J. Appl. Cryst.の発刊に際して

Spirooxindoles are important synthetic targets possessing extended biological activity and drug discovery applications. This review focuses on the various strategies for the enantioselective synthesis of spirocyclic oxindoles relying on reports over the past decade and from earlier work. The spirooxindoles in this review are separated into three structural classes, and then further categorized into the method type from which the spirocycle is generated.

Molecular diversity of spirooxindoles. Synthesis and biological activity

Catalytic asymmetric construction of the biologically important spiro[pyrrolidin-3,2'-oxindole] scaffold with contiguous quaternary stereogenic centers in excellent stereoselectivities (up to >99:1 d.r., 98% ee) has been established by using an organocatalytic 1,3-dipolar cycloaddition of isatin-based azomethine ylides. This protocol represents the first example of catalytic asymmetric 1,3-dipolar cycloadditions involving azomethine ylides generated in situ from unsymmetrical cyclic ketones. In addition, theoretical calculations were performed on the transition state of the reaction to understand the stereochemistry. Preliminary bioassays with these spiro[pyrrolidin-3,2'-oxindole] revealed that several compounds showed moderate cytotoxicity to SW116 cells.

Scaffold‐Inspired Enantioselective Synthesis of Biologically Important Spiro[pyrrolidin‐3,2′‐oxindoles] with Structural Diversity through Catalytic Isatin‐Derived 1,3‐Dipolar Cycloadditions

The first catalytic enantioselective construction of a 3,3′-pyrrolidinyldispirooxindole scaffold has been established via organocatalytic asymmetric 1,3-dipolar cycloadditions of isatin-derived azomethine ylides with methyleneindolinones, which afforded structurally complex bis-spirooxindoles containing three contiguous and two quaternary stereogenic centers in generally high yields (up to 99%) and excellent diastereo- and enantioselectivities (up to >95:5 dr, 98% ee). This reaction also provides a good example for the application of catalytic asymmetric 1,3-dipolar cycloadditions in constructing enantioenriched bis-spirooxindole frameworks with structural complexity and rigidity.

Diastereo- and Enantioselective Construction of 3,3'-Pyrrolidinyldispirooxindole Framework via Catalytic Asymmetric 1,3-Dipolar Cycloadditions.

The first catalytic asymmetric construction of a new class of bispirooxindole scaffold-containing tetrahydro-β-carboline moiety has been established through chiral phosphoric acid-catalyzed three-component cascade Michael/Pictet-Spengler reactions of isatin-derived 3-indolylmethanols, isatins, and amino-ester, which afforded structurally complex and diverse bispirooxindoles with one quaternary and one tetrasubstituted stereogenic centers in excellent stereoselectivities (all >95:5 diastereomeric ratio (d.r.), up to 98:2 enantiomeric ratio (e.r.)). This intriguing class of chiral bispirooxindoles integrated the two important structures of tetrahydro-β-carboline and bispirooxindole, both of them possessing significant bioactivities. This approach also combined the merits of asymmetric organocatalysis and multicomponent tandem reaction, which provided a unique strategy for the preparation of structurally rigid bispiro-architectures with concomitant creation of multiple quaternary stereogenic centers.

Diastereo- and Enantioselective Construction of a Bispirooxindole Scaffold Containing a Tetrahydro-β-carboline Moiety through an Organocatalytic Asymmetric Cascade Reaction

Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3+2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives.

The synthesis of a series of novel dispiropyrrolidines has been accomplished by 1,3-dipolar cycloaddition reaction with 5-arylidene-1,3-thiazolidine-2,4-dione and 5-arylidene-4-thioxo-1,3-thiazolidine-2-one derivatives as dipolarophiles. The structure and stereochemistry of the cycloadduct have been established by single crystal X-ray structure and spectroscopic techniques. Molecular docking studies were performed on 1FM9 protein. The synthesized compounds were screened for their antidiabetic activity on male Wistar rats.

Synthesis and in vivo Antidiabetic Activity of Novel Dispiropyrrolidines Through [3 + 2] Cycloaddition Reactions with Thiazolidinedione and Rhodanine Derivatives.

Synthesis of novel spiroheterocycles through 1,3-dipolar cycloaddition of azomethine ylides with triarylideneacetylacetone through decarboxylation

In the title compound, C25H24N4O2S2, one of the pyrrolidine rings in the pyrrolizine ring system adopts an envelope conformation, whereas the other ring adopts a twist conformation. The five-membered ring in the indolone ring system also adopts a twist conformation. The crystal packing is stabilized by N—H⋯N and C—H⋯O inter­molecular hydrogen bonds, and C—H⋯π inter­actions. The N—H⋯N hydrogen bonds link the mol­ecules into cyclic centrosymmetric R22(22) dimers.

3-(4-Methyl-1,3-thiazol-5-yl)-1-[1′-(4-methyl-1,3-thiazol-5-yl)-2-oxo-2,3,2′,3′,5′,6′,7′,7a′-octahydro-1H-indole-3-spiro-3'-1H-pyrrolizin-2′-yl]­prop-2-en-1-one

In the title compound, C28H30N2O2, the cyclo­hexene ring system adopts a sofa conformation. The crystal structure is stabilized by C—H⋯O inter­actions between methyl H atoms of the ethyl substituents and the O atoms of carbonyl groups of adjacent mol­ecules, and by an inter­molecular carbon­yl–carbonyl inter­actions [3.207 (2) A]

https://journals.iucr.org/e/issues/2008/09/00/lx2064/lx2064.pdf

Ramalingam Murugan

Papers

Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3+2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives.

Synthesis and in vivo Antidiabetic Activity of Novel Dispiropyrrolidines Through [3 + 2] Cycloaddition Reactions with Thiazolidinedione and Rhodanine Derivatives.

Synthesis of novel spiroheterocycles through 1,3-dipolar cycloaddition of azomethine ylides with triarylideneacetylacetone through decarboxylation

3-(4-Methyl-1,3-thiazol-5-yl)-1-[1′-(4-methyl-1,3-thiazol-5-yl)-2-oxo-2,3,2′,3′,5′,6′,7′,7a′-octahydro-1H-indole-3-spiro-3'-1H-pyrrolizin-2′-yl]prop-2-en-1-one

9-Ethyl-2,3-dihydro-9H-carbazol-4(1H)-one.

Ramalingam Murugan

Papers

Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3+2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives.

Synthesis and in vivo Antidiabetic Activity of Novel Dispiropyrrolidines Through [3 + 2] Cycloaddition Reactions with Thiazolidinedione and Rhodanine Derivatives.

Synthesis of novel spiroheterocycles through 1,3-dipolar cycloaddition of azomethine ylides with triarylideneacetylacetone through decarboxylation

3-(4-Methyl-1,3-thiazol-5-yl)-1-[1′-(4-methyl-1,3-thiazol-5-yl)-2-oxo-2,3,2′,3′,5′,6′,7′,7a′-octahydro-1H-indole-3-spiro-3'-1H-pyrrolizin-2′-yl]­prop-2-en-1-one

9-Ethyl-2,3-dihydro-9H-carbazol-4(1H)-one.

3-(4-Methyl-1,3-thiazol-5-yl)-1-[1′-(4-methyl-1,3-thiazol-5-yl)-2-oxo-2,3,2′,3′,5′,6′,7′,7a′-octahydro-1H-indole-3-spiro-3'-1H-pyrrolizin-2′-yl]prop-2-en-1-one