Indole dimerisation

The biosynthesis of many bis-indole alkaloids has been postulated to proceed by dimerisation of appropriate precursors, and there is now a substantial amount of experimental evidence to support this hypothesis. For example, treatment of the alcohol 1 with acid gives the alkaloid yuehchukene 2, and 1 could arise biogenetically by in vivo prenylation of indole followed by enzymatic oxidation. A study of related 2-prenylated indoles has confirmed the ease with which such molecules can "dimerise". Thus, treatment of the secondary alcohol 3 in benzene with silica gel impregnated with TsOH gave a complex mixture of products from which 4 (5.1%) and 5 (2.1%) were isolated (3 is very sensitive to acid, and is easily decomposed). Treatment of the isomeric tertiary alcohol 6 with a catalytic amount of TFA in anhydrous benzene gave much higher yields of the two "dimeric" products 7 (31%) and 8 (25%). 

Indoles have been prepared from reactions of o-aminophenylketones with reactive , or stable " arsonium ylides. Oxo-stabilized ylides reacted with 2-chloro-oximes to give trans-5-acyl-A -isoxazolines, and isoxazoles have been obtained from reactive arsonium ylides and a-isonitrosoketones, and from triphenylarsonium methylide and nitrile oxides The latter ylide reacts similarly with nitrile imines to give pyrazoles. With triphenylarsonium benzylides and benzoylylides,benzene diazonium salts give 1,3,4,6-substituted 1,4-dihydro-1,2,4,5-tetrazines in a reaction in which initial coupling of the reagents is followed by a dimerisation. ... 

In order to identify the chromophore of a bisindole alkaloid, it is often enough to add the spectra of the two suspected monomers [e.g. the u.v. spectrum of geis-sospermine (105) was obtained by superimposition of the spectra of an indole (cinchonamine) and an indoline (geissoschizoline)]. Steric constraints introduced in the dimerisation process can, of course, result in small differences in actual and manufactured spectra but these do not affect first-order interpretations. In contrast, a decision concerning the position of an auxochrome e.g. 5-methoxy-or 6-methoxy-indoline ) can certainly be jeopardised. Whenever possible such distinctions must be made by examination of the monomeric products of cleavage. 

In the mineral-acid-catalysed dimerisation of indole, the indole is attacked by protonated indole, i.e. the iminium ion is protonated indole, hi all manipulations of indoles it is necessary to be aware of then-sensitivity to acidic conditions. 

Conversion of the initial cycloadducts through to the desired indoles was achieved using DDQ or activated Mn02. Whilst the eight-membered ring allene 1,2-cyclo-octadiene dimerises at ambient temperature, the compound with a t-butyl group at the... 

The iminium ion electrophile can be synthesised separately, as a crystalline solid known as Eschenmoser s salt (Me2N =CH2 1 ) and with this reactive electrophile the reaction is nonnally carried out in a non-polar solvent. Examples which illustrate the variation in iminium ion structure which can be tolerated, include the reaction of indole with pyrimidine, with benzylidene derivatives of arylamines catalysed by lanthanide triflates, and the mineral acid-catalysed dimerisation of indole. In the first example protonated pyrimidine is the electrophile, in the last indole is attacked by protonated indole as shown below. 

However, the a and p2 sub-units were shown to combine when mixed and in combination as the fully associated L-tryptophan synthetase a 2 complex they catalysed a reaction which is the sum of (0 and (h) but in which indole (40)—a product of (0 and a substrate for ( )—was not detectable as a free intermediate. Thus indole (40), although it can enter the pathway between indoleglycerol-3-phos-phate (38) and L-tryptophan (3) either as a growth supplement or an accumulated product, may not be a true physiological intermediate. Yanofsky and his collaborators have observed that the full a/ 2 complex has an enhanced catalytic activity relative to the component a and P2 sub-units and that there is a concomitant gain in specificity for the reaction (ii). Thus the a 2a complex was 100 times more active than the a sub-unit in reaction (i) and 30 times more active than the 2 sub-unit in reaction (ii). In addition these workers observed that the intermediate 0. 2 complex was about one half as active per p2 sub-unit as the tetrameric complex and they concluded that each a unit contributed equally to each of the two identical active sites in the full a 2 enzyme. During the process of synthesis of the complex it has been assumed that the /S chains dimerise rapidly and then become associated with the a chains to give the tetrameric species. 

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