Spirooxindoles synthesis

The retrosynthetic approach to welwitindolinone A isonitrile (6) used by the Wood group is shown in Scheme 33. After recognition of the possibility of deriving the vinyl isonitrile fragment from a ketone, the disconnection of 6 to 140 was proposed. A literature report of a samarium (II) iodide-mediated reductive coupling of acrylates with isocyanates to give amides, which could be expected to lead to a new spirooxindole synthesis, prompted the disconnection of 140 to 141. This compound was to be obtained from the readily available cyclohexadiene derivative 143, by way of bicyclic ketone 142. 

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). 

SCHEME 16.27. Optically active spirooxindole synthesis by a domino aldol/cyclization sequence. 

The group of Gong and coworkers explored a biomimetic 1,3-dipolar cycloaddition between a-ketoester 79 and benzylamine derivatives 80 with electron-deficient olefins 81a,b to devise a straightforward route to proline derivatives 82 in high yields and enantioselectivities [49]. The proposed biomimetic three-component 1,3-dipolar cycloaddition proceeds as illustrated in Scheme 2.22a. The azomethine ylide B is formed, via a transamination from ketimine ester A, which is in turn prepared from a-ketoesters 79 and benzyl-amine derivatives 80 then, the 1,3-dipolar cycloaddition with electron-poor olefins 81a takes place. For this purpose, the bisphosphoric acid 83 was found to be the catalyst of choice to promote such transformation (Scheme 2.22b). Replacing dimethyl maleate (previously used as deficient olefins) by methyleneindolinones, the same approach could be extended to spirooxindoles synthesis in high yields and... 

Recently, Curran described a procedure using triethylborane for the synthesis of spirooxindoles and spirodihydroquinolones through intramolecular addition of aryl radicals at the ipso position 4-alkoxy-substituted aromatic rings [15]. The key step for a formal synthesis of the vasopressin inhibitor SR121463A is described in Scheme 5. The initiation was performed with Et3B in an open to air reaction vessel. 

Scheme 36 Three-component synthesis of spirooxindole-containing tetrahydrochromene derivatives...

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

Zhu SL, Ji SJ, Zhang Y (2007) A simple and clean procedure for three-component synthesis of spirooxindoles in aqueous medium. Tetrahedron 63 9365-9372... 

Nair et al. (87,88) achieved a synthesis of spirooxindole-containing molecules by adding isatins to various carbonyl ylides (Scheme 4.46). There has been relatively little research regarding the efficiency of C=0 of 1,2-dicarbonyl compounds as dipolarophiles relative to their olefinic counterparts. As anticipated, Nair found that the more electrophilic carbonyl of the isatin 187 (non-amide carbonyl) reacted smoothly with the carbonyl ylide formed from diazoketone 186 to give the spirocyclic adduct 188. Nair s yields were moderate to good (44—83%), but were based on recovered isatin. 

Scheme 35 Samarium iodide-promoted synthesis of spirooxindoles related to welwitin-dolinone A...

A ligandless Heck cyclization was subsequently utilized by Hiemstra and Speckamp in their total synthesis of gelsemine (22) [5]. In this case, cyclization of 23 provided a 2 1 mixture of spirooxindoles 24/25. The lower stereoselectivity observed here is presumably due to the CHjOTDS group which adds further steric congestion to the concave face of 23. 

The spirooxindole system is the core unit of many natural products such as spirotryprostatin A, isopeteropodine, etc. Perumal and co-workers have developed a fast, clean and simple method for the synthesis of spirooxindoles and spiroindenoquinoxaline derivatives catalyzed by silica gel impregnated indium(in) chloride under solvent-free microwave irradiation (Scheme 5.36). 

Similar results have been obtained for the formation of 1-amidoalkyl radicals starting from A -ort/fo-halobenzyl amides. For instance, the synthesis of y-lactam from glycine derivatives was reported (Scheme 34, Eq. 34.1) [126]. A new route to spirooxindole based on 1,5-hydrogen transfer followed by cyclization onto an activated indole was recently published (Eq. 34.2) [127]. 

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... 

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