Organocatalytic Asymmetric Synthesis of Bridged Acetals with Spirooxindole Skeleton (original) (raw)

Abstract

sparkles

AI

The first highly diastereo-and enantioselective synthesis of bridged O,O-acetals embedded with spirooxindoles has been developed. Dioxindoles and 2-hydroxy cinnamaldehydes were employed as the reaction partners in this method. The desired products were obtained via diaryl prolinol TBS ether catalyzed Michael reaction followed by acetal formation with TFA.

Loading...

Loading Preview

Sorry, preview is currently unavailable. You can download the paper by clicking the button above.

References (49)

  1. Hz, 1H), 3.24 (d, J = 3.
  2. 9 Hz, 1H), 2.42 (d, J = 11.6 Hz, 1H), 1.83 (s, 3H), 1.73 (s, 3H). 13 C {1H} NMR (101 MHz, CDCl 3 ) δ 174.9, 151.9, 143.3, 137.1, 130.1, 129.6, 128.9, 125.9, 125.6, 122.4, 120.7, 118.1, 116.5, 108.8, 101.3, 90.9, 44.9, 38.3, 31.4, 25.8, 18.3. HPLC Analysis: ee = 99%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 6.7 min, t minor = 12.4 min). HRMS (+ESI-TOF): calcd. For C 22 H 22 NO 3 [M+H] + 348.1594, found 348.1596.
  3. H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.0
  4. Hz, 2H), 7.28 -7.24 (m, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 7.4
  5. Hz, 1H), 4.91 (q, J = 16.0 Hz, 2H), 3.64 (dt, J = 11.6, 3.
  6. 9 Hz, 1H), 2.48 (d, J = 11.6 Hz, 1H). 13 C {1H} NMR (101 MHz, CDCl 3 ) δ 175.6, 151.9, 142.7, 139.7, 130.2, 130.2(q, J C-F = 32.33 Hz), 129.8, 128.9, 127.7, 126.2, 126.1(q, J C-F = 3.03 Hz), 125.8, 125.5, 125.3, 124.1(q, J C-F = 272.70 Hz) 123.0, 120.9 116.6, 108.8, 101.3, 90.8, 45.2, 43.5, 31.5. HPLC Analysis: ee = 98%, Chiralpak IA Column Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 11.1 min, t minor = 19.4 min). HRMS (+ESI-TOF): calcd. For C 25 H 19 F 3 NO 3 [M+H] + 438.1312, found 438.1312.
  7. 'R,3S,5'S)-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]dioxepin]-2-one (3q) was obtained as a light pink solid in 64% (17.9 mg) yield after column chromatography. M.P. = 115- 117 o C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 7.25 (dd, J = 9.5, 6.0 Hz, 1H), 7.16 (t, J = Page 26 of 38
  8. Hz, 1H), 3.31 (d, J = 3.9 Hz, 1H), 2.44 (d, J = 11.6 Hz, 1H). 13 C {1H} NMR (101 MHz, CDCl 3 ) δ 177.8, 151.8, 140.9, 130.2, 129.7, 128.9, 126.2, 126.2, 125.4, 122.6, 120.8, 116.5, 110.1, 101.3, 91.2, 44.9, 31.2. HPLC Analysis: ee = 99%, Chiralpak IA Column n-Hexane/i-PrOH = 85/15, flow rate 1.0 mL/min, λ = 254 nm (t major = 8.8 min, t minor = 16.3 min). HRMS (+ESI-TOF): calcd. For C 17 H 14 NO 3 [M+H] + 280.0968, found 280.0970. (2'R,3S,5'S)-1-benzyl-5-fluoro-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]dioxepin]- 2-one (3r) was obtained as a light grey semi solid in 59% (22.9 mg) yield after column chromatography. 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 -7.29 (m, 2H), 7.25 (dd, J = 12.0, 4.1 Hz, 4H), 6.93 (d, J = 8.0 Hz, 1H), 6.82 -6.74 (m, 2H), 6.59 (d, J = 7.5 Hz, 1H), 6.54 (dd, J = 8.6, 4.1
  9. C {1H} NMR (101 MHz, CDCl 3 ) δ 175.3, 158.9 (d, J C-F = 241.39 Hz), 151.7, 138.9, 138.9, 135.3, 130.0, 129.1, 128.9, 128.1, 127.6 (d, J C-F = 8.08 Hz), 127.4, 127.4, 124.9, 121.0, 116.7, 116.4 (d, J C-F = 24.24 Hz), 114.1 (d, J C-F = 26.26 Hz), 109.6 (d, J C-F = 8.08 Hz), 101.4, 90.8, 90.7, 45.2, 44.1, 31.4. HPLC Analysis: ee = 97%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 11.9 min, t minor = 23.6 min). HRMS (+ESI-TOF): calcd. For C 24 H 19 FNO 3 [M+H] + 388.1343, found 388.1346. (2'R,3S,5'S)-1-benzyl-5-chloro-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]dioxepin]- 2-one (3s) was obtained as a light brown solid in 46% (18.6 mg) yield after column Page 27 of 38 ACS Paragon Plus Environment The Journal of Organic Chemistry chromatography. M.P. = 167-170 o C. 1 H NMR (600 MHz, CDCl 3 ) δ 7.34 (t, J = 7.3 Hz, 2H), 7.31 -7.25 (m, 4H), 7.07 (dd, J = 8.3, 2.1 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.84 (td, J = 7.5, 1.0
  10. 9 Hz, 1H), 3.29 (d, J = 3.9 Hz, 1H), 2.50 (d, J = 11.6 Hz, 1H). 13 C {1H} NMR (151 MHz, CDCl 3 ) δ 175.0, 151.7, 141.4, 135.2, 130.0, 129.9, 129.1, 128.9, 128.1, 128.1, 127.5, 127.4, 126.5, 124.9, 121.0, 116.7, 110.0, 101.4, 90.7, 45.2, 44.0, 31.3. HPLC Analysis: ee = 99%, Chiralpak IA Column, n- Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 12.6 min, t minor = 25.1 min). HRMS (+ESI-TOF): calcd. For C 24 H 19 ClNO 3 [M+H] + 404.1048, found 404.1049. (2'R,3S,5'S)-1-benzyl-5-bromo-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]dioxepin]- 2-one (3t) was obtained as a light yellow sticky solid in 37% (16.6 mg) yield after column chromatography. 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (dd, J = 14.8, 7.2 Hz, 3H), 7.21 (t, J = 5.0
  11. Hz, 3H), 7.16 (dd, J = 8.3, 2.0 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H), 6.03 (d, J = 3.5 Hz, 1H), 5.82 (d, J = 2.0 Hz, 1H), 4.82 (d, J = 15.7 Hz, 1H), 4.74 (d, J = 15.7 Hz, 1H), 3.56 (dt, J = 11.7, 3.
  12. 9 Hz, 1H), 3.23 (d, J = 3.9 Hz, 1H), 2.44 (d, J = 11.7 Hz, 1H). 13 C {1H} NMR (101 MHz, CDCl 3 ) δ 174.9, 151.7, 141.9, 135.1, 132.8, 130.0, 129.3, 129.1, 128.9, 128.1, 127.8, 127.4, 124.9, 121.0, 116.8, 115.5, 110.5, 101.4, 90.7, 45.3, 44.0, 31.3. HPLC Analysis: ee = 93%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 13.5 min, t minor = 26.0 min). HRMS (+ESI- TOF): calcd. For C 24 H 19 BrNO 3 [M+H] + 448.0543, found 448.0544. Page 28 of 38
  13. ACS Paragon Plus Environment The Journal of Organic Chemistry (2'R,3S,5'S)-1-benzyl-6-bromo-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]dioxepin]- 2-one (3u) was obtained as a light brown semi solid in 49% (22.0 mg) yield after column chromatography. 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 -7.78 (m, 2H), 7.78 -7.67 (m, 4H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 -7.21 (m, 3H), 7.05 (d, J = 7.5 Hz, 1H), 6.52 (d, J = 3.5 Hz, 1H), 6.16 (d, J = 8.6 Hz, 1H), 5.35 (d, J = 15.7 Hz, 1H), 5.20 (d, J = 15.7 Hz, 1H), 4.07 (dt, J = 11.7, 3.
  14. 9 Hz, 1H), 3.72 (d, J = 3.9 Hz, 1H), 2.91 (d, J = 11.7 Hz, 1H). 13 C {1H} NMR (101 MHz, CDCl 3 ) δ 175., 151.7, 144.3, 135.1, 129.9, 129.2, 128.9, 128.2, 127.4, 127.2, 125.6, 125.1, 124.7, 124.0, 121.0, 116.6, 112.5, 101.3, 90.4, 45.1, 44.0, 31.4. HPLC Analysis: ee = 98%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 9.7 min, t minor = 20.
  15. 9 min). HRMS (+ESI-TOF): calcd. For C 24 H 19 BrNO 3 [M+H] + 448.0543, found 448.0546. (2'R,3S,5'S)-1-benzyl-7-chloro-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3] dioxepin]-2-one (3v) was obtained as a brown semi solid in 55% (22.2 mg) yield after column chromatography. 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 (t, J = 7.2 Hz, 2H), 7.25 (dd, J = 14.3, 6.0
  16. Hz, 5H), 7.09 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.64 -6.56 (m, 2H), 6.08 (d, J = 3.5 Hz, 1H), 5.87 (d, J = 7.5 Hz, 1H), 5.32 (s, 2H), 3.64 (dt, J = 11.7, 3.
  17. 9 Hz, 1H), 3.28 (d, J = 3.9 Hz, 1H), 2.46 (d, J = 11.7 Hz, 1H). 13 C {1H} NMR (101 MHz, CDCl 3 ) δ 176.2, 151.8, 139.0, 137.2, 132.7, 129.9, 129.0, 128.8, 128.8, 127.5, 126.6, 125.1, 124.5, 123.5, 120.9, 116.5, 115.4, 101.4, 90.2, 45.6, 45.1, 31.4. HPLC Analysis: ee = 93%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 8.8 min, t minor = 15.
  18. 9 min). HRMS (+ESI-TOF): calcd. For C 24 H 19 ClNO 3 [M+H] + 404.1048, found 404.1046. Page 29 of 38 ACS Paragon Plus Environment The Journal of Organic Chemistry (2'R,3S,5'S)-1-benzyl-4-bromo-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3]dioxepin]- 2-one (3w) was obtained as a yellow semi solid in 22% (10.0 mg) yield after column chromatography. 1 H NMR (600 MHz, CDCl 3 ) δ 7.35 (t, J = 7.4 Hz, 2H), 7.29 (dd, J = 15.2, 7.4
  19. Hz, 3H), 7.22 (t, J = 7.8 Hz, 1H), 6.95 -6.93 (m, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.76 (t, J = 7.4
  20. Hz, 1H), 6.63 (dd, J = 8.6, 4.9 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 6.23 (d, J = 3.6 Hz, 1H), 5.00 (d, J = 15.7 Hz, 1H), 4.71 (d, J = 15.7 Hz, 1H), 3.71 (dt, J = 11.7, 3.8 Hz, 1H), 3.21 (d, J = 3.7 Hz, 1H), 2.24 (d, J = 11.7 Hz, 1H). 13 C {1H} NMR (151 MHz, CDCl 3 ) δ 176.4, 153.4, 144.5, 135.3, 130.6, 130.2, 129.2, 128.5, 128.4, 128.1, 127.4, 125.9, 123.9, 121.5, 120.8, 117.0, 108.3, 102.3, 94.3, 47.2, 44.2, 29.8. HPLC Analysis: ee = 85%, Chiralpak IA Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 12.6 min, t minor = 23.0 min). HRMS (+ESI- TOF): calcd. For C 24 H 19 BrNO 3 [M+H] + 448.0543, found 448.0547. General procedure for the preparation of compound 4/5: In an oven dried round bottom flask, compound 3e/3t (44.8 mg, 0.1 mmol), phenylboronic acid (1.5 eq), palladium (II) acetate (0.05eq), tricyclohexylphosphine (0.06eq) and Na 2 CO 3 (2eq) were taken, flushed with argon and then dry DMF (0.- Hexane (1-2%) as eluent to afford the compound 4/5. (2'R,3S,5'S)-1-benzyl-7'-phenyl-5'H-spiro[indoline-3,4'-[2,5]methanobenzo[d][1,3] dioxepin]-2-one (4) was obtained as a light yellow sticky solid in 43% (19.1 mg) yield after column chromatography. 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (dd, J = 8.4, 2.2 Hz, 1H), 7.40 - REFERENCES
  21. For selected reviews, see: (a) Perron, F.; Albizati, K. F. Chemistry of spiroketals. Chem. Rev. 1989, 89, 1617-1661. (b) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Nonanomeric Spiroketals in Natural Products: Structures, Sources, and Synthetic Strategies. Chem. Rev. 2005, 105, 4406-4440. c)
  22. Palmes, J. A.; Aponick, A. Strategies for Spiroketal Synthesis Based on Transition-Metal Catalysis. Synthesis. 2012, 44, 3699-3721.
  23. For reviews, see: Cala, L.; Fañanás, F. J.; Rodríguez, F. Enantioselective synthesis of spiroacetals: the conquest of a long-sought goal in asymmetric catalysis. Org. Biomol. Chem. 2014, 12, 5324-5330. Page 32 of 38
  24. For selected recent examples, see: (a) Kawamura, Y.; Kawano, Y.; Matsuda, T.; Ishitobi, Y.; Hosokawa, T. Palladium(II)-Catalyzed Asymmetric Coupling of Allylic Alcohols and Vinyl Ethers: Insight into the Palladium and Copper Bimetallic Catalyst. J. Org. Chem. 2009, 74, 3048- 3053. (b) Čorić, I.; Vellalath, S.; List, B. Catalytic Asymmetric Transacetalization. J. Am. Chem. Soc. 2010, 132, 8536-8537. (c) Čorić, I.; Müller, S.; List, B. Kinetic Resolution of Homoaldols via Catalytic Asymmetric Transacetalization. J. Am. Chem. Soc. 2010, 132, 17370-17373. (d) Asano, K.; Matsubara, S. Asymmetric Synthesis of 1,3-Dioxolanes by Organocatalytic Formal [3+2] Cycloaddition via Hemiacetal Intermediates. Org. Lett. 2012, 14, 1620-1623. (e) Handa, S.; Slaughter, L. M. Enantioselective alkynylbenzaldehyde cyclizations catalyzed by chiral gold(I) acyclic diaminocarbene complexes containing weak Au-arene interactions. Angew. Chem. Int. Ed. 2012, 51, 2912-2915. (f) Kim, J. H.; Čorić, I.; Vellalath, S.; List, B. The Catalytic Asymmetric Acetalization. Angew. Chem. Int. Ed. 2013, 52, 4474-4477. (g) Mondal, B.; Mondal, K.; Satpati, P.; Pan, S. C. Organocatalytic Asymmetric Dimerization of γ-Hydroxyenones to Acetals and Theoretical Investigations into the Diastereoselection. Eur. J. Org. Chem. 2017, 47, 7101-7106.
  25. a) Paz, B. M.; Klier, L.; Naesborg, L.; Lauridsen, V. H.; Jensen, F.; Jørgensen, K. A. Enantioselective Organocatalytic Cascade Approach to Different Classes of Benzofused Acetals. Chem. Eur. J. 2016, 22, 16810-16818. (b) Borrigo-Calleja, G. M.; Bizet, V.; Mazet, C. Palladium- Catalyzed Enantioselective Intermolecular Carboetherification of Dihydrofurans. J. Am. Chem. Soc. 2016, 138, 4014-4017. (c) Huang, H.; Kanda, S.; Zhao, J. C.-G. Diastereodivergent Catalysis Using Modularly Designed Organocatalysts:Synthesis of both cis-and trans-Fused Pyrano[2,3- b]pyrans. Angew. Chem. Int. Ed. 2016, 55, 2213-2216.
  26. For selected examples, see: (a) Čorić, I.; List, B. Asymmetric spiroacetalization catalysed by confined Brønsted acids. Nature. 2012, 483, 315-319. (b) Sun, Z.; Winschel, G. A.; Borovika, A.; Page 33 of 38 ACS Paragon Plus Environment The Journal of Organic Chemistry Nagorny, P. Chiral Phosphoric Acid-Catalyzed Enantioselective and Diastereoselective Spiroketalizations. J. Am. Chem. Soc. 2012, 134, 8074-8077. (c) Wu, H.; He, Y.-P.; Gong, L.-Z. Direct Access to Enantioenriched Spiroacetals through Asymmetric Relay Catalytic Three- Component Reaction. Org. Lett. 2013, 15, 460-463. (d) Cala, L.; Mendoza, A.; Fañanás, F. J.; Rodríguez, F. A catalytic multicomponent coupling reaction for the enantioselective synthesis of spiroacetals. Chem. Commun. 2013, 49, 2715-2717. (e) Yoneda, N.; Fukata, Y.; Asano, K.; Matsubara, S. Asymmetric Synthesis of Spiroketals with Aminothiourea Catalysts. Angew. Chem. Int. Ed. 2015, 54, 15497-15500. (f) Midya, A.; Maity, S.; Ghorai, P. Dynamic Kinetic Spiroketalization/Oxa-Michael AdditionCascade of Alkoxyboronates and Peroxyacetals:Enantio- and Diastereoselective Synthesis of Benzannulated Spiroketals. Chem. Eur. J. 2017, 23, 11216- 11220. (g) Liang, M.; Zhang, S.; Jia, J.; Tung, C.-H.; Wang, J.; Xu, Z. Synthesis of Spiroketals by Synergistic Gold and Scandium Catalysis. Org. Lett. 2017, 19, 2526-2529. (h) Hamilton, J. Y.; Rössler, S. L.; Carreira, E. M. Enantio-and Diastereoselective Spiroketalization Catalyzed by Chiral Iridium Complex. J. Am. Chem. Soc. 2017, 139, 8082-8085.
  27. Dumontet, V.; Hung, N. V.; Adeline, M.-T.; Riche, C.; Chiaroni, A.; Sévenet, T.; Guéritte, F. Cytotoxic Flavonoids and α-Pyrones from Cryptocarya obovate. J. Nat. Prod. 2004, 67, 858-862.
  28. Kamal, M. A.; Qu, X.; Yu, Q.-S.; Tweedie, D.; Holloway, H. W.; Li, Y.; Tan, Y.; Greig, N. H. Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis. J. Neural Transm. 2008, 115, 889-898.
  29. Talontsi, F. M.; Dittrich, B.; Schüfler, A.; Sun, H.; Laatsch, H. Epicoccolides: Antimicrobial and Antifungal Polyketides from an Endophytic Fungus Epicoccum sp. Associated with Theobroma cacao. Eur. J. Org. Chem. 2013, 3174-3180. Page 34 of 38
  30. a) Hao, X.-J.; Nie, J.-L. DITERPENES FROM SPIRAEA JAPONICA. Phytochemistry 1998, 48, 1213-1215. (b) Shen, Z.; Chen, Z.; Li, L.; Lei, W.; Hao, X. Antiplatelet and Antithrombotic Effects of the Diterpene Spiramine Q from Spiraea japonica var. incisa. Planta Med. 2000, 66, 287-289. (c) Li, L.; Shen, Y.-M.; Yang, X.-S.; Zuo, G.-Y.; Shen, Z.-J.; Chen, Z.-H.; Hao, X.-J. Antiplatelet aggregation activity of diterpene alkaloids from Spiraea japonica. Eur. J. Pharmacol. 2002, 449, 23-28.
  31. Polat, M. F.; Hettmancyk, L.; Zhang, W.; Szabo, Z.; Franzén, J. One-Pot, Two-Step Protocol for the Catalytic Asymmetric Synthesis of Optically Active N,O-and O,O-Acetals.
  32. ChemCatChem. 2013, 5, 1334-1339.
  33. Wang, F.; Chen, F.; Qu, M.; Li, T.; Liu, Y.; Shi, M. A Pd(II)-catalyzed asymmetric approach toward chiral [3.3.1]-bicyclic ketals using 2-hydroxyphenylboronic acid as a pro-bis(nucleophile). Chem. Commun. 2013, 49, 3360-3362.
  34. For selected reviews: (a) Galliford, C. V.; Scheidt, K. A. Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents. Angew. Chem. Int.
  35. Ed. 2007, 46, 8748-8758. (b) Singh, G. S.; Desta, Z. Y. Isatins As Privileged Molecules in Design and Synthesis of Spiro-Fused Cyclic Frameworks. Chem. Rev. 2012, 112, 6104-6155. (c) Hong, L.; Wang, R. Recent Advances in Asymmetric Organocatalytic Construction of 3,3'-Spirocyclic Oxindoles. Adv. Synth. Catal. 2013, 355, 1023-1052. (d) Cheng, D. J.; Ishihara, Y.; Tan, B.; Barbas III, C. F. Organocatalytic Asymmetric Assembly Reactions: Synthesis of Spirooxindoles via Organocascade Strategies. ACS Catal. 2014, 4, 743-762. (e) Mei, G.-j.; Shi, F. Catalytic asymmetric synthesis of spirooxindoles: recent developments. Chem. Commun. 2018, 54, 6607- 6621. Page 35 of 38 ACS Paragon Plus Environment The Journal of Organic Chemistry
  36. For selected recent examples, see: (a) Huang, J.-R.; Sohail, M.; Taniguchi, T.; Monde, K.; Tanaka, F. Formal (4+1) Cycloaddition and Enantioselective Michael-Henry Cascade Reactions To Synthesize Spiro[4,5]decanes and Spirooxindole Polycycles. Angew. Chem. Int. Ed. 2017, 56, 5853-5857. (b) Xiao, B.-X.; Du, W.; Chen, Y.-C. Asymmetric Dearomatizative Diels-Alder Reaction for the Construction of Hydrodibenzo[b,d]furan Frameworks with Tetrasubstituted Stereogenic Centers. Adv. Synth. Catal. 2017, 359, 1018-1027. (c) Zhang, J.-Q.; Li, N.-k.; Yin, S.-J.; Sun, B.-B.; Fan, W.-T.; Wang, X.-W. Chiral N-Heterocyclic Carbene-Catalyzed Asymmetric Michael-Intramolecular-Aldol-Lactonization Cascade for Enantioselective Construction of b-Propiolactone-Fused Spiro[cyclopentane-oxindoles]. Adv. Synth. Catal. 2017, 359, 1541-1551. (d) Jiang, X.-L.; Liu, S.-J.; Gu, Y.-Q.; Mei, G.-J.; Shi, F. Catalytic Asymmetric [4 + 1] Cyclization of ortho-Quinone Methides with 3-Chlorooxindoles. Adv. Synth. Catal. 2017, 359, 3341-3346. (e) Chen, X.-Y.; Chen, K.-Q.; Sun, D.-Q.; Ye, S. N-Heterocyclic carbene- catalyzed oxidative [3 + 2] annulation of dioxindoles and enals: cross coupling of homoenolate and enolate. Chem. Sci. 2017, 8, 1936-1941. (f) Wang, L.; Li, S.; Blümel, M.; Puttreddy, R.; Peuronen, A.; Rissanen, K.; Enders, D. Switchable Access to Different Spirocyclopentane Oxindoles by N-Heterocyclic Carbene Catalyzed Reactions of Isatin-Derived Enals and N- Sulfonyl Ketimines. Angew. Chem. Int. Ed. 2017, 56, 8516-8521.
  37. a) Zhou, Z.; Wang, Z.-X.; Zhou, Y.-C.; Xiao, W.; Ouyang, Q.; Du, W.; Chen, Y.-C. Switchable regioselectivity in amine-catalysed asymmetric cycloadditions. Nature Chem. 2017, 9, 590-594. (b) Zhou, Y.; Lu, Y.; Hu, X.; Mei, H.; Lin, L.; Liu, X.; Feng, X. Highly diastereo-and enantioselective synthesis of spirooxindole-cyclohexaneamides through N,N'-dioxide/Ni(II)- catalyzed Diels-Alder reactions. Chem. Commun. 2017, 53, 2060-2063. (c) Fan, W.-T.; Li, N.- Page 36 of 38
  38. ACS Paragon Plus Environment The Journal of Organic Chemistry K.; Xu, L.; Diao, C.; Wang, X.-W. Organo-Catalyzed Asymmetric
  39. Michael-Hemiketalization-Oxa-Pictet-Spengler Cyclization for Bridged and Spiro Heterocyclic Skeletons: Oxocarbenium Ion as a Key Intermediate. Org. Lett. 2017, 19, 6626-6629.
  40. a) Zhu, Y.; Zhou, J.; Jin, S.; Dong, H.; Guo, J.; Bai, X.; Wang, Q.; Bu, Z. Metal-free diastereoselective construction of bridged ketal spirooxindoles via a Michael addition-inspired sequence. Chem. Commun. 2017, 53, 11201-11204. (b) Zhu, Y.; Guo, J.; Jin, S.; Guo, J.; Bai, X.; Wang, Q.; Bu, Z. Construction of bridged cyclic N,O-ketal spirooxindoles through a Michael addition/N,O-ketalization sequence. Org. Biomol. Chem. 2018, 16, 1751-1759.
  41. a) Bergonzini, G.; Melchiorre, P. Dioxindole in Asymmetric Catalytic Synthesis: Routes to Enantioenriched 3-Substituted 3-Hydroxyoxindoles and the Preparation of Maremycin A. Angew.
  42. Chem. Int. Ed. 2012, 51, 971-974. (b) Retini, M.; Bergonzini, G.; Melchiorre, P. Dioxindole in asymmetric catalytic synthesis: direct access to 3-substituted 3-hydroxy-2-oxindoles via 1,4- additions to nitroalkenes. Chem. Commun. 2012, 48, 3336-3338. (c) Silvi, M.; Chatterjee, I.; Liu, Y.; Melchiorre, P. Controlling the Molecular Topology of Vinylogous Iminium Ions by Logical Substrate Design: Highly Regio-and Stereoselective Aminocatalytic 1,6-Addition to Linear 2,4- Dienals. Angew. Chem. Int. Ed. 2013, 52, 10780-10783.
  43. For seminal works, see: (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Enantioselective Organocatalyzed a Sulfenylation of Aldehydes. Angew. Chem. Int. Ed. 2005, 44, 794-797. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Diphenylprolinol Silyl Ethers as Efficient Organocatalysts for the Asymmetric Michael Reaction of Aldehydes and Nitroalkenes. Angew. Chem. Int. Ed. 2005, 44, 4212-4215. for a review, see: (c) Donslund, B. S.; Johansen, T. Page 37 of 38 ACS Paragon Plus Environment The Journal of Organic Chemistry K.; Poulsen, P. H.; Jørgensen, K. A. The Diarylprolinol Silyl Ethers:Ten Years After. Angew. Chem. Int. Ed. 2015, 54, 13860-13874.
  44. CCDC 1843516 contains the crystallographic data for 3r.
  45. a) Zu, L.; Zhang, S.; Xie, H.; Wang, W. Catalytic Asymmetric oxa-Michael-Michael Cascade for Facile Construction of Chiral Chromans via an Aminal Intermediate. Org. Lett. 2009, 11, 1627- 1630. b) Ramachary, D. B.; Prasad, M. S.; Laxmi, S. V.; Madhavachary, R. Asymmetric synthesis of drug-like spiro[chroman-3,3'-indolin]-2'-ones through aminal-catalysis. Org. Biomol. Chem. 2014, 12, 574-580.
  46. Ackrill, T. D.; Sparkes, H. A.; Willis, C. L. Synthesis of Diarylheptanoid Scaffolds Inspired by Calyxins I and J. Org. Lett. 2015, 17, 3884-3887.
  47. Zhao, B. L.; Du, D. M. Squaramide-Catalyzed Enantioselective Cascade Approach to Bispirooxindoles with Multiple Stereocenters. Adv. Synth. Catal. 2016, 358, 3992-3998.
  48. Murar, C. E.; Thuaud, F.; Bode, J. W. KAHA ligations that form aspartyl aldehyde residues as synthetic handles for protein modification and purification. J. Am. Chem. Soc. 2014, 136, 18140- 18148.
  49. Gao, D.; Cui, C. N-Heterocyclic Carbene Organocatalysts for Dehydrogenative Coupling of Silanes and Hydroxyl Compounds. Chem. Eur. J. 2013, 19, 11143 -11147. Page 38 of 38