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Review
. 2021 Jun 21;11(36):21926-21954.
doi: 10.1039/d1ra01170g.

Spirocyclic derivatives as antioxidants: a review

Karen Acosta-Quiroga  1 , Cristian Rojas-Peña  1 , Luz Stella Nerio  1 , Margarita Gutiérrez  2 , Efraín Polo-Cuadrado  2
Affiliations
Review

Spirocyclic derivatives as antioxidants: a review

Karen Acosta-Quiroga et al. RSC Adv. .

Abstract

In recent years, spiro compounds have attracted significant interest in medicinal chemistry due to their numerous biological activities attributed primarily to their versatility and structural similarity to important pharmacophore centers. Currently, the development of drugs with potential antioxidant activities is of great importance since numerous investigations have shown that oxidative stress is involved in the development and progression of numerous diseases such as cancer, senile cataracts, kidney failure, diabetes, high blood pressure, cirrhosis, and neurodegenerative diseases, among others. This article provides an overview of the synthesis and various antioxidant activities found in naturally occurring and synthetic spiro compounds. Among the antioxidant activities reviewed are DPPH, ABTS, FRAP, anti-LPO, superoxide, xanthine oxidase, peroxide, hydroxyl, and nitric oxide tests, among others. Molecules that presented best results for these tests were spiro compounds G14, C12, D41, C18, C15, D5, D11, E1, and C14. In general, most active compounds are characterized for having at least one oxygen atom; an important number of them (around 35%) are phenolic compounds, and in molecules where this functional group was absent, aryl ethers and nitrogen-containing functional groups such as amine and amides could be found. Recent advances in the antioxidant activity profiles of spiro compounds have shown that they have a significant position in discovering drugs with potential antioxidant activities.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Structures, reagents and conditions for the synthesis of spiro heterocycles [2.4.0] A1–A3. (a) H2O2 (30%), NaOH, CTAB, H2O, PTC, ultrasonic irradiation, (50% power, 1.0 A), rt, 12 min.
Scheme 2
Scheme 2. Structures, reagents and conditions for the synthesis of spiro heterocycle [2.4.0] A4. (a) Et3N, H2O, ultrasonic irradiation, 60 W, rt, 20 min.
Fig. 1
Fig. 1. Structure of the spiro heterocycle [2.7.0] compound B1.
Fig. 2
Fig. 2. Structures of spiro heterocycles [4.4.0] compounds C1–C2.
Scheme 3
Scheme 3. Reagents and conditions for the synthesis of compound C2. (a) I2 (2 equiv.), HC(OMe)3, rt, 6 h; reflux, 6 h; (b) LDA, THF; CH2CHCH2Br, −70 °C → rt, 7 h; (c) 10% NaOH, MeOH–H2O (1 : 1), reflux, 7 h; (d) DCC, DMAP (catalytic), Me2CCHCH2OH, DCM, rt, 5 h; (e) (1) LDA, THF; TMSCl, Et3N, −70 °C, 30 min; rt, 6 h; reflux, 3 h; (2) dil. HCl, 40 min; (3) CH2N2, Et2O, 0 °C, 30 min; (f) Cl2Ru(PCy3)2CHPh (5 mol%), DCM, rt, 5 h; (g) BBr3, DCM, −70 °C, 1.5 h; (h) K2CO3, PhCH2Br, acetone, rt, 6 h; (i) DIBAL-H, THF, rt → 70 °C, 1.5 h; (j) MeOH, HC(OMe)3, PPTS, reflux, 40 min; (k) (1) NaBH4, BF3·Et2O, THF, 0 °C → rt, 1 h; (2) 30% aq H2O2, 3 N aq NaOH, 0 °C → rt, 7 h; (l) PCC, silica gel, DCM, rt, 1 h; (m) AcOH–H2O (2 : 1), CF3COOH (catalytic), reflux, 14 h; (n) 10% Pd/C, H2, EtOH, 1 atm, 1.5 h.
Fig. 3
Fig. 3. Structures of the spiro heterocycles [4.4.0] compounds C3–C10.
Scheme 4
Scheme 4. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.4.0] C11. (a) (1) tert-BuOCl, Et3N, rt; (2) AgClO4; MeOH–H2O, HClO4, rt; (b) (1) AlH3; THF; −50 °C, 1 h; (2) NaBH3CN, MeOH–H2O, HOAc, rt, 1 h.
Scheme 5
Scheme 5. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.4.0] C12 and C13. (a) KNO3, H2SO4, rt, 2 h; (b) ethylene glycol, PTSA, benzene, reflux, 24 h; (c) cyclohexene, 10% Pd–C, EtOH, reflux, 2 h; (d) aldehyde derivatives, Et3N, EtOH, reflux, 8 h.
Scheme 6
Scheme 6. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.4.0] C14–C17. (a) MeOH, l-proline, reflux 1.5 h for C14, 1 h for C15, 2 h for C16, 3 h for C17.
Scheme 7
Scheme 7. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.4.0] C18–C21. (a) MeOH, thiazolidine-4-carboxylic acid, reflux; (b) MeOH, methylglycine, reflux.
Scheme 8
Scheme 8. Structure, reagents, and conditions for the synthesis of spiro heterocycles [4.4.0] C22–C26. (a) EtOH, reflux, 5 h for C22 and C23, 3–6 h for C24–C26.
Scheme 9
Scheme 9. Structures, reagents, and conditions for the synthesis of spiro heterocycle [4.4.0] C27. (a) Eutectic mixture of quaternary ammonium salt, acetylcholine iodide–ethylene glycol, stirring, 50 °C, 1 h.
Scheme 10
Scheme 10. Structures, reagents, and conditions for the synthesis of spiro heterocycle [4.4.0] C28. (a) CH3CN, reflux, 1.5 h.
Scheme 11
Scheme 11. Structures, reagents, and conditions for the synthesis of spiro heterocycles [4.4.0] C29 and C30. (a) EtOH, reflux, 10 h.
Scheme 12
Scheme 12. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.4.0] C31. (a) Bromoethane, DMSO, NaOH, stirring, rt; (b) indoline-2,3-dione, EtOH, diethylamine, reflux, 5 h; (c) AcOH, HCl (2 drops), 80 °C, 30 min; (d) N2H4·H2O (98%), EtOH, AcOH (2 drops) reflux.
Scheme 13
Scheme 13. Structures, reagents, and conditions for the synthesis of spiro heterocycle [4.4.0] C32. (a) AcOH, 10 °C, NaNO2, after 12 h; water was added.
Scheme 14
Scheme 14. Structures, reagents, and conditions for the synthesis of spiro heterocycle [4.4.0] C33. (a) POCl3, rt.
Scheme 15
Scheme 15. Structures, reagents, and conditions for the synthesis of spiro heterocycle [4.4.0] C34. (a) MeOH–H2O (3 : 1) in boiling, methylglycine, MCDC.
Scheme 16
Scheme 16. Structure, reagents, and conditions for the synthesis of spiro heterocycle [4.4.0] C35. (a) H2O2.
Scheme 17
Scheme 17. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.4.0] C36. (a) MeOH, reflux, 30 min.
Scheme 18
Scheme 18. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.4.0] irbesartan, (C37). (a) (1) Et3N, DCM, stirring, 0–5 °C, 15 min; (2) stirring, 0–5 °C, 2 h; (b) (1) HCl, stirring, 55–60 °C, 2 h; (2) EtOAc–H2O, stirring, 25–35 °C; (c) (1) NaN3, DMF, stirring, 30–40 °C; (2) TPP, ethyl acetate H2O, stirring, 25–35 °C, 2 h; (3) HCl, stirring, 0–5 °C, 1 h; (d) (1) DCC, methylene chloride, HOBT, diisopropylamine, reflux, 7 h → rt; (2) stirring, 0–5 °C, 1 h; (e) (1) Bu3SnCl, NaN3, N2 atmosphere, stirring, rt, 30 min; (2) DMF, stirring, rt, 30 min; (3) O-xylene, stirring, 150–155 °C, 20 h → rt; (4) CH2Cl2, O-xylene, HCl, stirring, rt, 3 h.
Fig. 4
Fig. 4. Structure of spiro heterocycle [4.5.0] Ribesin H (D1).
Scheme 19
Scheme 19. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] Acortatarin A (D2). (a) NaBH4, THF, 0 °C; (b) (1) THF, NaHMDS, Hg(OAC)2, stirring, −78 °C, 25 min; (2) stirring, −78 °C → 0°, 1 h; (3) stirring, 0 °C → rt, 5 h. (4) NaBH4, stirring, rt, 2 min; (c) THF, TBAF, stirring, 0 °C, 2 h.
Scheme 20
Scheme 20. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] Acortatarin B (D3). (a) Dimethyldioxirane, DCM, stirring, 1 h, 0 °C; (b) (1) Bu4NBH4, DCM, stirring, 1 h, 0 °C; (2) stirring, 2 h, rt; (c) THF, TBAF, stirring, 2.5 h, rt.
Fig. 5
Fig. 5. Structures of spiro heterocycles [4.5.0] lysidicins J (D4) and D5.
Scheme 21
Scheme 21. Structures and reagents for the synthesis of spiro heterocycle [4.5.0] D6. (a) SnCl2·2H2O, DCM; (b) NaBH4, CeCl3·7H2O, DCM, MeOH; (c) m-CPBA, NaHCO3, DCM; (d) DMP, NaHCO3, DCM; (e) p-TsOH, toluene; (f) TFA, DCM.
Scheme 22
Scheme 22. Structures, reagents and conditions for the synthesis of the spiro heterocycles [4.5.0] D7 and D8. (a) NaBH4, CeCl3·7H2O, MeOH, stirring, 0 °C, 1 h; (b) methyl-2-nitroacetate, DABCO, MeOH, reflux, 5 d; (c) PCC/Al2O3, DCM. (d) (1) NaOMe, rt, reflux, 12 h; (2) Me2SO4, rt, reflux, 24 h; (e) LHMDS, THF, −78 °C, Br2; (f) DABCO, reflux, 3 h; (g) NBS, DCM, 24 h; (h) Zn(BH4)2, DCM; (i) MeOH, stirring, rt, overnight.
Scheme 23
Scheme 23. Structures, reagents and conditions for the synthesis of the spiro heterocycles [4.5.0] D9 and D10. (a) (1) NBS, DMF, stirring, 0 °C, 50 min (93% yield); (2) BnCl, NaI, K2CO3, DMF, stirring, rt, 13 h; (b) N-acetylglycine, NaOAC, AC2O stirring, 120 °C, 6 h; (c) Ba(OH)2·8H20, 1,4-dioxane-H2O, stirring, 60 °C, 1 h, then O-benzylhydroxylamine; (d) (1) TMSCH2N2, PhMe–MeOH, stirring, 0° → rt, 1 h, 95% yield; (2) Pd-black, H2, dioxane/AcOH, stirring, rt, 3 h; (e) PhI(OAc)2, MeCN, stirring, 0 °C, 1 h; (f) Zn(BH4)2, DCM, stirring, rt; (g) LiOH–H2O, MeOH–H2O, stirring, rt, 1 h; (h) T3P, DIPEA, stirring, 0 °C, 2 h.
Scheme 24
Scheme 24. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D11–D13. (a) Fe3O4-NPs, EtOH, reflux.
Scheme 25
Scheme 25. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D14–D17. (a) H2O-CAN, ultrasonic irradiation, rt, 10 min for D14 and 20 min for D15 (b) H2O, CeO2-NPs, stirring, 90 °C, 5 h for D16 and D17.
Scheme 26
Scheme 26. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D18. (a) toluene–MeOH, reflux, 2 h.
Scheme 27
Scheme 27. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D19 and D20. (a) AcOH–H2O, stirring, 120 °C, 8–11 h.
Scheme 28
Scheme 28. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D21. (a) Malononitrile, MeCN, stirring, rt, 0.5 h; (b) carbon disulfide, Et3N, acetonitrile, stirring, rt, 1 h. (c) Multicomponent synthesis, Fe3O4@gly@CE, stirring, rt, 5.5 h.
Scheme 29
Scheme 29. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D22. (a) Malononitrile, MeCN, rt. (b) Carbon disulfide, MgO NPs, rt. (c) Multicomponent synthesis, rt, 2.5 h.
Scheme 30
Scheme 30. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D23–D25. (a) ZnCl2 + urea, 80 °C, 67 min for D23, 80 min for D24, and 75 min for D25.
Scheme 31
Scheme 31. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] 26. (a) (1) GTBSA, H2O, stirring, reflux, 1 h; (2) 100 °C → rt; (3) MeOH, stirring, reflux, 3 min; (4) centrifuge (1000 rpm) to separate the catalyst.
Scheme 32
Scheme 32. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D27 and D28. (a) CSA, ultrasonic irradiation, (low power), 70 °C, 30 min, EtOH.
Scheme 33
Scheme 33. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D29. (a) H2O, SBA-15-DABCO, reflux, 2 h.
Scheme 34
Scheme 34. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D30. (a) EtOH–H2O, SBA-15-PhSO3H, stirring, 80 °C, 5 h.
Scheme 35
Scheme 35. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D31. (a) (1) Ethyl cyanoacetate, NH4OAc–AcOH, benzene, stirring, 90 °C, 4 h. (2) Reflux, Dean–Starkwater trap, 24 h; (3) NH4OAc–AcOH, stirring, 90 °C, 1 h; (4) reflux, 24 h and cold to rt; (b) KCN, EtOH–H2O, stirring, 60 °C, 17 h; (c) AcOH, H2SO4, stirring, 110 °C, 2 h; (d) 1,5-dibromopentane, acetone, K2CO3, reflux, 24 h; (e) KSeCN, crown ether, THF, stirring, rt, 1 h.
Scheme 36
Scheme 36. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D32. (a) (1) NH3, MeOH, −5 °C, 20 h; (2) H2SO4–H2O, 170 °C, 1 h; (b) (NH4)2CO3, stirring, 200 °C, 30 min; (c) polyethylene glycol-400, Na2CO3, reflux, 7 h; (d) MeCN, TBAB, K2CO3, microwave, 120 °C, 4 min.
Scheme 37
Scheme 37. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D33 and D34. (a) APVPB, H2O, reflux, 5 h.
Scheme 38
Scheme 38. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D35. (a) KCN, (NH4)2CO3, EtOH, stirring, 55–60 °C, 15 h. (b) Arylsulfonyl chloride, Et3N, DCM, DMAP, stirring, rt, 15 h.
Scheme 39
Scheme 39. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D36 and D37. (a) Toluene, stirring, 110 °C, 48 h.
Scheme 40
Scheme 40. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D38–D41. (a) EtOH, reflux, 8 h.
Scheme 41
Scheme 41. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D42–D44. (a) (1) Aniline; (2) Br2, AcOH, reflux, 2 h. (b) Malononitrile, EtOH-piperidine. (c) Thiourea, EtOH-piperidine, microwave at 500 W and 140 °C for 15 min. (d) Hydrazine, EtOH-piperidine, microwave at 500 W and 140 °C for 15 min. (e) and (f) Sodium ethoxide, EtOH, microwave at 500 W and 140 °C for 15 min.
Scheme 42
Scheme 42. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D45, [5.5.0] G5 and [5.6.0] H1. (a) (1) Cyclopentanone (D45) or cyclohexanone (G5), or cycloheptanone (H1), pyrrolidine, toluene, reflux, 2 h. (2) MsCl, Et3N, DMC, rt, 12 h; (b) (1) NaBH4, MeOH, reflux, 1 h; (2) p-TsOH, toluene, reflux, 1 h; (c) OsO4, N-methylmorpholine-N-oxide, t-BuOH, THF, H2O, rt, 2 d; (d) acetone, H2SO4, 80 °C, 3 h; (e) (1) NaOH 10%, EtOH, reflux 48 h; (2) Meldrum's acid, toluene, reflux, 1 h; (f) (CF3CO)2O, DMC, rt, 20 h; (g) CF3CO2H, MeOH, rt, 24 h.
Scheme 43
Scheme 43. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D46. (a) AcNH4, AcOH, reflux, 24 h. (b) AcOH, AC2O, reflux, 9 h.
Scheme 44
Scheme 44. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D47. (a) BOC2O, DCM, TEA, rt, 2 h; (b) LDA, furan-2-carbaldehyde, −78 °C, 30 min; (c) MnO2, DCM, rt, 4 h; (d) NH2NH2–H2O, EtOH, AcOH, rt, 4 h; (e) KMnO4, acetone, water, 60 °C, 4 h; (f) DMF, DIPEA, HATU; HCl in 1,4-dioxane, rt, 5 h.
Scheme 45
Scheme 45. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D48. (a) BF3OEt2·DCM, 24 h.
Scheme 46
Scheme 46. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D49. (a) AcNH4, EtOH; (b) benzene, anhydrous K2CO3, reflux, 24 h.
Scheme 47
Scheme 47. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.5.0] D50. (a) 4-Iodophenol, Et3N, Nájera's catalyst, DMF, 110 °C, 3 h. (b) PIFA, anhydrous CH3CN, −10 °C, N2, 10–15 min.
Scheme 48
Scheme 48. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.5.0] D51, [5.5.0] G9–G11. (a) Toluene, pyrrolidine, reflux, 3 h; (b) K2CO3, microwave at 100 W for 5 min; (c) (4-chlorophenyl)boronic for G10, (4-fluorophenyl)boronic acid for G11 Toluene, EtOH, H2O, Pd(PPh3)4, Na2CO3, microwave at 100 W for 20 min.
Scheme 49
Scheme 49. Structures, reagents and conditions for the synthesis of spiro heterocycle [4.6.0] E1. (a) H2SO4 98%, 0 °C → 40–45 °C, 1 h (for 8 d); 75–80 °C, 3 h; (b) acetone–H2O, Na2WO4·2H2O, H2O2 50%, rt, 5 h.
Scheme 50
Scheme 50. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.6.0] E2–E6. (a) Et3N, THF, reflux, 20 min.
Scheme 51
Scheme 51. Structures, reagents and conditions for the synthesis of spiro heterocycles [4.6.0] F1–F5. (a) MeCN-PTSA, reflux, 80 °C, 24 h.
Fig. 6
Fig. 6. Structures of spiro heterocycles [5.5.0] G1 and G2.
Fig. 7
Fig. 7. Structures of spiro heterocycles [5.5.0] xilapirosides (G1) and xilapirosides A2 (G2).
Scheme 52
Scheme 52. Structures, reagents and conditions for the synthesis of spiro heterocycle [5.5.0] xilapirosides (G3). (a) TFA, DCM, stirring, 2 h; (b) TBSCI, Et3N, DCM, stirring, r.t, overnight; (c) BnBr, NaH, DMF, stirring, 0 °C, 30 min; (d) CeCl3·7H2O, NaI, MeCN, stirring, rt, 5 h; (e) DMP, DCM, stirring, rt, 3 h; (f) K2CO3, DMF, stirring, rt, 6 h; (g) 4 N, HCl, THF, 0 °C, 4 h; (h) TiCl4, DCM, stirring, −78 °C, 40 h.
Scheme 53
Scheme 53. Structures, reagents and conditions for the synthesis of spiro heterocycle [5.5.0] G6. (a) (1) C2HK, THF, stirring, rt; (2) HCl, CaCl2, hydroquinone, stirring; (b) K2CO3, KI, CuI, acetone, stirring, 60 °C, 4 h; (c) N,N-diethylaniline, stirring, 180 °C, 1 h.
Scheme 54
Scheme 54. Structures, reagents and conditions for the synthesis of spiro heterocycle [5.5.0] G7. (a) (1) NaNO2, H2SO4–H2O, rt, 1 h; (2) EtOH, CuSO4, reflux, 30 min; (3) SnCl2·2H2O, acetone, reflux, 12 h; (b) (1) diethyl malonate, 190 °C, 15 h; (2) NaOH, EtOH, rt, 2 h; (c) (CF3CO)2O, DCM, rt, 24 h.
Scheme 55
Scheme 55. Structures, reagents and conditions for the synthesis of spiro heterocycle [5.5.0] G12. (a) Pyrrolidine, EtOH, microwave, 4 min.
Scheme 56
Scheme 56. Structures, reagents and conditions for the synthesis of spiro heterocycle [5.5.0] G13. (a) KOH, microwave; (b) pyrroline-[bmim]Cl·FeCl3, microwave, 60 °C, 5 min.
Scheme 57
Scheme 57. Structures, reagents and conditions for the synthesis of spiro heterocycle [5.5.0] G14. (a) EtOH, reflux, 18 h.
Fig. 8
Fig. 8. Structure of the spiro heterocycle [5.6.0] H1.
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