Spiro oxindole formation

In another early application to natural product synthesis, Fleming and coworkers utilized this approach in the efficient formation of the gelsemine model (47) from 45 according to Scheme 8. The cyclization step to form the spiro-oxindole (46) proceeded in 85% yield and provided a means of generating the spiro-fused quaternary carbon without the need for carbenium ion or carbanion chemistry. 

By converting the enol triflate 41 to the spiro-tricyclic dienone 42, Overman and co-workers had already shown in 1989 that the direct enantio-selective formation of quaternary chiral carbon centers ean be carried out through an intramolecular Heck reaction. While the enantioselectiv-ities were only moderate at the beginning [ 16], the same authors later succeeded in achieving the Pd(0)-BINAP-catalyzed cyclizalion of substrates of type 43 to spiro-oxindoles 44 with up to 95 % ee (Scheme 12) [17]. 

The key step remaining involved the conversion of the ketone functionality in 260 to a spiro-oxindole. The conversion of a sterically hindered ketone to an oxindole by applying most of the conventional methods for the creation of a quaternary center at the spiro position was not an easy process. A process involving C—C bond formation by combination of two radical centers generated by photolysis of the alkoxy-substituted-1-alkenylbenzotriazole was then investigated (Scheme 35). By applying Wender s procedure (102), the benzotriazole derivative 261 was converted to 262 by metallation-silylation, and then the trimethylsilyl derivative was... 

The total synthesis of d/-21-oxo-gelsemine reported by Hart and collaborators (107) features two free radical cyclizations (C-5-C-16 bond formation in gelsemine) to construct both a tricyclic substructure 314 in the terpene part of gelsemine and the spiro-oxindole moiety. The synthesis was initiated with the Diels-Alder reaction between A-methylmaleimide and the diene 302, followed by treatment of the crude cycloadduct with 2,2-dimethyl-l,3-propanediol and a catalytic amount of p-toluenesulfonic acid, to give the perhydro-isoindole 304 in 43% yield. By application of the Grieco dehydra-... 

Okita, T. and Isobe, M. 1994. Synthesis of the pentacyclic intermediate for dynemicin a and unusual formation of spiro-oxindole ring. Tetrahedron 50 11143-11152. 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

When 7-aeyl-7 -reserpine derivatives (XV) are refluxed in dilute methanol with a few drops of acetic acid, conversion into the corresponding oxindole (XIX) with concomitant formation of the five-membered spiro-ring C takes place. Under these conditions, also, carbon... 

The attempted total synthesis " of 6-hydroxy-2 -(2-methylpropyl)-3,3 -spiro-(tetrahydropyrrolidino)-oxindole (127), an alkaloid of the dried root bark of Eleagnus communis (Wolf willow, or silverberry), " resulted in the formation of the epimer (128), or a mixture of (127) and (128) (Scheme 14). The final product showed great similarity to, but was not identical with, the alkaloid (127) however, (127) and the synthetic material gave the same product on acetylation, the reaction conditions for which presumably allowed epimerization at C-2. ... 

SCHEME 2.35 Working hypothesis for the formation of spiro[4//-pyran-3,3 -oxindoles] 117. 

SCHEME 40 Mechanism of formation of dihydropyridine spiro-fused 2-oxindoles. 

Catalyst 3 was also used in the construction of substituted 3-hydroxy-2-oxindoles by the reaction of 5-methoxy substituted isatins with various indoles [28]. Up to 91% ee could be obtained in 1,4-dioxane as the solvent and benzoic acid as an additive. Similarly, 3 was apphed as catalyst for the formation of spiro[4H-pyran-3,3 -oxindoles] via a one-pot domino Knoevenagel, conjugate addition, cyclization sequence (Scheme 6.12) [29]. 

---