Carbolines aromatic, reactions

Dehydration of a spirocyclic quaternary salt such as 147 gives rise to a 3,4-dihydro-y-carboline (148). This reaction is not, however, of general applicability since both 149 (R = C2H5) and 149 (R = CH2C6H5) yield the fully aromatic carbolinium salt 150 under the same conditions. 

A. Reactions of the Fully Aromatic Carbolines i. Substitutions at Carbon... 

The Pictet-Spengler reaction has also seen much use in the synthesis of lavendamycin methyl ester. Both Hibino [31] and Behforouz [32] used it as a key step in their syntheses of this molecule (Fig. 10). In Hibino s synthesis, /i-methyltryptophan ethyl ester 27 was condensed with quinoline aldehyde 28 to give the corresponding lelrahydro- -carbohnc, which was aromatized by heating with palladium on carbon in xylenes, giving /1-carboline 29 in 75% yield. A five-step sequence (which included conversion to the methyl ester for easier comparison with known compounds) yielded bromoquinone 24 in 27% yield for the five steps. This completed Hibino s formal total synthesis of lavendamycin methyl ester, since this was the same intermediate used in Kende s synthesis. 

For the preparation of 3,4-dihydro-/3-carbolines the Bischler-Napieralski reaction is widely used (510R74). Since this reaction requires rather drastic conditions, A-acetyl tryptophan and its analogs yielded l-methyl-/8-carboline (harman) rather than l-methyl-3,3-dihydro-j8-carboline-3-carboxylic acid derivatives owing to accompanying decarboxylation and aromatization (41JCS153 50JA2962). 

Plants have taken advantage of this successful synthetic principle for their enzymatic production of isoquinoline (as well as p-carboline ) alkaloids. In the chemical laboratory, this synthetic approach has been exploited for nearly 80 years in numerous biomimetic-type syntheses. This special form of the Mannich reaction requires electron-rich aromatics, if possible with ftee phenolic oxygen functions in ortho or para positions (Scheme 9). As for the carbonyl compound, aldehydes or 1,2-dicarbonyls (and very recently 1,2,3-tricarbonyls - ) are preferred. Due to the mild physiological reaction conditions required with such ideally reactive partners (often pH = 7, room temperature, aqueous medium), this condensation was also found to play a role in human organisms, leading to endogenous mammalian alkaloids... 

In view of the multifold important biological activities of isoquinoline and P-carboline alkaloids, increasing efforts have been made to perform Pictet-Spengler reactions stereoselectively. The most obvious chiral auxiliary to induce asymmetric control is the stereogenic center of the corresponding aromatic amino acids, such as DOPA or tryptophan. 

A collection of tetrahydro-P-carbolines has been prepared [401] by first attaching various tryptamines to Novabiochem s vinylsulfonytmethyl resin (560) by Michael addition involving the tryptamine amino groups. Subsequent reaction with various aromatic aldehydes in the presence of catalytic p-TSA in toluene at 80 °C afforded the desired tetrahydro-P-carboline derivatives (563) in excellent yields (Scheme 117). 

The Pictet-Spengler reaction is important for the preparation of tetrahydro-(3-carbolines and tetrahydroquinolines. List and co-workers applied phosphoric acid catalysis to the Pictet-Spengler reaction starting from geminally disubstituted tryptamines (Equation 10.41) [85, 86], The presence of the bis(ethoxycarbonyl) group facilitated the cyclization reactions by virtue of the Thorpe-Ingold effect. Both aliphatic and aromatic aldehydes turned out to be good substrates. 

Since its discovery the Pictet-Spengler cyclization has formed the basis of numerous syntheses of alkaloids containing aromatic subunits. This high-yielding reaction involves, in its broadest sense, nucleophilic attack on an iminium ion by the Tr-electrons of a tethered aromatic moiety. In the classical reaction a substituted P-phenethylamine is condensed with an aldehyde under acidic conditions to produce a te-trahydroisoquinoline (Scheme 16). A useful variant of the Pictet-Spengler reaction, which provides tetr ydro-(3-carbolines and their derivatives, involves the condensation of a tryptamine derivative and an aldehyde (Scheme 16). Whether nucleophilic attack on the resulting iminium ion occurs initially at the a- or -indole carbon is a topic of current debate and, indeed, there is evidence to suggest that the mechanistic pathway could be substrate dependent. ... 

Aromatic cyclodehydration has been used in the preparation of several indolo[2,3-a]acridizinium salts (43) (Chart V). Reaction of l-formyl-)3-carboline (LXIX) with benzyl bromides in dimethyl formamide at room temperature provided the quaternary salts (LXX R = H or OMe) which were smoothly converted to the desired indolo-[2,3-a]acridizinium salts (LXXI) by action of polyphosphoric or concentrated hydrochloric acid (when R = OMe). 

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