Recent synthetic strategies of spiro-azetidin-2-one, -pyrrolidine, -indol(one) and -pyran derivatives-a review

Abstract

Spiro-heterocycles have received special attention in medicinal chemistry because of their promising biological activity. Over the years, many synthetic methodologies have been established for the construction of spirocyclic compounds. Spiro heterocycles such as spiro-azetidin-2-one, -pyrrolidine, -indol(one) and -pyran derivatives have been found to exhibit diversified biological and pharmacological activity in addition to their therapeutic properties. In view of these facts, we decided in this review to present representative synthetic approaches of the aforementioned spiro heterocycles, especially in the past 20 years.

Fig. 1. Different structures of spiroazetidin-2-ones.

Fig. 2. Biologically active spiro azetidin-2-one derivatives I–VI.

Fig. 3. Representative examples of biologically active spiro cyclic β-lactam VII–X.

Fig. 4. Alkaloids naturally occurring pyrroldin-2-ones XI–XII.

Fig. 5. Natural C-2 and C-3 spiroindol and spiroindol(one) containing compounds XIII–XVII.

Fig. 6. Selected pharmaceutical structures containing spiro indol(one) scaffolds XVIII–XXI.

Fig. 7. 2′-Aminospiro[pyrano[3,2-c]quinoline]-3′-carbonitrile derivatives XXIIa–f as ATP-non-competitive Src inhibitors that suppress breast cancer cell migration and proliferation.

Scheme 1. Staudinger synthesis of spiro-β-lactams 3 containing the xanthene moiety.

Scheme 2. Synthesis of dispirocyclic N-vinyl-β-lactam 7 from diazo Meldrum's acids (6) and 2H-azirines or 5-alkoxyisooxazoles 5.

Scheme 3. Mechanism described the formation of compound 7.

Scheme 4. HBTM catalyzed Mannich/lactamization cascade reaction of isatin derived imine 14 with aryl acetic acids 15.

Scheme 5. A plausible mechanism for the formation of 17a.

Scheme 6. Zinc mediated reaction between N,N-bis(arylmethylidene)benzidines 22 and a α-bromoalkancarboxylate 23.

Scheme 7. Rationale for the formation of compound 24.

Scheme 8. Carbonylation of acyclic diaminocarbenes leading to spiro β-lactams 36 containing cycloalkyl substituents.

Scheme 9. Steroidal spiro β-lactams 38; synthesis from dienamides 37 through a cascade 4-endo N-cyclization/aerobic oxidation sequence.

Scheme 10. Plausible mechanism for the formation of compound 38.

Scheme 11. Chartelline-core spiroindolenine-β-lactam 42 synthesis via bromide mediated spirolactamization of a bromoenamide.

Scheme 12. 1,3-Dipolar cycloaddition between 6-alkylidene penicillanates 43 and nitrones 44.

Scheme 13. P(NMe₂)₃-mediated cyclopropanation of α-methylene-β-lactams 48.

Scheme 14. Synthesis of spirocyclic-bis-β-lactams-lactams 54 from four-component Ugi-adducts precursors.

Scheme 15. Synthesis of β-lactam grafted spiro acenaphthenopyrrolidines 58.

Scheme 16. Formal [3 + 2] cycloaddition reaction of N-itaconimides 59 and isocyanoacetates 60 catalyzed by a chiral squaramide.

Scheme 17. Synthesis of spiro-pyrrolidine tethered indenoqunoloxaline 68.

Scheme 18. Synthesis of dispiropyrrolo[2,1-a]isoquinoline fused pyrrolidine-2,5-diones 74 and 75.

Scheme 19. Spiropyrrolo[2,1-a]isoquinolines containing the indenoquinoxaline 79.

Scheme 20. Synthesis of spiro[indene-2,8′-isoxazolo[5,4-c]pyrrolo[2,1-a]isoquinolines 84.

Fig. 8. Diagram showed different spiro indol(one) derivatives.

Scheme 21. Oxidative rearrangement of tetrahydro-β-carbolines for the formation of spirooxindole natural compounds 86, 88 and 90.

Scheme 22. Synthesis of spiro oxindolopyrrolidine 92.

Scheme 23. Asymmetric synthesis of tri-and tetracyclic spiro oxindoles 96 and 97.

Scheme 24. C(sp²)–H activation/annulation on to synthesis spiro oxindole pyrrolone scaffolds 101.

Scheme 25. Rational mechanism for the synthesis of spiro oxindolpyrrolone 101.

Scheme 26. Synthesis of isoxazole-dispiro-bis-oxindoles 109 from 3-isothiocyanato oxindoles 107 and isatylidenyl isoxazoles 108 by an organocatalytic process promoted by quinine.

Scheme 27. Synthesis of spiroindoles 113.

Scheme 28. 1,3-Dipolar cycloaddition reaction of isoquinolinium salts 114 with 3-arylidene-indoline-2-ones 110.

Scheme 29. Formation of hexahydrospiro[indoline-3,3′-pyrrolizine]-2-ones 120.

Scheme 30. Three component azomethine ylide cycloadditions catalyzed by unsupported partially aggregated ZnO nanoparticles (NPs).

Scheme 31. Synthesis of spirooxindole-pyrrolidine hybrids 128.

Scheme 32. Synthesis of spiro-indolones 131.

Scheme 33. Synthesis of spiroindoles 134.

Scheme 34. Synthesis of dispiro[indene-2,3′-pyrrolidine-2′,3′′-indoline]-1,2′′(3H)-diones 136.

Scheme 35. Synthesis of spiro[indeno[2′,1′:4,5]pyrrolo[1,2-c]imidazole-10,3′-indoline]-tetraone derivatives 139.

Scheme 36. Synthesis of spiro[indoline-3,5′-pyrrolo[1,2-c]thiazol]-2-ones 142 with four stereogenic centers.

Scheme 37. Nitrilimine cycloaddition to 3-alkylidene-2-oxindoles 110 hydrazonoyl chloride 143.

Scheme 38. Cycloaddition between isatin-3-imines 14 and pyridinium or isoquinolinium ylides 145 and 147.

Scheme 39. Intramolecular cycloaddition of the indolic carbonyl ylide 151.

Scheme 40. Fe₃O₄@SiO₂@Au-catalyzed three component reactions between 2-oxindole, aromatic aldehydes and dibromoaldoxime.

Scheme 41. TFA-mediated N-Boc deprotection/intramolecular N-acylation reaction of oxoindole-derived α-aryl-β-amino acids.

Scheme 42. NHC-catalyzed [2 + 4] spiroannulation of aliphatic aldehydes 161 with oxoindole-derived α,β-unsaturated imines 162.

Scheme 43. Cyclization of a S-tyrptophanol derived chiral bicyclic spiro δ-lactam 166.

Scheme 44. Cooperative Pd/Cu-catalyzed tandem three-component reaction involving δ-lactams 170, amines 51 and 2-bromobenzyl bromides 171.

Scheme 45. The proposed mechanism for the formation of 172.

Scheme 46. Synthesis of spiro-indolino-pyrido[2,1-a]isoquinolines 178.

Scheme 47. Rational pathway for the formation of 178.

Scheme 48. Synthesis of spirooxindoles 185 and 186 under microwave (MW) irradiation.

Scheme 49. Synthesis of spiro compounds 189 and 191.

Scheme 50. Synthesis of fused spirooxindooles 193 and 194via the reaction of 4-hydroxy coumarin derivatives 192 and amino pyrazole 187.

Scheme 51. A rational mechanism for the formation of 193 and 194.

Scheme 52. Formation of spirooxindole scaffolds 202 containing coumarin-dihydropyridine-isoxazol tetracycles.

Scheme 53. Synthesis of various spiroindole quinazoline derivatives 204.

Scheme 54. Formation of spiro [indoline-3,6′-[1,3]thiazine]-5′-carbonitriles 207a–g and the mechanism describes their formation.

Scheme 55. Utility of NMSM for the one-pot synthesis of fused spiro 4H-pyrans 210.

Scheme 56. Ultrasound-assisted organocatalytic domino synthesis of spiro[indoline-3,4′-pyrano[3,2-b]pyran 213.

Scheme 57. Synthesis of spiro-tropanyl oxindoles 217.

Scheme 58. Synthesis of spiroketals 220.

Scheme 59. Conversion of C,N-glycosides to spiro[pyran-4-quinolines] (R)-223 and (S)-224.

Scheme 60. Synthesis of spiro-pyrano-cage framework 231 and 232.

Scheme 61. Ultrasound-assisted organocatalytic domino synthesis of 2′-amino-6′-(hydroxymethyl)-8′-oxo-8′H-spiro[indeno[1,2-b]quinoxaline-11,4′-pyrano[3,2-b]pyran]-3′-carbonitrile/carboxylate derivatives 233.

Scheme 62. Synthesis of spiroindenopyridazine-4H-pyran derivatives 235a–i.

Scheme 63. Proposed mechanism for the formation of products 235.

Scheme 64. Spirocyclization by oxa-Pictet–Spengler reaction furnishing separable trans-isomers 243 and cis-isomers 244.

Scheme 65. Synthesis of spiro-pyran 246.