Spiroindolenine

Bischler-Napieralski reactions of N-acyl tryptamine derivatives 16 are believed to proceed via a related mechanism involving the initial formation of intermediate spiroindolenines (17) that rearrange to the observed 2-carboline products (18). The presence of these intermediates has been inferred by the observation of dimerized products that are presumably formed by the intermolecular trapping of the spiroindolenine by unreacted indole present in the reaction mixture." ... 

Studies on the Bischler-Napieralski cyclization of A -acetyltryptamine in the presence of indole have led to the isolation of numerous products, among which the indolocarbazole 186 could be found in 3.5% yield. This outcome was rationalized as a result of the intermediacy of a spiroindolenine species formed under these conditions [89H(28)175]. During detailed studies on the polymerization of indole, formation of a low yield of the related indolo[3,2-h]carbazole 187 was discovered in the product mixture originating from the treatment of indole with p-toluenesulfonic acid at elevated temperature [88JCS(P1)2387]. In an investigation of the condensation of p-benzoquinone with 4-substituted anilines, an indolo[3,2-h]carbazole derivative has been reported to be formed in 2% yield (80JOC1493). 

The mechanism of this reaction is still not clear. It has always been thought that the Pictet-Spengler reaction proceeds via a spiroindolenine intermediate 20 followed by a Wagner-Meenvein rearrangement to 21 (way A). On the other hand in the case of very reactive electrophiles it was shown that the cyclization can occur by direct attack at the C-2 position of the indole (way B). However, after deprotonation of 21 compound 7 is formed.10... 

Treatment of the following indole amides (46) and (48) with Bu3SnH in the presence of AIBN provides spiroindolenine (47) and hexahydropyrrolo[3,4-b]indole (49), through... 

On the basis of a rapid and reversible spiroindolenine mechanism, a pathway for the Pictet-Spengler reaction was proposed recently, which is consistent with all these stereochemical fmdings. ... 

Taylor, M. S., Jacobsen, E. N. Highly enantioselective catalytic acyl-Pictet-Spengler reactions. J. Am. Chem. Soc. 2004, 126, 10558-10559. Kowalski, P., Mokrosz, J. L. Structure and spectral properties of P-carbolines. Part 9. New arguments against direct rearrangement of the spiroindolenine intermediate into P-carboline system in the Pictet-Spengler cyclization. An MNDO approach. Bull. Soc. Chim. Belg. 1997, 106, 147-149. 

Reactions of indoles with inorganic radical ions 79UK1968. Spiroindolenines as intermediates 78H(9)1O89. 

A similar reaction affords a simple route to cyclopent[b]indoles. Indole-3-carbinol (68) reacts with j8-methylstyrene in the presence of titanium tetrachloride to give compound (70) <93TL8527>. The presumed four-membered spiroindolenine (69) in this sequence receives support from the observation that the conversion of the D-tryptophan derived compound (71) to its mesylate leads to the formation of racemic cyclopent[b]indole (73) via the achiral intermediate (72) (Scheme 17) <93TL439>. 

A recent synthesis of spiroindolenine derivatives has employed a tandem radical-oxidation sequence [86]. Enamides 137 were subjected to a mixture of tributyl-tin hydride and DLP to produce the corresponding indolenine as a single diastereomer (confirmed from 2D NMR experiments). The mechanism is thought to involve the cyclization of the initial aryl radical to the vinyl group in a 6-endo fashion to generate an a-amidoyl radical which is oxidized by DLP to an acyU-minum ion prior to cyclization at the C-3 position of the indole ring. 

Zuleta-Prada H, Miranda LD (2009) Synthesis of spiroindolenine derivatives by a tandem radical-oxidation process. Tetrahedron Lett 50 5336-5339... 

Eneouraged hy Bandini s pioneering studies, You and co-workers introduced indolyl carbonates 180 into Ir-catalyzed intramolecular asymmetric allylic alkylation reactions. Interestingly, spiroindolenine derivatives 181 are obtained in 50-98% yields with up to >99/1 dr and 97% ee (Scheme 6.83). Chiral phosphoramidite ligand (/ ,/ a)-170d (Me-THQphos), newly developed by the You group, was responsible for excellent reactivity, diastereo- and enantioselectivity of this process. 

Scheme 6.84 Asymmetric synthesis of six-membered aza-spiroindolenines by Ir-catalyzed intramolecular allylic dearomatization of indoles reported by You.

Table 6.16 Enantioselective synthesis of polycyclic indole derivatives 190 via the in situ formation and migration of spiroindolenine intermediates reported by You.

Also, a large number of indole alkaloids are formed by Mannich reactions involving tryptophan or its decarboxylation product tryptamine with various aldehydes. Both the a- and p-position of the indole nucleus are electronegative, and a Mannich reaction with tryptamine can yield a p-carboline derivative or a 3,3-spiroindolenine [30]. A further example is provided by the tropinone biosynthesis (Figure 1.29) [31 ]. 

Figure 1.29 Examples of Mannich reactions, (a) Biosynthesis of alkaloids bearing the 1,2,3,4-tetrahydroisoqumoline ring, (h) biosynthesis of indole alkaloids (P-carboline, 3,3-spiroindolenine), and (c) tropinone biosynthesis.

Scheme 39 Br0nsted acid-catalyzed synthesis of spiroindolenines via [l,5]-hydride shift/cyelization sequence...

In 2012, Zhao and coworkers developed an enantioselective strategy for the synthesis of spiroindolenines 94 by a Michael-hemiaminal formation/Pictet-Spengler cascade reaction [54]. The indoles 93 bearing a ketoamido group in 3-position reacted with the enals 16 in the presence of the Jprgensen-Hayashi catalyst (XXIV) to afford the corresponding spiroindolines in excellent yields and enantioselectivities but moderate diastereoselectivities (Scheme 10.33). 

Treatment of amine 58 with formaldehyde under acidic conditions led to the formation of the methylene iminium ion 59, which induced a Mannich cyclization at the C3 position of the indole to produce the spiroindolenine 60. Compound 60 underwent... 

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