Intramolecular Aminoalkylation The Pictet-Spengler Reaction

Evidence of the sp/ro-indolenine mechanism also comes from the cyclization of certain a-aryl tryptamines with aromatic aldehydes. In the case of aryl substiments that are particularly electrrMi-rich (3,4-dimethoxy 3,4-methylenedioxy), isomeric tetrahydro-y-carbolines resulting from the competing migration of the electron-rich benzyl group predominate in a ratio of about 4 1 [319]. 

Microwave conditions are useful in condensing L-tiyptophan with ketones, which react only slowly under conventional crmditions [320]. 

Nitrones are also satisfactory reactants for Pictet- pengler cyclization with tryptamine. Among the reagents used for cyclization are Yb(OTf)3-TMS-Cl [321]. 

Synthetic routes have been developed to several 9-methoxy (indole-4) [328] and 12-methoxy (indole-7) [329] alkaloids, starting with the corresponding D-methoxytryptophan. 

Bailey and coworkers have explored the stereoselectivity of the Pictet-Spengler reaction with L-tryptophan esters [330]. They found that use of TFA could effect kinetically-controlled cyclization. For 1,3-disubstituted p-carbolines, the preference was for the cA-1,3 product (diequatorial). For 1,2,3-trisubstituted (A-benzyl) analogs, the kinetic preference is for cw-l,3-diaxial product. A particularly useful derivative was obtained by converting the ester group to cyanomethyl. Originally the cyanomethyl derivative was cyclized via the enamide prepared from methyl propiolate, and gave a 3 1 cis trans ratio [331]. 

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