Substituted indole nucleus

J.M. Cook et al. accomplished the enantiospecific total synthesis of the indole alkaloid tryprostatin A." The substituted indole nucleus was assembled at the beginning of the synthesis, and the necessary arylhydrazone was prepared via the Japp-Kiingemann reaction using the diazonium salt derived from m-anisidine and the anion of ethyl-a-ethylacetoacetate. The regioselectivity of the Fischer indoie synthesis favored the 6-methoxy-3-methylindole-2-carboxylate regioisomer in a 10 1 ratio. 

The possibility of activating the indole nucleus to nucleophilic substitution has been realized by formation of chromium tricarbonyl complexes. For example, the complex from TV-methylindole (215) undergoes nucleophilic substitution with 2-lithio-l,3-dithiane to give a product (216) which can be transformed into l-methylindole-7-carbaldehyde (217) (78CC1076). 

As for regioselectivity in the electrophilic substitution reactions, we have assumed that introducing a methoxy group to the 1 position of indole nucleus might alter its positional reactivity. 

N-benzylation had occurred as expected rather than substitution at the 2-position of the indole nucleus. 

Increasing the size of the ether substituent (5i) led to a further increase in potency and efficacy in vitro. However, this improvement in vitro, which might be accounted for by secondary lipophilic interactions, did not improve efficacy in vivo. Substitution at the 5-position of the indole nucleus by larger polar or lipophilic substituents (5j) abolished activity in vitro. 

Undoubted, 2-haloaniline derivatives still maintain most vored precursor status for the preparation of the indole nucleus. Larock now reports the frill details of his examination of the asymmetric addition of IV-tosyl-2-iodoaniline (63) to allenes 64 (e.g. 1,2-undecadadiene) in the presence of palladium catafysts and chiral bisoxazoline ligand to afford chiral indolines 65 in up to 88% ee <99JOC7312>. Cook has utilized the palladhjm-catafyzed heteroannulation of iodoanilines with alkynes derivatized with the Schollkopf chiral auxiliary as a reliable route to optically active ring-A substituted tryptophans <99TL657>. 

Abbott (Brooks et al. (Abbott), 1998a Woods et al. (Abbott), 1998) published two patent applications in which the carboxyl moiety of indomethacin was substituted with an iminooxy or substituted thiazole. On the other hand, Kotobuki Seiyaku (Tomiyama et al. (Kotobuki Seiaku Co. LTD), 1998) used a novel approach, exchanging the indole nucleus for an azulene (Jimenez et al., 2000). 

The intramolecular C-acylation into position 4 becomes possible after hydrogenation of the C2—C3 bond in the indole nucleus. Thus, by the action of aluminum chloride, l-benzoyI-2,3-dihydroindo ylpropionyl chloride 197 is converted into pentahydrobenzo[crf]indolone 198 (54J A5256 56JA3087). Intramolecular electrophilic substitution is favored also by conjugation between a carbonyl or a nitrile group at the /3-substituent containing three carbon atoms and the indole nucleus. 

Deoxygenation of l,2-dimethyl-3-(o-nitrophenylthio)indole (133) with an excess of triethyl phosphite, either neat or with cumene as solvent, at 160°C afforded indolo[2,3-c][l,5]benzothiazepine (134) in 34% yield. This product may arise via //wo-substitution by the initially formed nitrene to the 3-position of the indole nucleus to give the intermediate 135 (Scheme 41) [88JCR(S)272]. 

A new iodine-catalysed, remarkably simple Michael reaction of indoles with enones, e.g. PhCH=CHCOR, has been developed.183 The Sml3-catalysed reaction of indoles with electron-deficient alkenes (e.g. enones) afforded the corresponding Michael adducts in high yields. As in the previous case, the substitution on the indole nucleus occurred exclusively at the 3-position and A-alkylation products have not been observed.184... 

The vast majority of indole alkaloids contain a tryptamine unit in which Nb is linked to the j9-position of the indole nucleus by an ethylene chain. On biogenetic grounds and also from the mass spectral similarity with aspidospermine (II), it is reasonable to expect this feature in the aspidofractinine-type alkaloids. Furthermore, in kopsine lactam A (CLXXV), in which C-ll is substituted by the C-3 bridge and C-10 has been oxidized (five-membered lactam), the residual hydrogen atom on C-ll shows as a singlet (2.82 S) in the NMR-spectrum and C-12 is therefore quaternary. 

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