Oxindoles spirooxindoles

Keywords Chiral quaternary center Oxindole Spirooxindole... 

Spirocyclic oxindole 60 was synthesized by [3,3]-sigmatropic rearrangement of the Af-phenyl-O-acylhydroxamic acid 58 (equation 19). The potassium enolate formed by treatment of 58 with potassium hexamethyldisilazide at low temperature rearranged to 59, which easily cyclized to the spirocyclic oxindole 60. Spirooxindoles were previously synthesized by Wolff and Taddei. The spirooxindole 60 was formed in 51% yield from cyclohexanecarboxylic acid after heating the preformed lithium salts of phenyl hydrazide 61 to 205-210 °C. 

Surugatoxin (319), with its unique spirooxindole moiety connected to a tetrahydropteridine ring, is an interesting marine natural product. Inoue et al. have synthesized the pentacyclic ring system (318) of su-rugatoxin in 10 steps from the oxindole derivative (317), which is obtained in 79% yield by a Knoevena-gel condensation of isatin (316) and 4-phthalimidoacetoacetate. ... 

Pummerer-like cyclization reactions were utilized to prepare spirocyclic oxindole derivatives <04OL1869, 04OL2849>. For example, treatment of 2-sulfenylindole 215 with an iodonium reagent in the presence of 2,6-lutidine produced thioimidate 216. Oxidation of the latter with cerium ammonium nitrate (CAN) gave spirooxindole 217. 

The easy condensation of aldehydes with 3-monosubstituted oxindoles has been further exploited by Ban and co-workers, who synthesized several 3-spirooxindole derivatives 48). The approach was used in the stereospecific synthesis of racemic iV-methylrhynchophyllane (Chart X). The Iraws-diethylcyclopentanone CVIIIa was subjected to Baeyer-Villiger oxidation to yield the threo lactone CIX, which was converted to the chloroaldehyde CXI, by successive reaction with phosphorus... 

This chapter is a survey of recent works in the general area of oxindole and spirooxindole synthesis with specific attention on strategies for the installation of the C3 quaternary centers that characterize members of this unique family of indole alkaloids. As investigations that have resulted in modest observed selectivities represent important opportunities for further synthetic advancement, those studies will be described alongside illustrations of chemical technologies that represent the state of the art of the discipline. 

Chiral indole-2-sulfoxides have been employed by Feldman and Karatjas for asymmetric spirooxindole synthesis [70]. In one example, treatment of 115 with triflic anhydride initiated a Pummerer-type cyclization of the silyl enol ether side chain onto C3 (Scheme 30). Sequential hydrolysis of the resulting thioimidate intermediate with aqueous HgCl2 afforded the spirocyclohexanone functionalized oxindole 116 in modest yield and enantioselectivity at —78°C (33, 67% ee). Improved selectivity (58, 86% ee) was observed at lower reaction temperature (-110°C). 

The Trost group has devised a strategy for stereoselective spirocyclic ring installation across 3-alkylidene oxindoles via palladium-catalyzed [3-1-2] cycloaddition with cyano-substituted trimethylenemethane (Scheme 33) [74, 75]. As illustrated, the opposite sense of diastereoselectivity was observed depending on the choice of chiral ligand 125 or 126. Preferential orientation of the benzenoid portion of the oxindole as dictated by the varied steric environments of the naphthyl ring systems on the catalysts has been put forth as a rationale for the observed difference in stereochemical outcomes. Spirooxindoles 127 and 128 were obtained in 92% ee and 99% ee, respectively. A variation of this methodology has been applied in the racemic synthesis of marcfortine B [75]. 

Two independent reports have appeared that detail methodology for the introduction of pyran or oxepene spirocychc moieties onto oxindole scaffolds by means of a Prins cyclization (Scheme 35). In one study by Zhang and Panek, treatment of isatin dimethylketal 134 with sUyl alcohol (S )-135 afforded predominately c -137 or trans-Vi9 depending on reaction time and solvent polarity [78]. A mechanism involving epimerization of the cis-product to the trans adduct was put forward to explain the observed frans-selectivity with increased reaction time in polar solvents. A cyclic transition state involving a (Z)-oxonium intermediate formed via condensation of silyl alcohol 135 with isatin 134 was invoked to rationalize the preferential formation of the cis-spirocycle under kinetic control. Further optimization led to the formation of spirooxindoles 138, e.g., R, = Me, as single... 

In a separate investigation by Porco, Jr. and coworkers, the isatin derivative 134 (R = H) was converted to spirooxindole pyran 141 in 13 1 dr and 99% ee by means of a Prins-type cyclization involving homoaUyhc alcohol 140 [79]. The diastereos-electivity of the transformation has been proposed to arise from a preferred chairlike transition state with the benzenoid ring of oxindole in a pseudoequatorial orientation. Spirooxindole oxepenes also were prepared via diastereoselective spiro-annulation of isatins with bis-homoallyhc alcohols. 

A palladium-catalyzed spirocychzation between isatin and y-methylidene-8-valerolactones, e.g., 142 and 143 (Scheme 36), has been developed by Shintani, Hayashi, and coworkers for the preparation of tetrahydropyranyl fused oxindoles [80]. An enantioselective variant of the transformation was observed using phos-phoramidite ligand 144 for the Pd-catalyzed decarboxylative cychzation. In the event, spirooxindole 145 was produced in 88 12 dr and 87% ee. 

Additional examples of synthetic applications of hypervalent iodine-induced heterocyclizations include the following the metal-free one-pot synthesis of 2-acylbenzothiazoles by oxidative cyclization of multiform substrates [434], iodine(III)-mediated tandem oxidative cyclization for construction of 2-nitrobenzo[ ]furans [435], hypervalent iodine mediated oxidative cyclization of o-hydroxystilbenes into benzo- and naphthofu-rans [436], PhI(OCOCF3)2-mediated synthesis of 3-hydroxy-2-oxindoles and spirooxindoles from anilides [437], synthesis of isoxazoles by hypervalent iodine-induced cycloaddition of nitrile oxides to alkynes [438],... 

In 2012, Yuan and co-workers presented one example of chiral phosphoric acid-catalyzed asymmetric [l,5]-hydride transfer/cyclization reaction of oxindole derivative 31 (Scheme 4.15). The corresponding spirooxindole... 

A similar approach was reported by Wang et al. [60] a year later, consisting of a double Michael reaction of simple oxindoles with dienones. The reaction was simply catalyzed by a cinchona-based primary amine catalyst (XIII). The reaction afforded the final spirocyclic oxindoles in good yields and excellent enantioselectivities when diaryldienones were used. The only limitation of the reaction was the need to use carbamate-protected oxindoles thus, the use of unprotected or benzylated oxindoles is ineffective for this transformation. In 2010, the same research group proposed a similar approach [61]. They performed a reaction with an oxindole derivative decorated with a ketone in position 3 of the oxindole and acyclic enones. This reaction was catalyzed by chiral primary amines, affording the final spirooxindoles in good yields and enantioselectivities. 

The same research group developed a similar cascade leading to the synthesis of spirooxindoles bearing four stereogenic centers. The starting material this time was a-methylene oxindoles (90) instead of 2-cyanoacrylate derivative. The reaction renders the spirooxindole derivatives 110 in excellent yields and enantioselectivities [59]. In 2011, Rios and co-workers [70] expanded the scope of the reaction using a-methylene pyrazolones 111, leading to spiropyrazolones 112 with excellent results (Scheme 10.29). 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

Yuan and co-workers used a similar strategy to synthesize spirooxindoles by a domino aldol/cyclization of 3-isothiocyanato oxindoles with simple ketones catalyzed by a bifunctional thiourea-tertiary amine catalyst [55]. An interesting feature of this methodology is the creation of two adjacent quaternary carbon atoms with high stereocontrol. 

A related synthesis of 3,3 -cyclopropyl oxindoles was reported by Takemoto et al. [32], Carbamoyl chloride 47, containing a cyclopropyl ring at the ortho position, undergoes a Pd-catalyzed cyclization onto the benzylic C-H bond of the cyclopropane to provide the corresponding spirooxindole 44 in 60% yield (Scheme 13). Intramolecular competition reactions investigated the chemoselectivity of the... 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

Williams has reported a MCR in the synthesis of spirotryprostatin B 50, a spirooxindole-substituted diketo-piperazine with a prenylsubstituent at C-18 (Scheme 6.7). In the key step, diphenylmorphoUnone 66 reacts with isovaleraldehyde 67 to form azomethine ylide 69, which is attacked by the oxindole 68 to build the latter 70 in a [3+2]-dipolar cycloaddition [24]. 

For important reviews abont 3,3 -disnbstitnted oxindole strnc-tural motif, see (a) F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352, 1381-1407. Catalytic asymmetric synthesis of oxindoles bearing a tetrasubstituted stereocenter at the C-3 position, (b) J. J. BadiUo, N. V. Hanhan, A. K. Franz, Curr. Opin. Drug Discov. Dev. 2010, 13, 758-776. Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery, (c) A. Kumar, S. S. Chimni, RSC Advances 2012, 2, 9748-9762. Catalytic asymmetric synthesis of hydroxyoxindole a potentially bioactive molecule, (d) S. Mohammadi, R. Heiran, R. P. Herrera, E. Marques-L6pez,... 

Hypervalent iodine reagents have successfully been employed in the oxidative functionalization of enolizable carbonyl compounds over the years [6]. This methodology has allowed the construction of diverse C-C bonds in the context of heterocychc synthesis and has enriched the otherwise rare repertoire of such chemistry. Zhao, Du, and coworkers [37] have recendy realized a metal-free PIFA-mediated synthesis of 3-hydroxy-2-oxindoles 34 and spirooxindoles 35 starting from anilide derivatives 33 (Scheme 8 (1)). These processes showcase an oxidative cross coupling between an aromatic carbon and a pendant aliphatic carbon, followed by further oxidative hydroxylation or spirocycUzation. Later, the authors extended the same concept to achieve C(sp )-C(sp ) bond formation, where anilide derivatives possessing terminal enol functionality underwent PIDA-... 

Scheme 8 PIFA-mediated synthesis of oxindoles and spirooxindoles...

---