Iminium acyl Pictet-Spengler reaction

Acyl Pictet-Spengler Reactions of Iminium Ions... 

Another important set of bi-component reactions involving C-N and C-C bond formation is based on the Pictet-Spengler reaction, consisting in the cycUzation of electron-rich aromatic moieties onto iminium intermediates. This weU-known sequence constitutes an important domino transformation used for the synthesis of bioactive polyheterocycles. Its organocatalytic asymmetric version was pioneered by Jacobsen and revisited by List, who developed two complementary highly enantioselective accesses to tetrahydro- 3-carbolines from tryptamine-derived imines (Scheme 16.33). Thus, Taylor and Jacobsen [64] reported an enantiomerically pure thiourea-catalyzed cyclization of an acyl iminium intermediate, whereas List and co-workers [65] described the cyclization of an iminium diester intermediate in the presence of a chiral phosphoric acid catalyst. Recently, this methodology has been applied to the synthesis of chiral pyrrolopiperazines [66]. 

Jacobsen has also developed an organocatalysed asymmetric addition of nucleophiles with iV-acyl-iminium ions (Pictet-Spengler) and oxocarbe-nium ions, potentially useful reactions in medicinal chemistry (Scheme 14.97). The mechanism involves the formation of an anionic catalyst-chloride complex which acts as a chiral counter ion directing the approach of nucleophiles to one face of the cationic species. 

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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