Indoles intramolecular approaches

As with the corresponding section on pyrroles, indole syntheses have been categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step (2 examples shown below). In addition, the synthesis of azaindoles,... 

Muthusamy et al. (89) approached the formation of decahydrobenzocarbazoles 191 utilizing an indolic five-membered olefin 190 as the dipolarophile in reaction with a carbonyl yhde derived from 189. This intermolecular approach is strategically similar to an intramolecular approach to aspidosperma alkaloids developed by Padwa (Scheme 4.47). 

In the second part of the chapter, the intramolecular approach has been reviewed. After several trials, we have found the adequate methodology to join the lactam and the indole part, which will allow the synthesis of an advance intermediate [146]. However, using enantiomerically pure lactam 111-53 and the ind-olylvinyl iodide III-56, the desired alkenylindole III-60 was only obtained in a very low yield (Scheme 4.78). We believe that this is mainly due to the high steric hindrance around the quaternary center of the lactam III-53. 

As was the case with reactions of vinylindoles, the most elaborate synthetic targets approached by the indole-2,3-quinodimethane route have been alka-loids[18]. The route has been applied to aspidospenna[l9 ] and kopsine[20] structures. The fundamental reaction pattern is illustrated in equation 16.7. An indole-2,3-quinodimethane is generated by W-acylation of an Ai-(pent-4-enyl)-imine of a 2-methyl-3-formylindole. Intramolecular 2 -P 4 cydoaddition then occurs. 

A novel approach to 3-substituted indolines and indoles via the anionic cyclization of 2-bromo-lV,lV-diallyanilines has been developed simultaneously by Bailey <96JOC2596> and Liebeskind <96JOC2594>. Thus, treatment of 2-bromo-lV,lV-diallylanilines 78 with 2 equivalents of BuLi at -78 °C leads to the formation of the intermediate 79 which may be trapped with an electrophile to afford 3-substituted indolines 80. Aside from ease of preparation, an additional benefit of the intramolecular carbolithiation of <7-lithio-W,Al-diallyl-anilines is the production of Al-allyl-protected indolines, which are easily deprotected using... 

In addition to the radical ipso-substitution of indolyl sulfones producing stannanes described earlier <96T11329>, Caddick has also reported an approach to fused [l,2-a]indoles based on the intramolecular cyclization of alkyl radicals. Thus, treatment of 112 with BuaSnH leads to the fused ring derivatives 113 (n = 1-4) <96JCS(P1)675>. 

The occurrence of the indole subunit is well established within the class of natural products and pharmaceutically active compounds. Recently, the Reissig group developed an impressive procedure for the assembly of highly functionalized in-dolizidine derivatives, highlighting again the versatility of domino reactions [8]. The approach is based on a samarium(II) iodide-mediated radical cydization terminated by a subsequent alkylation which can be carried out in an intermolecular - as well as in an intramolecular - fashion. Reaction of ketone 3-11 with samarium(ll) iodide induced a 6-exo-trig cydization, furnishing a samarium enolate intermediate... 

Nakagawa devised a concise synthetic route to physostigimine (169) where the key step involves the alkylative cyclization of 1,3-dimethylindole (167) with (Z)-aziridine catalyzed by Sc(OTf)3 and TMSC1 to give 168, which, in turn, can be converted into 169 . A similar asymmetric approach to this natural product was also developed by these authors via treatment of tryptophan carbamates with the Corey-Kim reagent so as to induce intramolecular cyclization to the pyrrolo-indole skeleton . 

Reduced indole derivatives can be synthesized by using the phenolic oxidation approach. Thus, A-alkyl-A-benzoyltyramines 120, on treatment with IBTA in trifluoroethanol (TFE), followed by aqueous workup, afford the hexahydroindol-6-ones 122. The formation of 122 is rationalized by intramolecular Michael-type addition of amino group to the double bond of the intermediate dienone 121 (91JOC435) (Scheme 33). 

One of the first examples of radical cydization reactions in the total syntheses of indole alkaloids was Stork s approach towards ( )-gelsemine (55) [58] featuring a mixed acetal 6-exo radical cydization as the pivotal step (Scheme 23). Thus, exposure of cyclopentene bromide 117 to standard radical cydization conditions led to the cii-fiised bicyclic ester 118. A relatively dilute concentration (0.02 M) was needed to minimize possible intermolecular reactions although the intramolecular reaction was kinetically more favored. Diastereomeric phenylselenides were easily obtained by treating 118 with LDA and quenching the enolate with diphenyl diselenide. The a,P-unsaturated ester 119 was secured when the selenide underwent... 

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