Total synthesis of (-)-spirotryprostatin B: synthesis and related studies

The total synthesis of spirotryprostatin B, a cytostatic spiro[pyrrolidine-3,3'-oxindole] alkaloid, is described. The key step of the synthetic approach consists of the application of the MgI2-mediated ring-expansion reaction of a spiro[cyclopropane-1,3'-oxindole] with an aldimine, leading to rapid assembly of the spirotryprostatin core. The route documents the installation of the prenyl side chain by Julia-Kocieński olefination of a key aldehyde precursor, a transformation that ultimately allows for facile synthesis of analogues and facilitates structure-activity relationships studies.     

Highly diastereoselective synthesis of spiro[cyclopropane-1,3′-indolin]-2′-ones via catalyst-free cyclopropanation using ethyl diazoacetate

Substituted 3-methyleneindolin-2-ones were efficiently cyclopropanated with ethyl diazoacetate to yield spiro[cyclopropane-1,3′-indolin]-2′-ones in a catalyst-free and highly diastereoselective reaction in a mixture of ethanol–acetonitrile (1:1 v/v) as solvent.     

Copper-catalyzed 1,3-dipolar cycloaddition of methyleneindolinones and N,N'-cyclic azomethine imines

A copper-catalyzed stereoselective 1,3-dipolar cycloaddition of methyleneindolinones and N,N''-cyclic azomethine imines has been developed under mild reaction conditions. The spiro[pyrazolidin-3,3''-oxindoles] were obtained in moderate to high isolated yields (up to 82%) with good stereoselevtivities (up to 15:1) in the presence of 5 mol% of Cu(OAc)2 at room temperature.     

Reduction of substituted spiro[cyclopropane-3-(1-pyrazolines)] to spiro[cyclopropane-3-pyrazolidines] and 1-(2-aminoethyl)cyclopropylamine derivatives

Raney nickel-catalyzed hydrogenation of 5-substituted spiro[cyclopropane-3-(1-pyrazoline)]-5-carboxylates occurs with N—N bond cleavage with simultaneous cyclocondensation to give 3-aminopyrrolidin-2-ones containing a spirocyclopropane fragment. The presence of the second ester group in the pyrazoline side chain, in the position ensuring the formation of a five-membered ring results in 6,11-diazadispiro[2.1.4.2]undecane-7,10-dione, the product of double cyclocondensation of the intermediate diamine. Hydrogenation of the aryl-substituted spiro[cyclopropane-3-(1-pyrazolines)] in the presence of acetone affords hexahydrospiro[cyclopropane-4-pyrimidines], which can be converted into the cyclopropane-containing 1,3-diamines in the individual state or as salts. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2482–2490, November, 2005.     

Efficient construction of highly functionalized endo′-selective spiro[pyrrolidin-2,3′-oxindoles] via a regioselective 1,3-dipolar cycloaddition reaction between 3-amino oxindoles as azomethine ylide precursors and nitroalkenes

An efficient synthesis of novel endo′-selective spiro[pyrrolidin-2,3′-oxindoles] has been achieved via a three component regioselective 1,3-dipolar cycloaddition reaction. The azomethine ylides generated in situ from 3-amino oxindoles and aldehydes reacted with the nitroalkenes to furnish novel pyrrolidine–spirooxindole derivatives bearing one spiro quaternary center and multiple chiral centers in moderate to high yields (up to 99%) with high diastereoselectivities (up to 99:1). The structure and relative stereochemistry of cycloadducts were confirmed by NMR spectra and single crystal X-ray diffraction. The possible mechanism was proposed and the cycloaddition proceeded via endo′-transition state.     

Reactions of bromine-containing organozinc compounds derived from α,α-dibromo ketones with 2-arylmethylideneindan-1,3-diones and 5-arylmethylidene-2,2-dimethyl-1,3-dioxane-4,6-diones

Bromine-containing organozinc compounds generated from 1,1-dibromo-3,3-dimethylbutan-2-one reacted with 2-arylmethylideneindan-1,3-diones and 5-arylmethylidene-2,2-dimethyl-1,3-dioxane-4,6-diones to give 3-aryl-2-(2,2-dimethylpropanoyl)spiro[cyclopropane-1,2′-indan]-1′,3′-diones and 1-aryl-6,6-dimethyl-2-(2,2-dimethylpropanoyl)-5,7-dioxaspiro[2.5]octan-4,8-diones, respectively. Reactions of 2-arylmethylideneindan-1,3-diones with bromine-containing zinc enolates derived from 1-aryl-2,2-dibromopropan-1-ones and 2,2-dibromo-1,2,3,4-tetrahydronaphthalen-1-one resulted in the formation of 2-aroyl-3-aryl-2-methylspiro-[cyclopropane-1,2′-indan]-1′,3′-diones and 2,3: 8,9-dibenzo-12-phenyldispiro[4.0.5.1]dodecane-1,4,7-trione, respectively.     

One-pot,three-component synthesis of spiro[indeno[1,2-b]quinoline-10,3′-pyrroles] via the Hantzsch-type reaction of 1H-pyrrole-2,3-diones

A new methodology for the synthesis of spiro[indeno[1,2-b]quinoline-10,3′-pyrrole] derivatives via a Hantzsch-type reaction has been developed. This process involves the one-pot, three-component reaction of a 1H-pyrrole-2,3-dione, an aminocyclohexenone and 1,3-indanedione in acetic acid at reflux. Operationally simple, metal-free reaction conditions, simplicity of product isolation and good yields are key advantages of this methodology.     

An efficient and stereoselective cycloaddition of C-aryl and C-amido nitrones to dimethyl 2-benzylidenecyclopropane-1,1-dicarboxylate

1,3-Dipolar cycloadditions of dimethyl 2-benzylidenecyclopropane-1,1-dicarboxylate and a number of C-aryl or C-amido nitrones proceed with high efficiency and selectivity with the formation of only one isomeric spiro[cyclopropane-1,4-isoxazolidine] cycloadduct.     

Synthesis and conversions of polyhedral compounds. 25. Synthesis and convepsions of certain oxindole derivatives of 1,3-diazaadamantane and 3,7-diazabicyclo[3.3.1]nonane

By the reaction of 1,5-dimethyl-9-oxo-3,7-diazabicyclo[3.3.1]nonane with isatin and a number of its derivatives, spiro(1,3-diazaadamantane-2,3′-oxindoles) have been synthesized. In the case of 5-bromoisatin, either 3-(3-hydroxyoxindolyl)-3,7-diazabicyclo[3.3.1]nonane or the corresponding spirane is obtained, depending on the temperature. The interaction of these products with acetic anhydride has been studied. For communication 24, see [1]. A. L. Mndzhoyan Institute of Fine Organic Chemistry, Academy of Sciences of the Republic of Armenia, Erevan 375014. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1490–1493, November, 1997.     

Reactivity of spiroanthraceneoxazolidines with cyclopropanes: An approach to the oxindole alkaloid scaffold

The reaction of N-methylspiro[anthracene-oxazolidine] with spiro[cyclopropane-3,3′-indolin]-2-ones in the presence of MgI₂ formed the corresponding spiro[pyrrolidine-3,3′-indolin]-2-ones in 42–65% yields. The use of N-benzylspiro[anthracene-oxazolidine] in this reaction led to the formation of a mixture of the corresponding N-methyl- and N-benzylpyrrolidines.     

Catalytic cyclopropanation of spiro[2.4]hepta-4,6-diene with diazomethane

Catalytic cyclopropanation of spiro[2.4]hepta-4,6-diene with diazomethane in the presence of copper or palladium compounds results in mono- and dicyclopropanation products, namely, spiro[bicyclo[3.1.0]hex-3-ene-2,1′-cyclopropane] and spiro[cyclopropane-1,5′-tricyclo[4.1.0.0^2,4]heptane], with different efficiency. The use of Pd compounds as catalysts allows the cyclopropanation to be performed under conditions of simultaneous generation and decomposition of diazomethane.     

Domino Michael/aza-Wittig reaction in the diastereoselective construction of spiro[azepane-4,3′-oxindoles]

A convenient synthetic strategy for the diastereoselective assembly of spiro[azepane-4,3′-oxindoles] was developed via a Staudinger/Michael/aza-Wittig/reduction/N-deprotection reaction sequence starting from PMB-protected oxindole-substituted ethylazides. The key step of the method is a domino self-catalytic Michael/aza-Wittig reaction wherein the phosphazene moiety acts first as the catalyst and then as the reactant, resulting in the formation of a seven-membered N-heterocycle.     

Scaffold-inspired enantioselective synthesis of biologically important spiro[pyrrolidin-3,2'-oxindoles] with structural diversity through catalytic isatin-derived 1,3-dipolar cycloadditions

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.     

Grindstone chemistry: one-pot synthesis of spiro[diindenopyridine-indoline]triones and spiro[acenaphthylene-diindenopyridine]triones

A one-pot, pseudo four-component, and simple synthesis of spiro[diindenopyridine-indoline]triones and spiro[acenaphthylene-diindenopyridine]triones via the reaction of 1,3-indandione, aromatic amines and isatins or acenaphthylene-1,2-dione using a ‘Grindstone Chemistry’ method is reported.     

Photochemically Induced Ring Opening of Spirocyclopropyl Oxindoles: Evidence for a Triplet 1,3-Diradical Intermediate and Deracemization by a Chiral Sensitizer

The photochemical deracemization of spiro[cyclopropane-1,3′-indolin]-2′-ones (spirocyclopropyl oxindoles) was studied. The corresponding 2,2-dichloro compound is configurationally labile upon direct irradiation at λ=350 nm and upon irradiation at λ=405 nm in the presence of achiral thioxanthen-9-one as the sensitizer. The triplet 1,3-diradical intermediate generated in the latter reaction was detected by transient absorption spectroscopy and its lifetime determined (τ=22 μs). Using a chiral thioxanthone or xanthone, with a lactam hydrogen bonding site as a photosensitizer, allowed the deracemization of differently substituted chiral spirocyclopropyl oxindoles with yields of 65–98 % and in 50–85 % ee (17 examples). Three mechanistic contributions were identified to co-act favorably for high enantioselectivity: the difference in binding constants to the chiral thioxanthone, the smaller molecular distance in the complex of the minor enantiomer, and the lifetime of the intermediate 1,3-diradical.     

1,3-Dipolar cycloaddition for selective synthesis of functionalized spiro[indoline-3,3'-pyrrolizines]

The 1,3-dipolar cycloaddition reaction of dimethyl hex-2-en-4-ynedioate with azomethine ylides derived from reaction of L-proline with various isatins in methanol selectively resulted in the formation of functionalized spiro[indoline-3,3'-pyrrolizine]acrylates as main products and spiro[indoline-3,3'-pyrrolizine]propiolates as minor products.This result indicated that the electron-deficient alkyne has higher reactivity than that of electron-deficient alkene in 1,3-dipolar cycloaddition reaction.     

Syntheses of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid and cyclopropa[c]quinoline-7b-carboxylic acid and their derivatives

The synthesis of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid, including novel 3-(2- and 3-pyridyl)-substituted analogues and the novel cyclopropa[c]quinoline-7b-carboxylic acid and their ester and amide derivatives is described. These syntheses involve diastereoselective cyclopropanation reactions of methyl 2-(2-nitrophenyl)acrylate and (3E)-(pyridin-2-ylmethylene)- and (3E)-(pyridin-3-ylmethylene)-1,3-dihydro-2H-indol-2-one with ethyl (dimethyl sulfuranylidene) acetate (EDSA). The synthesis of methyl cyclopropa[c]quinoline-7b-carboxylate involves a regioselective reductive cyclization of a nitro-diester precursor. The relative stereochemistry of key compounds has been determined by single-crystal X-ray structural analysis.     

Two approaches toward the regio- and stereoselective synthesis of N-unsubstituted 3-aryl-4-(trifluoromethyl)-4H-spiro-[chromeno[3,4-c]pyrrolidine-1,3'-oxindoles]

Chemistry of Heterocyclic Compounds - A regio- and stereoselective method for the synthesis of N-unsubstituted 3-aryl-4-(trifluoromethyl)-4H-spiro[chromeno[3,4-c]-pyrrolidine-1,3'-oxindoles] in...     

Stereoselective synthesis of spiro[pyrrolidin-3,3′-oxindoles] via organocatalyzed asymmetric Mannich-type reaction

The organocatalyzed asymmetric Mannich-type spirocyclization was employed to access the spiro[pyrrolidin-3,3′-oxindoles], a biologically privileged ring structure, from readily available 2-oxotryptaphan methyl ester and aromatic aldehydes. The stereoselectivity of this cyclization are closely correlated with the organocatalyst and solvent used for the reaction. The best diastereoselectivity (d.r. ≥99%) was achieved using only 5% loading of the bifunctional organocatalyst, Takemoto’s thiourea, and dioxane as solvent, resulting in the formation of the the spirocycle with the (2′R, 3R) configuration. The yield could be increased up to 97% when excess of benzaldehyde was used to overcome its trimerization.     

Investigation of reactions of the organozinc reagents prepared from zinc and dialkyl dibromomalonates with the derivatives of 2-arylmethyleneindan-1,3-dione and 5-arylmethylene-2,2-dimethyl-1,3-dioxane-4,6-dione

Organozinc compounds prepared from dialkyl dibromomalonates and zinc react with 2-arylmethyl-eneindan-4,6-diones, 5-arylmethylene-2,2-dimethyl-1,3-dioxane-4,6-diones, as well as with 2-[4-(1,3-dioxoindan-2-ylidenemethyl)phenyl]methyleneindan-1,3-dione and 5-[4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-2-ylidenemethyl)phenyl]methylene-2,2-dimethyl-1,3-dioxane-4,6-diones to form dialkyl 3-aryl-1′3′-dioxaspiro(cyclopropane-2,2′-indan)-1,1-dicarboxylates, dimethyl 3-aryl-6,6-dimethyl-5,7-dioxa-4,8-dioxaspiro[2,5]octan-2,2-dicarboxylates, dialkyl 2-{4-[3,3-bis (alkoxycarbonyl)-1′,3′-dioxaspiro(cyclopropane-2,2′-indan)-1-yl]phenyl}-1′,3′-dioxaspiro[cyclopropane-2,2′-indan]-1,1-dicarboxylates, and dialkyl 2-{4-[2,2-bis(alkoxycarbonyl)-6,6′-dimethyl-4,8-dioxo-5,7-dioxaspiro[2,5]oct-1-yl]phenyl}-6,6-dimethyl-4,8-dioxo-5,7-dioxaspiro[2,5]octan-1,1-dicarboxylate respectively.