Indole analogues approaches

In 1996, the same group 87) reported further work on the synthesis of indole analogues of the cephalotaxine ring system (Scheme 52). The key intermediate in this ring-expansion approach, bromoiminium ion 300, was prepared in three steps from tryptamine and the chloro diester 298 via enamine 299. On treatment with several bases, the iminium ion 300 underwent rearrangement, presumably via the intermediate alkoxide 301, to give the azepinone derivative 302, which was reduced with sodium borohydride to a mixture of isomeric alcohols 303. The alcohols 303 underwent rapid intramolecular cyclization when treated with a 95% solution of sulfuric acid to yield pentacyclic ketone 304. 

MedebieUe M, Fuji S, Kato K (2000) An electrochemical approach for the synthesis of perfluroalkylated purine and indole analogues of plant growth regulators. Tetrahedon 56 2655-2664... 

The Fischer indole synthesis is quite tolerant of additional functional groups in the starting material. Thus reaction of 4-dimethylaminocyclohexanone (18-2) with phe-nylhydrazine (18-1) in acetic acid leads directly to cyclindole (18-3) [18], a compound described as an antidepressant. A shghtly different approach is used to prepare the fluorinated analogue. The tricyhc indole (18-5), in this case, is obtained by reaction of 2,4-diiluorophenylhydrazine (18-4) with 4-hydroxy-cyclohexanone. The hydroxyl... 

Amino Acids and Peptides. - Wasserman s method of one-carbon homologation of carboxylic acids to give a-ketocarboxylates involves reaction with cyanomethylenetriphenyl-phosphorane followed by ozone (Scheme 24) and has been used as a key step in a chemo-enzymatic synthesis of isotopically labelled L-valine, L-isoleucine, and o/fo-isoleucine. Alkylation of the carbanion derived from the imino-substituted methylphosphonate diphenyl ester (186) with indol-3-ylmethyl bromide followed by appropriate deprotection has been used to prepare the phosphonate analogue (187) of tryptophan (Scheme 25). The deprotected analogue (188) and derived peptides show activity as inhibitors of chymotrypsin. Two approaches to solid phase Wadsworth-Enunons reactions which have applications in combinatorial chemistry have been reported. In one diethylphosphonoacetamide is bound to PEG-PAL resin via a peptide link, while... 

Indolizines, indolizidines, indoles, and other bicyclic or polycyclic compounds containing a fused pyrrole or pyrrolidine moiety often possess potent and useful biological activities. There have been several approaches to the preparation of fluorinated analogues of these heterocycles, mainly based on 1,3-dipolar addition reactions using fluorinated synthons either as the dipole or as the dipolarophile. Several examples of this strategy are given below. 

Other approaches. Treatment of an analogue of (—)-indolactam V (1) with prenyl bromide in HOAc/NaOAc afforded 7-prenylated, 7-tcrt-prenylated and 2-prenylated products [228]. It was also possible to build up the indole ring of... 

Davies has further exploiled his previously reporied approach to (he tropanc skeleton related to cocaine based on the rhodium catalyzed decomposition of the vinyidiazomethane 81 in the presence of A/-Boc-pyrroIe (82) <01BMCL487>. Reduction of the non-conjugated double bond followed by A -deprotection and N-alkylation provided substrate 83 which was susceptible to conjugate addition of nucleophiles such as 84 in the presence of CuBr to afford 3-p-aryl tropanes which exhibited potent binding affinity for both the dopamine and serotonin transporters. Additionally, this author described the synthesis of various methyl heteroaryldiazoacetate analogues of 81, (me of which possessed an indole function, for use in catalytic asymmetric cyclopropanations . 

Macor also exploited the Mori-Ban indole synthesis to synthesize several anti-migraine analogues of sumatriptan and homo-tiyptamines as potent and selective serotonin reuptake inhibitors (SSRIs). Noticeably, the presence of the second bromine (the bromine passenger ) on the substrate was not significantly deleterious to the reaction although a small amount of the 7-bromoindole might be sacrificed at the end of the reaction to consume the active palladium catalyst. The approach to 7-bromoindole could provide a general method to access 7-bromoindoles (a rare class of indole derivatives), which then could be further manipulated for the synthesis of more complex 7-substituted indoles. 

Beyond serotonin and tryptophan, the indole ring is embedded in myriad natural products. This section presents those naturally occurring indoles and related unnatural analogues that have been synthesized via Fischer indolization. In a few cases only the approach to an indole natural product is reported. 

Sevai-membwed Rings.—Oxazepines and dioxepines constitute an important class of biologically active compounds, hence a new approach to these ring systems and their thia-analogues is always interesting. The reaction of carbon suboxide with benzene derivatives (Y = O, NH, or S) in dilute solution in ether gives acceptable yields of (61). A new aspect of indole chemistry allows the... 

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