Pictet-Spengler condensation iminium ions

The most prominent intramolecular reaction of iminium ions with aromatic C-nucleophiles is the long-known Pictet-Spengler condensation of 2-phenylethylamines (8) with reactive carbonyl compounds (9)—by far the most important route to natural and synthetic tetrahydroisoquinolines (10 Scheme 8). 

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. ... 

Electrophilic substitutions on the indole ring overwhelmingly favor the C3 position. However, when the energy outcome is favorable, C2 electrophilic substitutions do occur, especially for intramolecular substitutions. For instance, in the synthesis of tadalafil (Cialis), the Pictet-Spengler reaction is used to prepare the cw-p-carboline where the C2 electrophilic substitution takes place. In the presence of trifluoroacetic acid (TFA), Z)-tryptophan methyl ester is condensed with piperonal. The C2-carbon of the indole adds to the resulting iminium ion to give a mixture of the cA-B-carboline and the... 

The Pictet-Spengler reaction is an important reaction involving condensation of an unsubstituted or substituted tryptamine 145 with an aldehyde RiCHO, usually in the presence of a Bronsted acid to afford an iminium ion 146 which undergoes intramolecular cyclization to afford biologically important tetrahydro- 3-carboline (147). Although the cyclization affords the C-2 adduct, the initial F-C product is the spirocyclic C-3 adduct, which... 

NCS catalyzes isoquinoline formation via an asymmetric Pictet-Spengler reaction (ii). The reaction entails an acid-catalyzed electrophilic addition of an iminium ion. The mechanism is a two-step process in which the iminium ion is generated first from the condensation reaction between the aldehyde carbonyl (such as 4-HPAA) and dopamine. Two types of NCS (CjNCSl and CjPRlOA) have been isolated from Coptis japonica cells and characterized [21]. CjPRlOA has been sufficiently expressed in an active form in E. coli. Conversely, CjNCSl forms a larger complex in plant cells. Therefore, the recombinant enzyme expressed in E. coli cells has considerably lower activity than that of the native enzyme. 

In the first catalytic, enantioselective version of the Pictet-Spengler reaction, Jacobsen utilized the chiral thiourea derivative 171 as catalyst (Equation 12) [132], Such thioureas have emerged as a versatile class of chiral promoters and have proven to be of general utility in a number of enantioselective transformations [40], A particularly interesting feature of this study is the fact that in situ acetylation of the intermediary aldimine leads to an N-acyl iminium ion as the reactive species that subsequently undergoes cyclization. A priori, the more basic imine resulting from condensation of aldehyde 170 with tryptamine 169 would have been expected to be more likely than the N-acyl iminium ion to interact with catalyst 171. Nonetheless, the latter species was responsive to the H-donor catalyst, leading to N-acetylated tetrahydro-/ -carboline 172 in 81 % yield and 93 % ee [132],... 

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