Spirooxindoles 1,3-dipolar cycloaddition

Spirooxindoles, such as, for example ( )-coerulescine (101) have been prepared employing a sequence starting from 2-fluoronitrobenzene, which was initially subjected to treatment with the anion of dimethyl malonate, followed by decarboxylation and concomitant installation of the methylene group using formaldehyde in the presence of potassium carbonate to produce the intermediate 102 in good yield. This material readily underwent dipolar cycloaddition with the azomethine ylide generated from sarcosine and formaldehyde, followed by a reductive cyclization of adduct 103 to furnish the natural product 101 <02TL9175>. 

Various 3-methyleneoxindoles have been converted to spirooxindoles in enan-tioselective fashion by Gong and coworkers who made use of a chiral organic catalyst to direct 1,3-dipolar cycloadditions across the exocyclic Jt-system [76]. As illustrated in Scheme 34, azomethine ylide formation arising from condensation of... 

The asymmetric, catalytic, three-component 1,3-dipolar cycloaddition which have been reported by Gong and co workers, of a broad range of methyleneindolinones with aldehydes and amino esters, in the presence of the chiral phosphoric acid (137) produced spirooxindole derivatives in high yield with unusual regiochemistry and excellent stereoselectivities (up to 98% ee), under mild conditions (Scheme 36). ... 

An asymmetric organocatalytic three-component 1,3-dipolar cycloaddition of methyleneindolinones 252 with aldehydes 249 and amino malonates 253, catalyzed by phosphoric acid 254, affording compounds 255 with spirooxindole skeleton was... 

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... 

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]. 

The 3 + 2-cycloaddition reaction of azomethine ylides with c-deficient alkenes produced polysubstituted l- and D-unnatural prolines. Also, phosphoramidite-(7u(OTf)2 complexes catalyse the 1,3-dipolar cycloaddition reactions of azomethine ylides with nitroalkenes to yield exo-tetrasubstituted proline esters." The 1,3-dipolar cycloaddition of non-stabilized azomethine ylides, from iV-alkyl-a-amino acids and aldehydes, with 3-substituted coumarins provides l-benzopyrano[3,4-c]pyrrolidines in good yields and high regio- and stereo-selectivity." The organocatalytic 1,3-dipolar cycloaddition of azomethine ylides, derived from azlactones, with methyleneindolinones produced spirooxindoles with high yields (up to 95%) and high diastereo- (93 7 dr) and enantioselectivity (98% ee). ... 

Scheme 42.45 Phosphoric acid-catalyzed enantioselective synthesis of spirooxindoles by enantioselective domino 1,3-dipolar cycloaddition of in situ formed azomethine ylides and methylene-indolinones.

SCHEME 2.15 Phosphoric acid-catalyzed asymmetric 1,3-dipolar cycloaddition for the synthesis of spirooxindoles. 

SCHEME 5.7. Microwave-assisted diastereoselective synthesis of an original bis-spirooxindoles via a hydrazone formation/Wolff rearrangement/1,2-hydrogen shift/l,3-dipolar cycloaddition consecutive sequence. 

Presset M, Mohanan K, Hamann M, Coquerel Y, Rodriguez J. 1,3-Dipolar cycloaddition of hydrazones with a-oxo-ketenes a three-component stereoselective entry to pyrazolidinones and an original class of spirooxindoles. Org. Lett. 2011 13 4124- 127. 

The spirocyclic oxindole core structure was constructed by an asymmetric 1,3-dipolar cycloaddition in the total synthesis of (—)-spirotryprostatin B. A reaction of oxazi-none 137 with aldehyde 138 and oxindole 139 resulted in spirooxindole 141 via the chiral azomethine yhde 140, simultaneously creating three bonds and four stereogenic centers in one step (Scheme 16.20). ... 

Based on the asymmetric 1,3-dipolar cycloaddition, a library of spirooxindoles was prepared by using building blocks having diverse properties and orthogonal chemical reactivities. The spirooxindole skeleton was assembled on macrobeads by using macrobead-anchored aldehydes 146, the oxazinone 137, and isatin-derived dipolarophile 147 or 148 (Table 16.1). As the reaction condition (MS 3 A, toluene) that was used in the solution-phase 1,3-dipolar cycloaddition was found to be unsuccessfid in the solid-... 

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