Pictet-Spengler cyclization substituted indoles

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. ... 

The factors that control diastereoselection in the construction of 1,3-disubstituted tetrahydro-p-car-bolines are not, as yet, well understood. With many aldehydes a slight preference for forming the trans diastereomer is observed. " This preference is somewhat greater when the indole nitrogen (Na) of the tryptamine is alkylated. Pictet-Spengler cyclizations of Nb-benzyltryptophan methyl ester under Cook s aprotic conditions are reported to provide nearly exclusively the rr 2ni-A b-benzyl-3-methoxycarbonyl-1 -substituted-1,2,3,4-tetrahydro-P-carbolines. ... 

SCHEME 3.9. Pictet-Spengler cyclization in the construction of substituted indoles. 

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