Spirocyclic indoles

Conjugate addition reaction is also promoted by superbases. Novikov et al. reported that the intramolecular Michael addition of a,p-unsaturated ester 31, which was obtained from vinyl diazoacetate in the presence of rhodium acetate [Rh2(OAc)4], proceeded with DBU to give the spirocyclic indole skeleton 32 in 90% yield [7] (Scheme 7.5). This strucmre can be seen in intriguing, complex natural products, such as marcfortines 33 and 34. 

The spirocyclic cyclopenta[g]indole derivatives represented by 31 have also been prepared via the Madelung indole process. ... 

MgS04, the tetracycles 2-648 were obtained with excellent diastereoselectivity in reasonable yield. The reaction presumably starts with a condensation of the aldehydes 2-645 with the benzyl-protected amine moiety of 2-644 to give an iminium ion which can subsequently cyclize to afford the spirocyclic intermediates 2-646. A [3,3] sigmatropic Cope rearrangement then forms the nine-membered cyclic enamines 2-647 which, after protonation, act as the starting point for another indole iminium cyclization to provide the tetracycles 2-648 via 2-647. 

Scheme 17.26 Generation of a novel spirocyclic structure by indole oxidation.

The final, critical oxidative spirocyclization of the 2,3-disubstituted indole to the spiro oxindole was effected by treatment of 124 with tert-butyl hypochlorite in pyridine to provide the labile 125 [Fig. (34)]. The Pinacol-type rearrangement was conducted by treating compound 125 with p-toluenesulfonic acid in THF/water. It is assumed that the chlorination of 124 proceeds from the least hindered face of the indole, to give the a-chloroindolene 125. The hydration of the imine functionality must also occur from the same a-face that is syn to the relatively large chlorine atom furnishing the syn-chlorohydrin 126, that subsequently rearranges stereospecifically to the desired spiro oxindole 127. 

More recently, the radical cyclization onto azide groups pioneered by Kim was applied in the construction of the B/E spirocyclic junction found in the [6.5.6.5] ABCE ring system of indole alkaloids such as strychnine, the clinically used anticancer agents vincristine and vinblastine and, in particular, aspidospermine87. In model system studies, cyclization of the iodoazide 24, prepared in 6 steps, in the presence of (TMS SiH, produced the N—Si (TMS>3 protected alkaloid 25, that after washing with dilute acid afforded the amine 26 in 95% yield from 24 (equation 58). The formation of the liable N—Si(TMS)3 bond was considered to arise from the reaction of the product amine 26 with the byproduct (TMS)3SiI. 

Phenylsulfinyl)indole 187 bearing a pendant nucleophile at C3 undergoes a Pummerer-like rearrangement upon treatment with Tf20 to furnish 3,3-spirocyclic-2-(phenylthio)indolenine 188 in high yield (Equation 85)... 

Other symmetrical intermediates originaliy identified by radioactive labelling include the cyciopropanone in the Favorskii rearrangement in Chapter 37, p. 990, and a spirocyclic intermediate in electrophilic substitution on an Indole in Chaptar 43, p. 1170. 

When the enamine is terminally disubstituted, the photocyclization can lead to the formation of a spirocyclic ring system (equation 3)7,8. This spirocyclization proceeds in good yield both with substituted phenyl rings as well as with furan, thiophene, pyridine or indole heteroaromatic rings. 

Additions to a,)S-unsaturated amides are represented by relatively few examples. In the cases shown, the double bond is exocyclic and f urther activated by an ester substituent, but the reactions lead to interesting spirocyclic penicillin 24 and indole 25 derivatives. It should be noted that in both cases, the thermal decomposition proceeds with retention of stereochemistry. 

Cyclization that eventualy places the resulting double bond endocyclic also occurs, as in the annulation of indoles and the formation of spirocyclic furanones and pyrrolones which involves a rearrangement process. ... 

Novel heterocycles. Some novel heterocycles have been prepared by de-oxygenation of indoiyl o-nitrophenyl sulfides, prepared by reaction of indoles with 2-nitrobenzenesulfenyl chloride. The reaction involves intermediate spirocyclic compounds. 

In another elegant experiment, the intervention of a 3,3-disubstituted 3//-indolium intermediate in an indole overall o -substitution was proved by cyclisation of the mesylate of an optically active alcohol to give an optically inactive product, via an achiral, spirocyclic intermediate from initial attack at the /3-position. ... 

Other aromatic rings that were studied as radical acceptors in this investigation included naphthalene and indole [75]. As such, spirocycles of the type 106-109 were synthesized with moderate success when HMPA was replaced with the additive LiBr. 

A radical tpso-type substitution on indoles and benzofurans has resulted in other dearomatized spirocycles [83]. Aryl, vinyl, and alkyl radicals added to the C-2 position of the indole to give novel compounds, 128,130, and 132, in moderate to excellent yields. In the case of the addition of alkyl radicals, significant amounts of the reduced starting material were also isolated. 

The intriguing architectures that characterize the spirooxindole family of indole alkaloids have stimulated a wealth of investigations directed toward precision spirocyclization. As with the preceding section, examples of spirooxindole syntheses have been organized on the basis of the specific type of bond that has been set at C3 (C3-carbon, C3-oxygen, or C3-nitrogen functionalization). 

In an approach to the gastrin receptor antagonist (+)-AG-041, the Iwabuchi group has prepared the nitrogen-substituted spirocycle 153 by means of an oxidative intermolecular aza-spiro-annulation (Scheme 38) [82], Accordingly, indole 151 was treated with dirhodium catalyst 152 in the presence of PHl(OAc)2 and MgO to afford spirocycle 153 in 70% yield and 96% ee. The deuterium labeling was necessary for successful implementation of the spirocyclization. 

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