur. J. 2016; 22: 2856
• 5b Song J, Chen DF, Gong LZ. Natl. Sci. Rev. 2017; 4: 381
• 5c Bariwal J, Voskressensky LG, Van der Eycken EV. Chem. Soc. Rev. 2018; 47: 3831
• 5d Saya JM, Ruijter E, Orru RV. A. Chem. Eur. J. 2019; 25: 8916
• 5e Chavan LN, Mainkar PS, Chandrasekhar S. Eur. J. Org. Chem. 2019; 41: 6890
• 5f Chen G.-S, Lin X.-T, Liu Y.-L. Synlett 2020; 31: 1033
• 5g Liu Y.-Z, Song H, Zheng C, You S.-L. Nat. Synth. 2022; 1: 203
• 5h Buttard F, Guinchard X. ACS Catal. 2023; 13: 9442

For representative examples of the synthesis of spiroindolines, see:
• 6a He F, Bo YX, Altom JD, Corey EJ. J. Am. Chem. Soc. 1999; 121: 6771
• 6b Jones SB, Simmons B, Mastracchio A, MacMillan DW. C. Nature 2011; 475: 183
• 6c Andrews IP, Kwon O. Chem. Sci. 2012; 3: 2510
• 6d Zhu J, Cheng Y.-J, Kuang X.-K, Wang L, Zheng Z.-B, Tang Y. Angew. Chem. Int. Ed. 2016; 55: 9224
• 6e Kong AD, Mancheno E, Boudet N, Delgado R, Andreansky ES, Blakey SB. Chem. Sci. 2017; 8: 697
• 6f Xu H, Li YP, Cai Y, Wang GP, Zhu SF, Zhou Q.-L. J. Am. Chem. Soc. 2017; 139: 7697
• 6g Matsuoka J, Kumagai H, Inuki S, Oishi S, Ohno H. J. Org. Chem. 2019; 84: 9358
• 6h Huang X.-Y, Xie P.-P, Zou L.-M, Zheng C, You S.-L. J. Am. Chem. Soc. 2023; 145: 11745
• 6i Zhang Z.-X, Wang X, Jiang J.-T, Chen J, Zhu X.-Q, Ye L.-W. Chin. Chem. Lett. 2023; 34: 107647
• 6j Tan T.-D, Qian G.-L, Su H.-Z, Zhu L.-J, Ye L.-W, Zhou B, Hong X, Qian P.-C. Sci. Adv. 2023; 9: eadg4648

For selected reviews, see:
• 7a Bag D, Sawant SD. Chem. Eur. J. 2021; 27: 1165
• 7b Wei K.-F, Jiang X.-L, Ru G.-X, Zhu X.-H, Shen W.-B. Synlett 2023; 34: 211
• 7c Taylor RJ. K, Unsworth WP. Tetrahedron Chem 2024; 100055
• 7d Behera A. Adv. Synth. Catal. 2024; 366: 1044
• 8a James MJ, Cuthbertson JD, O’Brien P, Taylor RJ. K, Unsworth WP. Angew. Chem. Int. Ed. 2015; 54: 7640
• 8b Liddon JT. R, James MJ, Clarke AK, O’Brien P, Taylor RJ. K, Unsworth WP. Chem. Eur. J. 2016; 22: 8777
• 8c Clarke AK, James MJ, O’Brien P, Taylor RJ. K, Unsworth WP. Angew. Chem. Int. Ed. 2016; 55: 13798
• 8d Ho HE, Stephens TC, Payne TJ, O’Brien P, Taylor RJ. K, Unsworth WP. ACS Catal. 2019; 9: 504
• 8e Li C, Xue L, Zhou J, Zhao Y, Han G, Hou J, Song Y, Liu Y. Org. Lett. 2020; 22: 3291
• 8f Ru G.-X, Zhang M, Zhang T.-T, Jiang X.-L, Gao G.-Q, Zhu X.-H, Wang S, Fan C.-L, Li X, Shen W.-B. Org. Chem. Front. 2022; 9: 2621
• 8g Bag D, Sawant SD. Chem. Commun. 2023; 59: 12649
• 9 Fedoseev P, Van der Eycken EV. Chem. Commun. 2017; 53: 7732
• 10a Fedoseev P, Coppola G, Ojeda GM, Van der Eycken EV. Chem. Commun. 2018; 54: 3625
• 10b Zhou X.-J, Liu H.-Y, Mo Z.-Y, Ma X.-L, Chen Y.-Y, Tang H.-T, Pan YM, Xu Y.-L. Chem. Asian J. 2020; 15: 1536
• 10c Zhang B, Li X, Ai Z, Zhao B, Yu Z, Du Y. Org. Lett. 2022; 24: 390
• 11a Ho HE, Pagano A, Rossi-Ashton JA, Donald JR, Epton RG, Churchill JC, James MJ, O’Brien P, Taylor RJ. K, Unsworth WP. Chem. Sci. 2020; 11: 1353
• 11b Chen Z, Zhang H, Zhou S.-F, Cui X. Org. Lett. 2021; 23: 7992
• 11c Inprung N, Ho HE, Rossi-Ashton JA, Epton RG, Whitwood AC, Lynam JM, Taylor RJ. K, James MJ, Unsworth WP. Org. Lett. 2022; 24: 668
• 11d Luo J, Zeng G, Cao X, Yin B. Adv. Synth. Catal. 2022; 364: 2197
• 12a Donets PA, Van der Eycken EV. Org. Lett. 2007; 9: 3017
• 12b Eichner S, Eichner T, Floss HG, Fohrer J, Hofer E, Sasse F, Zeilinger C, Kirschning A. J. Am. Chem. Soc. 2012; 134: 1673
• 12c Vacala TL, Carlson PR, Arreola-Hester A, Williams CG, Makhoul EW, Vadola PA. J. Org. Chem. 2018; 83: 1493
• 12d Nogami M, Hirano K, Morimoto K, Tanioka M, Miyamoto K, Muranaka A, Uchiyama M. Org. Lett. 2019; 21: 3392
• 12e Li X, Ma X, Wang Z, Liu P.-N, Zhang L. Angew. Chem. Int. Ed. 2019; 58: 17180
• 12f Ma J, Luo J, Jiang K, Zhang G, Liu S, Yin B. Org. Lett. 2021; 23: 8033
• 13a Modha SG, Kumar A, Vachhani DD, Jacobs J, Sharma SK, Parmar VS, Meervelt LV, Van der Eycken EV. Angew. Chem. Int. Ed. 2012; 51: 9572
• 13b Peshkov VA, Pereshivko OP, Van der Eycken EV. Adv. Synth. Catal. 2012; 354: 2841
• 13c Ranjan P, Ojeda GM, Sharma UK, Van der Eycken EV. Chem. Eur. J. 2019; 25: 2442
• 13d Schröder F, Sharma UK, Mertens M, Devred F, Debecker DP, Luque R, Van der Eycken EV. ACS Catal. 2016; 6: 8156
• 14a Rossi-Ashton JA, Clarke AK, Taylor RJ. K, Unsworth WP. Org. Lett. 2020; 22: 1175
• 14b Cera G, Chiarucci M, Mazzanti A, Mancinelli M, Bandini M. Org. Lett. 2012; 14: 1350
• 15 Yao CZ, Tu XQ, Zhao ZY, Fan SH, Jiang HJ, Li Q, Yu J. Org. Lett. 2024; 26: 8713
• 16a Yao CZ, Xie ZK, Wang JY, Zhang JY, Zhao ZY, Li Q, Yu J. J. Org. Chem. 2023; 88: 6146
• 16b Yao CZ, Zhao ZY, Tu XQ, Xie ZK, Jiang HJ, Li Q, Yu J. Eur. J. Org. Chem. 2023; 26: e202300760
• 17 See the Supporting Information for details.
• 18 Spirocycloadduct 2a; General Procedure The reaction was carried out in a 25 mL tube by adding 1a (24.1 mg, 0.05 mmol, 1.0 equiv), AcOH (100 μL, 1 M in CH₂Cl₂, 0.10 mmol, 2.0 equiv), TBAI (3.7 mg, 0.01 mmol, 20 mol%), and C2 (10 μL, 0.5 M in CH₂Cl₂, 0.005 mmol, 10 mol%) in CH₂Cl₂ (2.0 mL) at room temperature, followed by the addition of KF (5.8 mg, 0.10 mmol, 1.0 equiv). The mixture was vigorously stirred at rt under air for 12 h. The mixture was then filtered through a pad of silica gel, washed with EtOAc twice, and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with PE/EtOAc/DCM (3:1:1) as the eluent to give the enantioenriched product 2a. Yield: 16.2 mg (88%); white solid; [α]_D ²⁰ +218.8 (c 0.022, THF). ¹H NMR (600 MHz, CDCl₃): δ = 8.23 (d, J = 8.4 Hz, 1 H), 7.73–7.70 (m, 2 H), 7.44 (t, J = 8.4 Hz, 1 H), 7.34 (t, J = 9.6 Hz, 1 H), 7.28–7.25 (m, 1 H), 7.12 (d, J = 8.4 Hz, 1 H), 6.96 (t, J = 8.4 Hz, 1 H), 6.64 (t, J = 6.6 Hz, 1 H), 6.51 (s, 1 H), 6.45 (d, J = 7.2 Hz, 1 H), 5.75 (s, 1 H), 4.84 (s, 1 H), 4.10 (d, J = 12.0 Hz, 1 H), 3.74 (d, J = 12.0 Hz, 1 H), 3.59 (q, J = 7.8 Hz, 2 H), 3.50 (d, J = 11.4 Hz, 1 H), 1.17 (t, J = 7.2 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 165.2, 152.8, 148.0, 141.9, 131.9, 130.9, 130.7, 129.4, 128.7, 128.3, 127.8, 124.7, 124.3, 124.2, 119.8, 119.7, 119.2, 117.2, 108.6, 93.0, 55.6, 52.7, 41.6, 12.6. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₀N₂NaO₂: 391.1417; found: 391.1418. Enantiomeric ratio: 88.5:11.5, determined by HPLC (Daicel Chiralpak IA, i-PrOH/n-hexane = 30:70, flow rate = 1.0 mL/min, T = 30 °C, λ = 254 nm): t _R = 9.34 min (minor), t _R = 18.10 min (major).
• 19 The absolute configuration of compound 3 was confirmed based on our prior work (see ref. 15 above).
• 20a Shan C, Zhang T, Xiong Q, Yan H, Bai R, Lan Y. Chem. Asian J. 2019; 14: 2731
• 20b Liu H, Li K, Huang S, Yan H. Angew. Chem. Int. Ed. 2022; 61: e202117063