Indole protection

In order to exploit the reactions of the C-lithio derivatives of iV-unsubstituted pyrroles and indoles, protecting groups such as t-butoxycarbonyl, benzenesulfonyl and dimethyl-amino have been used 81JOC157). This is illustrated by the scheme for preparing C-acylated pyrroles (211) (8UOC3760). 

An indole protected by a Mannich reaction with formaldehyde and dimethyl-amine is stable to lithiation. The protective group is removed with NaBH4 (EtOH, THE, reflux). The related piperidine analogue has been used similarly for the protection of a triazole. ... 

The relative merits of many of these protecting groups have been discussed previously [e.g., 84JCS(P1)481 85H417 88JOC1107, 88JOC5685], but as with the various pyrrole and indole protection systems it is sometimes difficult to make direct comparisons because of the nature of the different electrophiles employed by different research groups. 

In Fmoc-based SPPS, Trp is most often incorporated with no indole protection, but this can be problematic for sequences containing Arg protected by the 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), or 2,2,4,6,7-pentamethyldihydroben-zofuran-5-sulfonyl (Pbf) protecting groups, which can readily alkylate the indole ring of Trp [143,144]. This is sequence dependent and difficult to predict, although it appears that the worst-case scenario is Arg-Xxx-Trp... 

Preparation of indole-protected derivatives is usually straightforward, involving reaction of A "-Z or Boc protected carboxyl-tBu, Bzl, or phenacyl Trp ester with di-t-butyl dicarbonate or the appropriate chloroformate or in the presence of a tertiary base (Scheme 26). Subsequent removal of the carboxyl and/or amino groups followed by AT-terminal derivatization yields the Boc or Fmoc derivatives [141,142,147-149]. The formyl group is introduced with excess formic acid [150]. 

Indole protection, temporary blocking of the side-chain group of tryptophan in peptide synthesis. When applying Boc/Bzl tactics, a popular choice for protecting the Trp indole group is the formyl (For) group, as this is removable by treatment with a... 

Cationic 2-azadienes have also proven to be good diene partners in IDA cycloaddition reactions [17], As an example, the reaction of A-tosyl indole (14) with the A-alkenyl iminium species 13 (generated in situ from the corresponding A -alkoxymethyl enamine derivative 12), followed by deprotonation, produced the tricyclic indole product 15 with excellent stereochemical control (Scheme 5). The choice of tosyl group for indole protection proved crucial, as A-tosyl indole (14) is electron-rich enough to effect the [4-t-2] cycloaddition reaction but lacks the nucleophilicity to add to the resulting cycloadduct intermediate [18]. 

In their green catalytic method for the C—H alkylation of alkenes with alcohols, Yi and co-workers employed ruthenium complex 114 to alkylate Af-methylindole (113) in almost quantitative yields (116-117) whilst only generating water as the by-product (Scheme 10.38). Mechanistic experiments led the authors to propose a cationic Ru-indole-alkyl intermediate (115) that would arise from C2—H activation the exact mechanism of the C—O cleavage step is unknown. A related example with A-methoxycarbonyl-L-tryptophan methyl ester demonstrated that an indole protecting group was not necessary. 

A more efficient route to the pentacyclic ketone 367 not requiring indole protection has been developed by the Ninomiya group (Scheme 3.63) (66,67). Harmalane (336) was condensed with 3,4-dimethoxybenzoyl chloride (368) to provide enamide 369 which upon irradiation under reducing conditions afforded a mixture of desired bis-enol ether 370 and corresponding ketone 371. Lactam 370 was reduced, and the C(16), C(17) enol ether was hydrolyzed to afford predominantly 367 in addition to a small amount of the regio-isomeric hydrolysis product 372. Treatment of367 with methyl cyanoformate... 

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